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WO2009070979A1 - Préparation à libération rapide dans la cavité orale et son procédé de préparation - Google Patents

Préparation à libération rapide dans la cavité orale et son procédé de préparation Download PDF

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Publication number
WO2009070979A1
WO2009070979A1 PCT/CN2008/001890 CN2008001890W WO2009070979A1 WO 2009070979 A1 WO2009070979 A1 WO 2009070979A1 CN 2008001890 W CN2008001890 W CN 2008001890W WO 2009070979 A1 WO2009070979 A1 WO 2009070979A1
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WIPO (PCT)
Prior art keywords
oil
dispersant
oily
preparation
chinese medicine
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PCT/CN2008/001890
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English (en)
Chinese (zh)
Inventor
Yu He
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Individual
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Individual
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8968—Ophiopogon (Lilyturf)
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the invention provides a Chinese medicine oral instant release preparation and a preparation method thereof, and belongs to the technical field of traditional Chinese medicine preparations.
  • oral immediate release dosage form is more and more popular among consumers because of its unique superiority.
  • the tablet does not need water to be taken, and the saliva dissolves rapidly in the mouth, giving some patients with poor swallowing function and inconvenient water intake.
  • the medicine is convenient and has broad market prospects.
  • These dosage forms can disintegrate and dissolve rapidly, have a quick onset, increase the absorption and bioavailability of the drug, and reduce the stimulating effect of the drug on the esophagus and gastrointestinal tract.
  • oral immediate release preparations include both oral cavity quick-dissolving preparations and oral fast-disinfecting preparations, all of which adopt the rapid absorption of oral water as the quick release method of the preparation.
  • These preparations have many defects such as: graininess after disintegration, complicated preparation methods, difficulty in preserving excessive water absorption, and low tablet strength. Since the immediate release of the tablet is inversely proportional to the strength of the tablet, the amount of the auxiliary material is large and the main amount is limited.
  • These dosage forms rely entirely on a small amount of water in the mouth to produce an immediate release, and when the saliva secretion is insufficient in the mouth, the tablet adheres to the oral mucosa and causes discomfort. These problems are difficult to break through the existing preparation methods.
  • the object of the present invention is to: revise the existing traditional Chinese medicine preparation method by providing a traditional Chinese medicine oral immediate release preparation using a hot melt mechanism and a manufacturing method thereof, and to form a very
  • the ideal oral immediate release dispersion system, the water-soluble dispersant and the main ingredient are uniformly distributed in the oil dispersant, and can improve the dispersion speed of the Chinese medicine component in the mouth and the absorption rate of the active ingredient under the premise of achieving better mouthfeel.
  • the preparation is a solid pre-emulsified dispersion system. After receiving oral heat and absorbing a small amount of saliva, it enters the body in a water-in-oil emulsified liquid state. When the stomach liquid phase is converted to form an oil-in-water dispersion, the functional ingredients absorb water quickly and disperse (Fig. 1). . Since the surface is adsorbed with an emulsifier and an oil-soluble dispersant, secondary agglomeration does not occur.
  • the oily dispersant of the present invention is an important component of the present invention, and its function is to uniformly disperse the solid component in the oily dispersant.
  • the melting point of the oily dispersant is close to the body temperature, that is, liquid when it is close to the body temperature, and solid when it is lower than the body temperature (normal temperature). This hot melt oral release is quite different from the traditional aqueous immediate release mechanism.
  • the solid preparation of the present invention enters the mouth, and the oral temperature causes the oily dispersant to be melted by heat, with the oily dispersant being The step melts, and the solid component containing the drug is distributed in the mouth as a liquid oil dispersant in the form of a slurry to complete the preliminary release process of the drug.
  • All the solid components in the components of the present invention are uniformly dispersed in the oily dispersant, in a slurry state at a temperature exceeding normal temperature, in a solid state at normal temperature, and the solid component is encapsulated in an oily dispersant in a solid form. .
  • this hot state is a slurry, and the cold state is solid and reversible.
  • the present invention utilizes such a reversible property, and can maintain the dispersion stability of a solid component at a normal temperature storage (preventing solid component agglomeration or sedimentation which is easily generated in a slurry state, and depositing fat) and stability of the component itself (hygroscopicity, Oxidation, etc.).
  • the invention discloses a traditional Chinese medicine oral immediate release preparation, wherein the basic raw material of the preparation is a main material and an auxiliary material, wherein the main ingredient is a traditional Chinese medicine, comprising a Chinese herbal medicine, a Chinese herbal medicine piece or a Chinese medicine extract; the auxiliary material is an oily dispersing agent; 9% ⁇
  • the weight percentage of the auxiliary material is 0% to 99%, the weight percentage of the auxiliary material is 20% to 99.9%.
  • the water-soluble dispersing agent, the flavoring agent and the emulsifier may be added to the auxiliary material; the water-soluble dispersing agent, the flavoring agent and the emulsifier occupying not more than 85% by weight of the auxiliary material.
  • the invention provides a method for manufacturing a Chinese medicine oral immediate release preparation, and the technical scheme thereof is as follows:
  • the basic raw materials are the main materials and auxiliary materials; the main ingredients are traditional Chinese medicines, including Chinese herbal medicines, Chinese herbal medicine pieces or Chinese medicine extracts; the auxiliary materials are oily dispersants, and if necessary, water-soluble dispersing agents, flavoring agents and emulsifiers are added. 9% ⁇ The weight percentage of the excipient is from 0% to 99.9%.
  • slurry preparation including refinement and liquefaction, thereby refining and uniformly dispersing the solid particles in the oily dispersant;: into a slurry, the final fineness of the refining is 95% of the weight of the formulation at 200 microns
  • the liquefaction process is to disperse the solid particles in the oily dispersant by stirring; the weight percentage of the oily dispersant added should satisfy the oil content of the finished product not less than 15%, and the slurry is at 22 ⁇ 60'C.
  • the refining method is dry pulverization, semi-dry pulverization and wet pulverization; wherein in the wet pulverization process, the liquefaction process is also carried out simultaneously.
  • the dry pulverization and the semi-dry pulverization are first refined and then liquefied.
  • the finished product is prepared by a cooling molding method or a powder molding method.
  • the basic raw material of the preparation consists of two parts, a main ingredient and an auxiliary material.
  • the main ingredients of the main ingredients are traditional Chinese medicines, including Chinese herbal medicines, Chinese herbal medicines or Chinese herbal medicine extracts; including but not limited to Vietnamese medicine, Mongolian medicine, Japanese Kampo medicine, Korean Kampo medicine (or Korean medicine), and some varieties of Western medicine are also included in this category.
  • Some ingredients may be species of animal and plant and mineral-derived substances in the non-traditional Chinese medicine category.
  • the main component may be in the form of a virgin medicinal material, a fresh drug, a decoction piece, a granule, a powder, an extract and a purified or purified product thereof, an extract and a purified or purified product thereof, a fermentation product, a hydrolyzed or hydrolyzed substance, and an effective part. , monomer components, etc., alone or in combination.
  • a functional filler can be added to the main ingredient according to actual needs.
  • the functional filler has a weight ratio of the main material of not more than 98%.
  • peppermint oil, cinnamon oil, camphor or other volatile and oily ingredients in the main ingredients can be used. It may be added directly as an oily dispersant, or may be added as a solid component after solidification of the functional filler (including inclusion, adsorption, solid dispersion, etc.) to protect the component from loss during preparation.
  • a functional filler may be added to improve the dosage stability and convenience of preparation, administration.
  • Functional fillers may also be optionally added to the main ingredient in order to adjust the efficacy and protective ingredients.
  • a filler such as lactose, dextrin or variable starch is often added before drying to avoid sticking in the drying process.
  • Functional fillers include, but are not limited to, high molecular weight polymers of natural origin, sugars, celluloses and derivatives thereof, starches and derivatives thereof, cyclodextrins and derivatives thereof, polymers, inorganic salts, pH adjusters.
  • high-molecular polymers of natural origin include, but are not limited to, shellac, peach gum, gum arabic, xanthan gum, locust bean gum, 'guaiac gum, bismuth gum, pectin, carrageenan , gelatin, karaya gum, gum, gum, gum, gum, red algae, scutellaria, scutellaria, carrageenan, tower 3 ⁇ 4, locust bean gum, guar gum, acacia, Gua gum, gum bean gum, karaya gum, carrageenan, alginic acid and its salts, apricot gum, agar, dextran, chitin and its derivatives, corn mash, casein and the like.
  • Sugars include but are not limited to:
  • Glucose fructose, sucrose, brown sugar, brown sugar, white sugar, rock sugar, starch sugar, maltose, vermiculite, chyle, dextrin, erythritol, xylitol, fructositol, mannitol, sorbitol, Lactitol, galactitol, maltitol, isomalt, isomalt, palatin, isomalt, oligo-isomalt, arabitol, oligo-isomalt, soy oligosaccharide, Oligogalactose, oligomannose, oligofructose, oligomaltose, xylooligosaccharide, oligoglucoside, oligofructose, oligosaccharide, low polydactose fructose, branched oligofructose, milk Oligosaccharides, trehalose,
  • Cellulose and its derivatives include but are not limited to:
  • Starch and its derivatives include but are not limited to:
  • Modified starch carboxymethyl starch, sodium carboxymethyl starch, methylol starch, hydroxy starch propionate, pregelatinized starch, dextrin, and the like.
  • Cyclodextrins and their derivatives include, but are not limited to:
  • Cyclodextrin methyl cyclodextrin, hydroxypropyl cyclodextrin, hydroxyethyl cyclodextrin, polymer cyclodextrin, ethyl cyclodextrin, branched cyclodextrin, and the like.
  • Polymers include, but are not limited to:
  • Polyvinyl alcohol polyvinyl butyral, styrene-vinyl pyridine copolymer, acrylic resin, crosslinked polyacrylic acid Resin (carbomer), crospovidone, povidone, polyvinyl acetate, methyl acrylate copolymer, polylactic acid, polyamino acid, polycarboxyacetic acid, polyethylene glycol, polyether, ion exchange resin, etc. .
  • Inorganic materials include but are not limited to:
  • Talc powder calcium carbonate, magnesium carbonate, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, magnesium oxide, aluminum hydroxide, silica, activated carbon, activated clay, alumina, sodium chloride, titanium dioxide, and the like.
  • pH adjusting agents include, but are not limited to:
  • Oily dispersant oily dispersant:
  • the melting point of the oily dispersant needs to satisfy the solid form of the finished preparation at normal temperature, and the oily dispersant melts when it is close to the body temperature.
  • the melting point of the preparation is between 23 and 46 ° C, more preferably between 26 and 39 ° C, and most preferably between 27 and 36 ° C.
  • the melting point can be as low as 18 °C.
  • the melting point of the formulation essentially depends on the melting point of the oily dispersant.
  • the oily dispersing agent is used alone or in combination, and the blending amount of the oil or the blending amount of the two or more different melting point oils is adjusted to meet the melting point requirement of the preparation.
  • the oily grease dispersing grease is generally in the range of - 20 to 70 Torr, "preferably, the melting point is in the range of 10 ° C to 60 ° C, and more preferably the melting point is in the range of 22 to 40 ° C. Between 26 and 36 ⁇ .
  • the oily dispersing agent includes, but is not limited to, artificial oils, natural fats or processed (including but not limited to refining, refining, degumming, wintering, crystallization separation, hydrogenation, solidification, transesterification, esterification, fat recombination, fractionation
  • Oils and fats such as oil, hydrogen separation, hydrolysis, alcoholysis, acid hydrolysis, etc., are used alone or in combination.
  • the oily dispersant can be classified into two types, namely, vegetable fats and animal fats.
  • the vegetable fat refers to vegetable-derived fats and oils including, but not limited to, vegetable oils, refined vegetable oils, hydrogenated vegetable oils or hydrogenated refined vegetable oils.
  • vegetable oils such as cocoa butter (CB), cocoa butter (CBS or CBR), cocoa butter (CBE), and palm oil, palm kernel oil, coconut oil, corn oil, soybean oil, rapeseed oil, cottonseed oil, peanut oil, sunflower seeds Oil, sesame oil, rice bran oil, olive oil, safflower oil, kapok oil, evening primrose oil, shea oil, eucalyptus oil, wheat germ oil, Litsea cubeba oil, fragrant fruit fat, black glutinous rice, peach oil, Walnut oil, grape seed oil, sea buckthorn oil, pumpkin seed oil, pine nut oil, canola oil, apple seed oil, pomegranate seed oil, sesame seed oil, carrot seed oil, blackcurrant oil, perilla oil, indigo oil , processed or unprocessed fats, such as flax
  • the animal fat refers to animal-derived fats, including but not limited to butter, cream substitutes, and the use of butter, chicken oil, sheep oil, lard, fish oil, whale oil, porpoise, squalene, etc.
  • the raw materials are processed or unprocessed greases, which are used singly or in combination.
  • Oily dispersants can also be used in oil-soluble surfactants, including but not limited to lecithin, polyethylene glycol (PEG), polyether (poloxamer), span, tween, sucrose fatty acids Ester, single fat Acid glycerides, diglycerides, triglycerides, glycerol fatty acid esters, xylitol monoesters, sorbitan fatty acid esters, fatty acids and their derivatives, stearyl alcohol, cetyl alcohol, half Synthetic fatty acid esters, propylene glycol fatty acid esters, organic acid monoglycerides, monool fatty acid esters, which are used singly or in combination, partially or completely in place of vegetable oils or animal fats and oils.
  • oil-soluble surfactants including but not limited to lecithin, polyethylene glycol (PEG), polyether (poloxamer), span, tween, sucrose fatty acids Ester, single fat Acid glycerides, diglycerides
  • the amount of the oily dispersant to be added needs to satisfy the formulation in the slurry state, and the oil is the continuous phase.
  • the main material also contains a certain amount of oily components, it can be used as a substitute for some oily dispersants to some extent, and the amount of the oily dispersant can be adjusted as needed.
  • the oily ingredients in the main ingredient may affect the melting point of the finished product, and the melting point of the oily dispersant may be adjusted as needed.
  • the freezing point and the melting point of the grease may be different, and the difference in melting point of the different crystals formed by the oil may occur.
  • the melting point may be adjusted by adjusting the crystal type and ratio. 'Other excipients: water-soluble dispersants, flavoring agents, emulsifiers, etc.
  • Water-soluble dispersant The oil in the oral cavity can be absorbed and dissolved after the oily dispersant is melted, thereby further improving the immediate release characteristics of the preparation.
  • the water-soluble dispersing agent is a saccharide, and its main feature is water solubility, which is divided into monosaccharides, disaccharides, sugar alcohols, oligosaccharides and polysaccharides.
  • the saccharide includes, but is not limited to, glucose, fructose, sucrose, brown sugar, brown sugar, white sugar, rock sugar, starch sugar, maltose, verbasnic sugar, lactose, dextrin, erythritol, xylitol, fructositol, mannose.
  • Alcohol sorbitol, lactitol, galactitol, maltitol, isomalt, isomalt, palatinitol, isomalt, oligo-isomalt, arabitol, oligo-isomalt , soy oligosaccharides, galactooligosaccharides, oligomannose, oligofructose, oligomaltose, xylooligosaccharides, oligoglucoside, oligofructose, oligosaccharide, low poly cane fructose, Branches of fructooligosaccharides, cow's milk oligosaccharides, trehalose, chitosan oligosaccharides, inulin oligosaccharides, gentiooligosaccharides, chitosan oligosaccharides, raffinose, panose, glucosyl sucrose, coupling sugar
  • the main material sometimes has a certain water-soluble component, which can replace the water-soluble dispersant to some extent.
  • the addition or addition ratio of the water-soluble dispersant can be determined according to the content of the water-soluble component in the specific main ingredient. If the main raw material is a water extract, it is possible that the water-soluble dispersant is not added or added less.
  • Water-soluble dispersants generally have a flavoring function, and if the amount added is insufficient, no addition, or insufficient flavoring, a suitable flavoring agent is added.
  • Flavoring agent In order to improve the mouthfeel of the preparation, a flavoring substance (flavoring agent) may be added.
  • the flavoring agent can be selectively added according to the taste characteristics of the main ingredient and the final product positioning.
  • Flavoring agents include, but are not limited to, non-sugar sweeteners, flavoring agents, inclusion agents, adsorbents, flavoring agents, sour agents, flavoring agents, flavoring agents; also include, but are not limited to, cocoa powder commonly used in the food industry (cocoa Liquid block), coffee, milk powder, cream, vanillin, ethyl maltol and food flavors, spices. If the flavoring agent contains a grease or a surfactant, it may serve as a substitute for a part of the oily dispersant to some extent, and the amount and melting point of the oily dispersant may be adjusted as needed.
  • Emulsifier To help form the continuous phase of the grease, a surfactant is added to reduce the surface energy.
  • Surfactants are generally water-in-oil type for the purpose of reducing material viscosity or reducing oil usage. They can also be formulated with water-in-oil/oil-in-water surfactants. This may also be omitted if the oily dispersant in the formulation already contains a surfactant.
  • the surfactants include, but are not limited to, lecithin, polyethylene glycol (PEG), polyether (poloxamer), span, tween, sucrose fatty acid ester, mono-fatty acid glyceride, double Fatty acid glycerides, triglyceride fatty acids, polyglycerol fatty acid esters, xylitol monoesters, sorbitan fatty acid esters, fatty acids and derivatives thereof, stearyl alcohol, cetyl alcohol, semi-synthetic fatty acid esters , propylene glycol fatty acid ester, organic acid monoglyceride, monool fatty acid ester.
  • PEG polyethylene glycol
  • polyether polyether
  • span tween
  • sucrose fatty acid ester sucrose fatty acid ester
  • mono-fatty acid glyceride double Fatty acid glycerides
  • triglyceride fatty acids polyglycerol fatty acid esters
  • the weight percentage of the main ingredient and the auxiliary material the weight percentage of the main material in the proportion of the overall formulation of 0. 1% ⁇ 80%, the weight percentage of the auxiliary material accounts for 20% ⁇ 99. 9% of the overall preparation ratio.
  • the auxiliary material is an oil dispersing agent and a water-soluble dispersing agent, a flavoring agent and an emulsifier, wherein the water-soluble dispersing agent, the flavoring agent and the emulsifier account for not more than 85% by weight of the auxiliary material.
  • the preparation of the slurry includes refining and liquefaction, whereby the refined solid particles are uniformly dispersed in the oily dispersant to form a slurry, and the final fineness of the refining is 95% of the weight of the preparation being 200 ⁇ m or less.
  • the liquefaction process The solid particles are dispersed in the oily dispersant by stirring; the weight percentage of the oil dispersant should be equal to not less than 15% in the finished product, and the slurry can be free under the condition of 22 ⁇ 60 ⁇ (or forced
  • the flow is subject to change; according to the stage of oil dispersant addition, the refining method is dry pulverization, semi-dry pulverization and wet pulverization; wherein in the wet pulverization process, the liquefaction process is also carried out simultaneously, and dry The pulverization and the semi-dry pulverization are first refined and then liquefied.
  • the polishing methods used for the refining include a roll grinding method, a refining method, a ball milling method, a vibration grinding method, and a mixing method.
  • Liquefaction is a necessary process for the solid raw material to become a slurry. The purpose is to make the solid material into a dispersed phase (non-continuous phase) and the oily dispersant as a liquid continuous phase. Stirring is a necessary means to achieve dispersion.
  • the temperature of the oily dispersant must be such that the oily dispersant in the material is in liquid form, in principle not lower than 22 ° C (when the oil of the liquid forms crystals, it will be below the melting point but still liquid), generally Above 26 °C; the oily dispersant reaches the continuous phase to ensure that the weight percentage of the added amount should meet the oil content of the finished product not less than 15%, generally more than 20%, the thicker the solid material, the lower the necessary addition amount, oily The lower the amount, the worse the fluidity, and vice versa.
  • three methods can be used in combination, such as dry pulverization, and some oily dispersant is added to the wet pulverization condition before the final fineness is reached, and then wet pulverization is performed until the final fineness is obtained.
  • the combination of these three comminution methods is carried out in the dry-semi-dry-wet process sequence, in two or three ways.
  • Dry pulverization (Fig. 3): This process uses a method of refining and reliquefying. It is refined under the condition that the oil content of the material is low, and the material is pulverized in the form of a dry powder having fluidity. The addition or non-existing amount of the oily dispersant depends on whether the total oil content of the pulverized material satisfies the dry pulverization state and the process requirement, and the original oil content of the solid material is included in the total oil content. Refining - specifically, mixing all the oil-insoluble solid materials (.
  • the main material and water-soluble dispersing agent adding (or not adding) part of the oily dispersing agent, pulverizing to the final fineness, and after the fineness is reached, it is dry powder
  • the pulverization is a heat production process. In principle, no temperature limit is imposed, but the deterioration of the functional ingredients should be avoided, and the oil content of the material is 10% or less and the maximum is 15% or less.
  • oily dispersant is added and stirred to form a slurry, and the oily dispersant can be added separately.
  • This dry pulverization may also be carried out by adding a part of the oily dispersant to a semi-dry pulverization condition at any fineness before pulverization to the final fineness, and then semi-dry pulverization until final fineness.
  • This dry pulverization may also be carried out by adding a part of the oily dispersant to the wet pulverization condition at any fineness before pulverization to the final fineness, followed by wet pulverization until final fineness.
  • Dry pulverizing equipment includes but is not limited to: vibrating mill, rotor mill, jet mill, ball mill, sand mill (bead mill), Raymond mill, planetary mill, impact mill, hammer crush Machine, roller mill, vertical mill, etc. *
  • the material temperature during pulverization is generally above 26 °C, the pulverization process produces heat, and the continuous production needs to be cooled.
  • the oil content of the material is in principle 103 ⁇ 4 23%, generally 15% ⁇ 20%.
  • oily dispersant is added and stirred to form a slurry, and the oily dispersant can be added separately.
  • This half-milling pulverization may also be carried out by adding a part of the oily dispersant to the wet pulverization condition at any fineness before pulverization to the final fineness, and then performing the wet pulverization until the final fineness.
  • Semi-dry pulverizing equipment includes but is not limited to: roller mill, vibrating mill, rotor mill, hammer mill, ball mill, sand mill (bead mill), drum refiner (scraper type grinding) Machine), colloid mill, etc.
  • Refinement and liquefaction specifically mixing all the oil-insoluble solid materials (main material and water-soluble dispersant), adding (or not adding) part (or all) of the oily dispersant into a slurry, pulverizing to the final fineness, After the fineness is reached, the slurry state is obtained, and the oily dispersant can be added in stages.
  • the material temperature is above 32 °C during pulverization, the heat generated during the pulverization process is insufficient to offset the temperature drop caused by the environmental temperature difference. Continuous production requires heating of the equipment.
  • the oil content of the material More than 20%, generally more than 23%.
  • Wet pulverizing equipment includes but is not limited to: drum refiners (scraper refiners), ball mills, sanders (bead mills), basket mills, roller mills, vibratory mills, rotor mills Machine, colloid mill, planetary mill, high shear dispersant, homogenizer, etc.
  • the addition of the oily dispersant is required to grasp the addition time and the addition amount depending on whether the viscosity characteristics of the material are adapted to the process efficiency of the stage.
  • the final amount of finished product is based on the flow rate of 22 ⁇ 60 °C.
  • the original oil content of the solid material varies from material to material. In some extreme cases, the original oil content of the solid material has reached the oil content requirement of the finished product, and no additional oil dispersant is required.
  • the oily dispersant can be made into a liquid state by heating if it is solid at normal temperature.
  • the weight percentage of the oily dispersant added should satisfy the finished oil content of not less than 15%, more preferably not less than 20%, and most preferably not less than 26%.
  • the finished oil content refers to the sum of the weight percentage of the finished product including the grease, the oil-soluble surfactant and other oil-soluble substances in the finished product.
  • the final fineness of the slurry 95% of the weight of the formulation may be below 200 microns (gP95% is less than 200 microns, not limited to fine), and preferably 95% of the weight of the formulation is below 74 microns (g
  • the preparation is preferably in the form of a slurry before molding. If the solid particles in the slurry are coarse, there is a grainy feeling in the mouth, and the particles may pass through the rules.
  • the fineness test can be carried out before molding or after heating or adding a solvent to a liquid or slurry state, and the preparation should avoid mixing water as much as possible during the test, otherwise the result will be affected.
  • the main material is controlled below 10 mesh, and more preferably the main material is controlled to be more than 95% below 100 mesh, most The good thing is that the main material is controlled to be over 95% below 200 mesh.
  • Lecithin is generally used to add an emulsifier, and can be added at any time before molding as needed.
  • the preparation is a solid dispersion hot melt immediate release system
  • the solid material should be well dispersed in the oil phase dispersant and must be stirred well.
  • the process of refining the solid particles is also a process of stirring and dispersing, and the discharge state is liquid state, in which the solid particles have been refined and dispersed.
  • the agitation is to increase the uniformity of the solid material in the grease to prevent the formation of large agglomerates, and to appropriately reduce the moisture.
  • the agitation here can also be referred to as refining.
  • the agglomerated particles are gradually opened by stirring, and the oily dispersant is gradually applied to the surface of the solid particles until the solid particles are completely wetted and coated by the oily dispersant, and the oily dispersant is formed into a continuous phase and liquefied.
  • Cooling molding method using the thermal fluidity of the material and the cooling and solidification characteristics. These include mold casting, flat casting, cold compression molding, slitting, extrusion, and release-free casting.
  • the mold casting method is to quantitatively pour the finished and liquefied material (22 ⁇ 60'C) into a preset mold, and then cool and solidify, demould, and take out the package.
  • Planar casting means that the material which has been refined and liquefied (22 ⁇ 60 ⁇ ) is quantitatively discontinuously poured on the plane of static or continuous motion, and after cooling and solidification, the package is taken out.
  • Cold press molding means that the material that has been refined and liquefied (22 ⁇ 60 °C) has not been cooled and molded, and is cooled and formed by low temperature (less than 20 °C) metal mold positioning and pressing, demoulding, and taking out the package.
  • Cut-to-form refers to continuous extrusion or casting of the finished and liquefied material (22 to 48 ° C) on a stationary or continuous moving surface, quantitatively cutting before solidification and solidification, and solidifying and taking out the package.
  • Extrusion means that the material that has been refined and liquefied (22 ⁇ 46 ° C) is extruded from two equal speed inwardly rotating circular rolls with symmetrical impressions before being completely cooled and solidified. After deburring, it can be polished, coated with sugar or film.
  • the mold release molding means that the material which has been refined and liquefied (22 to 60 ° C) is quantitatively poured into a predetermined mold, and then the seal is cooled and solidified, and can also be sealed during solidification or after solidification. This method of mold is sold with the product. :
  • Powder molding method The material is cooled and solidified into powder or granules, and then press-formed.
  • the preparation of the powder or granules includes, but is not limited to, spray granulation, extrusion granulation, agitation granulation, cutting, and the like.
  • the press forming method can be formed by a tablet press or other mold pressing method.
  • Spray granulation method means that the material (22 ⁇ 60'C) which is finished refining and liquefying is sprayed by the nozzle in the form of droplets, and the cooled gas cools the moving droplets to cool and solidify the material into powder or granules. .
  • the extrusion granulation method means that the material (22 to 48'C) which is subjected to refining and liquefaction is continuously extruded into pellets by an extruder.
  • the agitation granulation method means that the material which has been subjected to refining and liquefaction (22 to 46'C) is continuously stirred into granules or powder under cooling.
  • the cutting method refers to forming a granule or a powder by cutting, hoisting, smashing, pulverizing, etc., which have been finished refining and liquefying and solidifying.
  • Granules or powders made by these methods can also be used directly.
  • the moisture content of the finished preparation should not be more than 7% by weight of the finished preparation, preferably 3%, and most preferably 1%.
  • the finished product of the present invention has a melting point of 23 to 46 ⁇ , and the preparation may be contained or chewed.
  • chewing not only the immediate surface effect is increased by increasing the surface area of the preparation, but also the process of chewing is a process in which mechanical energy is converted into heat energy.
  • the heat generation by chewing also promotes the melting of the oily dispersant to increase the release rate of the drug.
  • the preparation described in the patent is used by a consumer, the preparation may be heated to a paste or a liquid.
  • the cooling temperature is generally between 6 and 26 ° C. The lower the temperature, the faster the solidification rate.
  • the preparation of the invention may be compounded twice after molding, and may be compounded by all the preparations prepared by the method of the present patent, or the preparation may be used as a raw material of other dosage forms together with other ingredients.
  • the dosage form is solid or heated to a liquid or paste form, and the molding method can be formed according to the method of the patent, or can be formed according to other dosage forms.
  • the invention provides a Chinese medicine oral instant release preparation and a preparation method thereof, the advantages and effects thereof are as follows:
  • the medicament prepared according to the method can improve the dispersion rate of the traditional Chinese medicine component in the mouth under the premise of achieving better taste, lOOOOmg
  • the preparations are generally liquefied within 10 to 20 seconds (this data may vary depending on temperature, formulation and shape), and it is convenient to take without drinking water.
  • Figure 1 is a schematic view showing the existence state of various components in a Chinese medicine oral immediate release preparation
  • FIG. 2 is a flow chart of a method for manufacturing a Chinese medicine oral immediate release preparation according to the present invention
  • Figure 3 is a dry pulverization process flow chart
  • Figure 4 is a semi-dry pulverization process flow chart
  • Figure 5 is a flow chart of the wet pulverization process
  • Figure 6 is a flow chart of the roll grinding process of the specific embodiment 1.
  • Figure 7 is a flow chart of the finishing process of the specific embodiment 2
  • Figure 8 is a flow chart of the ball milling process of the specific embodiment
  • Figure 9 is a flow chart of the vibration grinding method of the specific embodiment 4.
  • Figure 10 is a flow chart of the mixing method of the specific embodiment 5
  • the specific embodiment of the present invention takes the modification of the ancient Fangshengmai as an example.
  • the prescription of Shengmaisan comes from "Medical Enlightenment", which consists of ginseng, Ophiopogon japonicus and Schisandra. It has the effects of nourishing qi, nourishing yin, reversing yang, and replenishing phlegm.
  • Example 1 Method for producing Shengmai preparation
  • Slurry preparation semi-dry method and roll-type grinding method (see Fig. 6). Specifically: ginseng 100Kg, Ophiopogon japonicus 200Kg, Schisandra 100Kg pulverized to 200 mesh, add 300Kg white sugar and 180Kg hydrogenated vegetable oil (37 ⁇ 60 ° C) to mix, enter the two-roll mill (or three-roll mill) pre-grind to 60 ⁇ 160 microns, and then into a five-roll mill (or three-roll mill) to grind to 20 to 36 microns.
  • the material is put into a mixer (refiner) for stirring (refining) for 3 to 6 hours, during which 90 Kg of hydrogenated vegetable oil is gradually added according to the viscosity of the material, and 30 kg of the solution is added together with lecithin 1 hour before the end.
  • This process can also be made into sugar powder as raw material. After mixing the ingredients, they can be directly ground into a five-roll mill (or three-roll mill) without pre-grinding. The other processes are the same.
  • Example 2 Method for producing Shengmai preparation (1) Preparation: Ingredients (Ginseng 100Kg, Ophiopogon 200Kg, Schisandra 100Kg), Excipients (sugar 300Kg, hydrogenated vegetable oil 300K g , lecithin 10kg)
  • Slurry preparation Wet method and fine grinding method (see Figure 7). Specifically: ginseng 100Kg, Ophiopogon japonicus 200Kg, Schisandra lOOKg pulverized to 200 mesh, and 300Kg of sugar powder and 270Kg of hydrogenated vegetable oil (36 ⁇ 60 ° C) are added (or mixed) and then scraped by a scraper type grinder to 22 to 28 microns. 30 Kg of hydrogenated vegetable oil was reserved for 1 hour before the end of the addition.
  • Slurry preparation Mixing method (see Figure 10). Specifically: ginseng 100Kg, Ophiopogon japonicus 200Kg, Schisandra lOOKg pulverized to 300 mesh, adding pre-milled milk powder 200Kg, white sugar 300Kg and hydrogenated vegetable oil 370Kg mixed slurry, in a blender (refiner) or scraper refiner Stir (refining) or grinding for 2 to 6 hours, and reserve 3'OKg hydrogenated vegetable oil (38 ⁇ 60 °C) with lecithin 1 hour before the end.
  • Molding Stirring (refining) or grinding after discharging, pouring into a preset mold, then cooling and solidifying, and taking out the package, 10g/block.
  • the temperature of the whole process is controlled below 70 , preferably below 6 (TC, more preferably below 48 ⁇ ).
  • the oil phase-encapsulated phase dispersion system is used, and the oil is to be ensured.
  • the oil ratio For continuous phase, you must add enough oil. The larger the oil ratio, the lower the viscosity of the slurry before it has set, and vice versa.
  • the oily dispersing agent of the preparation needs to receive the heat of the oral cavity and is converted into a liquid, and the solid particles wrapped in the oily dispersing agent can be released to contact with the saliva in the oral cavity, and then the solid particles formed by the mixing and pulverization are mixed.
  • the aqueous dispersant is rapidly dissolved in the saliva in the oral cavity, so that the main component of the solid is rapidly dispersed in the oral cavity.
  • the aqueous dispersant and the main material must be evenly distributed in the oil dispersant, and the higher the release rate of the aqueous dispersant, the better the release rate, which is directly related to the dosage of the main ingredient;
  • the dispersant should be deuterated as quickly as possible.
  • Increasing the melting rate of the oily dispersant can be solved by reducing the melting point of the oil, but it has a great influence on the temperature resistance of the finished product; a more practical method is to reduce the amount of the oily dispersant to reduce the absorption of the oil from the oral cavity. Heat, which improves the immediate release effect.
  • the preparation often contains a certain amount of water, especially the solid discontinuous phase wrapped by the oily component, which is more easily combined with water than the oily component, thereby causing water to swell and gel, and increasing the volume and surface area of the discontinuous phase.
  • the slurry viscosity is abnormally increased before it is solidified. In order to maintain proper fluidity, the oil content has to be increased, but this is not the best solution.
  • the material is exchanged with air at a certain temperature in the mixing and stirring process to evaporate water.
  • the mixing and agitation process is a heat production process.
  • the oil component ratio and temperature of the material By adjusting the oil component ratio and temperature of the material, it is in an effective viscosity. The higher the viscosity, the higher the torque requirement of the equipment, and the heat generation of the material increases, and vice versa.
  • the material can be heated and ventilated. However, if the temperature required by the process is exceeded during the preparation process, cooling is required.
  • the aforementioned grinding device can also achieve the effect of refining the material while evaporating moisture by temperature adjustment, ventilation or closed vacuuming of the equipment crushing chamber.
  • the removal of moisture not only helps to reduce the viscosity of the slurry before the solidification, but also increases the density of the solid discontinuous phase, increases the density of the finished product, improves the hardness of the finished product, helps to form a good oil dispersion system, and prevents moisture from being stored outside during storage. Migrate and improve the preservation of finished products. More importantly, by avoiding the hydration of the solid discontinuous phase, the oral release performance is improved and the mouthfeel is improved.

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Abstract

L'invention concerne une préparation à libération rapide orale et le procédé de production de cette préparation. La matière première de cette préparation est composée de 0,1% à 80 % en poids de médecine chinoise traditionnelle comme matière première principale et de 20 % à 99, 9 % en poids d'un agent de dispersion huileux comme adjuvant. Ce procédé de production comprend les étapes suivantes : préparation en une granulomértie fine de la matière première et fluidification de celle-ci afin de former la suspension épaisse et, moulage de cette suspension épaisse. À l'étape de la préparation en granulométrie fine, la finesse de grain final de 95 % en poids de la matière de la préparation est inférieure à 200 microns. À l'étape de la fluidification, les particules solides sont dispersées dans l'agent de dispersion huileux dans des conditions de brassage et cet agent de dispersion huileux est utilisé en quantité telle que le contenu en huile dans la préparation n'est pas inférieure à 15 % en poids
PCT/CN2008/001890 2007-11-22 2008-11-19 Préparation à libération rapide dans la cavité orale et son procédé de préparation Ceased WO2009070979A1 (fr)

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CNA2007101880206A CN101439053A (zh) 2007-11-22 2007-11-22 一种中药口腔速释制剂及其制造方法

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CN112891377A (zh) * 2021-03-26 2021-06-04 宋亚红 一种贵细蒙药粉配方颗粒及其制备方法

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CN111529573A (zh) * 2020-06-11 2020-08-14 湖南宜仁堂中药饮片有限责任公司 一种中药饮片的制备方法
CN112868973A (zh) * 2021-02-09 2021-06-01 通辽市皓心餐饮管理有限公司 一种含有l-阿拉伯糖的甜味剂及其制备方法和应用

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CN1593621A (zh) * 2004-06-22 2005-03-16 张晴龙 一种生脉口腔崩解片及其制备方法
CN1764440A (zh) * 2003-03-26 2006-04-26 辉瑞健康公司 包含活性成分和可可粉的制剂及其用途
CN1939505A (zh) * 2005-09-26 2007-04-04 刘凤鸣 生脉饮滴丸及其制备方法
CN101194916A (zh) * 2007-11-22 2008-06-11 何煜 一种口腔速释制剂及其制备方法

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CN1561214A (zh) * 2001-09-27 2005-01-05 法马西亚公司 新制剂及其用途
CN1764440A (zh) * 2003-03-26 2006-04-26 辉瑞健康公司 包含活性成分和可可粉的制剂及其用途
CN1593621A (zh) * 2004-06-22 2005-03-16 张晴龙 一种生脉口腔崩解片及其制备方法
CN1939505A (zh) * 2005-09-26 2007-04-04 刘凤鸣 生脉饮滴丸及其制备方法
CN101194916A (zh) * 2007-11-22 2008-06-11 何煜 一种口腔速释制剂及其制备方法

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Publication number Priority date Publication date Assignee Title
CN112891377A (zh) * 2021-03-26 2021-06-04 宋亚红 一种贵细蒙药粉配方颗粒及其制备方法
CN112891377B (zh) * 2021-03-26 2023-09-19 那生桑 一种贵细蒙药粉配方颗粒及其制备方法

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