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WO2012006961A1 - Formulation à libération contrôlée - Google Patents

Formulation à libération contrôlée Download PDF

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Publication number
WO2012006961A1
WO2012006961A1 PCT/CN2011/077179 CN2011077179W WO2012006961A1 WO 2012006961 A1 WO2012006961 A1 WO 2012006961A1 CN 2011077179 W CN2011077179 W CN 2011077179W WO 2012006961 A1 WO2012006961 A1 WO 2012006961A1
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Prior art keywords
controlled release
group
cyclodextrin
hydrochloride
cyclodextrin derivative
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Chinese (zh)
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钟术光
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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)

Definitions

  • the present invention relates to a controlled release formulation. More particularly, the present invention relates to a controlled release preparation coated with an outer controlled release coating film having improved overall performance, particularly a zero-order release controlled release preparation, the controlled release preparation being coated with a drug-containing core material
  • the polymer controlled release coating film contains a cyclodextrin derivative having a water-soluble average number of substitutions (or DS) of not less than 5 per hydroxyl unit dispersed in a single molecule state and/or in a micelle state.
  • the invention also relates to a process for the preparation of a controlled release formulation. Background technique
  • Some water insoluble polymers control drug release by coating in controlled release formulations, particularly zero release sustained release formulations. Due to the water insolubility of the polymer, it is often necessary to form micropores in the coating film to improve the permeability of the controlled release coating to facilitate the penetration of water and the release of the drug, especially the solubility of the drug. When the total surface area of the preparation is small.
  • the second is represented by US5472712 and US5639476:
  • This type of technology dissolves water-soluble porogen in an aqueous dispersion containing a water-insoluble polymer, and the water-soluble substance is present in the water-insoluble polymerization by coating.
  • the water-soluble substance in the film is dissolved in the digestive tract by the digestive juice to form small pores.
  • the advantage of this technique is that the use of organic solvents is avoided.
  • the water-soluble porogen is present in the film in a single molecule.
  • the pore size of the pores is determined by the molecular size of the water-soluble porogen, and the molecular size of most water-soluble porogens is extremely large.
  • US6974591 This type of technology generally disperses and suspends a porogen which is insoluble in water but soluble in an acidic or alkaline digestive solution in an Aqueous polymeric dispersion containing a water insoluble polymer.
  • the porogen is present in the coating film of the water-insoluble polymer, and the porogen in the coating film is dissolved in the digestive tract by the digestive juice to form larger micropores.
  • the formation of micropores or the dissolution of porogens are affected by the acidity or alkalinity of the digestive juice or the pH value and the amount of digestive juice, however,
  • the pH value of the patient's digestive juice and the amount of digestive juice often change, affecting many factors, such as the patient's physical condition, physical condition, diet, and other factors such as the patient's circadian rhythm at different times of the day.
  • the pH of the digestive juice is also different; even the strength of the gastrointestinal motility function is greatly affected by the formation of micropores or the dissolution of porogens.
  • the strength of the gastrointestinal motility function is also affected by many factors such as patients. Effects of physical fitness, physical condition, diet and circadian rhythms.
  • the region of apparent concentration gradient constitutes the interfacial layer between the two phases.
  • the thickness of the interfacial layer is primarily determined by the compatibility of the two polymers. As the compatibility increases, the degree of diffusion increases, the phase interface becomes more and more blurred, and the thickness of the interface layer becomes larger and larger, so that the final phase interface disappears completely and becomes a homogeneous blend, achieving complete compatibility (polymer alloy Compatibility and Compatibilization, Journal of Qingdao University, May 1995, Vol. 10, No. 1, p. 91).
  • the interface between the macroporous porogen and the controlled release coating becomes more and more blurred with time, and the micropores that can be formed also change with time. It becomes more and more blurred, and the pore size also becomes non-constant, so that the release behavior of the drug becomes unstable, and the drug release storage stability is deteriorated.
  • the granular porogen will also become a stress concentration point in the film, which becomes a weak link in the film, and the mechanical strength of the film is greatly reduced.
  • W02001012163 contains poly(ethylene glycol) 3350 (PEG 3350), sorbitol, sucrose, polyol, xylitol, mannitol, carbohydrates, sugar, in the controlled release coating of the listed controlled release formulations.
  • a water-soluble substance such as lactose, maltose, glucose, water-soluble cyclodextrin or urea.
  • W00041704 prepares additional osmotic pump tablets according to Example 2 and evaluates their dissolution characteristics.
  • Pore-forming agents evaluated include poly(ethylene glycol) 3350 (PEG 3350), sorbitol, sucrose, polyol, xylitol, mannitol, carbohydrates, sugar, lactose, maltose, glucose, water-soluble cyclodextrin , and urea.
  • PEG 3350 poly(ethylene glycol) 3350
  • sorbitol sucrose
  • polyol polyol
  • xylitol mannitol
  • carbohydrates sugar, lactose, maltose
  • glucose water-soluble cyclodextrin
  • urea urea
  • a primary object of the present invention is to provide a controlled release preparation having improved overall performance, particularly a controlled release preparation of zero order release, and a process for the preparation thereof.
  • the controlled release preparation and the preparation method thereof can inherit or further carry forward the advantages of the prior art mentioned above, and can overcome or alleviate the defects of the prior art mentioned above, for example, the preparation of the preparation may be carried out without using an organic solvent, and the release of the preparation medicine is The effects in vivo and in vitro are relatively small, the drug release is relatively fast, the time lag is relatively small, the drug bioavailability is higher, the drug release storage stability and production reproducibility are improved; and the controlled release film of the preparation Mechanical strength has also been improved, and so on.
  • the present invention provides a controlled release preparation coated with an outer controlled release coating film, in particular a zero-order release controlled release preparation comprising: 1) a core material containing at least one drug 2), a controlled release coating film covering the above core material,
  • the controlled release coating comprises a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and a digestive juice of the stomach and intestines and at least one of which is dispersed in a single molecule state and/or in a micellar state in a non-particulate form.
  • the average degree of substitution (DS) of any physiologically acceptable water solubility therein is not less than 5/n (where n represents the number of glucose units contained in the cyclic structure of the cyclodextrin, and ⁇ ⁇ ⁇ 6, is a positive integer) Cyclodextrin derivatives.
  • the invention also provides a preparation method of a controlled release preparation coated with an outer controlled release coating film, in particular a zero-order release controlled release preparation, which comprises the following basic steps: 1), preparation a core material containing at least one drug; 2) water having a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and stomach and intestinal digestive juices containing at least one of the following cyclodextrin derivatives
  • the dispersion-coated release film of the above core material, the above cyclodextrin derivative is any physiologically acceptable water-soluble average degree of substitution (DS) of not less than 5/n (where n represents a cyclodextrin ring) a cyclodextrin derivative having a number of glucose units contained in the structure, ⁇ ⁇ ⁇ 6 , which is a positive integer), wherein the cyclodextrin derivative is all dissolved in the aqueous dispersion of the above polymer; 3) if necessary,
  • the controlled release coating is subjected to healing (
  • controlled release coating film means a material containing a sufficient amount of hydrophobic (polymeric) material coated on the outer surface of the core of the controlled release preparation and having sufficient mechanical strength to maintain the controlled release preparation.
  • the non-ruptured coating film during the release of the aqueous solution, the coating film can delay the release of the drug or therapeutic active agent contained in the controlled release preparation when it is placed in an aqueous solution.
  • active ingredient means any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.
  • a as used in the present invention means at least one, and may be one type or two or more types.
  • pharmaceutically acceptable as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without deteriorating the stability and/or efficacy of the preparation and is suitable for topical or systemic administration.
  • the porogen in the controlled release coating of the present invention has an average degree of substitution (DS) of any physiologically acceptable water solubility of not less than 5/n (where n represents a glucose contained in the cyclic structure of the cyclodextrin)
  • DS average degree of substitution
  • n represents a glucose contained in the cyclic structure of the cyclodextrin
  • the number of units, ⁇ ⁇ ⁇ 6, is a positive integer) cyclodextrin derivative.
  • porogen refers to a substance that facilitates the formation of pores in the controlled release coating film of the present invention or enhances the permeability or water permeability of a controlled release coating film.
  • the environment can be dissolved, leached or leached from the controlled release coating to form ⁇ L.
  • water-soluble as used herein means that the solubility in water (temperature 25 ° C) is not less than 30 m g / ml, preferably not less than 100 mg / ml, more preferably not less than 500 mg / ml, most preferably The ground is not less than 1000mg/ml.
  • the cyclodextrin has a cyclic structure, and various homologues (such as 6-12 glucose units in the ring) are known, and these are cyclic compounds which are linked by ⁇ - 1 and 4 glycosidic bonds.
  • X-ray diffraction and nuclear magnetic resonance studies have confirmed that the three-dimensional structure of the cyclodextrin is a hollow cylindrical shape with a wide open end and a wide open end. Its primary hydroxyl group is located at the opening of the small end of the cavity, and the secondary hydroxyl group is arranged at the opening of the hollow end ("New Drug Formulations and New Technologies", Lu Bin, People's Medical Publishing House, 1st edition, April 1998, 29 pages).
  • the three most common cyclodextrins containing glucose units are ⁇ -cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin, and their (bobbin) peripheral diameters are 1.46 nm, 1.54 nm, respectively.
  • 1. 75nm, (bobbin) ring height is 0. 79nm (Handbook of Pharmaceutical Excipients) (original fourth edition), RC Luo, P. Jishsky, PJ Weller, Zheng Junmin translation, Chemical Industry Press, 1st edition, January 2005, p. 220).
  • peripheral diameter of these cyclodextrins is higher than that of common water-soluble porogens such as sodium chloride (0.28 nm in diameter), potassium chloride (0.22 nm in diameter), glucose (0.52 nm in diameter), and amino acids (diameter 0). 66nm), urea (diameter 0. 32nm), etc. are much larger, but the height of the bobbin ring (or tube length) appears to be somewhat insufficient, and the application is limited.
  • the primary and secondary hydroxyl groups are located at the openings at both ends of the tube cavity And can be substituted by other groups, so that when at least 5 (or 9) hydroxyl groups in the bobbin structure of the cyclodextrin are replaced by other longer and/or larger groups, the bobbin of the cyclodextrin can be ensured.
  • At least one side of the structure has 3 (or 5) hydroxyl groups substituted (3 or more substituent groups can be enclosed in a bobbin, 5 or more substituent groups can enclose a more rounded tube Tube), such that the bobbin structure corresponding to the cyclodextrin is extended and/or the outer circumference is enlarged.
  • cyclodextrin derivatives can form longer and larger tubes after dissolution from the controlled release coating. Therefore, the use of such a water-soluble cyclodextrin derivative substituted in a molecular state dispersed in a controlled release coating film as a porogen is more generally a molecularly dispersed water-soluble porogen in a controlled release coating film including other conventional Cyclodextrins have more and greater advantages. For example, 1), longer and larger pores can be obtained, which facilitates the penetration of larger drug molecules, thereby reducing the number of drugs used, increasing the rate of drug release, or higher bioavailability; As in 2), the mechanical properties of the controlled release film will be enhanced due to the longer and larger channels.
  • the cyclodextrin derivative is water-soluble, it can be dissolved in a polymer aqueous dispersion prepared by preparing a controlled release coating film instead of being suspended and dispersed in a controlled release coating film in a molecular form, so that there is an advantage. : 3), to avoid the use of organic solvents in production, and to improve the mechanical properties of controlled release film
  • any physiologically acceptable water-soluble average degree of substitution can be used in the present invention.
  • n represents the number of glucose units contained in the cyclic structure of the cyclodextrin
  • n S ⁇ 6 preferably, 7 niS 12, more preferably, 9 niS 12
  • n_l 3 k 2 iS3 (n_l) /2
  • 3 13 ⁇ 4 n 5iSk 4 iSn, n, k 2 , k 3 , k 4 are positive integers, the larger the value
  • the substituent group on the glucose unit in the cyclodextrin derivative includes, but is not limited to, a hydroxy fluorenyl group, a decyl carboxy group, a
  • the substituent group in the above cyclodextrin derivative preferably further contains a certain amount of a lipophilic group such as an unsubstituted indenyl group, a cyclodecyl group, an aryl group and a mixed group thereof.
  • the amount of the above-mentioned lipophilic group is usually 0.5 to 50%, preferably 2 to 30%, based on the total number of the substituent groups of the above cyclodextrin derivative.
  • base It is often meant to include saturated or unsaturated straight or branched chain hydrocarbon groups containing from 1 to 30, preferably from 3 to 24, more preferably from 4 to 20, most preferably from 6 to 18 carbon atoms.
  • it is a saturated hydrocarbon group such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl, octyl Base, sulfhydryl, dodecyl, tetradecyl, hexadecanyl, octadecyl, etc.
  • the term "average degree of substitution (DS) means the average of substituted hydroxyl groups per glucose unit. The number, since each glucose unit of the cyclodextrin has three hydroxyl groups at the 2, 3, and 6 positions, the maximum DS is 3.
  • a cyclodextrin derivative which is preferably used in the present invention is an ether cyclodextrin derivative which satisfies the above definition, as described by M. Nogradi at 3 ⁇ 4 ⁇ 4 ⁇ /3 ⁇ 4tore: 9 (8) 577-578 (1984), for example Hydroxypropyl-cyclodextrin, hydroxybutyl-cyclodextrin, hydroxyethyl-cyclodextrin and branched (branched) cyclodextrin derivatives (eg, glucosylcyclodextrin, di-glucosin) Glycosyl cyclodextrin, triglucosylcyclodextrin, maltosylcyclodextrin, dimaltosylcyclodextrin, trimaltosylcyclodextrin) and mixtures thereof.
  • 2-hydroxyethyl-cyclodextrin 2-hydroxypropyl-cyclodextrin and (2-carboxymethoxy)propyl-cyclodextrin, diglucosylcyclodene which satisfy the above definition.
  • 2-hydroxyethyl-cyclodextrin 2-hydroxypropyl-cyclodextrin and (2-carboxymethoxy)propyl-cyclodextrin, diglucosylcyclodene which satisfy the above definition.
  • triglucosylcyclodextrin dimaltosylcyclodextrin, trimaltosylcyclodextrin and mixtures thereof.
  • a particularly preferred example of this is a hydroxybutenyl ether cyclodextrin which satisfies the above definition, as described in WO-2001/044305.
  • a cyclodextrin derivative useful in the present invention is a polyether cyclodextrin derivative which satisfies the above definition, as described in U.S. Patent No. 3,457,731.
  • the unsubstituted cyclodextrin is usually reacted with an alkylene oxide in the presence of a basic catalyst, preferably at superatmospheric pressure and at elevated temperature.
  • a basic catalyst preferably at superatmospheric pressure and at elevated temperature.
  • the average molar substitution (MS) of the present invention is used to indicate the average number of moles of the substituent in each glucose unit. Measure. MS can be greater than 3, and there is no theoretical limit.
  • the MS is usually from 1.5 to 24, preferably from 2 to 12, more preferably from 3 to 9.
  • An example which is more preferably suitable for use in the present invention, particularly for external use, is a quaternary ammonium cyclodextrin derivative (QACD) which satisfies the above definition, as described in US- 524,109, US Pat. No. 3,453,257, WO-2003/105867.
  • QACD quaternary ammonium cyclodextrin derivative
  • a specific example thereof is 3-(trimethylammonium)- 2-hydroxypropyl- ⁇ -cyclodextrin which satisfies the above definition.
  • a sulfobutyl (ether) cyclodextrin and a salt thereof such as a sodium salt or a potassium salt, as described in US-5134127-A, are more preferably used in the examples of the present invention.
  • a cyclodextrin having an average degree of substitution (DS) of a mercaptoether group of not less than 3/ ⁇ and not more than 3 and an average degree of substitution (DS) of a mercaptoether group of not less than 2/ ⁇ and not more than 3
  • the SAE-AE-CD) derivative more preferably, the average degree of substitution (DS) of the sulfodecyl ether group satisfying the above definition is not less than 5/ ⁇ and not higher than 3 and the average substitution of the mercaptoether group.
  • SAE-AE-CD cyclodextrin
  • the cyclodextrin derivative suitable for use in the present invention is a sulfated cyclodextrin derivative which satisfies the above-defined high sulfhydryl group as disclosed in WO 96/20222.
  • the higher thiol group has an average degree of substitution (DS) of not less than 3/n and not more than 3 and a sulfate group average degree of substitution (DS) of not less than 2/n and not more than 3, preferably , the higher thiol group has an average degree of substitution (DS) of not less than 5/n and not more than 3 and a sulfate group average degree of substitution (DS) of not less than 4/n and not more than 3, wherein n represents a ring The number of glucose units contained in the cyclic structure of dextrin.
  • the higher sulfhydryl groups described herein are typically lipid, aliphatic or aromatic carbon chains having a C6-C30 carbon number.
  • R is preferably selected from the group consisting of H, Na, K, Li and/or NH 4 .
  • the above cyclodextrin derivative preferably contains a hydroxyl group in which the combined total of the higher thiol group, the sulfate group and the hydroxyl group does not exceed N, and further, wherein N is the hydroxyl group number of the cyclodextrin from which the derivative is obtained.
  • Preferred examples are sodium sulfonate-dodecyl (laurel) (or guanidine)-cyclodextrin, ammonium sulphate-based squalane y - ⁇ (or ⁇ )-cyclodextrin, potassium sulphate-based one.
  • a highly substituted water-soluble cyclodextrin derivative which does not contain a lipophilic group or has a low lipophilic group content (e.g., the amount of the entire substituent group of the above cyclodextrin derivative is not more than 25%) a lower substituted water-soluble cyclodextrin derivative or an unsubstituted water-soluble cyclodextrin, which helps to prevent hydrophobic groups on the polymer chain from entering the cavity in the cyclodextrin derivative molecule
  • the water-soluble cyclodextrin derivative used in the present invention (usually having a higher content of a lipophilic group (e.g., the amount of the entire substituent group of the above cyclodextrin derivative is more than 50%)
  • Highly substituted water-soluble cyclodextrin derivatives The voids (holes) in the molecule are preferably pre-occupied, ie water-soluble cyclodextrin derivatives are pre-packaged, which reduces drug release in controlled release formulations Lag time (lagtime).
  • the voids (holes) in the molecule of the water-soluble cyclodextrin derivative can be controlled to release the hydrophobic group on the polymer chain in the coating film, that is, the polymer chain.
  • the hydrophobic group enters the cavity (hole) in the molecule of the cyclodextrin derivative, and the time for the dissolution of the cyclodextrin derivative from the controlled release film (polymer) is prolonged or even dissolved, so that the formulation exhibits a certain degree of performance. Drug release time lag.
  • the above water-soluble cyclodextrin derivatives are usually pre-compounded with pharmaceutically acceptable substances which they can contain, such as drugs in the core material and/or pharmaceutically acceptable excipients such as preferred fat-soluble adjuvants.
  • pharmaceutically acceptable substances which they can contain, such as drugs in the core material and/or pharmaceutically acceptable excipients such as preferred fat-soluble adjuvants.
  • the drug in the core material to be wrapped therein can be released as an immediate release portion.
  • excipients for inclusion such as animal and vegetable fats, semi-synthetic oils, natural or artificial waxes, high-grade fat (C8-C24) acid, high-grade fat (C8-C24) acid esters and high-grade mercapto groups (C8) -C24) Alcohol, high-grade mercapto (C8-C24) ether, polyoxyethylene high-grade mercapto (C8-C24) ether (such as polyoxyethylene oleyl ether), sorbitan higher fat (C8-C24) acid ester (Span class), polyoxyethylene sorbitan higher fat (C8-C24) acid ester (Tween), polyoxyethylene high fat (C8-C24) acid ester (such as polyoxyethylene monooleate, Polyethylene glycol mono or bis stearate) and mixtures thereof.
  • excipients for inclusion such as animal and vegetable fats, semi-synthetic oils, natural or artificial waxes, high-grade fat (C8-C24) acid
  • Preferred exemplary fat-soluble excipients include, but are not limited to, hexadecanyl ester wax, sorbitan monolaurate, sorbitan monomyristate, sorbitan monostearate, propylene glycol Monolaurate, propylene glycol monomyristate, propylene glycol monopalmitate, propylene glycol monostearate, sorbitan monopalmitate, octanol, decyl alcohol, decadiol, tetradecanol, hexadecyl Alcohol, octadecyl alcohol, polycetitol emulsion wax, emulsifying wax, lauric acid isopropanolamide, octanoic acid, citric acid, dodecanoic acid, ten Tetradecanoic acid, hexadecanoic acid, octadecanoic acid, ethylene glycol monostearate, self-emulsifying
  • the amount of porogen, i.e., the cyclodextrin derivative described above, in the controlled release coating is determined by the skilled artisan skilled in the art based on the nature of the drug and the desired rate of release. 5% ⁇
  • the porogen, the amount of the above-mentioned cyclodextrin derivative is usually determined by the particle size, the type of the controlled release film polymer and its amount, the nature of the drug, the desired rate of release, etc., usually 0.5% ⁇ 80% (by weight), preferably 1% to 60% by weight, preferably 3% to 50% by weight, more preferably 5% to 40% by weight, It is based on the dry weight of the controlled release coating component.
  • the 5% to 80%, preferably 1% to 60%, of the porosity of the controlled release coating film is usually from 0.5% to 80%, preferably from 1% to 60%, because the amount of the porogen is the main factor that affects or determines the porosity of the controlled release film.
  • the term is 3% to 50% (more preferably 5% to 40%.
  • the term "porosity" as used herein refers to the space left by the porogen dissolved or degraded in the release film.
  • the ratio of the volume of the complete controlled release coating film For the sake of simple calculation, and because the dissolution or degradation of the porogen does not affect the intrinsic or external size of the original release coating film, the "porosity" can also be controlled release film.
  • the ratio of the weight of the porogen in the weight of the entire original release film is approximately expressed. Therefore, the "porosity" can be calculated by the following two calculation formulas in the present invention:
  • Formula 1 Volume of the carrier agent 3 ⁇ 4 hole ⁇ weight / carrier density
  • a pharmaceutically acceptable polymer insoluble or nearly insoluble in water and a digestive juice of the stomach and intestine suitable for use in the controlled release coating of the present invention may be pharmaceutically acceptable in water-insoluble or nearly water-insoluble in aqueous solution.
  • Suitable polymers may be selected from, but not limited to, cellulose esters, acrylic polymers, polyvinyl acetates, polyvinyl chlorides, and combinations thereof that are insoluble or hardly soluble in water and gastric and intestinal digestive juices. Things.
  • suitable polymers of preferred examples include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cel lulose acetate propionate, nitrocellulose, three Cellulose pentoxide, cellulose tridodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylate polymer, vinyl chloride-vinyl alcohol Terpolymer of vinyl acetate, polycarbonate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, ethylene acetate-vinyl chloride copolymer, polyvinyl chloride, polyethylene, poly Isobutylene, poly
  • Another useful example is an aqueous dispersion coating containing 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer.
  • the proportion of the controlled release coating polymer in the dry coat is determined by the type of polymer selected, the type of porogen and its amount, the nature of the drug, the selected dosage form, and the desired mode of release. It is 20% to 99.5% by weight, preferably 40% to 99% by weight, more preferably 50% to 97% by weight, most preferably 60% to 95% by weight. ), which is based on the dry weight of the controlled release coating component.
  • the present invention can be incorporated into a controlled release coating film to add a polymer reinforcing agent and/or a toughening agent and other mechanical property improving agent.
  • Enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable filler reinforcing agents, fiber reinforcing agents, and mixtures thereof.
  • Suitable filler reinforcing agents may be surface-modified rigid inorganic particles and rigid organic particles.
  • Rigid inorganic particles include, but are not limited to, fine or ultrafine particles of carbonates, sulfates, metal oxides, metal powders, carbon compounds, silicon-containing compounds, and mixtures thereof.
  • Preferred examples of the rigid inorganic particles include, but are not limited to, attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, carbon black, silica, kaolin, mica, talc, calcium phosphate, magnesium carbonate, magnesium oxide, Magnesium silicate, magnesium trisilicate.
  • the average particle diameter of the above inorganic particles is usually less than (inclusive) ⁇ ⁇ ⁇ , preferably less than (inclusive) 400 nm, more preferably less than (inclusive) 100 nm, more preferably less than (inclusive) 20 calendars, and most preferably less than ( Contains) 5nm. Nano-sized particles (less than 100 calendars) are preferred because they can simultaneously improve strength, toughness, impact resistance, and dimensional stability.
  • the above inorganic particles are preferably treated with a surface active material such as a fatty acid, a resin acid and a salt thereof, an ester or a coupling agent such as a silicon germanium coupling agent or a chemically bonded macromolecule or other suitable on the surface of the particle such as an acid anhydride.
  • the inorganic particles are more preferably surface-modified by treatment with a surface active material such as a fatty acid, a resin acid, a salt thereof or an ester.
  • a surface active material such as a fatty acid, a resin acid, a salt thereof or an ester.
  • rigid organic particles include, but are not limited to, polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrene copolymer (MMA/ST), and styrene/acrylonitrile copolymer. (SA).
  • Fiber reinforcing agents useful in the present invention include pharmaceutically acceptable inorganic fibers, organic fibers, and metal fibers.
  • Inorganic fibers are chemical fibers made from mineral materials, and examples thereof include glass fibers, quartz glass fibers, boron fibers, ceramic fibers, and metal fibers.
  • useful organic fibers such as synthetic fibers such as aramid fibers, aramid fibers, polyester fibers, nylon fibers, vinylon fibers, polypropylene fibers, polyimide fibers, etc.; natural organic fibers such as cotton fibers, sisal fibers, Wood fiber and so on.
  • Examples of metal fibers are metal synthetic fibers such as silver, copper, and nickel. Natural organic fibers and metal fibers are preferred.
  • the toughening agent can have a reduced brittleness of the composite and an improved impact resistance of the composite.
  • the active toughening agent and the non-active toughening agent may be used in the present invention.
  • the active toughening agent refers to an active group having a molecular chain which can react with the matrix resin, which can form a network structure and add a part of the flexible chain, thereby improving the impact resistance of the composite.
  • Inactive Tougheners are a class of toughening agents that are well compatible with the matrix resin but do not participate in the chemical reaction. Inactive toughening agents are preferred for better compatibility with organisms and lower production costs.
  • the toughening agent used in the present invention may be a suitable rubber-based toughening agent, a thermoplastic elastomer-based toughening agent, and other toughening agents, and mixtures thereof.
  • the rubber-based toughening agent are liquid polysulfide rubber, liquid polybutadiene rubber, nitrile rubber, ethylene propylene rubber, and styrene-butadiene rubber.
  • Thermoplastic elastomers are generally a class of synthetic materials that exhibit rubber elasticity at room temperature and plasticize at high temperatures.
  • thermoplastic elastomer examples include, but are not limited to, polyurethanes, styrenes, polyolefins, polyesters, syndiotactic 1, 2-polybutadienes, and polyamides, and the like, preferably polyesters and polyolefins.
  • Other toughening agents include, but are not limited to, low molecular polyamides and low molecular weight inactive toughening agents such as phthalates.
  • the present invention can simultaneously add a toughening agent and a reinforcing agent to the aqueous dispersion suspension to obtain a film which is more comprehensive and excellent in mechanical properties.
  • the mechanical property improving agent is usually used in an amount of from 0.5 to 40% by weight, preferably from 1% to 25%, more preferably from 2% to 15%, based on the dry weight of the film component.
  • a general additive material may be added to the coating liquid of the present invention.
  • the amount and application of the universal additive material in the drug coating layer is well known to those skilled in the art.
  • Common additives include, but are not limited to, anti-adhesives (separators), stabilizers, pigments, defoamers, antioxidants, penetration enhancers, shine agents, perfumes or flavoring agents. They are used as processing aids and should ensure safe and reproducible preparation methods as well as long-term storage stability or additional advantageous properties imparted to pharmaceutical dosage forms. They are added to the formulated polymer prior to processing and can affect the permeability of the coating, which can also be used as an additional conditioning parameter.
  • plasticizers are often added to the coating formulation to lower the glass transition temperature (Tg) of the polymer to a suitable range, and to improve the film forming ability of the coating material and enhance the flexibility of the film. Sex and strength, improve the adhesion of the film to the substrate.
  • Tg glass transition temperature
  • a suitable glass transition temperature (Tg) is usually in the range of 0 to 70 ° C, preferably 10 to 50 ° C, and most preferably 15 to 40 ° C.
  • plasticizers of different properties such as water-soluble, water-insoluble or water-insoluble plasticizers can be used to adjust the release rate of the controlled release film.
  • the plasticizer is generally a liquid substance having a high boiling point, a low volatility and being miscible with a polymer (Mr is about 150 to 800, preferably 300 to 500), or a solid substance having a low melting point.
  • plasticizers can be used as a physiologically compatible C 6 ⁇ c 40 (.
  • a plasticizer are dibutyl phthalate or diethyl phthalate.
  • plasticizers examples include glycerin, propylene glycol, polyethylene glycol, castor oil.
  • the amount of the plasticizer depends on the properties of the desired film, such as the glass transition temperature, mechanical properties, etc., the type of plasticizer, the type and amount of the film-forming agent (ie, the water-insoluble film-forming polymer), and usually The amount is 5 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 10 to 30% by weight, based on the dry weight of the film component.
  • Anti-adherents are generally beneficial hydrophobic materials and are typically added to the spray suspension. They prevent the accumulation of nuclei during the film formation. Preference is given to using talc, magnesium stearate or calcium stearate, finely divided silicic acid, kaolin or a nonionic emulsifier having an HLB value of from 3 to 8. 5 ⁇ 100% ( ⁇ )
  • the polymer is usually used in the coating layer of the present invention.
  • the separating agent is added as a final coating in concentrated form. The coating is carried out in the form of a powder or by spraying from a suspension of 5 to 30% solids. 1 ⁇ 2% ⁇ The amount of the dosage of the pharmaceutical dosage form is 0. 1 ⁇ 2%.
  • the stabilizer is preferably an emulsifier or a surfactant, that is, a certain interface active material, which stabilizes the aqueous dispersion.
  • suitable stabilizers are diethanolamine, monoethanolamine, triethanolamine, fatty acids, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), nonoxynol ether, octoxynol, oil Acid, poloxamer, polyoxyethylene 50 stearate, polyoxyl fatty acid, polyoxyl hydrocarbon ether, polysorbate (Tween), dehydration Sorbic acid ester (Span), fatty acid salts, povidone, sodium lauryl sulfate, sodium decyl stearyl sulphate, sucrose stearate, polysorbate and mixtures thereof.
  • the stabilizer is contained in an amount of from 1 to 15% by weight, preferably from 5 to 10% by weight, based on the wet weight of the component of the aqueous dispersion coating liquid.
  • Alumina or an iron oxide pigment is generally dispersed and added. Titanium dioxide is used as a white pigment.
  • the pigment is added in the coating layer of the present invention in an amount of from 20 to 60% by weight based on the polymer mixture. However, due to the high pigment binding ability, the addition amount can be as high as 100% by weight.
  • the antifoaming agent is generally dimethicone.
  • the final coating is used directly in concentrated form.
  • the coating is carried out in powder form or by spraying with an aqueous suspension of 5 30% solids. 1 2% ⁇
  • the amount of the dosage of the pharmaceutical dosage form is 0.12%
  • Core materials useful in the present invention include, but are not limited to, regular, irregular forms of tablets, granules, pellets, crystals, drug-loaded resins.
  • the active ingredient (or drug or biologically active substance) used in the present invention is usually not particularly limited.
  • the active ingredient to be used in the present invention may be any of the above-mentioned pharmaceutically or nutritionally therapeutic or preventive substances.
  • active ingredients useful in the present invention are central stimulants, analgesics, antipyretic analgesics, anti-inflammatory analgesics, anti-gout agents, anti-shock palsy drugs, antipsychotics, anxiolytics, antidepressants, Antiepileptic drugs, sedatives, hypnotics, anticonvulsants, autonomic nervous system drugs, calcium antagonists, drugs for treating chronic cardiac insufficiency, antiarrhythmic drugs, angina pectoris drugs, peripheral vasodilators, blood pressure lowering drugs, regulation Blood lipids and anti-atherosclerotic drugs, respiratory drugs, antacids and peptic ulcer drugs, gastrointestinal antispasmodics, digestive drugs, antiemetics, emetics and
  • Examples of preferred drugs for use in the present invention include, but are not limited to, LEC0Z0TAN (SRA-333), amoxicillin, amoxicillin-clavulanate potassium compound, asdamamo, aspirin-phosphoric acid ligustrazine compound, aspirin-dipyridamole Compound, piperazine ferulate, acyclovir, paracetamol-pseudoephedrine-d- maleic acid dextrobromide compound, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, vinegar Clofenac, isosorbide mono-aspirin compound, isosorbide mononitrate, diazepam, metformin-roglitazone combination, famciclovir, felodipine, fenofibrate, fesotedine hydrochloride pseudoephedrine hydrochloride Compound, fluvastatin sodium, acyclovir and compound, fel
  • Glipizide-Metformin Hydrochloride Glipizide, Glimepiride-Metformin Compound, Gliclazide, Potassium Citrate, Tamoxifen Citrate, Tamoxifen Citrate, Succinic Acid Desvenlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolpidem tartrate, clarithromycin, oxymatrine, ranolazine, liba Wein, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-paracetamol-pseudoephedrine compound, loratadine-pseudoephedrine compound, rosiglitazone, roxithromycin , lovastatin, trimebutine maleate, enalapril
  • the actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.
  • the core material may contain other pharmaceutical auxiliary agents besides the active substance, such as slow release materials, porogens, fillers, binders, disintegrants, disintegrators, lubricants (including flow aids, anti-adhesives). ) an essential component such as an osmotic active substance (ie, an osmotic pressure promoter) or a permeation-promoting polymer (a penetration enhancer).
  • an osmotic active substance ie, an osmotic pressure promoter
  • a permeation-promoting polymer a penetration enhancer
  • it may also contain solubilizers, suspending agents, sweeteners, fragrances, pigments, absorbents and surfactants (such as wetting, dispersing, solubilizing, emulsifying, etc.).
  • the pharmaceutical auxiliaries and their amounts are selected by those skilled in the art based on actual conditions such as the nature of the drug, the desired rate of drug release, and the like.
  • the present invention relates to a method for the preparation of a controlled release coating coated controlled release formulation, in particular a zero order release controlled release formulation. The basic steps in the preparation method of the controlled release preparation are described in detail below.
  • the method of preparing the core material containing at least one drug is not particularly limited. Usually prepared by extrusion of the pharmaceutically active substance, and / or no pharmaceutical auxiliaries by direct extrusion, dry, wet or sintered granules, extrusion and subsequent rounding, wet or dry granulation or The pellets are directly pelletized (for example on a disc) or the powder (powder layer) is bonded to spheres (particles) of the active substance or to the particles containing the active substance, or further into a sheet in a certain manner such as pressing.
  • a porogen that is, any physiologically acceptable water-soluble substituted cyclodextrin derivative satisfying the above definition, is all dissolved in an aqueous dispersion of the water- and digestive-insoluble film-forming polymer, if necessary, or Do not add medicinal active substances and other additives for controlled release coatings, and mix well.
  • the content of the polymer in the aqueous dispersion suspension is usually from 2 to 30%, preferably from 5 to 20%, more preferably from 8 to 15%.
  • the aqueous dispersion suspension may also contain a certain amount of an organic solvent, usually in an amount of from 1 to 20%, preferably from 1 to 10%, more preferably from 2 to 5%.
  • the coating layer is prepared from the core material by a coating method such as casting, dipping, painting or spraying using the aqueous dispersion suspension obtained above. It is preferably carried out by spraying.
  • the film formation process is carried out by energy input independent of the coating method. This can be done by convection (heat), radiation (infrared or microwave) or conduction.
  • the water used as a suspending agent for the coating is thus evaporated off, and if necessary, vacuum accelerated evaporation may be applied. This process requires high drying efficiency, so the present invention often employs high efficiency coating equipment (e.g., fluidized bed, high efficiency coating pan).
  • the amount of the controlled release film material is usually 0.5 to 50% by weight, preferably 5 to 30% by weight, optimally 10 to 20% by weight;
  • the thickness of the coating layer is usually 5 to 500 ⁇ m, preferably 50 to 300 ⁇ m, more preferably 100 to 200 ⁇ m.
  • the surface temperature of the core should be higher than the minimum film formation temperature (MFT) of the water dispersion.
  • MFT minimum film formation temperature
  • the minimum film formation temperature refers to the lowest temperature at which the aqueous dispersion forms a continuous film. Below the minimum film formation temperature, the polymer particles cannot The deformation merges into a film).
  • the core surface temperature is generally higher than the minimum film forming temperature of 10 to 20 ° C in the present invention. If the surface temperature of the core material is too low, cracks may occur in the film, which may affect the release characteristics of the preparation; if the surface temperature of the core material is too high, the polymer will be excessively softened, resulting in adhesion of the film.
  • the core material is usually preheated to 20 to 90 ° C, preferably 30 to 70 ° C, more preferably 30 to 50 ° C, first coated at a lower spray rate to the core material. After the surface has been coated with a thin layer of film, the spray rate is increased to the end of the coating. This operation prevents moisture from penetrating into the core material and causes changes in the properties of the core material during storage.
  • the core material Before the aqueous dispersion is coated, the core material may be coated with a separator according to the actual conditions, which helps: 1 Avoid water sensitive drugs The substance is hydrolyzed during the coating process; 2 the water-soluble drug is prevented from migrating to the coating film as the water evaporates; 3) the surface flatness of the core material is increased, the porosity is reduced, and the film continuity is ensured; 4 the hydrophobicity of the core material surface is improved, In order to facilitate the spreading of the aqueous coating liquid; 5 to improve the brittleness of the core material, to avoid the phenomenon of breakage during the coating process.
  • a separator according to the actual conditions, which helps: 1 Avoid water sensitive drugs The substance is hydrolyzed during the coating process; 2 the water-soluble drug is prevented from migrating to the coating film as the water evaporates; 3) the surface flatness of the core material is increased, the porosity is reduced, and the film continuity is ensured; 4 the hydrophobicity of the core material surface is improved, In order
  • a water-soluble material such as a solution of hydroxypropylmethylcellulose and hydroxypropylcellulose
  • a polymer organic solution may be selected for the barrier coating.
  • any of these coatings should be sufficiently thin to avoid the release properties of the formulation.
  • the most suitable or suitable process parameters are determined by those skilled in the art based on the coating material and core properties and experimental results.
  • the fluidized bed coating is used for pouring, and the process conditions such as coating temperature, fluidizing air volume, atomization pressure and liquid spraying rate can be optimized according to actual conditions.
  • nitrogen can be used to replace the air in a confined environment such as a closed enclosure.
  • the polymer particles in the film are often not completely fused, that is, the film healing is not complete. Under the interfacial tension of polymer and air, further fusion may occur during storage to form a denser film.
  • the fusion phenomenon takes a long time to complete, and a post-coating heat treatment process is usually used to accelerate the healing of the film to ensure a relatively stable release rate between batches.
  • the curing treatment process is usually carried out by evaporating the water after the film is placed at a certain temperature or at a certain humidity for a certain period of time, so that the polymer particles in the film are further fused to form a dense film.
  • the selected temperature should be higher than its glass transition temperature or minimum film forming temperature, preferably higher than 10 ° C, more preferably higher than 20 ⁇ 30 ° C, the above temperature should be such that the coating material is not allowed
  • the ingredients in the composition are completely softened or melted or the film adhesion does not occur.
  • the humidity selected is usually from 30 to 100%, preferably from 40 to 95%, more preferably from 50 to 90%.
  • the time required is from several hours to several tens of hours, preferably from 20 to 72 hours, preferably from 24 to 48 hours.
  • the end point of the healing process is usually the dissolution test data of the sample obtained by healing under certain conditions and the accelerated healing test (for example, the accelerated healing test at a temperature of 40 ° C and a relative humidity of 75%) (according to the Chinese Pharmacopoeia 2005).
  • the second appendix XD release method is determined).
  • the healing treatment can be carried out by heat treatment such as an oven and a fluidized bed.
  • the fluidized bed heat treatment has the characteristics of high efficiency and time saving, and the coating and heat treatment operations can be completed in the same equipment, and the industrial applicability is high.
  • the temperature of the system is raised, and the material is continuously fluidized and dried in the same fluidized bed apparatus, which promotes the healing of the membrane in a short time.
  • the fluidized bed method compared with the oven mode, the fluidized bed method has higher requirements on the mechanical properties of the film, and the degree of film healing after heat treatment is relatively low. Therefore, the present invention preferably employs an oven heat treatment method.
  • the drug-loading core may be provided with a barrier layer. Clothing, or reduce the heat treatment temperature.
  • the formulations prepared by any of the above methods may be coated with a thin layer of coating material to improve the surface integrity of the formulation or to prevent the formulations from sticking to one another during storage.
  • Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the release properties of the formulation.
  • the pharmaceutical dosage form prepared by any of the above methods can be used substantially directly, such as directly orally.
  • the tablets, granules or pellets prepared as described above may also be incorporated into a capsule, bag (small sachet) or a suitable multi-meter container by means of a metering device. If possible, the granules or pellets prepared above are obtained by compression after mixing with other auxiliaries, and the preparation is decomposed after administration, and most of the coated small units are released. It is also conceivable to embed aggregates in polyethylene glycol or lipids to prepare suppository or vaginal pharmaceutical dosage forms.
  • the coated tablets are packaged in hemispherical containers or multi-dose containers and taken directly before the patient takes them.
  • Example 1 In order to illustrate the invention, the following examples are provided. However, it should be understood that the invention is not limited to the embodiments. Example 1
  • the core of the film is coated according to the following prescriptions and techniques:
  • the aqueous dispersion had a solids content of 16% by weight.
  • the cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: spray speed, lml/min; inlet temperature, 70 ⁇ 80 °C; outlet temperature, 40 ⁇ 42 °C; core temperature 40 °C; coat thickness 250 ⁇ 350 ⁇ .
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 50 ° C and the healing time was 30 hours.
  • Sample 1 was obtained.
  • DS 2.63 to 2.75
  • diacetin used as a plasticizer
  • the diacetin was 1:2:1 (by weight)
  • the coating liquid was prepared by diluting with water to a suspension containing 3% cellulose acetate.
  • the core film was coated with a release coating film using the prepared coating liquid.
  • the controlled release film coating weight gain was 6%.
  • the coating condition parameters are: spraying time is about 20 seconds, blasting time is about 30 ⁇ 40 seconds, blasting temperature is 50 ⁇ 70 °C, core temperature is 45 ⁇ 50 °C.
  • the healing treatment is carried out in a closed oven.
  • the healing temperature was 65 ° C and the healing time was 30 hours.
  • Test Example 1 In vitro release test
  • Diltiazem hydrochloride is determined by the Chinese Pharmacopoeia 2005 version of the paddle method (Appendix X C Dissolution Second Method).
  • the rotation speed is 50r/min
  • the temperature is (37 ⁇ 1) V
  • the transmitter is 900mL of artificial gastric juice (pH1.2 hydrochloric acid solution).
  • the samples of the examples and the comparative examples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of dissolved transmitter was added.
  • the release of the drug was monitored by HPLC at a wavelength of 238 nm.
  • Nifedipine was determined by the Chinese Pharmacopoeia 2005 version of the paddle method (Appendix X C Dissolution Second Method).
  • the rotation speed is 50r/min
  • the temperature is (37 ⁇ 1)V
  • the transmitter is 900mL of artificial gastric juice (pH1.2 hydrochloric acid solution).
  • the samples of the examples and the comparative examples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of dissolution transmitter was added.
  • the release of the drug was monitored by HPLC at a wavelength of 237 nm.
  • Example 1 and its comparative examples 1, 2 sample drug release rate test results (x ⁇ r ( ) (n 9) test article 4h (%) lOh (%) 15 (%) 20h (%)
  • test article 5h (% lOh (%) 15 (%) 20h (%)
  • Example 5 37.4 ⁇ 3.7 71.5 ⁇ 4.5 87.4 ⁇ 4.6 94.3 ⁇ 4.9
  • Comparative Example 9 23.2 ⁇ 3.5 45.6 ⁇ 4.6 63.3 ⁇ 4.7 75.4 ⁇ 4.8
  • Comparative Example 10 19.3 ⁇ 3.3 38.6 ⁇ 4.0 56.7 ⁇ 4.5 67.5 ⁇ 4.6
  • the test results show that the sample of the sample of the example is faster than the sample of the small size molecule as the porogen.
  • the drug release rate is faster than that of the granules soluble in the digestive solution.
  • the sample drug release rate is comparable, but the drug release reproducibility is higher.
  • Test Example 2 Preparation drug release stability test
  • Test method for the amount of drug eluted into the dissolution medium See Test Example 1; Test Method for Drug Amount in Preparation: The drug was completely extracted into the preparation and then determined by HPLC. The test results are shown in Tables 6 and 7.
  • Example 5 68.7/100 68.2/99.3 67.8/98.7
  • Comparative Example 10 39.3/100 33.5/85.2 26.8/68.2 None performed a dissolution test
  • the release coating film was taken from the samples of Example 3 and Comparative Example 6 for 0 month and accelerated June, and observed with a microscope. It was found that Comparative Example 6 accelerated the porogen and controlled release in the controlled release coating of the June sample.
  • the interpenetrating film was interpenetrated with respect to the 0 month sample, and the interface became blurred; the above phenomenon was not observed in the sample of the example.
  • Test Example 3 Preparation of controlled release film mechanical properties test The controlled release film coating liquid used in the preparation of the sample and the comparative sample in the examples was cast on a polytetrafluoroethylene plate to form a film having a thickness of 150 ⁇ m, and the film was cut into a size of IX 7 cm. The tensile strength was then measured under an INSTRON tensile strength tester. The results are shown in Table 9.
  • Example 2 283 102 Comparative Example 3 186 63 Comparative Example 4 125 41
  • Example 3 324 110 Comparative Example 5 197 75 Comparative Example 396 95
  • Example 5 470 185 Comparative Example 9 309 103 Comparative Example 10 197 62
  • the results show that a film containing a higher substituted water-soluble cyclodextrin derivative dispersed in a molecular form contains a lower-substituted water-soluble solution dispersed in a molecular form.
  • a film of a cyclodextrin derivative and a water-soluble substance dispersed in a molecular form has superior mechanical properties.
  • Test Example 4 Preparation of in vivo release test

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Abstract

L'invention porte sur une formulation à libération contrôlée et, particulièrement, sur une formulation à libération contrôlée ayant une libération d'ordre zéro, laquelle formulation comprend : (1) un noyau contenant au moins un médicament ; (2) une membrane d'enrobage à libération contrôlée enrobée à l'extérieur du noyau. La membrane d'enrobage à libération contrôlée comprend au moins un polymère insoluble dans l'eau et un fluide digestif gastro-intestinal et un dérivé de cyclodextrine, le dérivé de cyclodextrine étant un dérivé de cyclodextrine soluble dans l'eau avec une valeur de substitution moyenne (ou DS) non inférieure à 5 du groupe hydroxyle sur chaque unité de glucose, et se dispersant dans la membrane d'enrobage à libération contrôlée en une seule forme moléculaire et/ou en une forme micellaire. La libération de médicament de la formulation à libération contrôlée est relativement moins affectée in vivo et in vitro et est relativement plus rapide avec un retard relativement plus petit. La biodisponibilité du médicament est supérieure, la stabilité de la libération de médicament est accrue, et la résistance mécanique de la membrane d'enrobage à libération contrôlée de la formulation est également accrue.
PCT/CN2011/077179 2010-07-16 2011-07-15 Formulation à libération contrôlée Ceased WO2012006961A1 (fr)

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