WO2003043602A1 - Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations - Google Patents

Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations Download PDF

Info

Publication number
WO2003043602A1
WO2003043602A1 PCT/KR2002/002151 KR0202151W WO03043602A1 WO 2003043602 A1 WO2003043602 A1 WO 2003043602A1 KR 0202151 W KR0202151 W KR 0202151W WO 03043602 A1 WO03043602 A1 WO 03043602A1
Authority
WO
WIPO (PCT)
Prior art keywords
cyclodextrin
water
acetate
insoluble
substituted
Prior art date
Application number
PCT/KR2002/002151
Other languages
French (fr)
Inventor
Si-Young Chang
Jae-Shin Song
Original Assignee
Korea Dds Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Korea Dds Pharmaceutical Co., Ltd. filed Critical Korea Dds Pharmaceutical Co., Ltd.
Priority to AU2002366042A priority Critical patent/AU2002366042A1/en
Publication of WO2003043602A1 publication Critical patent/WO2003043602A1/en

Links

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a method of manufacturing solid dispersions, which comprises dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water and removing the solvent under a reduced pressure or spray drying, and a pharmaceutical composition comprising the solid dispersions prepared thereby.
  • the bioavailability of the inclusion complex of ⁇ -cyclodextrin and glibornuride is higher than that of the physical complex by twice or thrice (J. J. Torres-Labandeira, et al. 1994).
  • the inclusion complex of drug and ⁇ -cyclodextrin shows improved solubility compared with that of the physical mixture of ⁇ -cyclodextrin and tolnaftate or that of isolated drug (D, Peri, 1994).
  • ⁇ -cyclodextrin and naproxen it is found that the inclusion complex has higher solubility than the physical mixture by six to nine times (Otero-Espinar, et al., 1991).
  • the complex of cyclodextrin and drug is manufactured separately before being inserted into an end pharmaceutical preparation.
  • a conventional inclusion complex has been manufactured by including drug into a cyclodextrin complex in aqueous system with water.
  • lots of monitoring and control are required to many complicated processes.
  • the manufacturing processes are carried out in an aqueous system, the pharmaceutical compositions consisting of water-insoluble active components are hard to be developed.
  • the solubility and bioavailability of a component can be increased by forming its inclusion complex with ⁇ -cyclodextrin or its derivatives, the large amount of water or auxiliary solvent required to the water-insoluble active component obstructs its production in industrial scale. Accordingly, the defect of this manufacturing process is clear.
  • a solid mixture of cyclodextrin is prepared by melt extruding.
  • the process of preparing the solid mixture comprises a melt-extruding step in which itraconazole or loviride, as an active component, is immersed in cyclodextrin carrier. Since the process of melt extruding requires no solvent, it is well applied to the active components that are susceptible to water or organic solvent. Further, no drying step is needed to the process of melt extruding, which makes the process convenient.
  • the dissolution and solubility of the solid mixture in which a drug is dispensed homogeneously in cyclodextrin, are definitely superior to those of physical mixture and similar to those of inclusion complex.
  • the dissolution rate of the solid dispersions prepared by melt extruding is about three times higher than that of the corresponding physical mixture.
  • the temperature should be raised over the melting point of the drug and carrier for melting them, which affects adversely on the stability of the drug. Further, at the time of cooling the melted, the condition may have an effect on the performance of preparation. There is also a problem that those drugs, which are unstable to heat or have melting point with a remarkable difference from carrier, are hard to be melted. Disclosure of the Invention
  • a pharmaceutical composition comprising a solid dispersion which is prepared by dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water to make a mixture and drying under a reduced pressure or spray drying the mixture, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention makes use of the solubility of substituted cyclodextrin in organic solvents. Contrary to unsubstituted one, the substituted cyclodextrin is easily soluble in alcohol, and is soluble in those solvents mixed with alcohols or lipid-soluble solvents (for example, dichloromethane) to be transparent. Therefore, it is possible to obtain lots of solid dispersions by dissolving water-insoluble substances and substituted cyclodextrin in organic solvents and drying under a reduced pressure or spray drying the dissolved mixtures. In the present invention, the manufacturing process of solid dispersion is not carried out at a high temperature or in an aqueous system, so that it can be favorably applied to those drugs susceptible to temperature or water.
  • the solid dispersion obtained by dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water and removing the solvent shows greatly increased dissolution rate and speed in proportion to the amount of cyclodextrin when contacted with water-soluble medium.
  • the pharmaceutical composition of the present invention promotes the solubilization of a water-insoluble drug to minimize the gastrointestinal adverse effect caused by the drug and to increase the absorption into body, and therefore, enhancing the bioavailability of drug and relieving the irritation in the mucosa.
  • the present invention provides a solid dispersion having an increased rate of drug release and absorption by using a substituted cyclodextrin which is pharmaceutically stable and is dissolved rapidly in an aqueous medium as a carrier, when preparing a dosage form of an active substance unstable in an aqueous system, and a pharmaceutical composition containing the dispersion.
  • the present invention has been made to overcome the insufficient dissolution rate of pharmaceutical composition containing a physical mixture of water-insoluble active substance and cyclodextrin. That is, the present invention has improved the delivery system of water-insoluble drug by introducing a solid dispersion which is more finely dispersed compared to the physical mixture of active substance and cyclodextrin.
  • the pharmaceutical composition containing the solid dispersion of water-insoluble drug and cyclodextrin has the solubility, solubility profile, and/or bioavailability similar to those of their inclusion complex.
  • the present invention provides a method of manufacturing a solid dispersion containing a water-insoluble drug and a substituted cyclodextrin by using only organic solvents, neither processing in an aqueous system nor using a melting process at a high temperature, and a pharmaceutical composition containing the solid dispersion.
  • the present invention is characterized by the application of an amorphous substituted cyclodextrin as a water-soluble carrier, and it provides a pharmaceutical composition for the purpose of improving the bioavailability of active substances.
  • the pharmaceutical composition provides the advantage of obtaining lots of solid dispersions by dissolving a substituted cyclodextrin and a water-insoluble drug in an organic solvent and carrying out simple processes such as drying under a reduced pressure or spray drying, without using an aqueous system which has difficulty in dissolving a water-insoluble drug and evaporating under a low temperature to obtain an inclusion compound.
  • the interested ones are those containing substituted cyclodextrin ether derivatives as a carrier of solid dispersions.
  • the cyclodextrin derivatives are ⁇ -, ⁇ - and ⁇ -cyclodextrin ether derivatives or mixed ether derivatives.
  • Such cyclodextrin derivatives are described in US Patent No. 3,459,731, EP-A-O 149,197 and EP-A-O 197,571.
  • the ether derivatives or mixed ether derivatives include ⁇ -, ⁇ - and ⁇ -cyclodextrin in which one or more of the hydroxyl groups are substituted by
  • the substituted cyclodextrins are preferably ethers in which one or more of the hydroxyl groups are substituted by C 1-3 alkyl, hydroxy C 2-4 alkyl or carboxy C 1-2 alkyl, more preferably, by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.
  • DS degree of substitution, the mean number of substituted hydroxy functional group per glucose unit
  • MS mole substitution, the mean number of moles of substitutes per glucose unit
  • At least one of the hydroxyl groups of cyclodextrin may be substituted by sugars to be maltosyl, glucosyl, maltotriosyl, etc. Further, at least one of sulfoalkyl C ⁇ - ether substitutes may be introduced into cyclodextrins, in which sulfopropylether- ⁇ -cyclodextrin or sulfobutylether- ⁇ -cyclodextrin is preferable.
  • unsubstituted cyclodextrins have some restriction in forming solid dispersions using organic solvents due to the low water/oil solubility.
  • suitable substituted cyclodextrins are 2,6-dimethyl- ⁇ -cyclodextrin, 2-hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, 2- hydroxyethyl- ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin, (2- carboxymethoxy)propyl- ⁇ -cyclodextrin and sulfobutylether-7- ⁇ -cyclodextrin.
  • the cyclodextrins used in the present invention is preferably amorphous substituted cyclodextrins. Especially preferred is hydroxypropyl ⁇ -cyclodextrin.
  • cyclodextrin derivatives used in the composition of the present invention are hydroxypropyl- ⁇ -cyclodextrin having the MS value ranging from
  • Hydroxypropyl- ⁇ -cyclodextrin is a water-soluble white crystal. Since it is more soluble in an organic solvent (e.g., not less than 2 g/ml dissolve in 95% ethanol) than ⁇ -cyclodextrin, the solid dispersions of the present invention containing a water-insoluble drug and substituted cyclodextrin may easily be obtained by dissolving the components in an organic solvent and then removing the solvent. The dissolution rate and speed of the solid dispersions obtained according to the present invention increase suddenly in proportion to the amount of cyclodextrin when contacted with aqueous medium. The best dissolution is achieved at the ratio of 1 : 1 by mole or more.
  • novel solid dispersions of the present invention comprise 1) one or more of water-insoluble drugs;
  • solid dispersion means a system of solid state containing at least two components wherein the one component is dispersed rather uniformly in the other(s), which is opposed to solution or gas state.
  • the dispersed materials maintain the system in chemically or physically uniform or homogeneous state, or consist of one phase as defined in thermodynamics.
  • the solid dispersions contain materials in super-homogeneous state such as glassy solid solution as well as in less homogeneous state.
  • water-soluble carrier substituted cyclodextrin
  • the components of the solid dispersions dissolve into minute particles, which makes the surface area of drug increased.
  • the progress of drug dissolution according to the mole ratio of drug and carrier of the present composition suggests that a part of drug is included in the process of preparing the solid dispersion or the composition has the possibility to be included when simply dispersed preparations are exposed to water or aqueous body fluids. Especially, a supersaturated solution may be formed while minutely dispersed insoluble drug is included in a hydrophobic cavity.
  • Solvents used in the present invention are preferred to be physiologically acceptable materials of which the boiling points are 100 °C or less. Such solvents may be used in preparing the composition of the present invention since it has very little remains in the preparing process.
  • the solvent which may be employed in the present invention are C 1-6 alkanol (e.g., ethanol, isopropanol and propanol), acetone, ethyl acetate, methylethylketone, DMF (dimethylformamide), dichloromethane, chloroform, straight chain or ring-shaped ether (e.g., diethyl ether and dimethyl ether, or tetrahydrofuran (THF), cyclohexane and dimethylsulfoxide) and mixtures thereof.
  • Ethanol is preferred solvent to be used alone, and ethanol mixed with dichloromethane is more preferred to solubilize cyclodextrin and water-insoluble compound.
  • the solubilization temperature of solvent is generally 0 to 100 °C, preferably 10 to
  • the solid dispersion of an active substance and substituted cyclodextrin may be obtained easily by dissolving the components in an organic solvent and then removing the solvent.
  • the solvents of the components may be removed by natural drying, heated drying, drying under reduced pressure or spray drying.
  • spray drying has the advantage that residual solvent is effectively removed from the solid dispersions by using spray drier and a large quantity of solid dispersions may be obtained.
  • the amount of organic solvent varies according to the concentration of cyclodextrin which may be 3 to 30 % (w/w), preferably 5 to 15 % (w/w), in which condition the yield of solid dispersion exceeds 95%.
  • the solid dispersion of the present invention is preferred to be used in the form of fine powders or particles to increase the dissolution rate. More preferably 80% or more, most preferably 90% or more of the dispersion is passed through 100 mesh (150 ⁇ m) screen. Particle size is a principal factor of determining the dissolution rate and speed as well as the rate of producing the tablet of sufficient hardness in large quantities.
  • composition of the present invention has an obvious advantage in water-insoluble drugs. Further, the solid dispersions containing a drag and substituted cyclodextrin have remarkable advance in dissolution rate, therefore, even in water-soluble drags, dissolution rate and absorption improve greatly and irritation is sharply relieved at the time of disintegration.
  • the solid dispersions of the present invention contain a water-insoluble drug and substituted cyclodextrin in which the amount of substituted cyclodextrin ranges from 0.01 to 100 parts by weight, preferably from 0.5 to 25 parts by weight, more preferably from 0.1 to 10 parts by weight, per 1 part by weight of drag.
  • Water-insoluble drags which may be used in the present invention have the solubility in water of 10 mg/ml or less at physiological pH (pH 6.5 to 7.4).
  • drags examples include analgesic and antiphlogistic agents, antihypertensive agents, diuretics, cardiac stimulants, antifungals, antiepileptics, psychotropics, antidiabetics, anticancer agents, gastro-intestinal agents, antihistamines, antihyperlipidemics, vasodilators, immunosuppressives, antipsoriatics, hepatoprotectants, vitamins and derivatives thereof, sex hormones and adrenocorticotrophic hormones.
  • analgesic and antiphlogistic agents antihypertensive agents, diuretics, cardiac stimulants, antifungals, antiepileptics, psychotropics, antidiabetics, anticancer agents, gastro-intestinal agents, antihistamines, antihyperlipidemics, vasodilators, immunosuppressives, antipsoriatics, hepatoprotectants, vitamins and derivatives thereof, sex hormones and adrenocorticotrophic
  • What is suitable to be used in the present invention is a water-insoluble drug which is practically insoluble in water and extremely insoluble in the mixture of water and polar solvent miscible with water so that it is difficult for the drug to be used in an aqueous system.
  • the drug are piroxicam, tretinoin, danazol, isotretinoin and glibenclamide. Since the drag has extremely low solubility in the mixture of water and polar solvent, inclusion proceeds very slowly in an aqueous system and the inclusion ratio of drug and cyclodextrin increases.
  • those drugs solubilized in a specific pH such as ketoconazole and domperidone, have pH-dependent solubility and are practically insoluble in water or saline, so it is commercially unfavorable to obtain the inclusion compound in an aqueous system.
  • an organic solvent is selected for dissolving a water-insoluble drag and added to alcohol solution containing substituted cyclodextrin to dissolve the two components, and then the resulting transparent solution is dried to form a solid dispersion containing the water-insoluble drag and substituted cyclodextrin.
  • lipophilic solvents are used for easily dissolving water- insoluble drags, and therefore, lots of solid dispersions may be produced by using a little amount of solvent.
  • Drags used in the present invention include such drags of low solubility that dissolution is a major factor of rate-determination step to control the bioavailability, e.g., griseofulvin, digoxin, dipyridamole, amphotericin B. 6-mercaptopurine, dexamethasone, etc.
  • Preferred active components used in the present invention are drugs that exert topical physiological action as well as systemic action after passing through mucous membrane or being transported into gastrointestinal with saliva.
  • the dosage form manufactured from the composition of the present invention not only provides a rapid-acting solubility at a low ratio of carrier to a transocular, transnasal or parenteral form which is water-insoluble and difficult to be solubilized in distilled water, buffer solution or saline, but also improves a patient adaptability to the drags which produce an adverse effect on gastrointestinal tract when solubilized.
  • analgesic and antiphlogistic agents e.g., ibuprofen, S-ibuprofen, ketoprofen, rofecoxib, celecoxib, indomethacin, piroxicam, nimesulide, diacerein and aceclofenac
  • antihypertensive agents e.g., nifedipine, nimodipine, felodipine, nitrendipine, isradipine, nisoldipine, nilvadipine and reserpine
  • diuretics e.g., acetazolamide, indapamide, furosemide, spironolactone and chlorthalidone
  • cardiac stimulants e.g., amrinone, milrinone, digitoxin and digoxin
  • antifungals e.g., itraconazole, saperconazole, amphoter
  • composition according to the present invention may be formulated using at least one of physiologically acceptable additives by a conventional method.
  • the composition may be given by oral administration (e.g., rapid- acting, enteric and long-acting preparations), parenteral administration such as intravenous, subcutaneous, intradermal, transdermal, transocular, transnasal, vaginal and anal administration, or by inspiration.
  • preparations for oral administration are tablets, pills, powders, granules, liquids, suspensions, syrups and capsules.
  • Oral compositions such as tablets and capsules, may be prepared by a conventional method using pharmaceutically acceptable additives including adhesives (e.g., gelatinized corn starch, polyvinyl pyrrolidone and hydroxypropylmethyl cellulose); fillers (e.g., spray dried or anhydrous lactose, microcrystalline cellulose and calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc and silica); disintegrants (e.g., potato starch and starch sodium glycolate); and hydrating agents (e.g., sodium lauryl sulfate). Tablets may be coated by a conventional method in the art. Pills, powders and granules may be formulated by a conventional method using the above-mentioned additives.
  • adhesives e.g., gelatinized corn starch, polyvinyl pyrrolidone and hydroxypropylmethyl cellulose
  • fillers e.g., spray dried or anhydrous lacto
  • Liquids for oral administration are prepared as solutions, syrups or suspensions (e.g., composition coated with gastric acid-resistant agent and composition suspended in water or syrup), and can be prepared as a dry product which is mixed with water or other additives before being used.
  • Such liquids may be prepared by a conventional method using pharmaceutically acceptable additives including suspending agents (e.g., lecithin and acacia); non-aqueous solvent (e.g., almond oil, oily ester, ethyl alcohol and fractionized vegetable oils); and antiseptics (e.g., methyl- or propyl-p-hydroxy benzoate, benzyl alcohol and sorbic acid).
  • the preparation includes a buffer, flavoring agent, coloring agent and sweetener.
  • organic acids such as tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, succinic acid, oxalic acid, benzoic acid, malonic acid, mandelic acid and ascorbic acid, inorganic acids such as phosphoric acid, or bases such as sodium hydroxide and sodium carbonate may also be used.
  • Capsules are manufactured by filling gelatin capsules or so with powders, granules, liquids, etc.
  • Preparations for oral administration provide a controlled-release of one or more active substances after being formulated suitably.
  • the present invention considers pharmaceutical preparations containing a solid dispersion of an active substance and cyclodextrin, e.g., osmosis pump tablets, layered tablets, coated tablets, reconstituted powders, capsules and coated granules.
  • a conventional method may be applied to coating for tablets of the composition according to the present invention.
  • a drug and water- soluble polymer substances such as sugar, sugar/bees wax coating, polyvinyl pyrrolidone, polyvinyl alcohol and hydroxypropyl cellulose are to be absorbed in intestinal tract or in case of sustained-release, a gastric acid-resistant Eudragit manufactured by Rohm GmbH, a sustained-release Eudragit or a sustained-release polymer may be used.
  • the coated tablets, granules and pellets of the composition according to the present invention may include film coating or core tablets.
  • a film forming agent such as cellulose acetate, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose, wax, Eudragit El 00, Eudragit RL, Eudragit RS, Eudrigit RS, Eudragit S and hydroxypropylmethyl cellulose acetate succinate and a pore forming agents such as polyethylene glycol 3350, sorbitol, sucrose and organic acid may be used.
  • a plurality of film forming agents and/or pore forming agents may be used in film coating, and a mixture of film forming agents may also be used in a certain film coating.
  • pore forming agent means the agent that promotes formation of pores in the film coating or enhances water permeability of film.
  • Examples of intravenously, subcutaneously or intramuscularly administrated preparations include injections made of sterilized aqueous or non- aqueous solvents.
  • aqueous solvents are saline, etc.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable organic ester such as ethyl oleate, and fatty acid ester of iodized poppy-seed oil.
  • the preparations may contain, if necessary, isotonic agents, antiseptics, emollients, emulsifiers, dispersing agents, stabilizer, etc.
  • the preparations may be sterilized by a suitable process such as filtration through bacteria-reserving filter, addition of disinfectants and radiation.
  • Sterilized solid dispersions may be formulated into water-soluble forms in sterilized distilled water or sterilized solvent for injection, or preferably, into powders consisting of acceptable additives, such as sterilized pyrogen-free substances, for being dissolved prior to use.
  • transdermal preparations are ointments, creams, lotions and liquids, and transparent gel type is preferred. Further preparations to be used include pastes, cataplasmas and aerosols. Such preparations may be manufactured by using a conventional method. As examples of transocular preparations, transparent liquids are preferred to suspensions.
  • the manufacturing process may include steps such as solubilizing the solid dispersions, preferably dissolving the powders or tablets in a suitable aqueous solution prior to use.
  • desired buffering agents are phosphate, boric acid, sodium borate, organic acid such as acetic acid and citric acid, and salts thereof.
  • suitable isotonic agents are boric acid, salts such as sodium chloride and potassium chloride, and glycerol.
  • Examples of preferred thickeners are hydroxyethyl cellulose and its salt.
  • suitable suspending agents are surfactants such as polysorbate 80 and water-soluble polymers such as sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and polyvinyl alcohol.
  • desired solubilizers are non- ionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene stearate, triglyceride and polyethylene glycol.
  • Examples of preferred pH adjusting agents are alkaline compounds such as sodium hydroxide, boric acid and sodium dihydrogen phosphate, and acids such as hydrochloric acid, boric acid, phosphoric acid and acetic acid.
  • suitable chelating agents are disodium edetate, sodium citrate and sodium polyphosphate.
  • Transnasal preparations are made in liquid or powder compositions.
  • transparent liquids are preferred to suspensions.
  • the manufacturing process may include steps such as solubilizing the solid dispersions, preferably dissolving the powders or tablets in a suitable aqueous solution prior to use.
  • solvents are water, saline, phosphate buffer and acetate buffer.
  • Surfactants, anti-oxidants, stabilizers, preservatives and thickeners may be included.
  • bases for the powders are polyacrylates such as water-soluble sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate, cellulose-lower alkyl ethers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, amylose, pulluran, celluloses such as water-insoluble crystalline cellulose, ⁇ -cellulose and cross-linked sodium carboxymethyl cellulose, starches such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin and pectins, proteins such as gelatin, casein and sodium casein, gums such as arabia gum, tragacanth gum and glucomannan, cross-linked polyacrylic acid and its salts, cross-linked polyvinyl alcohol, and mixtures thereof.
  • polyacrylates such as water-soluble sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate,
  • Powdered preparations may contain anti-oxidants, coloring agents, preservatives and antiseptics.
  • the liquids and powders may be administered by using a spray device, etc.
  • the present composition for vaginal or anal administration may be formulated in suppositories including conventional suppository bases such as glyceride and cocoa butter, or in reserving enemas.
  • the present composition may be administered to the site in trouble by using the devices such as a spray, nebulizer and atomizer, in the form of powdered or liquid preparations containing the solid dispersions with or without pharmaceutically acceptable additives.
  • the composition may be administered to the site in trouble after being suspended in injection agents for aerosol such as freon.
  • Fig. 1 is a graph showing the dissolution rate of ibuprofen/cyclodextrin solid dispersion according to the ratio of the components under an acidic condition
  • Fig. 2 is a graph showing the dissolution rate of ketoconazole/cyclodextrin solid dispersion according to the ratio of the components under a basic condition (pH 6.8).
  • Fig. 3 is a graph showing the dissolution rate of domperidone/cyclodextrin solid dispersion according to the ratio of the components under a basic condition (pH 6.8).
  • Fig. 4 is a graph showing the dissolution rate of ketoprofen/cyclodextrin solid dispersion according to the ratio of the components under an acidic condition (pH 1.2).
  • Fig. 5 is a graph showing the dissolution rate of the ketoconazole tablets manufactured in Preparation Example 1 and Comparative Example 1 under a basic condition (pH 6.8).
  • Fig. 6 is a graph showing the dissolution rate of the domperidone tablets manufactured in Preparation Example 2 and Comparative Example 2 under a basic condition (pH 6.8).
  • Examples 1 to 3 Preparation of the solid dispersion of ibuprofen and cyclodextrin As shown in the following Table 1, an appropriate amount of hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) was dissolved in 200 ml of ethanol in 1,000 ml-round flask. The resultant solution was added with 100 ml of dichloromethane and 2 g of ibuprofen, and then stirred to be transparent. The solution was dried under a reduced pressure to obtain a white solid, which was sieved with #120 screen. The amount of 100 mg measured in terms of ibuprofen was to be a dose for one time. Table 1 shows the ratio of the components for the oral ibuprofen solid dispersions prepared in Examples 1 to 3.
  • Table 3 shows the ratio of the components for the oral domperidone solid dispersions prepared in Examples 7 to 9.
  • Table 4 shows the ratio of the components for the oral ketoprofen solid dispersions prepared in Examples 10 to 12.
  • ketoconazole HP- ⁇ -CD (1:3) 400 mg
  • Hydroxypropyl- ⁇ -cyclodextrin and the above active substance were weighed in the same ratio of the above preparation examples and pulverized.
  • the resultant fine powder was pressed and crashed into granules, which were then formulated according to the same method of Preparation Examples 1 and 2.
  • ibuprofen powder shows a slow dissolution and low dissolution rate at an acidic condition, while in the solid dispersions of ibuprofen and cyclodextrin, the dissolution of hydroxypropyl- ⁇ -cyclodextrin increases easily. Especially, when the ratio of active substance to carrier is about 1:7, the dissolution rate rapidly exceeds 90%.
  • ketoconazole powder shows very low dissolution rate and speed, while the solid dispersions show marked increases in the dissolution rate and speed in proportion to the amount of carrier. Especially, when the ratio of active substance to carrier is about 1:3, the dissolution rate and speed reaches the greatest.
  • domperidone powder shows little dissolution under an basic condition since it is a weak alkaline drug which ionizes only under an acidic condition.
  • the dissolution rate increases remarkably in proportion to the amount of carrier.
  • ketoprofen powder shows slow dissolution of more than 50% within 30 minutes under an acidic condition, while the solid dispersions show accelerated dissolution in proportion to the amount of carrier. Therefore, it is understood that the drags of easy dissolution have more improved dissolution according to the present invention.
  • Fig. 5 shows the dissolution rate of solid dispersion of ketoconazole and cyclodextrin and its corresponding physical mixture under an basic condition, in which the solid dispersion shows rapid and high dissolution rate compared to the physical mixture.
  • Fig. 6 shows the dissolution rate of solid dispersion of domperidone and cyclodextrin and its corresponding physical mixture under an basic condition, in which the solid dispersion shows rapid and high dissolution rate compared to the physical mixture.
  • the present invention relates to a method of manufacturing solid dispersions which provide an enhanced drag release and absorption, by using a substituted cyclodextrin which is pharmaceutically stable and dissolved in a short time when administered, and a pharmaceutical composition comprising the solid dispersions.
  • the solid dispersions may be obtained in large quantities by easily solubilizing a water-insoluble drag and substituted cyclodextrin in an organic solvent, neither using aqueous system nor heating them at high temperatures, and by drying under a reduced pressure or spray drying the solubilized mixture.
  • the pharmaceutical composition of the present invention improves the dissolution rate and speed of water-insoluble drags and maximizes the bioavailability.

Abstract

The present invention relates to pharmaceutical solid dispersions containing substituted cyclodextrin and their preparations. The solid dispersions are prepared by dissolving water-insoluble drugs and substituted cyclodextrin in organic solvents without water and drying dispersions enhance the dissolution rate of the water-insoluble drugs and maximize its bioavailability.

Description

SOLID DISPERSIONS CONTAINING SUBSTITUTED CYCLODEXTRIN AND INSOLUBLE DRUG AND THEIR
PREPARATIONS
Technical Field
The present invention relates to a method of manufacturing solid dispersions, which comprises dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water and removing the solvent under a reduced pressure or spray drying, and a pharmaceutical composition comprising the solid dispersions prepared thereby.
Background Art
The difference of solubility in water between the inclusion complex of water-insoluble drug and cyclodextrin and the simple mixture thereof has been mentioned in various literatures. Muranushi, et al. compare the solubility profiles of benexate alone, its physical mixture and inclusion complex with β-cyclodextrin (Nippon Yakurigaku Zasshi, 91(6), 377-83, 1988). It is reported that the physical mixture of Benexate and β-cyclodextrin has higher solubility in water than Benexate alone, while the inclusion complex of Benexate and β-cyclodextrin has eight times higher solubility than the physical mixture.
Similarly, it is also found that the bioavailability of the inclusion complex of β-cyclodextrin and glibornuride is higher than that of the physical complex by twice or thrice (J. J. Torres-Labandeira, et al. 1994). Further, it is reported that the inclusion complex of drug and β-cyclodextrin shows improved solubility compared with that of the physical mixture of β-cyclodextrin and tolnaftate or that of isolated drug (D, Peri, 1994). In case of β-cyclodextrin and naproxen, it is found that the inclusion complex has higher solubility than the physical mixture by six to nine times (Otero-Espinar, et al., 1991).
Other researches showing that the inclusion complex of β-cyclodextrin and drug enhances the solubility profile of drug have been made by Lin, et al. who tested the inclusion complex and physical mixture of β-cyclodextrin with acetaminophen, indomethacin, piroxicam or warfarin (Lin, et al., 1989). Further, Esclusa-Diaz, et al. reported that the inclusion complex of β-cyclodextrin and etoconazole showed better solubility than the physical mixture of them (Esclusa- Diaz, et al, 1996).
Similarly, it is reported that when measuring the solubility of ketoprofen, a non-steroidal analgesic, its physical mixture, and its inclusion complex by using skim milk, the solubility of inclusion complex is four-times as high as that of ketoprofen, and also even higher than that of physical mixture (Topaloglu, et al,
Farmaco, 54(10), 648-652, 1000).
The complex of cyclodextrin and drug is manufactured separately before being inserted into an end pharmaceutical preparation. A conventional inclusion complex has been manufactured by including drug into a cyclodextrin complex in aqueous system with water. For manufacturing the inclusion complex in large quantities, lots of monitoring and control are required to many complicated processes. Especially, the manufacturing processes are carried out in an aqueous system, the pharmaceutical compositions consisting of water-insoluble active components are hard to be developed. Even though the solubility and bioavailability of a component can be increased by forming its inclusion complex with β-cyclodextrin or its derivatives, the large amount of water or auxiliary solvent required to the water-insoluble active component obstructs its production in industrial scale. Accordingly, the defect of this manufacturing process is clear.
In WO 97/18839 published on May 29, 1997, it is described that a solid mixture of cyclodextrin is prepared by melt extruding. The process of preparing the solid mixture comprises a melt-extruding step in which itraconazole or loviride, as an active component, is immersed in cyclodextrin carrier. Since the process of melt extruding requires no solvent, it is well applied to the active components that are susceptible to water or organic solvent. Further, no drying step is needed to the process of melt extruding, which makes the process convenient. According to this method, the dissolution and solubility of the solid mixture, in which a drug is dispensed homogeneously in cyclodextrin, are definitely superior to those of physical mixture and similar to those of inclusion complex. In this invention, it is described that the dissolution rate of the solid dispersions prepared by melt extruding is about three times higher than that of the corresponding physical mixture.
In the method of WO 97/18839, however, the temperature should be raised over the melting point of the drug and carrier for melting them, which affects adversely on the stability of the drug. Further, at the time of cooling the melted, the condition may have an effect on the performance of preparation. There is also a problem that those drugs, which are unstable to heat or have melting point with a remarkable difference from carrier, are hard to be melted. Disclosure of the Invention
It is an object of the present invention to provide a pharmaceutical composition which may minimize gastrointestinal side effects and promote internal absorptions to increase a bioavailability by enhancing the solubilization of water- insoluble drugs, and a method of manufacturing the same.
In accordance with one aspect of the present invention, it is provided a pharmaceutical composition comprising a solid dispersion which is prepared by dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water to make a mixture and drying under a reduced pressure or spray drying the mixture, and a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention makes use of the solubility of substituted cyclodextrin in organic solvents. Contrary to unsubstituted one, the substituted cyclodextrin is easily soluble in alcohol, and is soluble in those solvents mixed with alcohols or lipid-soluble solvents (for example, dichloromethane) to be transparent. Therefore, it is possible to obtain lots of solid dispersions by dissolving water-insoluble substances and substituted cyclodextrin in organic solvents and drying under a reduced pressure or spray drying the dissolved mixtures. In the present invention, the manufacturing process of solid dispersion is not carried out at a high temperature or in an aqueous system, so that it can be favorably applied to those drugs susceptible to temperature or water.
According to the present invention, the solid dispersion obtained by dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water and removing the solvent shows greatly increased dissolution rate and speed in proportion to the amount of cyclodextrin when contacted with water-soluble medium.
The pharmaceutical composition of the present invention promotes the solubilization of a water-insoluble drug to minimize the gastrointestinal adverse effect caused by the drug and to increase the absorption into body, and therefore, enhancing the bioavailability of drug and relieving the irritation in the mucosa.
The present invention provides a solid dispersion having an increased rate of drug release and absorption by using a substituted cyclodextrin which is pharmaceutically stable and is dissolved rapidly in an aqueous medium as a carrier, when preparing a dosage form of an active substance unstable in an aqueous system, and a pharmaceutical composition containing the dispersion.
The present invention has been made to overcome the insufficient dissolution rate of pharmaceutical composition containing a physical mixture of water-insoluble active substance and cyclodextrin. That is, the present invention has improved the delivery system of water-insoluble drug by introducing a solid dispersion which is more finely dispersed compared to the physical mixture of active substance and cyclodextrin. The pharmaceutical composition containing the solid dispersion of water-insoluble drug and cyclodextrin has the solubility, solubility profile, and/or bioavailability similar to those of their inclusion complex. The present invention provides a method of manufacturing a solid dispersion containing a water-insoluble drug and a substituted cyclodextrin by using only organic solvents, neither processing in an aqueous system nor using a melting process at a high temperature, and a pharmaceutical composition containing the solid dispersion. The present invention is characterized by the application of an amorphous substituted cyclodextrin as a water-soluble carrier, and it provides a pharmaceutical composition for the purpose of improving the bioavailability of active substances. The pharmaceutical composition, described herein, provides the advantage of obtaining lots of solid dispersions by dissolving a substituted cyclodextrin and a water-insoluble drug in an organic solvent and carrying out simple processes such as drying under a reduced pressure or spray drying, without using an aqueous system which has difficulty in dissolving a water-insoluble drug and evaporating under a low temperature to obtain an inclusion compound.
Among the group of compositions mentioned above and below, the interested ones are those containing substituted cyclodextrin ether derivatives as a carrier of solid dispersions. Examples of the cyclodextrin derivatives are α-, β- and γ-cyclodextrin ether derivatives or mixed ether derivatives. Such cyclodextrin derivatives are described in US Patent No. 3,459,731, EP-A-O 149,197 and EP-A-O 197,571.
Typically, the ether derivatives or mixed ether derivatives include α-, β- and γ-cyclodextrin in which one or more of the hydroxyl groups are substituted by
Cι-6 alkyl, hydroxy C1-6 alkyl, carboxy C1-6 alkyl, C1-6 alkyloxycarbonyl or Cι-6 alkyl group. The substituted cyclodextrins are preferably ethers in which one or more of the hydroxyl groups are substituted by C1-3 alkyl, hydroxy C2-4 alkyl or carboxy C1-2 alkyl, more preferably, by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.
In the cyclodextrin derivatives, DS (degree of substitution, the mean number of substituted hydroxy functional group per glucose unit) ranges from 0.125 to 3, preferably from 0.3 to 2, more preferably from 0.3 to 1. MS (mole substitution, the mean number of moles of substitutes per glucose unit) ranges from 0.125 to 10, preferably from 0.3 to 3, more preferably from 0.3 to 1.5.
At least one of the hydroxyl groups of cyclodextrin may be substituted by sugars to be maltosyl, glucosyl, maltotriosyl, etc. Further, at least one of sulfoalkyl Cι- ether substitutes may be introduced into cyclodextrins, in which sulfopropylether-β-cyclodextrin or sulfobutylether- β-cyclodextrin is preferable.
Generally, unsubstituted cyclodextrins have some restriction in forming solid dispersions using organic solvents due to the low water/oil solubility. In the present invention, examples of suitable substituted cyclodextrins are 2,6-dimethyl- β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2- hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, (2- carboxymethoxy)propyl-β-cyclodextrin and sulfobutylether-7-β-cyclodextrin.
The cyclodextrins used in the present invention is preferably amorphous substituted cyclodextrins. Especially preferred is hydroxypropyl β-cyclodextrin.
The most preferable cyclodextrin derivatives used in the composition of the present invention are hydroxypropyl-β-cyclodextrin having the MS value ranging from
0.30 to 1.0.
Hydroxypropyl-β-cyclodextrin is a water-soluble white crystal. Since it is more soluble in an organic solvent (e.g., not less than 2 g/ml dissolve in 95% ethanol) than β-cyclodextrin, the solid dispersions of the present invention containing a water-insoluble drug and substituted cyclodextrin may easily be obtained by dissolving the components in an organic solvent and then removing the solvent. The dissolution rate and speed of the solid dispersions obtained according to the present invention increase suddenly in proportion to the amount of cyclodextrin when contacted with aqueous medium. The best dissolution is achieved at the ratio of 1 : 1 by mole or more.
The novel solid dispersions of the present invention comprise 1) one or more of water-insoluble drugs; and
2) one or more of pharmaceutically acceptable substituted cyclodextrins.
In the description of the present invention, "solid dispersion" means a system of solid state containing at least two components wherein the one component is dispersed rather uniformly in the other(s), which is opposed to solution or gas state. The dispersed materials maintain the system in chemically or physically uniform or homogeneous state, or consist of one phase as defined in thermodynamics. The solid dispersions contain materials in super-homogeneous state such as glassy solid solution as well as in less homogeneous state.
As the solid dispersions are exposed to water or gastro-intestinal juices, water-soluble carrier (substituted cyclodextrin) is released to the internal aqueous solution, simultaneously the components of the solid dispersions dissolve into minute particles, which makes the surface area of drug increased.
At this time, the drug particles become smaller and the carrier dissolves completely in a very short time, so that the solubilization of drug is achieved by the carrier in a diffusion layer, which is a minute environment around the drag particles at the early stage of dissolution. Therefore, it is understood that the above- mentioned factors work collectively to increase the solubility and initial dissolution rate of drug.
The progress of drug dissolution according to the mole ratio of drug and carrier of the present composition suggests that a part of drug is included in the process of preparing the solid dispersion or the composition has the possibility to be included when simply dispersed preparations are exposed to water or aqueous body fluids. Especially, a supersaturated solution may be formed while minutely dispersed insoluble drug is included in a hydrophobic cavity.
Solvents used in the present invention, excluding water, are preferred to be physiologically acceptable materials of which the boiling points are 100 °C or less. Such solvents may be used in preparing the composition of the present invention since it has very little remains in the preparing process. Examples of the solvent which may be employed in the present invention are C1-6 alkanol (e.g., ethanol, isopropanol and propanol), acetone, ethyl acetate, methylethylketone, DMF (dimethylformamide), dichloromethane, chloroform, straight chain or ring-shaped ether (e.g., diethyl ether and dimethyl ether, or tetrahydrofuran (THF), cyclohexane and dimethylsulfoxide) and mixtures thereof. Ethanol is preferred solvent to be used alone, and ethanol mixed with dichloromethane is more preferred to solubilize cyclodextrin and water-insoluble compound.
In the preparation method according to the present invention, the solubilization temperature of solvent is generally 0 to 100 °C, preferably 10 to
80 °C, more preferably 20 to 60 °C.
In the composition of the present invention, the solid dispersion of an active substance and substituted cyclodextrin may be obtained easily by dissolving the components in an organic solvent and then removing the solvent. The solvents of the components may be removed by natural drying, heated drying, drying under reduced pressure or spray drying. Especially, spray drying has the advantage that residual solvent is effectively removed from the solid dispersions by using spray drier and a large quantity of solid dispersions may be obtained. The amount of organic solvent varies according to the concentration of cyclodextrin which may be 3 to 30 % (w/w), preferably 5 to 15 % (w/w), in which condition the yield of solid dispersion exceeds 95%. The solid dispersion of the present invention is preferred to be used in the form of fine powders or particles to increase the dissolution rate. More preferably 80% or more, most preferably 90% or more of the dispersion is passed through 100 mesh (150 μm) screen. Particle size is a principal factor of determining the dissolution rate and speed as well as the rate of producing the tablet of sufficient hardness in large quantities.
The composition of the present invention has an obvious advantage in water-insoluble drugs. Further, the solid dispersions containing a drag and substituted cyclodextrin have remarkable advance in dissolution rate, therefore, even in water-soluble drags, dissolution rate and absorption improve greatly and irritation is sharply relieved at the time of disintegration.
The solid dispersions of the present invention contain a water-insoluble drug and substituted cyclodextrin in which the amount of substituted cyclodextrin ranges from 0.01 to 100 parts by weight, preferably from 0.5 to 25 parts by weight, more preferably from 0.1 to 10 parts by weight, per 1 part by weight of drag. Water-insoluble drags which may be used in the present invention have the solubility in water of 10 mg/ml or less at physiological pH (pH 6.5 to 7.4). Examples of the drags include analgesic and antiphlogistic agents, antihypertensive agents, diuretics, cardiac stimulants, antifungals, antiepileptics, psychotropics, antidiabetics, anticancer agents, gastro-intestinal agents, antihistamines, antihyperlipidemics, vasodilators, immunosuppressives, antipsoriatics, hepatoprotectants, vitamins and derivatives thereof, sex hormones and adrenocorticotrophic hormones.
What is suitable to be used in the present invention is a water-insoluble drug which is practically insoluble in water and extremely insoluble in the mixture of water and polar solvent miscible with water so that it is difficult for the drug to be used in an aqueous system. Examples of the drug are piroxicam, tretinoin, danazol, isotretinoin and glibenclamide. Since the drag has extremely low solubility in the mixture of water and polar solvent, inclusion proceeds very slowly in an aqueous system and the inclusion ratio of drug and cyclodextrin increases. Further, those drugs solubilized in a specific pH, such as ketoconazole and domperidone, have pH-dependent solubility and are practically insoluble in water or saline, so it is commercially unfavorable to obtain the inclusion compound in an aqueous system.
The above problems have been solved by the present invention in which, without including water-insoluble drags in cyclodextrin under an aqueous system, an organic solvent is selected for dissolving a water-insoluble drag and added to alcohol solution containing substituted cyclodextrin to dissolve the two components, and then the resulting transparent solution is dried to form a solid dispersion containing the water-insoluble drag and substituted cyclodextrin. In the present invention, lipophilic solvents are used for easily dissolving water- insoluble drags, and therefore, lots of solid dispersions may be produced by using a little amount of solvent.
Other water-insoluble drags used in the present invention include such drags of low solubility that dissolution is a major factor of rate-determination step to control the bioavailability, e.g., griseofulvin, digoxin, dipyridamole, amphotericin B. 6-mercaptopurine, dexamethasone, etc. Preferred active components used in the present invention are drugs that exert topical physiological action as well as systemic action after passing through mucous membrane or being transported into gastrointestinal with saliva. The dosage form manufactured from the composition of the present invention not only provides a rapid-acting solubility at a low ratio of carrier to a transocular, transnasal or parenteral form which is water-insoluble and difficult to be solubilized in distilled water, buffer solution or saline, but also improves a patient adaptability to the drags which produce an adverse effect on gastrointestinal tract when solubilized.
Examples of the drags which may be employed in the present invention are: analgesic and antiphlogistic agents (e.g., ibuprofen, S-ibuprofen, ketoprofen, rofecoxib, celecoxib, indomethacin, piroxicam, nimesulide, diacerein and aceclofenac), antihypertensive agents (e.g., nifedipine, nimodipine, felodipine, nitrendipine, isradipine, nisoldipine, nilvadipine and reserpine), diuretics (e.g., acetazolamide, indapamide, furosemide, spironolactone and chlorthalidone), cardiac stimulants (e.g., amrinone, milrinone, digitoxin and digoxin), antifungals (e.g., itraconazole, saperconazole, amphotericin B, clotrimazole, griseofulvin, ketoconazole and miconazole), antiepileptics (e.g., carbamazepine, oxcarbazepine, primidone, felbamate, lamotrigine, phenobarbital and phenytoin), psychotropics (e.g., alprazolam, estazolam, triazolam, risperidone, haloperidol, sulpiride, zotepine, thiothixene, chlorprothixene, clozapine, olanzapine, pimozide, diazepam, temazepam, oxazepam, lorazepam and clotiazepam), antidiabetics (e.g., gliclazide, glimepiride, glipizide, glibenclamide, tolbutamide and pioglitazone hydrochloride), anticancer agents (e.g., 9-aminocamptothecin, camptothecin, methotrexate, thioguanine, uracil mustard, tamoxifen citrate, carmustine, docetaxel, paclitaxel, danazol, chlorambucil, lomustine, etoposide, teniposide, busulfan, exemestane, 6- mercaptopurine, melphalan, flutamide, bicalutamide, megestrol acetate, progesterone, medroxyprogesterone acetate and altretamine), gastro-intestinal agents (e.g., domperidone, levosulpiride, domperidone maleate, cisapride, S- omeprazole, omeprazole, lansoprazole, bisacodyl and sulfasalazine), antiviral agents (e.g., acyclovir, ganciclovir, indinavir, nelfmavir, ritonavir, saquinavir, amprenavir and delavirdine), antihistamines (e.g., astemizole, loratadine and terfenadine), antihyperlipidemics (e.g., lovastatin, simvastatin, gemfibrozil, clofibrate, fenofibrate and probucol), vasodilators (e.g., dipyridamole, glyceryl trinitrate, amyl nitrate, isosorbide dinitrate and alprostadil), immunosuppressives (e.g., cyclosporins and tacrolimus), antipsoriatics (e.g., 8-methoxypsoralen), hepatoprotectants (e.g., ursodesoxycholic acid, silymarin, biphenyldimethyldicarboxylate (DDB) and alpha-lipoic acid), vitamins and derivatives thereof (e.g., calcitriol, tretinoin, isotretinoin, folic acid, dl-α-tocopherol and dl-α-tocopherol acetate), topical anesthetics (e.g., lidocaine and benzocaine), sex hormones (e.g., testosterone and methyltestosterone), adrenocorticotrophic hormones (e.g., beclomethasone dipropionate, flunisolide, paramethasone, paramethasone acetate, prednisone, methyl prednisolone, methyl prednisolon acetonate, prednisolone, prednisolone acetate, dexamethasone, dexamethasone acetate, dexamethasone palmitate, cortisone, cortisone acetate, triamcinolone, triamcinolone acetonide, budesonide, fluticasone propionate, betamethasone, hydrocortisone, hydrocortisone acetate, fluorocortisone, fluorocortisone acetate and deflazacort), and others (e.g, propofol, riluzole, bromocriptin mesylate, disulfiram, gamma-linoleic acid and sodium alendronate for osteoporosis).
The composition according to the present invention may be formulated using at least one of physiologically acceptable additives by a conventional method. For example, the composition may be given by oral administration (e.g., rapid- acting, enteric and long-acting preparations), parenteral administration such as intravenous, subcutaneous, intradermal, transdermal, transocular, transnasal, vaginal and anal administration, or by inspiration.
Examples of the preparations for oral administration are tablets, pills, powders, granules, liquids, suspensions, syrups and capsules.
Oral compositions, such as tablets and capsules, may be prepared by a conventional method using pharmaceutically acceptable additives including adhesives (e.g., gelatinized corn starch, polyvinyl pyrrolidone and hydroxypropylmethyl cellulose); fillers (e.g., spray dried or anhydrous lactose, microcrystalline cellulose and calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc and silica); disintegrants (e.g., potato starch and starch sodium glycolate); and hydrating agents (e.g., sodium lauryl sulfate). Tablets may be coated by a conventional method in the art. Pills, powders and granules may be formulated by a conventional method using the above-mentioned additives.
Liquids for oral administration are prepared as solutions, syrups or suspensions (e.g., composition coated with gastric acid-resistant agent and composition suspended in water or syrup), and can be prepared as a dry product which is mixed with water or other additives before being used. Such liquids may be prepared by a conventional method using pharmaceutically acceptable additives including suspending agents (e.g., lecithin and acacia); non-aqueous solvent (e.g., almond oil, oily ester, ethyl alcohol and fractionized vegetable oils); and antiseptics (e.g., methyl- or propyl-p-hydroxy benzoate, benzyl alcohol and sorbic acid). Preferably, the preparation includes a buffer, flavoring agent, coloring agent and sweetener. As a pH adjusting agent, organic acids such as tartaric acid, citric acid, fumaric acid, maleic acid, malic acid, succinic acid, oxalic acid, benzoic acid, malonic acid, mandelic acid and ascorbic acid, inorganic acids such as phosphoric acid, or bases such as sodium hydroxide and sodium carbonate may also be used. Capsules are manufactured by filling gelatin capsules or so with powders, granules, liquids, etc.
Preparations for oral administration provide a controlled-release of one or more active substances after being formulated suitably. The present invention considers pharmaceutical preparations containing a solid dispersion of an active substance and cyclodextrin, e.g., osmosis pump tablets, layered tablets, coated tablets, reconstituted powders, capsules and coated granules.
A conventional method may be applied to coating for tablets of the composition according to the present invention. In case that a drug and water- soluble polymer substances such as sugar, sugar/bees wax coating, polyvinyl pyrrolidone, polyvinyl alcohol and hydroxypropyl cellulose are to be absorbed in intestinal tract or in case of sustained-release, a gastric acid-resistant Eudragit manufactured by Rohm GmbH, a sustained-release Eudragit or a sustained-release polymer may be used.
The coated tablets, granules and pellets of the composition according to the present invention may include film coating or core tablets. For film coating, a film forming agent such as cellulose acetate, ethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose, wax, Eudragit El 00, Eudragit RL, Eudragit RS, Eudrigit RS, Eudragit S and hydroxypropylmethyl cellulose acetate succinate and a pore forming agents such as polyethylene glycol 3350, sorbitol, sucrose and organic acid may be used. A plurality of film forming agents and/or pore forming agents may be used in film coating, and a mixture of film forming agents may also be used in a certain film coating. The term "pore forming agent" means the agent that promotes formation of pores in the film coating or enhances water permeability of film.
Examples of intravenously, subcutaneously or intramuscularly administrated preparations include injections made of sterilized aqueous or non- aqueous solvents. Examples of aqueous solvents are saline, etc. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable organic ester such as ethyl oleate, and fatty acid ester of iodized poppy-seed oil. The preparations may contain, if necessary, isotonic agents, antiseptics, emollients, emulsifiers, dispersing agents, stabilizer, etc. Further, the preparations may be sterilized by a suitable process such as filtration through bacteria-reserving filter, addition of disinfectants and radiation. Sterilized solid dispersions may be formulated into water-soluble forms in sterilized distilled water or sterilized solvent for injection, or preferably, into powders consisting of acceptable additives, such as sterilized pyrogen-free substances, for being dissolved prior to use.
Examples of transdermal preparations are ointments, creams, lotions and liquids, and transparent gel type is preferred. Further preparations to be used include pastes, cataplasmas and aerosols. Such preparations may be manufactured by using a conventional method. As examples of transocular preparations, transparent liquids are preferred to suspensions. The manufacturing process may include steps such as solubilizing the solid dispersions, preferably dissolving the powders or tablets in a suitable aqueous solution prior to use. Examples of desired buffering agents are phosphate, boric acid, sodium borate, organic acid such as acetic acid and citric acid, and salts thereof. Examples of suitable isotonic agents are boric acid, salts such as sodium chloride and potassium chloride, and glycerol. Examples of preferred thickeners are hydroxyethyl cellulose and its salt. Examples of suitable suspending agents are surfactants such as polysorbate 80 and water-soluble polymers such as sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose and polyvinyl alcohol. Examples of desired solubilizers are non- ionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene stearate, triglyceride and polyethylene glycol. Examples of preferred pH adjusting agents are alkaline compounds such as sodium hydroxide, boric acid and sodium dihydrogen phosphate, and acids such as hydrochloric acid, boric acid, phosphoric acid and acetic acid. Examples of suitable chelating agents are disodium edetate, sodium citrate and sodium polyphosphate.
Transnasal preparations are made in liquid or powder compositions. As examples of transnasal preparations, transparent liquids are preferred to suspensions. The manufacturing process may include steps such as solubilizing the solid dispersions, preferably dissolving the powders or tablets in a suitable aqueous solution prior to use. Examples of solvents are water, saline, phosphate buffer and acetate buffer. Surfactants, anti-oxidants, stabilizers, preservatives and thickeners may be included. Examples of bases for the powders, preferably being absorbent, are polyacrylates such as water-soluble sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate, cellulose-lower alkyl ethers such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, amylose, pulluran, celluloses such as water-insoluble crystalline cellulose, α-cellulose and cross-linked sodium carboxymethyl cellulose, starches such as hydroxypropyl starch, carboxymethyl starch, cross-linked starch, amylose, amylopectin and pectins, proteins such as gelatin, casein and sodium casein, gums such as arabia gum, tragacanth gum and glucomannan, cross-linked polyacrylic acid and its salts, cross-linked polyvinyl alcohol, and mixtures thereof. Powdered preparations may contain anti-oxidants, coloring agents, preservatives and antiseptics. The liquids and powders may be administered by using a spray device, etc. The present composition for vaginal or anal administration may be formulated in suppositories including conventional suppository bases such as glyceride and cocoa butter, or in reserving enemas.
The present composition may be administered to the site in trouble by using the devices such as a spray, nebulizer and atomizer, in the form of powdered or liquid preparations containing the solid dispersions with or without pharmaceutically acceptable additives. The composition may be administered to the site in trouble after being suspended in injection agents for aerosol such as freon.
Brief Description of the Drawings The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:
Fig. 1 is a graph showing the dissolution rate of ibuprofen/cyclodextrin solid dispersion according to the ratio of the components under an acidic condition
(pH 1.2).
Fig. 2 is a graph showing the dissolution rate of ketoconazole/cyclodextrin solid dispersion according to the ratio of the components under a basic condition (pH 6.8). Fig. 3 is a graph showing the dissolution rate of domperidone/cyclodextrin solid dispersion according to the ratio of the components under a basic condition (pH 6.8).
Fig. 4 is a graph showing the dissolution rate of ketoprofen/cyclodextrin solid dispersion according to the ratio of the components under an acidic condition (pH 1.2).
Fig. 5 is a graph showing the dissolution rate of the ketoconazole tablets manufactured in Preparation Example 1 and Comparative Example 1 under a basic condition (pH 6.8).
Fig. 6 is a graph showing the dissolution rate of the domperidone tablets manufactured in Preparation Example 2 and Comparative Example 2 under a basic condition (pH 6.8).
Best Mode for Carrying Out the Invention
Hereinafter, the present invention will be described in detail, in conjunction with various examples. These examples are provided only for illustrative purposes, and the present invention is not to be construed as being limited to these examples.
Examples 1 to 3: Preparation of the solid dispersion of ibuprofen and cyclodextrin As shown in the following Table 1, an appropriate amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) was dissolved in 200 ml of ethanol in 1,000 ml-round flask. The resultant solution was added with 100 ml of dichloromethane and 2 g of ibuprofen, and then stirred to be transparent. The solution was dried under a reduced pressure to obtain a white solid, which was sieved with #120 screen. The amount of 100 mg measured in terms of ibuprofen was to be a dose for one time. Table 1 shows the ratio of the components for the oral ibuprofen solid dispersions prepared in Examples 1 to 3.
Table 1
Figure imgf000015_0001
Examples 4 to 6: Preparation of the solid dispersion of ketoconazole and cyclodextrin
As shown in the following Table 2, an appropriate amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) was dissolved in 200 ml of ethanol in 1,000 ml-round flask. The resultant solution was added with 100 ml of dichloromethane and 2 g of ketoconazole, and then stirred to be transparent. The solution was dried under a reduced pressure to obtain a white solid, which was sieved with #120 screen. The amount of 100 mg measured in terms of ketoconazole was to be a dose for one time. Table 2 shows the ratio of the components for the oral ketoconazole solid dispersions prepared in Examples 4 to 6.
Table 2
Figure imgf000015_0002
Examples 7 to 9: Preparation of the solid dispersion of domperidone and cyclodextrin
As shown in following Table 3, an appropriate amount of hydroxypropyl-β- cyclodextrin (HP-β-CD) and 2 g of domperidone were dissolved in 200 ml of ethanol in 1,000 ml-round flask, and then the resultant solution was stirred at 50 °C to be transparent. The solution was spray dried to obtain a white solid, which was sieved with #120 screen. The amount of 10 mg measured in terms of domperidone was to be a dose for one time.
Table 3 shows the ratio of the components for the oral domperidone solid dispersions prepared in Examples 7 to 9. Table 3
Figure imgf000016_0001
Examples 10 to 12: Preparation of the solid dispersion of ketoprofen and cyclodextrin
As shown in the following Table 4, an appropriate amount of hydroxypropyl-β-cyclodextrin (HP- β-CD) was dissolved in 200 ml of ethanol in 1,000 ml-round flask. The resultant solution was added with 100 ml of dichloromethane and 2 g of ketoprofen, and then stirred to be transparent. The solution was dried under a reduced pressure to obtain a white solid, which was sieved with #120 screen. The amount of 100 mg measured in terms of ketoprofen was to be a dose for one time.
Table 4 shows the ratio of the components for the oral ketoprofen solid dispersions prepared in Examples 10 to 12.
Table 4
Figure imgf000016_0002
Preparation of tablets
Preparation Example 1
Solid dispersion of ketoconazole:HP-β-CD (1:3) 400 mg
Microcrystalline cellulose 144 mg
Sodium carboxymethyl starch 16 mg
Lactose 236 mg
Magnesium stearate 3 mg
Preparation Example 2
Solid dispersion of domperidone:HP-β-CD (1:4) 50 mg
Microcrystalline cellulose 80 mg
Sodium carboxymethyl starch 10 mg Lactose Magnesium stearate
Comparative Preparation Examples 1 and 2: Preparation of physical mixture (not a solid dispersion) and tablet of active substance and cyclodextrin
Hydroxypropyl-β-cyclodextrin and the above active substance were weighed in the same ratio of the above preparation examples and pulverized. The resultant fine powder was pressed and crashed into granules, which were then formulated according to the same method of Preparation Examples 1 and 2.
Efficiency Test
The preparations manufactured in Examples 1 to 12, Preparation Examples 1 and 2 and Comparative Preparation Examples 1 and 2 were tested for Dissolution Test (Korean Pharmacopoeia 7th revised version) according to Method 2 (Paddle
Method). For dissolution test solutions of pH 1.2 and pH 6.8, the first and second solutions of Disintegration Test were used, respectively. Under the condition of 37 °C and 100 rpm, 5 ml of test solution was collected at a determined time and filtrated with 0.45 μm filter. The filtrate was analyzed with liquid chromatography.
The results are shown in Figs. 1 to 6.
According to Fig. 1, ibuprofen powder shows a slow dissolution and low dissolution rate at an acidic condition, while in the solid dispersions of ibuprofen and cyclodextrin, the dissolution of hydroxypropyl-β-cyclodextrin increases easily. Especially, when the ratio of active substance to carrier is about 1:7, the dissolution rate rapidly exceeds 90%.
According to Fig. 2, ketoconazole powder shows very low dissolution rate and speed, while the solid dispersions show marked increases in the dissolution rate and speed in proportion to the amount of carrier. Especially, when the ratio of active substance to carrier is about 1:3, the dissolution rate and speed reaches the greatest.
According to Fig. 3, domperidone powder shows little dissolution under an basic condition since it is a weak alkaline drug which ionizes only under an acidic condition. In case of the solid dispersions of domperidone, however, the dissolution rate increases remarkably in proportion to the amount of carrier.
According to Fig. 4, ketoprofen powder shows slow dissolution of more than 50% within 30 minutes under an acidic condition, while the solid dispersions show accelerated dissolution in proportion to the amount of carrier. Therefore, it is understood that the drags of easy dissolution have more improved dissolution according to the present invention.
Fig. 5 shows the dissolution rate of solid dispersion of ketoconazole and cyclodextrin and its corresponding physical mixture under an basic condition, in which the solid dispersion shows rapid and high dissolution rate compared to the physical mixture.
Fig. 6 shows the dissolution rate of solid dispersion of domperidone and cyclodextrin and its corresponding physical mixture under an basic condition, in which the solid dispersion shows rapid and high dissolution rate compared to the physical mixture.
Industrial Applicability
The present invention relates to a method of manufacturing solid dispersions which provide an enhanced drag release and absorption, by using a substituted cyclodextrin which is pharmaceutically stable and dissolved in a short time when administered, and a pharmaceutical composition comprising the solid dispersions.
According to the present invention, the solid dispersions may be obtained in large quantities by easily solubilizing a water-insoluble drag and substituted cyclodextrin in an organic solvent, neither using aqueous system nor heating them at high temperatures, and by drying under a reduced pressure or spray drying the solubilized mixture. The pharmaceutical composition of the present invention improves the dissolution rate and speed of water-insoluble drags and maximizes the bioavailability.

Claims

What is Claimed is:
1. A method of manufacturing a solid dispersion, which comprises dissolving a water-insoluble drug and a substituted cyclodextrin in an organic solvent without water to make a mixture and drying under a reduced pressure or spray drying the mixture.
2. The method according to claim 1, wherein the water-insoluble drag is one or more selected from the group consisting of ibuprofen, S-ibuprofen, ketoprofen, rofecoxib, celecoxib, indomethacin, piroxicam, nimesulide, diacerein, aceclofenac, nifedipine, nimodipine, felodipine, nitrendipine, isradipine, nisoldipine, nilvadipine, reserpine, acetazolamide, indapamide, furosemide, spironolactone, chlorthalidone, amrinone, milrinone, digitoxin, digoxin, itraconazole, saperconazole, amphotericin B, clotrimazole, griseofulvin, ketoconazole, miconazole, carbamazepine, oxcarbazepine, primidone, felbamate, lamotrigine, phenobarbital, phenytoin, alprazolam, estazolam, triazolam, risperidone, haloperidol, sulpiride, zotepine, thiothixene, chlorprothixene, clozapine, olanzapine, pimozide, diazepam, temazepam, oxazepam, lorazepam, clotiazepam, gliclazide, glimepiride, glipizide, glibenclamide, tolbutamide, pioglitazone hydrochloride, 9-aminocamptothecin, camptothecin, methotrexate, thioguanine, uracil mustard, tamoxifen citrate, carmustine, docetaxel, paclitaxel, danazol, chlorambucil, lomustine, etoposide, teniposide, busulfan, exemestane, 6- mercaptopurine, melphalan, flutamide, bicalutamide, megestrol acetate, progesterone, medroxyprogesterone acetate, altretamine, domperidone, levosulpiride, domperidone maleate, cisapride, S-omeprazole, omeprazole, lansoprazole, bisacodyl, sulfasalazine, acyclovir, ganciclovir, indinavir, nelfinavir, ritonavir, saquinavir, amprenavir, delavirdine, astemizole, loratadine, terfenadine, lovastatin, simvastatin, gemfibrozil, clofibrate, fenofibrate, probucol, dipyridamole, glyceryl trinitrate, amyl nitrate, isosorbide dinitrate, alprostadil, cyclosporins, tacrolimus, 8-methoxypsoralen, ursodesoxycholic acid, silymarin, biphenyldimethyldicarboxylate (DDB), alpha-lipoic acid, calcitriol, tretinoin, isotretinoin, folic acid, dl-α-tocopherol, dl-α-tocopherol acetate, lidocaine, benzocaine, testosterone, methyltestosterone, beclomethasone dipropionate, flunisolide, paramethasone, paramethasone acetate, prednisone, methyl prednisolone, methyl prednisolon acetonate, prednisolone, prednisolone acetate, dexamethasone, dexamethasone acetate, dexamethasone palmitate, cortisone, cortisone acetate, triamcinolone, triamcinolone acetonide, budesonide, fluticasone propionate, betamethasone, hydrocortisone, hydrocortisone acetate, fluorocortisone, fluorocortisone acetate, deflazacort, propofol, riluzole, bromocriptin mesylate, disulfiram, gamma-linoleic acid and sodium alendronate.
3. The method according to claim 1, wherein the water-insoluble drag is one or more selected from the group consisting of ibuprofen, S -ibuprofen, ketoprofen, piroxicam, ketoconazole, domperidone, docetaxel, paclitaxel, acyclovir and sodium alendronate.
4. The method according to claim 1, wherein the substituted cyclodextrin is one or more selected from the group consisting of 2,6-dimethyl-β-cyclodextrin, 2- hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, 2-hydroxypropyl-β- cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, (2-carboxymethoxy)propyl-β- cyclodextrin and sulfobutylether-7-β-cyclodextrin.
5. The method according to claim 4, wherein the substituted cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
6. The method according to one of claims 1 to 5, wherein the organic solvent is methanol, ethanol, isopropanol, propanol, acetone, ethyl acetate, methylethylketone, dimethylformamide (DMF), dichloromethane, chloroform, diethyl ether, dimethyl ether, tetrahydrofuran (THF), cyclohexane, dimethylsulfoxide (DMSO) and a mixture thereof.
7. The method according to claim 6, wherein the solid dispersion contains 0.1 to 10 parts by weight of the substituted cyclodextrin based on 1 part by weight of the water insoluble drug.
8. A pharmaceutical composition comprising a solid dispersion which is prepared by dissolving a water-insoluble drag and a substituted cyclodextrin in an organic solvent without water to make a mixture and drying under a reduced pressure or spray drying the mixture, and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition according to claim 8, wherein the substituted cyclodextrin is one or more selected from the group consisting of 2,6- dimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxyethyl-γ- cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, (2- carboxymethoxy)propyl-β-cyclodextrin and sulfobutylether-7-β-cyclodextrin.
10. The pharmaceutical composition according to claim 9, wherein the substituted cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.
PCT/KR2002/002151 2001-11-20 2002-11-18 Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations WO2003043602A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002366042A AU2002366042A1 (en) 2001-11-20 2002-11-18 Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR2001/72412 2001-11-20
KR1020010072412A KR20030041577A (en) 2001-11-20 2001-11-20 Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations

Publications (1)

Publication Number Publication Date
WO2003043602A1 true WO2003043602A1 (en) 2003-05-30

Family

ID=19716122

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2002/002151 WO2003043602A1 (en) 2001-11-20 2002-11-18 Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations

Country Status (3)

Country Link
KR (1) KR20030041577A (en)
AU (1) AU2002366042A1 (en)
WO (1) WO2003043602A1 (en)

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005079858A1 (en) * 2004-02-20 2005-09-01 I.Q.A., A.S. Stable, palatable syrup containing ibuprofen and method of its preparation
EP1594515A2 (en) * 2003-02-03 2005-11-16 Shire Laboratories Inc. Drug formulation and delivery using crystalline methylated cyclodextrins
WO2005110488A1 (en) * 2004-04-30 2005-11-24 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing benzimidazole derivatives and method of manufacturing the same
WO2006013039A2 (en) * 2004-08-02 2006-02-09 Chiesi Farmaceutici S.P.A. A process for the preparation of a piroxicam: beta­cyclodextrin inclusion compound
WO2006052921A2 (en) * 2004-11-08 2006-05-18 Eastman Chemical Company Cyclodextrin solubilizers for liquid and semi-solid formulations
EP1848722A1 (en) * 2005-02-04 2007-10-31 Hanmi Pharm. Co., Ltd. Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same
WO2007136219A1 (en) 2006-05-22 2007-11-29 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
WO2007141806A1 (en) * 2006-06-02 2007-12-13 Jubilant Organosys Ltd Pharmaceutical formulations comprising oxcarbazepine and methods thereof
WO2008031286A1 (en) * 2006-09-12 2008-03-20 Nanjing Normal University Pharmaceutical composition comprising cyclodextrin paclitaxel inclusion and preparation method thereof
WO2008056926A1 (en) * 2006-11-06 2008-05-15 Hanmi Pharm. Co., Ltd. Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
WO2007121119A3 (en) * 2006-04-10 2008-05-22 Esophamet Corp Apparatus and method for detecting gastroesophageal reflux disease (gerd)
EP1928464A2 (en) * 2005-09-30 2008-06-11 Ovation Pharmaceuticals, Inc. Novel parenteral carbamazepine formulation
WO2008092046A2 (en) * 2007-01-26 2008-07-31 Isp Investments Inc. Amorphous oxcarbazepine and the production thereof
WO2009007996A2 (en) * 2007-04-27 2009-01-15 Sun Pharmaceutical Industries Limited Cyclodextrin complexes of atovaquone
WO2009013594A2 (en) * 2007-07-25 2009-01-29 Archimica S.R.L. Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process
WO2010150144A2 (en) 2009-06-25 2010-12-29 Wockhardt Research Centre Low dose pharmaceutical compositions of celecoxib
CN101953837A (en) * 2010-09-20 2011-01-26 山西康宝生物制品股份有限公司 Felodipine sustained-release tablets and preparation method thereof
US20110166225A1 (en) * 2008-04-30 2011-07-07 Himanshu Verma Oral liquid compositions of rhein or diacerein
KR101131296B1 (en) * 2007-12-28 2012-03-30 라보라토리오스 안드로마코 에스.에이. An inclusion complex composed of disulfiram and a cyclodextrin, useful for the treatment of alcohol and ***e dependences
KR101132954B1 (en) * 2007-12-28 2012-04-24 라보라토리오스 안드로마코 에스.에이. Pharmaceutical composition which comprises an inclusion complex formed by disulfiram and cyclodextrin, useful for the treatment of alcohol and ***e dependences
CN102579395A (en) * 2012-03-30 2012-07-18 江苏万禾制药有限公司 Lipoic acid capsules as well as preparation process and application thereof
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
US20120328588A1 (en) * 2010-05-24 2012-12-27 The Second Military Medical University of Chinese PLA Compound preparation and its uses for prevention and treatment of hearing impairment
US8367685B2 (en) 2005-09-12 2013-02-05 Actelion Pharmaceuticals, Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
CN103142499A (en) * 2013-03-21 2013-06-12 青岛正大海尔制药有限公司 Etoposide particle
US8481511B2 (en) 2006-09-12 2013-07-09 Hainan Hdeton Science and Technology Co., Ltd. Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process
CN103690504A (en) * 2013-12-18 2014-04-02 北京华禧联合科技发展有限公司 Method for preparing rosuvastatin calcium tablet solid dispersion
CN103948550A (en) * 2014-04-22 2014-07-30 青岛市市立医院 Cisapride dispersible tablet and preparation method thereof
WO2015016698A1 (en) 2013-08-02 2015-02-05 Laboratorio Raam De Sahuayo, S.A. De C.V. Pharmaceutical composition with antiinflammatory agents and production process
CN104523615A (en) * 2014-12-12 2015-04-22 常州康普药业有限公司 Sulpiride tablet and preparation method thereof
WO2015152433A1 (en) * 2014-03-31 2015-10-08 Hanmi Pharm. Co., Ltd. Amorphous solid dispersion comprising paclitaxel, tablet comprising the same, and method for preparing the same
CN105106161A (en) * 2015-09-11 2015-12-02 苏州东瑞制药有限公司 Levamlodipine besylate tablet and preparing technology thereof
US20160136283A1 (en) * 2014-11-18 2016-05-19 Shin-Etsu Chemical Co., Ltd. Solution for spray drying comprising hypromellose acetate succinate and method for producing solid dispersion
CN105832680A (en) * 2016-05-12 2016-08-10 沈阳药科大学 Pharmaceutical composition for improving in-vitro dissolution and liquidity of spironolactone
CN106309373A (en) * 2016-09-21 2017-01-11 沈阳药科大学 Probucol solid dispersion and preparation method thereof
US20170056365A1 (en) * 2014-02-28 2017-03-02 Sun Pharmaceutical Industries Limited Dapagliflozin compositions
US9629797B2 (en) 2005-09-30 2017-04-25 Lundbeck Pharmaceuticals Llc Parenteral carbamazepine formulation
RU2627460C2 (en) * 2010-05-26 2017-08-08 Нейрофиксиа Б.В. Formulations of 2-iminobiotine and use thereof
CN107751576A (en) * 2017-11-13 2018-03-06 厦门大学 A kind of B B-complex liquid and preparation method thereof
CN108379229A (en) * 2018-04-05 2018-08-10 孙金霞 A kind of anti-inflammatory Claritin solid dispersion composition and preparation method thereof
CN109044967A (en) * 2018-10-17 2018-12-21 南京远航生物科技有限公司 A kind of Teniposide injection solution and preparation method thereof that dilution stability is good
CN109864971A (en) * 2019-04-08 2019-06-11 西安远大德天药业股份有限公司 A kind of granule and preparation method thereof of Lamotrigine solid dispersions
RU2692772C2 (en) * 2017-11-15 2019-06-27 Общество с ограниченной ответственностью "Технофарм" Composition and method for preparing rapidly soluble antifungal drug based on nitrofural
CN110652496A (en) * 2019-11-11 2020-01-07 中山大学 Solid dispersion of cryptotanshinone and preparation method and application thereof
RU2712123C1 (en) * 2018-12-14 2020-01-27 Общество с ограниченной ответственностью "Технофарм" Composition and method for preparing a rapidly soluble antimicrobial drug based on nitrofural (versions)
WO2020077564A1 (en) * 2018-10-17 2020-04-23 南京远航生物科技有限公司 Teniposide injection solution having good dilution stability and preparation method therefor
US10702568B2 (en) 2015-03-19 2020-07-07 Cydex Pharmaceuticals, Inc. Compositions containing silymarin and sulfoalkyl ether cyclodextrin and methods of using the same
CN111529497A (en) * 2020-02-11 2020-08-14 兆科（广州）肿瘤药物有限公司 Gemastecan drug solid dispersion composition and preparation method thereof
US10799599B2 (en) 2003-12-31 2020-10-13 Cydex Pharmaceuticals, Inc. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
US10940128B2 (en) 2009-05-29 2021-03-09 Cydex Pharmaceuticals, Inc. Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same
CN114831951A (en) * 2022-04-25 2022-08-02 扬子江药业集团广州海瑞药业有限公司 Ezetimibe tablets and preparation method thereof
CN116159034A (en) * 2023-04-23 2023-05-26 国药集团川抗制药有限公司 Tacrolimus sustained-release capsule and preparation method thereof

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100567131B1 (en) * 2004-01-05 2006-04-05 신일제약주식회사 Taste masking of oral ibuprofen and arginine solution
KR100726720B1 (en) * 2005-12-26 2007-06-11 코스맥스 주식회사 Nano capsule liposome composition double-stabilized water insoluble active material by hydroxy alkylated cyclodextrin and liposome
KR100809046B1 (en) * 2006-03-10 2008-03-03 가톨릭대학교 산학협력단 Self assembled nanoparticle having pullulan and methods of using thereof
KR100917810B1 (en) * 2006-06-02 2009-09-18 에스케이케미칼주식회사 Stable Pharmaceutical Composition containing Paclitaxel
KR20130069484A (en) * 2011-12-15 2013-06-26 주식회사 삼양바이오팜 Solid dispersion comprising celecoxib and a preparation method thereof
WO2021040440A1 (en) * 2019-08-30 2021-03-04 (주)셀트리온 Pharmaceutical composition for treating or preventing nonalcoholic steatohepatitis (nash)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
KR970058705A (en) * 1996-01-18 1997-08-12 이범진 Site-Specific Release Agents Containing Inclusion Compounds
WO2000041704A1 (en) * 1999-01-13 2000-07-20 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5324718A (en) * 1992-07-14 1994-06-28 Thorsteinn Loftsson Cyclodextrin/drug complexation
KR970058705A (en) * 1996-01-18 1997-08-12 이범진 Site-Specific Release Agents Containing Inclusion Compounds
WO2000041704A1 (en) * 1999-01-13 2000-07-20 Cydex, Inc. Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAGARSENKER MANGAL S. ET AL.: "Solid dispersion of hydroxypropyl beta-cyclodextrin and ketolorac: enhancement of in-vitro dissolution rates, improvement in anti-inflammatory activity and reduction in ulcergenicity in rats", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 52, no. 8, 2000, pages 949 - 956 *
NOZAWA Y. ET AL.: "Dissolution behavior of water-insoluble drugs roll mixed with beta-cyclodextrin and its complexations in amorphous solis mixture", PHARMACEUTISCHE INDUSTRIE, vol. 53, no. 7, 1991, pages 691 - 694 *

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1594515A2 (en) * 2003-02-03 2005-11-16 Shire Laboratories Inc. Drug formulation and delivery using crystalline methylated cyclodextrins
EP1594515A4 (en) * 2003-02-03 2009-05-27 Supernus Pharmaceuticals Inc Drug formulation and delivery using crystalline methylated cyclodextrins
US10799599B2 (en) 2003-12-31 2020-10-13 Cydex Pharmaceuticals, Inc. Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
WO2005079858A1 (en) * 2004-02-20 2005-09-01 I.Q.A., A.S. Stable, palatable syrup containing ibuprofen and method of its preparation
WO2005110488A1 (en) * 2004-04-30 2005-11-24 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing benzimidazole derivatives and method of manufacturing the same
WO2006013039A2 (en) * 2004-08-02 2006-02-09 Chiesi Farmaceutici S.P.A. A process for the preparation of a piroxicam: beta­cyclodextrin inclusion compound
WO2006013039A3 (en) * 2004-08-02 2007-08-23 Chiesi Farma Spa A process for the preparation of a piroxicam: beta­cyclodextrin inclusion compound
WO2006052921A2 (en) * 2004-11-08 2006-05-18 Eastman Chemical Company Cyclodextrin solubilizers for liquid and semi-solid formulations
WO2006052921A3 (en) * 2004-11-08 2006-07-06 Eastman Chem Co Cyclodextrin solubilizers for liquid and semi-solid formulations
EP1848722A4 (en) * 2005-02-04 2012-12-12 Hanmi Pharm Ind Co Ltd Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same
EP1848722A1 (en) * 2005-02-04 2007-10-31 Hanmi Pharm. Co., Ltd. Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same
US10117870B2 (en) 2005-09-12 2018-11-06 Actelion Pharmaceuticals Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US10946015B2 (en) 2005-09-12 2021-03-16 Actelion Pharmaceuticals Ltd Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US8367685B2 (en) 2005-09-12 2013-02-05 Actelion Pharmaceuticals, Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US11648249B2 (en) 2005-09-12 2023-05-16 Actelion Pharmaceuticals Ltd Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
US9265762B2 (en) 2005-09-12 2016-02-23 Actelion Pharmaceuticals Ltd. Stable pharmaceutical compositions comprising a pyrimidine-sulfamide
AU2006299501B2 (en) * 2005-09-30 2012-11-29 Lundbeck Llc Novel parenteral carbamazepine formulation
US9770407B2 (en) 2005-09-30 2017-09-26 Lundbeck Pharmaceuticals Llc Parenteral carbamazepine formulation
EP2444090A1 (en) * 2005-09-30 2012-04-25 Lundbeck Inc. Novel parenteral carbamazepine formulation
US9629797B2 (en) 2005-09-30 2017-04-25 Lundbeck Pharmaceuticals Llc Parenteral carbamazepine formulation
JP2009510123A (en) * 2005-09-30 2009-03-12 オベーション ファーマシューティカルズ インコーポレイテッド New parenteral carbamazepine preparation
EP1928464A2 (en) * 2005-09-30 2008-06-11 Ovation Pharmaceuticals, Inc. Novel parenteral carbamazepine formulation
JP2013040195A (en) * 2005-09-30 2013-02-28 Lundbeck Llc New parenteral carbamazepine formulation
EP1928464A4 (en) * 2005-09-30 2009-10-21 Ovation Pharmaceuticals Inc Novel parenteral carbamazepine formulation
GB2450662A (en) * 2006-04-10 2008-12-31 Esophamet Corp Apparatus and method for detecting gastroesophageal reflux disease (gerd)
WO2007121119A3 (en) * 2006-04-10 2008-05-22 Esophamet Corp Apparatus and method for detecting gastroesophageal reflux disease (gerd)
WO2007136219A1 (en) 2006-05-22 2007-11-29 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
EP2019664A4 (en) * 2006-05-22 2013-03-13 Sk Chemicals Co Ltd Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
AU2007252371B2 (en) * 2006-05-22 2013-07-25 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
US8791152B2 (en) 2006-05-22 2014-07-29 Sk Chemicals Co., Ltd. Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
EP2019664A1 (en) * 2006-05-22 2009-02-04 SK Chemicals, Co., Ltd. Stable pharmaceutical composition containing docetaxel and a method of manufacturing the same
WO2007141806A1 (en) * 2006-06-02 2007-12-13 Jubilant Organosys Ltd Pharmaceutical formulations comprising oxcarbazepine and methods thereof
US8481511B2 (en) 2006-09-12 2013-07-09 Hainan Hdeton Science and Technology Co., Ltd. Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process
US8426385B2 (en) 2006-09-12 2013-04-23 Hainan Hdeton Science And Technology Co. Ltd. Pharmaceutical composition comprising cyclodextrin paclitaxel inclusion and preparation method thereof
WO2008031286A1 (en) * 2006-09-12 2008-03-20 Nanjing Normal University Pharmaceutical composition comprising cyclodextrin paclitaxel inclusion and preparation method thereof
EP2091543A1 (en) * 2006-11-06 2009-08-26 Hanmi Pharm. Co., Ltd. Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
WO2008056926A1 (en) * 2006-11-06 2008-05-15 Hanmi Pharm. Co., Ltd. Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
EP2091543A4 (en) * 2006-11-06 2013-07-24 Hanmi Science Co Ltd Complex formulation for preventing or treating osteoporosis which comprises solid dispersion of vitamin d or its derivative and bisphosphonate
WO2008092046A2 (en) * 2007-01-26 2008-07-31 Isp Investments Inc. Amorphous oxcarbazepine and the production thereof
WO2008092046A3 (en) * 2007-01-26 2009-03-12 Isp Investments Inc Amorphous oxcarbazepine and the production thereof
WO2009007996A3 (en) * 2007-04-27 2009-03-05 Sun Pharmaceutical Ind Ltd Cyclodextrin complexes of atovaquone
WO2009007996A2 (en) * 2007-04-27 2009-01-15 Sun Pharmaceutical Industries Limited Cyclodextrin complexes of atovaquone
WO2009013594A2 (en) * 2007-07-25 2009-01-29 Archimica S.R.L. Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process
JP2010534234A (en) * 2007-07-25 2010-11-04 アルキミカ ソシエタ ア レスポンサビリタ リミタータ Method for preparing controlled release solid formulation containing oxcarbazepine and formulation obtained by the method
KR101519612B1 (en) 2007-07-25 2015-05-12 아르키미카 에스.알.엘. Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process
WO2009013594A3 (en) * 2007-07-25 2009-08-13 Archimica Srl Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process
US8324232B2 (en) 2007-08-17 2012-12-04 Actelion Pharmaceuticals Ltd. 4-pyrimidinesulfamide derivative
KR101131296B1 (en) * 2007-12-28 2012-03-30 라보라토리오스 안드로마코 에스.에이. An inclusion complex composed of disulfiram and a cyclodextrin, useful for the treatment of alcohol and ***e dependences
KR101132954B1 (en) * 2007-12-28 2012-04-24 라보라토리오스 안드로마코 에스.에이. Pharmaceutical composition which comprises an inclusion complex formed by disulfiram and cyclodextrin, useful for the treatment of alcohol and ***e dependences
US20110166225A1 (en) * 2008-04-30 2011-07-07 Himanshu Verma Oral liquid compositions of rhein or diacerein
US9119819B2 (en) * 2008-04-30 2015-09-01 Wockhardt Ltd. Oral liquid compositions of rhein or diacerein
US10940128B2 (en) 2009-05-29 2021-03-09 Cydex Pharmaceuticals, Inc. Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same
US11020363B2 (en) 2009-05-29 2021-06-01 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
US10864183B2 (en) 2009-05-29 2020-12-15 Cydex Pharmaceuticals, Inc. Injectable nitrogen mustard compositions comprising a cyclodextrin derivative and methods of making and using the same
WO2010150144A2 (en) 2009-06-25 2010-12-29 Wockhardt Research Centre Low dose pharmaceutical compositions of celecoxib
US20120328588A1 (en) * 2010-05-24 2012-12-27 The Second Military Medical University of Chinese PLA Compound preparation and its uses for prevention and treatment of hearing impairment
RU2627460C2 (en) * 2010-05-26 2017-08-08 Нейрофиксиа Б.В. Formulations of 2-iminobiotine and use thereof
CN101953837A (en) * 2010-09-20 2011-01-26 山西康宝生物制品股份有限公司 Felodipine sustained-release tablets and preparation method thereof
CN102579395A (en) * 2012-03-30 2012-07-18 江苏万禾制药有限公司 Lipoic acid capsules as well as preparation process and application thereof
CN103142499A (en) * 2013-03-21 2013-06-12 青岛正大海尔制药有限公司 Etoposide particle
WO2015016698A1 (en) 2013-08-02 2015-02-05 Laboratorio Raam De Sahuayo, S.A. De C.V. Pharmaceutical composition with antiinflammatory agents and production process
CN103690504A (en) * 2013-12-18 2014-04-02 北京华禧联合科技发展有限公司 Method for preparing rosuvastatin calcium tablet solid dispersion
US20170056365A1 (en) * 2014-02-28 2017-03-02 Sun Pharmaceutical Industries Limited Dapagliflozin compositions
US9867801B2 (en) 2014-03-31 2018-01-16 Hanmi Pharm. Co., Ltd. Amorphous solid dispersion comprising taxane, tablet comprising the same, and method for preparing the same
WO2015152433A1 (en) * 2014-03-31 2015-10-08 Hanmi Pharm. Co., Ltd. Amorphous solid dispersion comprising paclitaxel, tablet comprising the same, and method for preparing the same
CN103948550A (en) * 2014-04-22 2014-07-30 青岛市市立医院 Cisapride dispersible tablet and preparation method thereof
US20160136283A1 (en) * 2014-11-18 2016-05-19 Shin-Etsu Chemical Co., Ltd. Solution for spray drying comprising hypromellose acetate succinate and method for producing solid dispersion
US10493161B2 (en) * 2014-11-18 2019-12-03 Shin-Etsu Chemical Co., Ltd. Solution for spray drying comprising hypromellose acetate succinate and method for producing solid dispersion
CN104523615A (en) * 2014-12-12 2015-04-22 常州康普药业有限公司 Sulpiride tablet and preparation method thereof
CN104523615B (en) * 2014-12-12 2017-07-04 常州康普药业有限公司 A kind of Sulpiride tablet and preparation method thereof
US10702568B2 (en) 2015-03-19 2020-07-07 Cydex Pharmaceuticals, Inc. Compositions containing silymarin and sulfoalkyl ether cyclodextrin and methods of using the same
US11382944B2 (en) 2015-03-19 2022-07-12 Cydex Pharmaceuticals, Inc. Compositions containing silymarin and sulfoalkyl ether cyclodextrin and methods of using the same
CN105106161A (en) * 2015-09-11 2015-12-02 苏州东瑞制药有限公司 Levamlodipine besylate tablet and preparing technology thereof
CN105832680B (en) * 2016-05-12 2018-12-25 沈阳药科大学 A kind of pharmaceutical composition improving spirolactone In Vitro Dissolution and mobility
CN105832680A (en) * 2016-05-12 2016-08-10 沈阳药科大学 Pharmaceutical composition for improving in-vitro dissolution and liquidity of spironolactone
CN106309373A (en) * 2016-09-21 2017-01-11 沈阳药科大学 Probucol solid dispersion and preparation method thereof
CN107751576A (en) * 2017-11-13 2018-03-06 厦门大学 A kind of B B-complex liquid and preparation method thereof
RU2692772C2 (en) * 2017-11-15 2019-06-27 Общество с ограниченной ответственностью "Технофарм" Composition and method for preparing rapidly soluble antifungal drug based on nitrofural
CN108379229A (en) * 2018-04-05 2018-08-10 孙金霞 A kind of anti-inflammatory Claritin solid dispersion composition and preparation method thereof
CN109044967A (en) * 2018-10-17 2018-12-21 南京远航生物科技有限公司 A kind of Teniposide injection solution and preparation method thereof that dilution stability is good
JP2022505200A (en) * 2018-10-17 2022-01-14 江▲蘇▼▲領▼航生物科技有限公司 Teniposide injection solution with excellent dilution stability and its preparation method
WO2020077564A1 (en) * 2018-10-17 2020-04-23 南京远航生物科技有限公司 Teniposide injection solution having good dilution stability and preparation method therefor
JP7267640B2 (en) 2018-10-17 2023-05-02 江▲蘇▼▲領▼航生物科技有限公司 Teniposide injection solution with excellent dilution stability and its preparation method
RU2712123C1 (en) * 2018-12-14 2020-01-27 Общество с ограниченной ответственностью "Технофарм" Composition and method for preparing a rapidly soluble antimicrobial drug based on nitrofural (versions)
CN109864971A (en) * 2019-04-08 2019-06-11 西安远大德天药业股份有限公司 A kind of granule and preparation method thereof of Lamotrigine solid dispersions
CN109864971B (en) * 2019-04-08 2021-12-17 西安远大德天药业股份有限公司 Granules of lamotrigine solid dispersion and preparation method thereof
CN110652496A (en) * 2019-11-11 2020-01-07 中山大学 Solid dispersion of cryptotanshinone and preparation method and application thereof
CN111529497A (en) * 2020-02-11 2020-08-14 兆科（广州）肿瘤药物有限公司 Gemastecan drug solid dispersion composition and preparation method thereof
CN114831951A (en) * 2022-04-25 2022-08-02 扬子江药业集团广州海瑞药业有限公司 Ezetimibe tablets and preparation method thereof
CN114831951B (en) * 2022-04-25 2023-10-03 扬子江药业集团广州海瑞药业有限公司 Ezetimibe tablet and preparation method thereof
CN116159034A (en) * 2023-04-23 2023-05-26 国药集团川抗制药有限公司 Tacrolimus sustained-release capsule and preparation method thereof

Also Published As

Publication number Publication date
KR20030041577A (en) 2003-05-27
AU2002366042A1 (en) 2003-06-10

Similar Documents

Publication Publication Date Title
WO2003043602A1 (en) Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations
Vimalson Techniques to enhance solubility of hydrophobic drugs: an overview
Leuner et al. Improving drug solubility for oral delivery using solid dispersions
JP3310299B2 (en) Solid mixtures of cyclodextrins prepared by melt-extrusion
JP4334869B2 (en) Compositions with improved solubility or oral absorption
JPS63162627A (en) Sustained release medicinal pharmaceutical
JP6522853B2 (en) SOMCL-9112 solid dispersion, method for producing the same, and SOMCL-9112 solid preparation containing the same
CN107375945B (en) Donepezil cyclodextrin inclusion compound and oral instant film agent containing same
JP5731723B2 (en) Melt extrusion composition comprising cellulose ether
TW201639580A (en) Complexes of Abiraterone acetate, process for the preparation thereof and pharmaceutical compositions containing them
WO2012116238A1 (en) PHARMACEUTICAL FORMULATIONS OF ACETYL-11-KETO-β-BOSWELLIC ACID, DIINDOLYLMETHANE, AND CURCUMIN FOR PHARMACEUTICAL APPLICATIONS
RU2736245C2 (en) High-bioaccess oromucosal pharmaceuticals based on cyclodextrin and sucralose
TW201540303A (en) Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them
JP6666352B2 (en) Dutasteride-containing solid dispersion and composition containing the same
Varandal et al. Different approaches toward the enhancement of drug solubility: A review
Tran et al. Solubilization of poorly water-soluble drugs using solid dispersions
JP6050031B2 (en) Film formulation
Aldawsari et al. Combined use of cyclodextrins and hydroxypropylmethylcellulose stearoxy ether (Sangelose®) for the preparation of orally disintegrating tablets of type-2 antidiabetes agent glimepiride
CN114377147A (en) Alvatripopa clathrate compound, composition and preparation method thereof
Kumar et al. Solid dispersions: An approach to enhance solubility of poorly soluble drugs
JP6391730B2 (en) Wafer and capsule formulation with enhanced dissolution rate for fenofibrate
Saritha et al. Preparation and evaluation of solid dispersions of Ofloxacin
Chhater et al. Solid dispersion incorporated microcapsules: predictive tools for improve the half life and dissolution rate of pioglitazone hydrochloride
KR100438485B1 (en) Pharmaceutical compositions containing of azole antifungal drugs
Jiang et al. Cosolvent and Complexation Systems

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP