WO2018228441A1 - Composition pharmaceutique à libération contrôlée et son procédé de préparation - Google Patents

Composition pharmaceutique à libération contrôlée et son procédé de préparation Download PDF

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Publication number
WO2018228441A1
WO2018228441A1 PCT/CN2018/091103 CN2018091103W WO2018228441A1 WO 2018228441 A1 WO2018228441 A1 WO 2018228441A1 CN 2018091103 W CN2018091103 W CN 2018091103W WO 2018228441 A1 WO2018228441 A1 WO 2018228441A1
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Prior art keywords
hydrochloride
controlled release
pharmaceutical composition
composition according
release pharmaceutical
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English (en)
Chinese (zh)
Inventor
王捷
王立坤
顾国祥
张凤娥
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to CN201880008336.9A priority Critical patent/CN110214007A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention relates to a controlled release pharmaceutical composition, belonging to the field of pharmacy.
  • a controlled release formulation such as the cardro-dualopa modified release formulation disclosed in CN101910113A.
  • the oral gastric retention preparation prolongs the residence time of the drug at the upper end of the gastrointestinal tract, and even if the drug is poorly absorbed at the rear end of the intestinal tract, the drug can be effectively released and absorbed after 6 hours of administration.
  • the dosing interval and dose increase patient compliance.
  • the gastric floating preparation is one of the ways of gastric retention, which increases the residence time of the preparation in the stomach.
  • CN103037850A discloses a type of elongated intragastric retention capsule, which has been shown to prolong gastric retention time, however, such a design There is a risk of gastric obstruction or permanent retention of the system, so its actual value is small.
  • a large number of drugs have been made into a gastric floating drug delivery system combining immediate release and controlled release, but most of them are double-layer tablets or capsules.
  • Yin Lifang et al. disclose a gastric floating system.
  • the bilayer tablet has active ingredients of pioglitazone and metformin, wherein the immediate release component is pioglitazone and the controlled release component is metformin.
  • the bilayer tablet is obtained by adding sodium carbonate which can generate carbon dioxide and a low density floating aid stearyl alcohol. The effect of floating is achieved, with the most preferred formulation being able to float in the test solvent for at least 24 h (International Journal of Pharmaceutics 476 (2014) 223-231).
  • single tablets have various disadvantages such as poor floating ability, long drift time, and large individual differences.
  • Indian Patent Application No. 200900/00792 A discloses a dual particle intragastric delivery system comprising immediate release particles of ofloxacin and gastric floating controlled release particles, wherein the controlled release particles comprise a hydrophobic material and a hydrophilic material.
  • Hot melt extrusion is the process of pumping raw materials through a mold through a mold at a high temperature to a uniform shape product.
  • HME has many advantages over other drug treatment techniques in that the molten polymer can be used as a thermal adhesive during extrusion and as a drug depot and/or drug release blocker upon cooling and solidification. Since the process does not require solvent and water, the number of processing steps is reduced and the time consuming drying step is eliminated.
  • the matrix material can be assembled into larger units that are independent of the compression characteristics. The intense mixing and agitation exerted by the rotating screw causes the agglomeration of suspended particles in the molten polymer to make the dispersion more uniform.
  • Nakamichi et al. disclose a floating preparation of nicardipine hydrochloride prepared by a twin-screw extruder, which is hot melt extruded.
  • the polymer material was hydroxypropylmethylcellulose acetate succinate (HPMCAS). It was found that only the use of drugs and polymers did not result in a loose extrudate, and the third intermediate substance, dihydrate phosphoric acid, must be added. Calcium, when the amount of calcium phosphate dihydrate is 8%, floats in gastric juice for 6 hours (International Journal of Pharmace-Utics 218 (2001) 103-112).
  • US2016113906A discloses a hot melt extruded composition which, by adding a polar organic solvent to a hot melt extruded composition, reduces the decomposition of the active ingredient and increases the miscibility between the active ingredient and the polymer. Reduces the operating temperature and temperature of the hot melt extrusion and reduces the torque.
  • Nakamichi et al. examined the effect of moisture on solid dispersions prepared by twin-screw hot melt extruders. The results of the tests demonstrate that the addition of water reduces the flow temperature (Tfb) of the material, demonstrating that the material can be at temperatures below the melting point. Extrusion (International Journal of Pharmaceutics 241 (2002) 203-211).
  • Padma V. Devarajan et al. disclose a gastric floating controlled release multiparticulate formulation of metoprolol succinate prepared by hot melt extrusion to optimize the hot melt extruded material Eudragit RSPO The ratio between polyoxyethylene (PEO) and hydroxypropylmethylcellulose (HPMC) is used to balance the floating capacity and the controlled release ability, and the production of gas uses sodium carbonate (International Journal of Pharmaceutics 491 (2015) 345-351).
  • PEO polyoxyethylene
  • HPMC hydroxypropylmethylcellulose
  • Mamoru Fukuda et al. disclose a gastric retention floating sheet prepared by hot melt extrusion using Eudragit RSPO ( RS PO) and or Eudragit EPO ( E PO.) Matrix material, the effect of sodium carbonate on the physicochemical properties of the composition was examined (Journal of Controlled Release 115 (2006) 121-129).
  • the invention provides a controlled release pharmaceutical composition prepared by hot melt extrusion, which effectively prolongs the residence time in the gastrointestinal tract and increases the effective absorption time of the gastrointestinal tract to more than 10 hours, thereby effectively reducing the dosage. The number of times increases the compliance of patients taking medication.
  • the present invention provides a controlled release pharmaceutical composition
  • a controlled release pharmaceutical composition comprising: a) an immediate release component comprising an active drug, b) a delayed release floating component comprising an active drug, characterized in that said delayed release floating component is passed through a heat fusion The extrusion process is prepared.
  • the controlled release pharmaceutical composition of the present invention is characterized in that the delayed release floating component contains at least one enteric polymer.
  • the delayed release drug component containing the enteric polymer of the present invention releases the drug at a pH of ⁇ 5.5.
  • the controlled release pharmaceutical composition provided by the present invention is characterized in that the enteric polymer is selected from the group consisting of polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, and 1,2,4-benzenetricarboxylic acid acetic acid.
  • the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer corresponding to commercially available Eudragit 100-55 or Kollicoat MAE 100P.
  • the methyl vinyl ether-maleic anhydride copolymer is commercially available. series.
  • the methacrylic acid-methyl methacrylate copolymer is a 1:1 or 1:2 copolymer corresponding to Eudragit L100 and Eudragit S100, respectively.
  • the mixture of polyvinyl acetate and polyvinylpyrrolidone K30 is Kollidon SR.
  • the enteric polymer described herein is an Eudragit polymer, such as Eudragit L, Eudragit S or Eudragit L 100-55.
  • the enteric polymer described in the present invention is hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate succinate disclosed in the prior art US 4,266,981 B, CN 104208713 A, and CN 103153343 A. Cellulose is included within the scope of this application.
  • HPMCAS sold by Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan) is classified into three grades having different combinations of substituent levels to provide enteric protection at various pH levels.
  • AS-LF and AS-LG grades (“F” means fine and "G” means granules) provide enteric protection at a pH of up to 5.5.
  • the AS-MF and AS-MG grades provide enteric protection at pH values up to 6.0, while the AS-HF and AS-HG grades provide enteric protection at pHs up to 6.8.
  • the controlled release pharmaceutical composition provided by the present invention is characterized in that the ratio of the active drug to the enteric polymer in the delayed release floating component is selected from 1:0.1 to 1:100, preferably from 1:0.1 to 1:50, more preferably 1: 1-1:25.
  • the controlled release pharmaceutical composition provided by the present invention wherein the hot melt extrusion method optionally participates in a hot melt extrusion process, that is, in some embodiments, a solvent is added, and in other embodiments, a solvent is not added, in the present invention
  • a solvent is added, and in other embodiments, a solvent is not added, in the present invention
  • the participation of the solvent means that the solvent is added before the hot melt extrusion or during the hot melt extrusion process for the needs of the invention.
  • the solvent only needs to be able to be volatilized after the end of the hot melt extrusion process.
  • the present invention limits the boiling point of the solvent to 30. -110 ° C.
  • the controlled release pharmaceutical composition provided by the present invention is characterized in that the solvent is at least selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran.
  • the solvent is at least selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran.
  • One is preferably water and ethanol.
  • the present invention provides a controlled release pharmaceutical composition having a density of delayed release floating components in a controlled release pharmaceutical composition of from 0.1 to 1.0 g/cm3, preferably from 0.2 to 0.8 g/cm3, when a solvent is involved in the hot melt extrusion process. Most preferably, it is 0.3-0.7 g/cm3, which is porous under electron microscopy, and can be floated immediately in a solution of FaSSGF at pH 5.0 and maintained for a float time of more than 24 h.
  • the controlled release pharmaceutical composition provided by the present invention contains an alkaline substance which is exposed to an acid generating gas in the preparation process without adding a solvent, that is, the alkaline substance in the controlled release pharmaceutical composition of the present invention is not essential, and when the alkaline substance is contained
  • the basic substance is specifically an alkali metal carbonate, an alkali metal or an alkaline earth metal hydrogencarbonate, more specifically sodium hydrogencarbonate, sodium carbonate, sodium aminoacetate carbonate, potassium hydrogencarbonate, magnesium carbonate and calcium carbonate.
  • the controlled release pharmaceutical composition provided by the present invention does not contain calcium phosphate dihydrate, Nakamichi (International Journal of Pharmace-Utics 218 (2001) 103-112), and others add calcium phosphate dihydrate to the drug and the matrix, and by hot melt extrusion After that, a floatant was prepared.
  • the controlled release pharmaceutical composition provided by the present invention is less than 30%, more preferably less than 20% Most preferably less than 10%.
  • the controlled release pharmaceutical composition of the present invention is characterized in that the delayed release floating component is in a multi-unit form.
  • the controlled release pharmaceutical composition of the present invention is characterized in that the multi unit form is a microtablet, a pellet, a pellet, preferably a pellet.
  • the immediate release component of the controlled release pharmaceutical composition provided by the invention may be selected from the form of pellets, microtablets, granules and the like. Specifically, when the immediate release component is a pellet, the active drug and the blank pellet core may be contained. .
  • sustained-release preparation In general, pharmaceutical preparations reach the colon in most cases after oral administration in 3 to 6 hours. Therefore, the success of the sustained-release preparation is to increase the time of gastrointestinal absorption and increase absorption.
  • the Biopharmaceutical Classification System introduced by the FDA has classified drugs according to their solubility and intestinal permeability, see "The Biopharmaceutics Classification System (BCS) Guidance”. Jennifer B. Dressman and Christos Reppas, on page 273 of the Oral Drug Absorption: Prediction and Assessment, mention that drugs that have high solubility and permeability when administered orally (Class I) generally have good absorption throughout the gastrointestinal tract. It is the most preferred drug for the sustained release preparation, and such a drug is included in the range of the active drug of the delayed release floating component of the present invention.
  • Class I drugs in the BCS classification of the present invention include, but are not limited to, pabitatin, Cobimetinib, Patiromer, omarigliptin, bupropion, guanfacine, venlafaxine hydrochloride, methylphenidate hydrochloride, Tetrazolamide, flurbanin, eliglustat, alogliptin, dimethyl fumarate, pyrenoprene, lometanide, rosobinib, clozaban, dalfampridine, Prolia, drone Dalong hydrochloride, Pralatrexate, lacosamide, fesoterodine fumarate, alprazolam, amitriptyline hydrochloride, amlodipine besylate, benazepril, amoxicillin, anastrozole, azastroz Ting, bisoprolol, buspirone, caffeine, carbidopa, cetirizine, chloroquine
  • the composition of the present invention effectively uses the enteric polymerization to effectively prolong the residence time of the drug in the gastrointestinal tract due to the use of hot melt extrusion technology and gastric floating technology, especially the use of enteric polymerization.
  • the absorption rate of the drug in the small intestine shows a better effect for the drug of this kind.
  • the BCS classification of the present invention belongs to the class II to IV drugs including, but not limited to, febuxostat, ixazomib, Alectinib, Erismodegib, vandetanib, aprepitant, worapsar sulfate, aspirin, metformin, Engliflozin, linagliptin, naltrexone, dasabuvir, sofosbuvir, amphetamine, etravirine, everolimus, itraconazole, vemurafenib, telaprevir , tacrolimus, posaconazole, isikato, redipavir, Suvorexant, Ombitasvir, paritaprevir, daclatasvir, cariprazine, brexpiprazole, omemiprofen, levetiracetam, ivacaftor, eluxadoline , lumacaftor, ivacaftor
  • the controlled release pharmaceutical composition provided by the present invention is characterized in that the delayed release floating component further comprises at least one plasticizer selected from the group consisting of triethyl citrate and tributyl citrate. , polyethylene glycol, triethyl phthalate, tributyl phthalate, dibutyl sebacate, diethyl sebacate, glyceryl stearate, diethyl succinate, propylene glycol , castor oil and triacetin, preferably triethyl citrate, the plasticizer is present in an amount of from 0.01% to 50%, preferably from 0.1% to 30%, most preferably from 2.5% to 15% (% by mass, by solids) The total mass of the components is calculated as 100).
  • the plasticizer is present in an amount of from 0.01% to 50%, preferably from 0.1% to 30%, most preferably from 2.5% to 15% (% by mass, by solids) The total mass of the components is calculated as 100).
  • the immediate release component and/or the controlled release floating component of the controlled release pharmaceutical composition provided herein further comprises at least one pharmaceutically acceptable additional excipient, a pharmaceutically acceptable excipient
  • additional excipient include, but are not limited to, fillers, lubricants, glidants, binders, disintegrants.
  • excipients are conventionally incorporated into solid dosage forms to facilitate ease of handling and to improve the performance of the dosage form.
  • Common excipients include diluents or fillers, lubricants, glidants, binders, disintegrants, and the like. Wherein a diluent or filler is added to increase the weight of the individual dose to a size suitable for tablet compression.
  • Suitable diluents include powdered sugar, calcium phosphate, calcium sulfate, microcrystalline cellulose, lactose, mannitol, kaolin, sodium chloride, dried starch, sorbitol, and the like.
  • the lubricant reduces the friction between the particles and the mold wall during compression and discharge. This prevents the particles from adhering to the tablet punches, facilitating their discharge from the tablet press, and the like.
  • suitable lubricants include, but are not limited to, talc, stearic acid, vegetable oils, calcium stearate, zinc stearate, magnesium stearate, and the like.
  • Glidants are used to improve the flow characteristics of the particles.
  • suitable glidants include, but are not limited to, silica, corn starch, micronized silica gel, talc, polyethylene glycol.
  • a binder is usually used, and examples of suitable binders include, but are not limited to, pyrrolidone, polyvinylpyrrolidone, xanthan gum, cellulose gum such as carboxymethylcellulose, methyl Cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy cellulose, gelatin, starch and pregelatinized starch.
  • the disintegrant refers to a substance which can rapidly break up a tablet into fine particles in a gastrointestinal fluid, so that the functional component dissolves and absorbs rapidly, and functions.
  • the disintegrants described in the present invention include, but are not limited to, one or more of low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.
  • compositions provided herein include, but are not limited to, preservatives, antioxidants, or any other excipients commonly used in the pharmaceutical industry, and the like.
  • compositions provided by the present invention are ultimately presented in a pharmaceutically acceptable form for administration to a patient, optionally as a tablet or capsule.
  • the recommended mode of administration of the controlled release compositions of the present invention is after meals.
  • the controlled release pharmaceutical composition of the present invention is characterized in that the active drug in the delayed release floating composition optionally remains in a crystalline state or is converted to an amorphous state after the hot melt extrusion process.
  • compositions of the present invention may include more than one drug, ie, The immediate release component is the same as or different from the drug in the delayed release release component.
  • the present invention also provides a method of preparing the above controlled release drug combination.
  • the method for preparing a controlled release pharmaceutical composition comprises the steps of: 1) premixing at least one solvent, an active ingredient in a delayed release floating component, and at least one enteric polymer before hot melt extrusion.
  • at least one solvent, the active ingredient in the delayed release floating component and the at least one enteric polymer are mixed in advance to obtain a premixed crude product; 2) the premixed crude product passes through the heating screw zone of the extruder. After the die exits the extrudate.
  • the preparation method provided by the present invention is characterized in that the solvent only needs to satisfy the fact that it can be volatilized after the end of the hot melt extrusion process.
  • the present invention limits the boiling point of the solvent to 30-110 °C.
  • the preparation method provided by the present invention is characterized in that the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, pentane, hexane, heptane, cyclohexane, dichloromethane, tetrahydrofuran, preferably water, ethanol. , isopropanol.
  • the solvent is used in an amount of from 0.1% to 70%, preferably from 1% to 50%, most preferably from 10% to 30% by mass based on the total mass of the solid component of 100.
  • the temperature of the heated zone at the front end of the die should be greater than the glass transition temperature (Tg) of the extruded mixture.
  • the preparation method provided by the present invention is characterized in that the die temperature is from 70 to 200 ° C, preferably from 90 to 180 ° C, more preferably from 110 to 160 ° C.
  • the preparation method provided by the present invention is characterized in that the solvent injection screw zone temperature is 10-90 °C.
  • the esters including lactones
  • amides including lactones
  • the preparation method provided by the present invention is characterized by further comprising the steps of: 1) cooling the extrudate, 2) removing the extrudate from the solvent; 3) cutting the extrudate.
  • the solvent having a low boiling point and being relatively volatile may be substantially volatilized during extrusion according to the nature of the solvent itself and the temperature of the die, and the solvent having a low boiling point and being volatile is included, but not limited to, ethanol.
  • Substantially volatilized as used herein means that the residual amount of solvent in the extrudate is less than 15%, preferably less than 12%, and most preferably less than 10%.
  • the method provided by the present invention when a solvent having a higher boiling point is selected, may be followed by a step of desolvating the extrudate after the end of hot melt extrusion.
  • the solvent in the extrudate is removed under elevated temperature and/or vacuum conditions.
  • the elevated temperature is sufficient to convert the solvent from a liquid to a gaseous state.
  • the solvent in the extrudate is removed under reduced pressure conditions.
  • the method of preparation provided by the present invention further comprises the step of cooling the extrudate.
  • the present invention provides a method of preparing a controlled release floating component in a controlled release pharmaceutical composition, characterized by further comprising the step of cutting the extrudate.
  • the preparation method of the immediate release portion of the present invention includes wet granulation, dry granulation, powder direct pressing and the like.
  • the preparation method provided by the present invention is characterized in that the extruder is selected from the group consisting of a single screw hot melt extruder, an intermeshing screw extruder, a twin screw hot melt extruder, preferably a twin screw hot melt extruder.
  • delayed release refers to a type of improved release wherein the pharmaceutical dosage form exhibits a time delay between oral administration of the pharmaceutical dosage form and release of the drug from the dosage form.
  • the delayed release release dosage form will have little or no release of the active compound for a predetermined period of time or until predetermined conditions are met, such as exposure to a certain pH level, and then the release of the active compound occurs immediately thereafter.
  • controlled release in the context of the invention refers to a type of extended release formulation wherein the gradual release of the drug is controlled or manipulated for an extended period of time.
  • Figure 23 Powder diffraction pattern of hydrochlorothiazide before and after extrusion of Example 20.
  • HPMCAS used in the examples of the present invention was purchased from Shin-Etsu Chemical Co., Ltd., and the hot melt extruder was Thermo Fisher's twin-screw hot melt extrusion instrument.
  • the single capsule comprises an immediate release component and a delayed release floating component
  • the immediate release component is a microtablet containing 8 mg of febuxostat active ingredient
  • the delayed release floating component is a particulate A containing 32 mg of febuxostat active ingredient, granules A is released above pH 6.
  • the immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1 below.
  • the specific preparation process wet granulation mechanism granules, mixing raw materials and auxiliary materials, adding binder, stirring, 1500 rpm cutting, sieving, drying, to moisture ⁇ 3%, passing through 30 mesh sieve, and then using Chuangbo C&C600B single Stamping machine, 4.76mm punch press. Tablet weight: theory 61.5mg, the actual control is 59-65mg, the hardness is about 30N.
  • the febuxostat bleaching granule A was prepared by a hot melt extrusion process, the formulation of which is listed in Table 2 below.
  • the febuxostat and HPMCAS MG were weighed and mixed uniformly in a blender, and the hot melt extruder (Simofly) was set as shown in Table 3.
  • the speed is 700 ul/min
  • Zone 2 feeding the speed is 4 g/min
  • the rotation speed of the screw is set to 100 rpm
  • the extrudate is cut into segments, and then the extrudate is oven-dried at 60 ° C for 2 h.
  • the ethanol content is less than 0.5%, and is pulverized to 2 mm after drying.
  • a single capsule contains an immediate release component and a delayed release floating component
  • the immediate release component is a pellet containing 8 mg of febuxostat active ingredient
  • the remainder of the capsule contains a delayed release of febuxostat containing 32 mg of febuxostat.
  • Floating particles B this delayed release of floating enteric particles B is rapidly released above pH 6.
  • the immediate release febuxostat pellets were prepared by a blank pellet core drug preparation process, and the prescription composition is shown in Table 4.
  • the febuxostat controlled release floating granules B were prepared by a hot melt extrusion process, and the formulation composition thereof is shown in Table 5.
  • febuxostat 150 g of febuxostat and 90 g of HPMCAS MG and 360 g of hydroxypropylmethylcellulose were weighed and mixed uniformly in a blender.
  • the temperature setting of the hot melt extruder was as shown in Table 3.
  • the ethanol was added to the Zone 4 of the hot melt extruder at a speed of 700 ul/min, the Zone 2 was fed at a speed of 4 g/min, and the rotation speed of the screw was set to 100 rpm. After cutting into sections, the extrudate was oven-dried at 60 ° C for 2 h, and the ethanol content was ⁇ 0.5%. After drying, it is pulverized to 4 mm, and the controlled release granule B of febuxostat is obtained.
  • the single capsule comprises an immediate release component and a controlled release floating component
  • the immediate release component is a microtablet containing 8 mg of febuxostat
  • the remainder of the capsule comprises a total of 32 mg of febuxostat gastric floating particles C, the gastric floating particles C is released above pH 5.
  • the immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1 above.
  • the febuxostat controlled release floating granule C was prepared by a hot melt extrusion process, and its prescription composition is shown in Table 6.
  • hot melt extrusion was carried out, and the temperature parameter setting was the same as that of the preparation of the pellet A.
  • the hot melt extruder's Zone4 was added with ethanol at a speed of 600 ul/min, Zone 2 was fed at a speed of 2 g/min, the screw speed was 60 rpm, the extrudate was cut into segments, and the extrudate was oven dried at 60 ° C for 2 h.
  • the ethanol content is ⁇ 0.5%, and after pulverization, it is pulverized to 4 mm long particles, and the febuxostat floating particles C are obtained.
  • Example 4 is a febuxostat formulation consisting of 40% immediate release febuxostat microtablets and 60% febuxostat floating particles C which release the drug above pH 5
  • the single capsule contains an immediate release component and a controlled release floating component
  • the immediate release component is a microchip containing 16 mg of febuxostat
  • the remainder of the capsule contains a total of 24 mg of febuxostat delayed release floating particle C, which is delayed release.
  • the floating controlled release granule C is released above pH 5.
  • the immediate release febuxostat microchip was prepared by a wet granulation process, the formulation of which is listed in Table 1 above, and the febuxostat controlled release floating granule C was the same as in Example 3.
  • Example 5 a febuxostat formulation consisting of immediate release febuxostat pellets and delayed release febuxostat floating particles D 5
  • a single capsule contains an immediate release component and a controlled release floating component.
  • the immediate release component is a pellet containing 8 mg of febuxostat active ingredient, and the remainder of the capsule contains a delay of 32 mg of febuxostat containing 32 mg of febuxostat.
  • the floating particles D are released, and the gastric floating delayed release particles D are slowly released while floating in the gastric juice.
  • the immediate release febuxostat pellets were prepared by a blank pellet core drug preparation process, and the prescription compositions are listed in Table 4 above.
  • the febuxostat gastric floating controlled release granule D was prepared by a hot melt extrusion process, and the composition of the formulation is shown in Table 7.
  • the febuxostat After blending the febuxostat with the quaternary amino methacrylate copolymer type B and hypromellose, it was sheared in a wet granulator while slowly adding triethyl citrate dropwise.
  • the mixed materials were hot melt extruded, the temperature parameters were set as in Table 3, ethanol was added in Zone 4, the speed was 1000 ul/min, Zone 2 was fed, the speed was 4 g/min, the screw speed was set to 100 rpm, and the extrusion was performed.
  • the material was cut into sections, and then the extrudate was oven-dried at 60 ° C for 2 h, and the ethanol content was ⁇ 0.5%. After drying, it is pulverized to 4 mm long granules, and the controlled release granule D of febuxostat is obtained.
  • Example 6 is a non-busestat formulation consisting of an immediate release febuxostat microparticle and a delayed release of febuxostat floating particle E 6
  • the single capsule contains an immediate release component and a controlled release floating component.
  • the immediate release component is a microtablet containing 8 mg of febuxostat.
  • the remainder of the capsule contains a total of 32 mg of febuxostat delayed release floating particles E, which floats on the stomach.
  • the controlled release granule E is slowly released while floating in the gastric juice.
  • the immediate release febuxostat microchips were prepared by a wet granulation process, and the formulation of the compositions is shown in Table 1.
  • the febuxostat gastric floating delayed release granule E was prepared by a hot melt extrusion process, and its prescription composition is shown in Table 8.
  • the febuxostat was mixed with other excipients in a prescribed amount and then subjected to hot melt extrusion.
  • the temperature parameters were set as shown in Table 3.
  • the content is ⁇ 0.5%, pulverized to 4 mm long particles, and the obtained bupretaxer gastric floating controlled release granule E is obtained.
  • Example 7 is a non-busestat formulation consisting of an immediate release febuxostat microparticle and a controlled release febuxostat floating particle F
  • the single capsule contains the immediate release component and the controlled release floating component, and the immediate release component is a microchip containing 8 mg of febuxostat.
  • the remainder of the capsule contains a total of 32 mg of febuxostat floating particles F, which is controlled by the stomach.
  • the release granule E is slowly released while floating in the gastric juice.
  • the immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is listed in Table 1.
  • the febuxostat gastric floating controlled release granule F was prepared by a hot melt extrusion process, and its formulation composition is shown in Table 9.
  • the febuxostat was mixed with other excipients in a prescribed amount and then subjected to hot melt extrusion.
  • the temperature parameters were set as shown in Table 3.
  • the content is ⁇ 0.5%, and after pulverization, it is pulverized to 4 mm long particles, and the controlled release granule F of febuxostat is obtained.
  • Example 8 is a febuxostat formulation consisting of an immediate release febuxostat microplatelet and a febuxostat floating particle G which releases the drug above pH 5.5.
  • the single capsule comprises an immediate release component and a delayed release floating component
  • the immediate release component is a microtablet containing 8 mg of febuxostat active ingredient
  • the delayed release floating component is a particulate G containing 32 mg of febuxostat active ingredient, granules A is released above pH 5.5.
  • the immediate release febuxostat microtablets were prepared by a wet granulation process, the formulation of which is shown in Table 1, and the formulation of febuxostat delayed release floating granules G is shown in Table 10.
  • Table 11 The hot melt extrusion and temperature settings are shown in Table 11.
  • Zone4 is added with water, the feeding speed is 5g/min, the watering speed is 0.9ml/min, the screw rotation speed is set to 100rpm, the extrudate is cut into segments, and the extrudate is dried in an oven at 60°C for 2 hours. Moisture ⁇ 3%, pulverized to 2 mm after drying, test density was 0.5 g/cm 3 , and the obtained febuxostat granule G and the febuxostat microderage obtained in Example 1 were filled into capsules to obtain febuxostat preparation. 8.
  • Example 12 The human pharmacokinetic study was carried out together with the preparations obtained in Example 3 and Example 4 using a commercially available 40 mg-sized febuxostat as a reference preparation, and the results of the study are shown in Table 12 below.
  • T max maximum blood concentration time
  • AUC 0 ⁇ drug time curve area
  • Example 3 and Example 4 can reduce the maximum peak concentration of the drug compared with the commercially available febuxostat reference preparation, greatly prolong the duration of action, and exert controlled release of the drug.
  • pH5.0FaSSGF 300mL of pH5.0FaSSGF was used as the dissolution medium to observe the floating condition of the gastric floating particles under simulated gastric fluid. After observation, all the particles immediately floated and floated for a long time. After 24 hours, the particles remained floating and stopped. Observed.
  • the rate of dissolution can indicate the rate at which the drug is released from the formulation in the gastrointestinal environment, and the lower rate of release response is a lower Cmax and longer release time on the pharmacokinetic data.
  • the dissolution rate of the preparation prepared in the present invention is remarkably lowered, and it can be inferred that the preparations of the present invention (Examples 1 to 7) can achieve a lower Cmax value than the immediate release tablets.
  • the traits of the particle G were observed by scanning electron microscopy, and it was found that the particle G was porous under the electron microscope, as shown in Fig. 5.
  • the powder diffraction pattern for the crystalline state of the febuxostat and the non-busestat after extrusion, as shown in Fig. 6, is maintained in a crystalline state after hot melt extrusion.
  • hydrochlorothiazide and HPMC AS LG were uniformly mixed and subjected to hot melt extrusion, and the temperature parameters were set as shown in Table 13 (° C.).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.
  • Hydrochlorothiazide and HPMCP were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 14 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 500 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The sample is extruded smoothly and can be quickly floated.
  • hydrochlorothiazide starting material and the crystal form test powder diffraction pattern of the hydrochlorothiazide after extrusion in Example 11 hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 9; the dissolution profile of the formulation of Example 11 is shown in FIG. Shown.
  • Nifedipine and HPMC AS LG were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 15 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 1200 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The sample is extruded smoothly and can be quickly floated.
  • the tadalafil and HPMC AS LG were mixed uniformly for hot melt extrusion, and the temperature parameters were set as shown in Table 16 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 900 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.
  • Example 13 The powder diffraction pattern of the tadalafil raw material and the crystalline state of the tadalafil after extrusion in Example 13 was maintained, and the tadalafil remained in a crystalline state after hot melt extrusion, as shown in FIG. 13;
  • the dissolution profile of the formulation of Example 13 is shown in FIG.
  • the losartan and HPMC AS LG were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 17 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 600 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the sample is expanded, and it can be quickly floated.
  • the powder diffraction pattern of the losartan raw material and the crystalline state of losartan after extrusion in Example 14 was maintained, and the losartan remained in a crystalline state after hot melt extrusion, as shown in FIG. 15;
  • the dissolution profile is shown in Figure 16.
  • the dexamethasone and HPMC AS LG were mixed uniformly and hot melt extruded.
  • the temperature parameters were set as shown in Table 18 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the sample is expanded, and it can be quickly floated.
  • the dexamethasone and HPMCP were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 19 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water addition speed is 400 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the surface of the sample expands, and the bubbles rupture on the surface, but can quickly float.
  • Zone4 is added with water, the screw rotation speed is set to 50 rpm, the water adding speed is 600 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • Phenomenon The extrusion is smooth, the sample is expanded, and it can be quickly floated.
  • the febuxostat and HPMCP were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 21 (°C).
  • Zone4 is added with water, the screw rotation speed is set to 100 rpm, the water adding speed is 700-900 ul/min, the extrudate is oven-dried at 60 ° C for 2 h, the water content is ⁇ 3%, and the pulverization is 2 mm after drying.
  • the sample can expand and the sample can float.
  • Hydrochlorothiazide and HPMC AS LG were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 22 (°C).
  • Zone2 feeding Zone2 plus ethanol
  • the screw rotation speed was set to 60 rpm
  • the ethanol speed was 700 ul/min
  • the extrudate was oven-dried at 60 ° C for 2 h
  • the moisture was ⁇ 3%
  • the pulverization was 2 mm after drying.
  • Phenomenon The extrusion is smooth, the process is stable, the sample is expanded, and it can be quickly floated.
  • hydrochlorothiazide starting material and the crystal form test powder diffraction pattern of the hydrochlorothiazide after extrusion in Example 19 hydrochlorothiazide remained in a crystalline state after hot melt extrusion, as shown in FIG. 21; the dissolution profile of the formulation of Example 19 is shown in FIG. Shown.
  • hydrochlorothiazide and HPMCP were uniformly mixed and subjected to hot melt extrusion, and the temperature parameters were set as shown in Table 23 (° C.).
  • Zone2 feeding Zone2 plus ethanol
  • the screw rotation speed was set to 50 rpm
  • the ethanol speed was 700 ul/min
  • the extrudate was oven-dried at 60 ° C for 2 h
  • the moisture was ⁇ 3%
  • the pulverization was 2 mm after drying.
  • Phenomenon The sample is extruded smoothly and can be quickly floated.
  • the losartan and HPMC AS LG were mixed uniformly for hot melt extrusion, and the temperature parameters were set as shown in Table 24 (°C).
  • Zone2 feeding Zone2 plus ethanol
  • the screw rotation speed was set to 50 rpm
  • the ethanol speed was 700 ul/min
  • the extrudate was oven-dried at 60 ° C for 2 h
  • the moisture was ⁇ 3%
  • the pulverization was 2 mm after drying.
  • Phenomenon The sample is extruded smoothly and can be quickly floated.
  • the powder diffraction pattern of the losartan raw material and the crystal form state of losartan after extrusion in Example 21 was maintained, and the losartan remained in a crystalline state after hot melt extrusion, as shown in FIG. 25;
  • the dissolution profile is shown in Figure 26.
  • the febuxostat and HPMCP were uniformly mixed and hot melt extruded.
  • the temperature parameters were set as shown in Table 25 (°C).
  • the Zone2 feed, Zone4 plus ethanol, the screw rotation speed was set to 50 rpm, the ethanol speed was 700/min, the extrudate was oven-dried at 60 ° C for 2 h, the moisture was ⁇ 3%, and the pulverization was 2 mm after drying.
  • the sample can expand and the sample can float.

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Abstract

La présente demande concerne une composition pharmaceutique à libération contrôlée. Ladite composition pharmaceutique à libération contrôlée comprend : a) un composant à libération immédiate contenant un principe actif ; et b) un composant flottant à libération retardée contenant un principe actif, où le composant flottant à libération retardée est préparé par extrusion à chaud.
PCT/CN2018/091103 2017-06-14 2018-06-13 Composition pharmaceutique à libération contrôlée et son procédé de préparation Ceased WO2018228441A1 (fr)

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US20210275531A1 (en) * 2020-03-04 2021-09-09 VK Research Associates Inc Phosphodiesterase-5 inhibitor combinations, methods of making, and methods of use thereof
EP4023213A1 (fr) * 2020-12-29 2022-07-06 Sanovel Ilac Sanayi Ve Ticaret A.S. Compositions pharmaceutiques comprenant de l'alogliptine
CN116251069A (zh) * 2021-12-10 2023-06-13 山东新时代药业有限公司 一种酒石酸唑吡坦胃漂浮释放片及其制备方法
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CN116251069A (zh) * 2021-12-10 2023-06-13 山东新时代药业有限公司 一种酒石酸唑吡坦胃漂浮释放片及其制备方法
CN120698959A (zh) * 2025-05-29 2025-09-26 河北医科大学 一种达格列净-依折麦布共无定形物及其制备方法和应用

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