CN101330906A - HCV prodrug formulation - Google Patents
HCV prodrug formulation Download PDFInfo
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- CN101330906A CN101330906A CNA2006800474209A CN200680047420A CN101330906A CN 101330906 A CN101330906 A CN 101330906A CN A2006800474209 A CNA2006800474209 A CN A2006800474209A CN 200680047420 A CN200680047420 A CN 200680047420A CN 101330906 A CN101330906 A CN 101330906A
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Abstract
The present invention relates to a pharmaceutical composition comprising a solid suspension prepared by hot melt extrusion of isobutyric acid (2R,3S,4R,5R)-5-(4-amino- 2-oxo-2H-pyrimidin-1-yl)-2-azido-3,4-bis-iso-butyryloxy-tetrahydro-furan-2-ylmethyl ester; hydrochloride salt (I) and a polyethylene glycol (PEG)/polypropylene glycol (PPG) block copolymer.
Description
The present invention relates to contain as 4 ' of active component-'-azido cytidine-2 ' novel formulation of 3 ', 5 '-three-isobutyrate hydrochlorate (I) and the method for preparing said preparation.Said composition can be used for treating hepatitis C virus (HCV).
Nucleoside derivates is potent antiviral agent (for example anti-HIV, HCV, herpes simplex, CMV) and anticancer chemotherapy agent normally.It's a pity that their effect is subjected to two kinds of effects limit usually.At first, relatively poor pharmacokinetic property has usually limited the absorption of nucleoside from intestinal and the IC of nucleoside derivates, and secondly, inferior good physical property has limited the preparation that can be used to promote active component to transmit and selected.
Prodrug (people such as P.Ettmayer, J.Med Chem.200447 (10): 2393-2404; People such as K.Beaumont, Curr.Drug Metab.20034:461-485; H.Bundgaard, " design of prodrug: the bioreversible derivant of different functional groups and chemical entities in the prodrug design " (Design ofProdrugs:Bioreversible derivatives for various functional groups andchemical entities in Design of Prodrugs), H.Bundgaard (editor), like to think only your (Elsevier) Science Press, Amsterdam, 1985; People such as G.M.Pauletti, Adv.DrugDeliv.Rev.199727:235-256; R.J.Jones and N.Bischofberger, Antiviral Res.199527; 1-15; And people such as C.R.Wagner, Med.Res.Rev.200020:417-45) provide a kind of technology that improves drug absorption.The representative instance of prodrug comprises the chemical compound with the unsettled blocking group biologically that is connected with the reactive compound functional moiety.In the design of precursor nucleotide (pronucleotides), adopted the hydroxyl on the sugar moieties has been carried out alkylation, acidylate or the modification of other lipophilic.These precursor nucleotide can be hydrolyzed in vivo or take off alkyl and produce reactive compound.
It's a pity that many useful prodrugs in addition demonstrate limited water solublity, this has proposed huge formulation challenges.If traditional solution of poorly water-soluble comprises that micronization is to reduce granularity and feasible neutral compound to be converted into the bigger salt of water solublity.
Solid dispersion provides a kind of method for the preparation of the chemical compound of poorly water-soluble.Summarized the function of solid dispersion system in pharmaceutical preparation is used.(W.L.Chiou and S.Riegelman, J.Pharm.Sci.1971 60 (9): 1281-1302; C.Leuner and J.Dressman, Eur.J.Pharm.Biopharm.2000 50:47-60; A.T.M.Serajuddin, J.Pharm.Sci.199988 (10): 1058-1066, people Pharm.Technol.Eur.2002 such as A.Forster 14 (10): 27; J.Breitenbach Eur.J.Pharm.and Biopharm.2002:54:107-117; J.Breitenbach and M.
People such as Drugs and the Pharmaceutical Sciences 2003133:245-260 and K.A.Coppens, Pharm.Technol.200630 (1): 62-70).The solid dispersion system turnkey is drawn together eutectic mixture, solid solution and suspensoid, glass suspensoid and solution, the amorphous sediment in the crystallization carrier.Solid dispersion is the convenience of active component of preparation poorly soluble and otherwise effective technique.The disintegrate of solid solution or suspensoid and dispersion provide the thin micelle of active component, and this helps the absorption of active component (AI) in gastrointestinal (GI) road.
Solid dispersion can be undertaken that heat fusing is extruded by the molten mixture with AI and carrier or prepare by solvent is carried out rapid evaporation from the solution of AI and carrier.Multiple solid carrier has been added in the solid dispersion, comprise Polyethylene Glycol (PEG), polyethylene glycol oxide (PEO), polyvinylpyrrolidine (PVP), polyvinyl alcohol (PVA), hydroxypropyl emthylcellulose (HMPC), hydroxypropyl cellulose (HPC), carboxymethylethylcellulose (CMEC), hydroxypropylmethyl cellulose phthalate (HPMCP), polyacrylate, polymethacrylates, urea and sugar (for example mannitol) (Leuner sees above).Though clearly have multiple choices, for active component is individual, discern carrier molecule and remain important task with optimal properties.
At first and one of the solid dispersion preparation of further investigation be griseofulvin and PEG (W.L.Chiou and S.Riegelman see above).PEG is obtainable in the molecular weight ranges of non-constant width, and about 2,000 to 6,000 the PEG of molecular weight has the best physical property of solid dispersion that preparation is contained griseofulvin.The water solublity of griseofulvin is limited, and the absorption of its by oral route is poor especially.The solid dispersion conduct of griseofulvin and PEG
Gone on the market.PEG is not the surface of good activating agent, with emulsifying agent such as polyoxyethylene sorbitan monoleate, polyethylene lauryl ether (
35) or sodium lauryl sulphate join and promoted process in leaching in the solid dispersion.The rate of release of other medicines having been observed the preparation of the solid dispersion of conduct in PEG4000 increases, described medicine comprises oxazepam (people such as J.M.Gines, Int.J.Pharm.1996 143:247-253), piroxicam (people such as M.Fernandez, Int.J.Pharm.1993 98:29-35), zoldipem (zolpidem) (people such as G.Trapani, Int.J.Pharm.1999 184:121-130), ketoprofen (M.V.Margarit and I.C.Rodriguez, Int.J.Pharm.1994 108:101-107), Yi Xi difficult to understand dissolves (oxepam) (people such as R.Jachowicz, Int.J.Pharm.1993 99:321-325), nifedipine (people such as H.Suzuki, Chem.Pharm.Bull.1997 45:1688-1693), phenytoin (R.Jachowicz, Int.J.Pharm.1987 35:7-12), fenofibrate (people such as M.T.Sheu, Int.J.Pharm.1994103:137-146), prednisolone (R.Jachowicz, Int.J.Pharm.1987 35:1-5) and glibenclamide (people such as G.V.Betageri, Int.J.Pharm.1995 126:155-160).
Be among December in 1997 the disclosed WO 97/49384 on the 31st, J.McGinity and F.Zhang disclose the pharmaceutical preparation that comprises following material: treatment chemical compound and high-molecular-weight poly (ethylene oxide) but mixture that (PEO) heat fusing is extruded optionally contains Polyethylene Glycol as plasticizer.The molecular weight ranges that the PEO that adopts in this invention has is 1,000,000 to 10,000,000.This application was awarded patent right afterwards, was United States Patent (USP) 6,488,963.
Be in December in 2004 the disclosed US publication 2004/0253314 on the 16th that people such as H.-U.Petereit disclose and comprised active pharmaceutical ingredient and (methyl) acrylate copolymer (by the C of the acrylic or methacrylic acid of the complete copolymerization of 40 to 75 weight %
1-4Arrcostab is formed) melt extrude preparation.
Be in the disclosed US publication 2005/0048112 on March 3rd, 2005, people such as J.Breitenbach disclose the solid pharmaceutical dosage formulation that comprises following material: the solid dispersion of at least a hiv protease inhibitor, at least a pharmaceutically acceptable water soluble polymer and at least a pharmaceutically acceptable surfactant, the wherein T that has of water-soluble polymer
g(glass transition temperature) is at least about 50 ℃.
Be that people such as J.Rosenberg disclose the solid pharmaceutical dosage formulation that comprises following material: the solid dispersion of at least a hiv protease inhibitor, at least a pharmaceutically acceptable water soluble polymer and at least a pharmaceutically acceptable surfactant in the disclosed US publication 2005/0044529 on April 21st, 2005.
The present invention relates to comprise the pharmaceutical composition of solid suspensoid, described solid suspensoid passes through isopropylformic acid. (2R, 3S, 4R, 5R)-and 5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-pair-isobutyryl oxygen base-tetrahydrochysene-furan-2-ylmethyl ester hydrochloride (I; This paper also is called 4 '-'-azido cytidine-2 ', 3 ', 5 '-three-isobutyrate hydrochlorate) and Polyethylene Glycol (PEG)/polypropylene glycol (PPG) block copolymer carry out heat fusing and extrude and make.
The invention provides and be used for Orally administered 4 '-'-azido cytidine-2 ', 3 ', the pharmaceutical composition of 5 '-three-isobutyrate hydrochlorate, total weight based on compositions, this pharmaceutical composition comprises 4 ' of about 250mg to 500mg-'-azido cytidine-2 ', 3 ', 5 '-three-isobutyrate hydrochlorate (I).Have in the United States Patent (USP) 6,846,810 that this chemical compound is to authorize on January 2nd, 2005 and describe and requirement.People such as T.C.Connolly are that the disclosed U.S. disclosed and described the method for preparing the parent nucleoside in 20050038240 on February 17th, 2005.
Have been found that three acidylate nucleoside I can reduce the patient's who is infected by hepatitis C virus (HCV) virus load.Hepatitis C virus is the main reason (people such as N.Boyer, J.Hepatol.2000 32:98-112) of chronic hepatopathy in worldwide.The patient who is infected by HCV is in the risk of development liver cirrhosis and hepatocarcinoma subsequently, so HCV is the principal indication of liver transplantation.Though I can obtain with crystal form, it has the physicochemical property that pH relies on.And this chemical compound forms gel easily when contacting with water, and it is difficult to handle with aqueous solution.
Though reported with the limited chemical compound of solid dispersion preparation preparation water solublity to have obtained some successes, every kind of AI has unique character, makes the preparation optimization of specific AI remain challenging experiment effort.Release for the best needs active component to disperse effectively.The heat fusing preparation needs active component and carrier all to demonstrate enough heat stability.The heat stability that contains the AI of organic nitrine is paid close attention to very much.In addition, the chemotherapy of virus disease often needs high dose to reduce virus load and the condition of avoiding helping medicament-resistant mutation rapidly.It is big producing the amount of the needed active component of high concentration in dosage form, the capacity that this has further aggravated solubility problem and has limited other excipient that may use in others.
A reason of amorphous solution and suspensoid success is the moistening and the dissolubility (Forster is on seeing) in centering on particulate diffusion layer that may increase AI that the close existence of hydrophilic carrier and medicine has promoted active component.Have been found that and add wetting characteristics and the dissolubility that emulsifying agent can improve the chemical compound in solid solution/suspensoid sometimes.Surfactant such as sodium laurylsulfate and Tween 80 have improved the rate of release (C.Leuner and J.Dressman see on) of naproxen from PEG4000,6000 and 20,000.
Unexpectedly find the bioavailability that Polyethylene Glycol (PEG)/polypropylene glycol (PPG) block copolymer provides the required substrate of the solid dispersion of I and improved with other matrix phase ratio now.Compositions provided herein is amorphous suspensoid, and wherein block copolymer is that crystallization I is suspended in amorphous phase wherein.Compositions can be by fusing point than the low block copolymer of I and the temperature of the thermal treatment zone of extruder is remained between the fusing point of I and copolymer and prepare.
Term " block copolymer " refers to the copolymer be made up of the block (or fragment) of 2 or more a plurality of different homopolymer as used herein.The term homopolymer refer to the polymer be made up of single monomer.The multiple variation of block copolymer is possible, comprises simple diblock polymer with A-B structure and the triblock polymer with A-B-A or A-B-C structure.Poloxamer (poloxomers) (or
) be the A-B-A block copolymer, wherein the A fragment is hydrophilic Polyethylene Glycol homopolymer, the B fragment is hydrophobic polypropylene glycol homopolymer.Poloxamer can be by the commercially available acquisition of BASF (BASF) company.According to the relative size of block, copolymer can be solid, liquid or pasty state.
It is the trade mark of poloxamer.Term poloxamer and Lutrol can use in this article mutually.The mean molecule quantity that poloxamer 188 has is about 8600, and fusing point is 52 °-54 ℃, and HLB (hydrophile-lipophile balance value) is 18-29, and mean particle size range is 1 micron to 500 microns.The polyoxyethylene unit accounts for about 81% of molecular weight.Poloxamer 188 is easily molten in water.In the HCV prodrug formulation, block copolymer has limited with moisture (it causes undesirable AI gelling) and has contacted.Other solid carrier that can be used for preparing the solid dispersion of I comprises vitamin E TPGS (Yi Siman-Kodak (Eastman Kodak) company), Gelucire 44/14, Gelucire 50/13 (Jia Fasai (Gattefosse) company, NJ), Solutol HS15, poloxamer 407, Lutrol F77, cremophor RH40 (Cremophor RH40) (BASF AG, NJ), (standing grain is (Croda) company greatly, NJ) for sucrose dipalmitate and sucrose distearate.
In an embodiment of the present invention; the pharmaceutical composition that comprises the solid suspensoid is provided; described solid suspensoid passes through isopropylformic acid. (2R; 3S; 4R; 5R)-and 5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-is two-and isobutyryl oxygen base-tetrahydrochysene-furan-2-ylmethyl ester hydrochloride (I) and PEG/PPG block copolymer carry out heat fusing and extrude and make.In another embodiment of the present invention, solid suspensoid and at least a carrier, diluent and/or excipient are merged.
In another embodiment of the present invention, a kind of pharmaceutical composition is provided, it is the solid suspensoid of (I) and poloxamer.In another embodiment of the present invention, pharmaceutical composition and at least a carrier, diluent and/or excipient merge the solid suspensoid of (I) and poloxamer.In another embodiment of the present invention, (I) and the solid suspensoid of poloxamer that are included in compressed tablets or the capsule are provided, described compressed tablets or capsule can also contain other carrier, diluent and/or excipient.
In another embodiment of the present invention, provide the pharmaceutical composition of the solid suspensoid that contains (I) and poloxamer 188.In another embodiment of the present invention, the pharmaceutical composition of the solid suspensoid that contains (I) and poloxamer 188 is provided, wherein the solid suspensoid contains the poloxamer 188 of 20-40% weight.
In another embodiment of the present invention, a kind of compressed tablets is provided, the solid suspensoid that it contains (I) and poloxamer 188 contains microcrystalline Cellulose, mannitol, crospovidone, silica sol, corn starch (or Pulvis Talci), magnesium stearate.In addition, compressed tablets can also be chosen wantonly and contain sodium bicarbonate, arginine or maltodextrin and optional surrounded by coating material.
In another embodiment of the present invention, a kind of compressed tablets is provided, it contains the solid suspensoid of (I) and poloxamer 188, wherein the solid suspensoid contain maximum about 540mg I and about 175 to about 260mg poloxamer 188, about 125mg to about 225mg microcrystalline Cellulose (
PH 101), about 70 to about 125mg mannitol (Parteck
TM200), about 90mg to about 150mg crospovidone (
XL), about 10 to about 40mg silica sol (
380), about 10 to about 40mg corn starch (or Pulvis Talci), and about 10 to about 25mg magnesium stearate.Tablet in this embodiment can be chosen wantonly with yellow 03K 12429 coatings of Opadry (Opadry).
In another embodiment of the present invention, a kind of compressed tablets is provided, it contains the solid suspensoid of (I) and poloxamer 188, and wherein the solid suspensoid contains I and the about 230mg poloxamer 188 of maximum about 537mg, about 175mg microcrystalline Cellulose, about 72mg mannitol, about 120mg crospovidone, about 24mg silica sol, about 24mg corn starch (or Pulvis Talci), with about 18mg magnesium stearate, compressed tablets is optional with yellow 03K 12429 coatings of Opadry.
In another embodiment of the present invention, a kind of compressed tablets is provided, it contains the solid suspensoid of (I) and poloxamer 188, and wherein the solid suspensoid contains I and the about 179mg poloxamer 188 of maximum about 537mg, about 175mg microcrystalline Cellulose, about 123mg mannitol, about 120mg crospovidone, about 24mg silica sol, about 24mg corn starch, with about 18mg magnesium stearate, compressed tablets is optional with yellow 03K 12429 coatings of Opadry.
In another embodiment, provide the pharmaceutical composition of the solid suspensoid that contains I, poloxamer and plasticizer.In this embodiment, plasticizer can increase flexibility, machinability or the dilatancy of extrudate.In addition, plasticizer can also reduce the elastic modelling quantity of fused mass viscosity and reduction product.Glass transition temperature or softening point that plasticizer can reduce block copolymer usually reduce processing temperature, reduce extruder torque and pressure with permission in extrusion.Plasticizer also usually can reduce the viscosity that melt extrudes thing.The example of plasticizer that can be used according to the invention comprises: triacetin, propylene glycol, molecular weight are about 200 to about 1,000 Polyethylene Glycol (for example PEG 4600), dibutyl phthalate, dibutyl sebacate, triethyl citrate, vegetable oil and mineral oil, fatty acid, C
6-18The fatty glyceride of fatty acid such as Tween 80 etc.
In another embodiment of the present invention, the method for the solid suspensoid of preparation I and PEG/PPG block copolymer is provided, this method comprises the steps: that (i) mixes solid in blender; (ii) the gained solid mixture is joined in the thermal treatment zone of heat fusing extruder, wherein the temperature of the thermal treatment zone is in the scope of fusing point that is higher than described block copolymer and the fusing point that is lower than I; (iii) the gained fused mass is extruded; (iv) the solid suspensoid is ground to granularity about 20 and about 2000 microns between.In another embodiment of the present invention, granularity is milled between about 100 to about 600 microns.
In another embodiment of the present invention, a kind of pharmaceutical composition is provided, it comprises the solid suspensoid of I and poloxamer 188, solid suspensoid 55 to about 70% the I (w/w) that has an appointment wherein, about 5 to about 12% mannitol, and about 13 to about 16% microcrystalline Cellulose, about 8 to about 12% crospovidone, about 1 to about 3% silica sol, about 1 to about 3% corn starch (or Pulvis Talci) and about 1 to about 2% magnesium stearate.
In an embodiment of the present invention, the solid suspensoid is introduced in the compressed tablets together with carrier, diluent and excipient.Excipient is introduced into to give required character together with the solid suspensoid.The useful excipient that often is included in the compressed tablets comprises binding agent, surfactant, diluent, pressing aid agent (compression aids), disintegrating agent, antitack agent, stabilizing agent, antioxidant, coloring agent, wetting agent and lubricant.Being proved to be useful carrier, diluent and excipient is well-known in pharmaceutical field, they are at " Lei Shi: pharmaceutical science with put into practice " (Remington:The Science and Practice of Pharmacy) (1995, E.W.Martin writes, mark (Mack) publishing company, the 19th edition, Easton, Pennsylvania) in description is arranged.For some purposes, even can use multiple composition in same preparation, included excipient and the diluent of this paper can be replaced or change under the situation that does not deviate from aim of the present invention.
The tablet that contains the solid suspensoid is optional by coating.The film coating can also contain other coating excipient such as opacifier, pigment, coloring agent etc.Selection to this class material and consumption is considered within this area.
Terms excipient refers to give preparation with gratifying processing and compaction characteristics or give the inert material of finished tablet with required physical characteristic as used herein.
Thereby diluent is to be added into to adjust the inert fraction that volume produces feasible size for compacting.Diluent commonly used comprises calcium hydrogen phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, starch and Icing Sugar.The diluent of q.s such as mannitol, lactose, sorbitol, sucrose and inositol help the disintegrate of tablet, and they are everlasting and use in the chewable tablet.Microcrystalline Cellulose (
) in the direct compression prescription, be used as excipient.
Binding agent is added in the powder to give powder with bond property, and this can make compressed tablets keep its integrity.The material that is commonly used for binding agent comprises that starch, gelatin and sugar are as sucrose, glucose, dextrose, molasses and lactose.Natural and synthetic natural gum also is used as binding agent in some preparations, described natural gum comprises arabic gum, sodium alginate, the fertile glue (panwar gum) of Pan, Ficus elastica, carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, ethyl cellulose.
Lubricant is used to prevent tablet material and punch die and punch head surface adhesion.Lubricant commonly used comprises Pulvis Talci, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and PEG.Soluble oil comprises mixture, sodium chloride, leucine and the carbowax 4000 of sodium benzoate, sodium benzoate and sodium acetate.Fluidizer is added into to improve the flow behavior of tablet powder.Silica sol (
) be the fluidizer of using always.Pulvis Talci can be used as lubricants simultaneously.
Disintegrating agent is to be added into to break after promoting to use or the cracked material or the mixture of material.Drying and mealy corn starch or potato starch are the disintegrating agents of using always.They have high-affinity to glassware for drinking water, and they are inflatable and make tablet rupture when wetted.One group of material that is called superdisintegrant (super-disintegrants) comprises croscarmellose, cross-linked cellulose, crospovidone, cross linked polymer and primojel, crosslinked starch.Crospovidone (
) be synthetic, insoluble, but can expansible rapidly crosslinked-vinyl-pyrrolidone homopolymer.
Following examples have illustrated the preparation and the biological assessment of chemical compound within the scope of the invention.Provide subsequently these embodiment and preparation so that those skilled in the art can more be expressly understood and implement the present invention.They should not be considered to limitation of the scope of the invention, and only are to explain and example the present invention.Skilled Pharmaceutical Chemist will be known excipient, diluent and the carrier that can use mutually, and these changes do not deviate from aim of the present invention.
Embodiment 1
Following compositions is calculated the expression preparation based on % weight.
Those skilled in the art will approve: can be by some AI be replaced easily changing tablet or the capsule of the amount of I with the preparation varying strength with other diluent, and the amount that changes the solid dispersion of I or I does not deviate from aim of the present invention.
Active component I and poloxamer 188 and optional plasticizer are mixed in blender.Blended solid is sent in the Leistritz double screw extruder.The thermal treatment zone is transferred to 45,65,65,65,65,70,75 and 80 ℃.The variations in temperature of the thermal treatment zone is remained on ± 5 ℃.These conditions are enough to make poloxamer and excipient fusion and do not make the I fusion.Twin screw is 100 ± 30 rev/mins of down operations, the powder flow velocity 5 and 20g/min between, preferably 10 and 15g/min between.Under these conditions, polymer melt and form uniform coating around the active component.In the dual-layer lining polyethylene can, collect extrudate in room temperature (15 to 30 ℃).The material of extruding is ground by Fitz, ground material is mixed with AVICEL PH101, mannitol, POLYPLASDONE XL and corn starch (optional with Pulvis Talci instead of corn starch).At last, magnesium stearate is joined in the blended material.The granularity of being ground is between 100 and 2000 microns.The gained mixture is sent in the tablet machine, be pressed into label.
Can be by merging Opadry and purified water and mixing and disperseed to prepare the coating suspension fully until Opadry in 45 minutes.Label is placed the cellular type coating pan, and with 45 ± 5 ℃ intake air heating, and intermittently stirring reaches 40 ± 5 ℃ until aerofluxus.Then, inlet temperature is risen to 60 ± 5 ℃, use to be calibrated to the air-atomizing system that uses the 25mg film-coat according to every of dry basis label is carried out coating with the coating suspension of continuous stirring.By jog the coated tablet drying is lower than 2% until water content, then tablet is cooled to room temperature, in the double-layer polyethylene clad vessel of sealing, preserve.
Embodiment 2
Prepared following compositions:
With its concrete form or in the mode of implementing disclosed function or be used for reaching disclosed result's method or procedural representation, can be respectively when above-mentioned explanation or the disclosed feature of claims subsequently are suitable or be used to realize various forms of the present invention with the combination in any of this category feature.
For the purpose that is aware and understand, described foregoing invention in detail by explanation and embodiment.It will be apparent for a person skilled in the art that and to change within the scope of the appended claims and accommodation.Therefore, should be appreciated that above description is illustrative and nonrestrictive.Therefore, scope of the present invention should not determine with reference to above description, and should determine with reference to the four corner of the equivalent of following appended claim and this claim.
All patents, patent application and the publication of being quoted among the application is incorporated herein by reference by integral body with the degree of being quoted separately as each piece patent, patent application or publication and is used for all purposes.
Claims (14)
1. the pharmaceutical composition that comprises the solid suspensoid; described solid suspensoid passes through isopropylformic acid. (2R; 3S; 4R; 5R)-and 5-(4-amino-2-oxo-2H-pyrimidine-1-yl)-2-azido-3,4-is two-and isobutyryl oxygen base-tetrahydrochysene-furan-2-ylmethyl ester hydrochloride (I) and Polyethylene Glycol (PEG)/polypropylene glycol (PPG) block copolymer carry out heat fusing and extrude and make.
2. according to the compositions of claim 1, also comprise at least a diluent, carrier and/or excipient.
3. according to the pharmaceutical composition of claim 1, wherein said PEG/PPG block copolymer is a poloxamer.
4. according to the pharmaceutical composition of claim 3, also comprise at least a diluent, carrier and/or excipient.
5. according to the pharmaceutical composition of claim 3, wherein said compositions is included in capsule or the compressed tablets, optional one or more carriers, diluent and/or the excipient of containing of described tablet or described capsule.
6. according to the pharmaceutical composition of claim 5, wherein said solid suspensoid comprises I and poloxamer 188.
7. according to the pharmaceutical composition of claim 6, wherein said solid suspensoid is the poloxamer 188 of 20-40% (w/w).
8. according to the pharmaceutical composition of claim 7, wherein the solid suspensoid is included in the compressed tablets, and described tablet is also chosen wantonly and comprised the excipient that one or more are selected from microcrystalline Cellulose, mannitol, crospovidone, silica sol, corn starch (or Pulvis Talci), magnesium stearate, sodium bicarbonate, arginine, maltodextrin and coating material.
9. pharmaceutical composition according to Claim 8, wherein said compressed tablets comprises:
Wherein said compressed tablets is optional with yellow 03K 12429 coatings of Opadry.
10. according to the pharmaceutical composition of claim 9, comprise:
Wherein said compressed tablets is optional with yellow 03K 12429 coatings of Opadry.
11. the pharmaceutical composition according to claim 9 comprises:
Wherein said compressed tablets is optional with yellow 03K 12429 coatings of Opadry.
12. comprise the pharmaceutical composition of solid suspensoid, described solid suspensoid is extruded and is made by I, poloxamer 188 and plasticizer being carried out heat fusing.
13. the method for the solid suspensoid of preparation I and PEG/PPG block copolymer, described method comprises the steps:
(i) solid is mixed in blender;
(ii) the gained solid mixture is joined in the thermal treatment zone of heat fusing extruder, wherein the temperature of the thermal treatment zone is in the scope of fusing point that is higher than described block copolymer and the fusing point that is lower than I;
(iii) the gained fused mass is extruded; With
(iv) the solid suspensoid is ground to granularity about 20 and about 2000 microns between.
14. according to the method for claim 13, wherein the solid suspensoid be milled to about 100 and about 600 microns between.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US75014605P | 2005-12-14 | 2005-12-14 | |
| US60/750,146 | 2005-12-14 | ||
| US83059406P | 2006-07-12 | 2006-07-12 | |
| US60/830,594 | 2006-07-12 | ||
| PCT/EP2006/069262 WO2007068615A2 (en) | 2005-12-14 | 2006-12-04 | Hcv prodrug formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101330906A true CN101330906A (en) | 2008-12-24 |
| CN101330906B CN101330906B (en) | 2010-12-29 |
Family
ID=40206351
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006800474209A Expired - Fee Related CN101330906B (en) | 2005-12-14 | 2006-12-04 | Hcv prodrug formulation |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101330906B (en) |
| ES (1) | ES2350497T3 (en) |
| ZA (1) | ZA200804974B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ20033211A3 (en) * | 2001-05-03 | 2004-09-15 | F. Hoffmann-La Roche Ag | Pharmaceutical dosage form of amorphous nelfinavir mesylate |
| TWI332507B (en) * | 2002-11-19 | 2010-11-01 | Hoffmann La Roche | Antiviral nucleoside derivatives |
-
2006
- 2006-12-04 CN CN2006800474209A patent/CN101330906B/en not_active Expired - Fee Related
- 2006-12-04 ES ES06830328T patent/ES2350497T3/en active Active
-
2008
- 2008-06-06 ZA ZA200804974A patent/ZA200804974B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200804974B (en) | 2009-06-24 |
| ES2350497T3 (en) | 2011-01-24 |
| CN101330906B (en) | 2010-12-29 |
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