CN101066980A - Crystalline tenofovir fumarate and its medicine prepn - Google Patents
Crystalline tenofovir fumarate and its medicine prepn Download PDFInfo
- Publication number
- CN101066980A CN101066980A CN 200710014625 CN200710014625A CN101066980A CN 101066980 A CN101066980 A CN 101066980A CN 200710014625 CN200710014625 CN 200710014625 CN 200710014625 A CN200710014625 A CN 200710014625A CN 101066980 A CN101066980 A CN 101066980A
- Authority
- CN
- China
- Prior art keywords
- tdf
- crystal
- crystallization
- crystal form
- preparation
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides crystalline tenofovir disoproxil fumarate (TDF) A and TDF B in different crystal forms and their preparation process. The preparations may be used in preventing and treating hepatitis B and AIDS.
Description
The invention technical field
The invention provides fumaric acid tenofovir disoproxil (tenofovir disoproxil fumarate is called for short " TDF ") new crystal A and B and prepare these crystalline methods.In addition, the invention still further relates to the formulation method that contains the TDF new crystal.The preparation that is provided can be used for being administered to treatment and the prevention that the patient carries out Type B viral hepatitis and human immunodeficiency virus (HIV/AIDS) infection.
The invention technical background
The fumaric acid tenofovir disoproxil chemical name 9-[2-(R)-[[two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphono] methoxyl group] propyl group] the VITAMIN B4 fumarate; popular name tenofovir disoproxil fumarate; american goods name Viread} is a kind of acyclic bunch of efabirenz; it is believed that and to cause that by directly in conjunction with entering the viral DNA chain viral DNA chain synthesizes premature termination.This medicine has been made into compound medicines Truvada and ATRIPLA recently and has been used for the treatment of human immunodeficiency virus (HIV/AIDS) infection.
The composition and the synthetic method thereof that contain tenofovir disoproxil and fumaric acid (1: 1) of the invention of U.S. Gilead Sciences Inc in Chinese patent CN 1745755A (publication number), have been reported.Its patent has only been put down in writing a kind of crystal formation, and is different with the crystal formation that is provided among the present invention.
Crystalline tenofovir fumarate A that the present invention reported and B are different from the crystal formation of U.S. Gilead Sciences Inc invention.The crystal habit of not moisture substantially and other solvent of all these new crystal.This new TDF crystal formation has synthetic on a large scale or is mixed with the required performance of therapeutic preparation.
The invention provides crystalline tenofovir fumarate A and B and prepare these crystalline methods.It is easy that the new crystal that is provided has the preparation method, and can make advantages such as the manufacturing of the composition that contains TDF and preparation become easily.
In addition, the invention still further relates to the formulation method that contains per daily dose 10-1000mgTDF new crystal.
At last, the preparation that is provided can be used for being administered to treatment or the prevention that humans and animals carries out Type B viral hepatitis and human immunodeficiency virus (HIV/AIDS) infection.
Summary of the invention
Example of the present invention comprises (1) crystal form A: the XRD characteristic peak is expressed in about 5.1,7.0,10.7,11.9,12.9,13.7,15.2,15.6,16.4,19.0,20.3,21.5,22.3,25.5,26.0,27.4,30.7 and 31.1 places with 2 θ angles, and the DSC endotherm(ic)peak is at about 113.1 ℃; (2) crystal form B: the XRD characteristic peak is expressed in about 5.1,7.0,10.3,11.4,14.2,15.4,16.2,18.2,19.0,20.6,25.8 and 31.0 places with 2 θ angles, and the DSC endotherm(ic)peak is at about 115.5 ℃.
Example of the present invention comprise contain among Fig. 1-6 any or a plurality of shown in the TDF crystallization of crystal habit.
● Fig. 1 is the crystalline XRD figure of crystal form A.
● Fig. 2 carries out the differential scanning calorimetry and the differential thermogram that obtains to the crystallization of crystal form A.
● Fig. 3 carries out that infrared absorption is measured and the infrared absorption spectrum that obtains to the crystallization of crystal form A.
● Fig. 4 is the crystalline XRD figure of crystal form B.
● Fig. 5 carries out the differential scanning calorimetry and the differential thermogram that obtains to the crystallization of crystal form B.
● Fig. 6 carries out that infrared absorption is measured and the infrared absorption spectrum that obtains to the crystallization of crystal form B.
In other example, the invention provides the solution that contains have an appointment 6-45% TDF and about 55-94% crystallization and form crystallization, thus preparation TDF crystalline method.Wherein, described crystallization solvent is selected from following (I) or (I) and (II) mixed solvent.As the need mixed solution, about 1: 10 of its volume ratio is to 1: 1:(I) the first crystallization solvent, TDF has high-dissolvability therein, is selected from (a) C
1-4Alkyl formamides, (b) C
1-4Alkyl ethanamide, (c) C
1-6Alkanol, (d) formic acid C
1-4Alkyl ester, (e) acetate C
1-4Alkyl ester, (f) C
1-4Alkyl ketone (for example acetone and methyl ethyl ketone), (g) methyl-sulphoxide, (h) tetrahydrofuran (THF), (i) acetonitrile and (j) slightly acidic (pH 3-4) aqueous solution; (II) the second crystallization solvent, TDF has low solubility therein, by (1) formula R
1-O-R
2First dialkyl ether form, wherein, R
1Be the alkyl of 1,2,3,4,5 or 6 carbon atom, R
2Be the alkyl of 2,3,4,5 or 6 carbon atoms, wherein, R
1And R
2Identical or different, perhaps R
1And R
2Both link together, and form 5,6,7 or 8 yuan of rings, (2) hexane, (3) methylene dichloride, (4) 1,2-ethylene dichloride or chloroforms.
In this article, alkyl is rectilinear, ramose and cyclic stable hydrocarbon.Unless opposite explanation is arranged in addition, in this article, " alkyl " or " moieties " be meant contain 1,2,3,4,5 or 6 just, secondary, uncle or cyclic hydrocarbon." C
1-6Alkyl " speech is meant the alkyl that contains 1,2,3,4,5 or 6 carbon atom.Its example has-CH
3,-CH
2CH
3,-CH
2CH
2CH
3,-CH (CH
3)
2,-CH
2CH
2CH
2CH
3,-CH
2CH (CH
3)
2,-CH
2(CH
3) CH
2CH
3,-C (CH
3)
3,-CH
2CH
2CH
2CH
2CH
3,-CH (CH
3) CH
2CH
2CH
3,-CH (CH
2CH
3)
2,-C (CH
3)
2CH
2CH
3,-CH (CH
3) CH (CH
3)
2,-CH
2CH
2CH (CH
3)
2,-CH
2CH (CH
3) CH
2CH
3,-CH
2C (CH
3)
3,-CH
2CH
2CH
2CH
2CH
2CH
3,-CH (CH
3) CH
2CH
2CH
2CH
3,-CH (CH
2CH
3) CH
2CH
2CH
3,-C (CH
3)
2CH
2CH
2CH
3,-CH (CH
3) CH (CH
3) CH
2CH
3,-CH (CH
3) CH
2CH (CH
3)
2,-C (CH
3) (CH
2CH
3)
2,-CH (CH
2CH
3) CH (CH
3)
2,-C (CH
3)
2CH (CH
3)
2,-CH (CH
3) C (CH
3)
3, cyclopropyl, cyclobutyl, cyclopropyl methyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentyl-methyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl group, 2-cyclopropyl-1-propyl group, 3-cyclopropyl-1-propyl group, 2-cyclopropyl-2-propyl group and 1-cyclopropyl-2-propyl group.
Except as otherwise noted, in this article, temperature be meant centigradetemperature (℃).Room temperature is meant about 15-30 ℃.
Example of the present invention comprises pure crystallization TDF (for example, crystal form A and/or crystal form B).Example of the present invention also comprises and contains crystallization TDF (for example, crystal form A and/or crystal form B) and one or more compound compositions.
Example of the present invention comprises the method for preparing the TDF crystal formation, in the method, TDF is dissolved in easy broad dose (first solvent), makes it form crystallization.As the need mixed solvent, TDF is dissolved in easy broad dose (first solvent), then make it form crystallization with indissoluble solvent (second solvent).
Another example is a kind of like this crystallization TDF: it be fit to contain one or more and pharmaceutical carrier among the TDF of for example crystal form A and crystal form B, be used for the treatment of hepatitis B virus and human immunodeficiency virus (HIV/AIDS) infect among the human or animal pharmaceutical composition or pharmaceutical use.
In this article, the TDF for " crystalline material ", " crystallization " or " crystal " is meant the solid TDF of all basically component molecules with certain 3 D stereo pattern (that is lattice) ordered arrangement.Crystallization or crystalline TDF can comprise the composition of one or more types, can be that one or more crystal forms (as platelet, rod crystalline substance, lath or needle) occur.Unless offer some clarification on or based on context content determine that in this article, per-cent (%) is meant weight (w/w) per-cent.Therefore, the solution that contains at least about 40%TDF is meant the solution that contains at least about 40% (w/w) TDF.The solid TDF that contains 0.1% water is meant the water that contains 0.1% (w/w) in the solid.
Basically do not have the crystallization TDF of noncrystalline TDF to be meant a kind of like this solids composition, in said composition, about TDF more than 60% is that the form with crystalline material exists.Such composition generally contains one or more TDF crystal habits of about 80% (usually at least about 90%) at least.All the other TDF are noncrystalline TDF.
Example is included in the composition of instantaneous appearance when implementing method of the present invention or operation.The present invention includes the composition of the mixture that contains two or more not syncrystallization crystal formations (that is form) (as the crystallization of crystal form A and B, perhaps their mixture).These TDF crystalline compositions exist in can or making in medicine preparation, and in such composition, it is about 60% that the TDF of single crystal form accounts at least, accounts for about 90% usually at least.
The crystallization crystal formation present inventor of TDF has identified several different TDF crystal formations.The present inventor has used several method (normally using XRD diffractogram and DSC differential thermogram) that their characteristic is characterized.The operator generally uses XRD to characterize the crystalline composition or it is identified.The diffractogram that is obtained by crystalline compounds is distinctive often for a given crystal habit, though weak or very weak diffraction peak may always not occur in the same diffractogram that the crystallization by continuous lot number obtains.Especially have in sample under the situation of other crystal habit of significant quantity, [especially the relative intensity in low angle X-ray incident value (low 2 θ) may change because of the advantage orientation effect that is produced by the difference of for example crystal form, particle diameter and other condition determination bands of a spectrum.Therefore, the relative intensity of diffraction peak be not at last at crystal habit be distinctive.On the contrary, more it should be noted the relative position at peak rather than their amplitude, is a kind of in the described herein crystal formation to determine whether TDF crystallization.Generally in the about 0.3-12 θ degree that is broad peak, the XRD peak of broad can be made up of the two or more peaks that abut against together at each XRD peak in the various sample, for isolated spike, in the successive XRD analysis, finds the peak usually in about 0.12 θ degree.Suppose in the successive XRD analysis that with the XRD spectrum of identical a kind of compound of Instrument measuring what then the difference of XRD peak position was main is because in the specimen preparation process or due to the difference of sample self purity.When we identify one independently during the XRD spike in a given position (for example about 5.1), this means that this peak is 5.1 ± 0.1.When we when the given position of given 2 θ values identifies an XRD broad peak, this means that this peak is in this 2 θ value ± 0.3.
Be to be noted that in the present invention, need not to rely on observed whole bands of a spectrum in the highly purified control sample; Even bands of a spectrum may be distinctive to given TDF crystal habit also, as 5.1 for crystal form A.Evaluation should concentrate on the position and overall pattern of bands of a spectrum, especially select various crystal habits unique bands of a spectrum.
Can optionally be used in addition identifies that the diagnostic techniques of crystallization TDF comprises differential scanning calorimetry (DSC), fusing point test and infrared absorption spectrometry (IR).DSC measures when crystallization and changes owing to its crystalline structure or the crystal fusion absorbs or thermal transition temperature during rejected heat.In successive was analyzed, thermal transition temperature and fusing point were typically within about 2 ℃, usually within about 1 ℃.When we said that a compound has the DSC peak of a set-point or fusing point, this was meant that this DSC peak or fusing point are within ± 2 ℃.DSC provides a kind of alternative method of distinguishing different TDF crystal habits.Different crystal habits can (being partly at least) be discerned according to its different transition temperature characteristic.IR measures owing to the strong infrared Absorption that causes of the relevant particular chemical of the group that vibrates corresponding to light in the molecule.DSC and/or IR provide and can be used for describing TDF crystalline physical and chemical index.
The characteristic of crystal form A TDF crystal form A is that its XRD characteristic peak is expressed in about 5.1,7.0,10.7,11.9,12.9,13.7,15.2,15.6,16.4,19.0,20.3,21.5,22.3,25.5,26.0,27.4,30.7 and 31.1 places with 2 θ angles by use Cu-Ka radiating.Fig. 1 is the crystallization x-ray diffraction pattern of typical crystal form A.The crystallization of crystal form A generally contains the noncrystalline TDF less than about 20% (typically less than about 10%, often less than about 1%).Frequently, the crystallization of crystal form A does not contain noncrystalline TDF, and this can or amplify 100 times polarized light microscope determining and come out by DSC, XRD.
The crystallization of crystal form A has differential scanning calorimetric (DSC) endothermic transition peak (referring to Fig. 2) at about 113.1 ℃, and begins temperature in about 109.9 ℃ heat absorption and characterize, and has basically IR spectrum as shown in Figure 3.
The characteristic of the crystal form B of crystal form B TDF is that its XRD characteristic peak is expressed in about 5.1,7.0,10.3,11.4,14.2,15.4,16.2,18.2,19.0,20.6,25.8 and 31.0 places with 2 θ angles by use Cu-Ka radiating.Fig. 4 is the crystallization x-ray diffraction pattern of typical crystal form B.The crystallization of crystal form B generally contains the noncrystalline TDF less than about 20% (typically less than about 10%, often less than about 1%).Frequently, the crystallization of crystal form B does not contain noncrystalline TDF, and this can or amplify 100 times polarized light microscope determining and come out by DSC, XRD.
The crystallization of crystal form B has differential scanning calorimetric (DSC) endothermic transition peak (referring to Fig. 5) at about 115.5 ℃, and begins temperature 111.6 ℃ heat absorption and characterize, and has basically IR spectrum as shown in Figure 6.
The method of TDF crystallization is dissolved in the TDF of rough or other crystal formation in first solvent (easily broad dose) of warm (about 34-50 ℃ is typically 40 ℃), makes saturated solution, need the stirring of minimum degree in order to obtain homogeneous phase solution.As the need mixed solvent, under the stirring of minimum degree, add an amount of (1: the 1-10 volume ratio) second solvent (indissoluble solvent).Above solution is cooled to about 12-18 ℃, typical about 15 ℃, stops when beginning to form crystal stirring.Under 15 ℃, allow mixture leave standstill, typically about 12-30 hour, the pulpous state liquid that obtains is filtered at least about 12 hours.With premixed first solvent and second solvent solution (1: 9 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature the about 1-10 of vacuum-drying days.If desired, the exsiccant product can be chosen grinding wantonly, obtains the white fine powder powder crystal of required granular size.Improve product purity if desired, randomly recrystallization TDF.Embodiment comprises the composition of instantaneous generation when carrying out method steps or operation.The following example is illustrated the present invention in more detail, but does not limit the scope of the invention.
Pharmaceutical preparation and route of administration contain TDF crystallization (the normally crystallization of crystal form A or B, to call activeconstituents in the following text) composition of the present invention be by any administration that is fit to the disease treated, suitable way comprises per os, rectum, nose, part (comprising eyes, oral cavity and hypogloeeis), vagina and parenteral (comprising in subcutaneous, muscle, intravenously, intracutaneous, the sheath and exterior dura) administration.Usually, composition oral administration of the present invention, but the composition that contains crystallization TDF can carry out administration by any approach in above-mentioned other method.
Though the form administration that TDF can pure compound is good with the form of pharmaceutical preparation.Preparation of the present invention comprises TDF and one or more pharmaceutical excipients or carrier (" vehicle that meets the requirements "), optionally, also can contain other therapeutic component.Vehicle must compatible with other composition of preparation and to the patient harmless aspect " meeting the requirements ".
Preparation can be the preparation of those suitable parts or whole body administration, for example the preparation of those suitable per os, rectum, nose, oral cavity, hypogloeeis, vagina or parenteral (comprising in subcutaneous, muscle, intravenously, intracutaneous, the sheath and exterior dura) administration.Preparation is the unit dose form, is made by in the known method of pharmacy field any.These methods comprise activeconstituents and the carrier that constitutes one or more ancillary components or the step of mixed with excipients.Usually, the method for preparing preparation is, closely mixes with both of liquid vehicle or levigated solid carrier or they activeconstituents is all even, and is then, optionally, that products therefrom is dry or be shaped.
The present invention is fit to oral preparation can following form be provided: the dispersive unit, as sachet, cachet or the tablet of the activeconstituents that respectively contains predetermined amount; Pulvis or granule; Solution in waterborne liquid or non-aqueous liquid or suspension; Or oil-in-water liq emulsion or water-in-oil-type liquid emulsion.Activeconstituents also can bolus, the form of electuary or paste provides.
Preparation of the present invention comprises the composition of the vehicle that contains TDF and meet the requirements.These vehicle comprise tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant (antitack agent) and lubricant.Optionally, these compositions also can contain unit dose, and it comprises tablet and capsule.Optionally, these compositions can be the tablets that contains about 10-1000mg (being about 100-600mg usually) TDF, comprise that every contains about 100 or the tablet of 300mg TDF.Optionally, these tablets can contain about 1-10% tackiness agent, about 0.5-10% disintegrating agent, about 50-60% thinner or about 0.25-5% lubricant.These compositions can also be the wet granulars that contains liquid (for example water) TDF and one or more vehicle that meet the requirements, and the described vehicle that meets the requirements is selected from tackiness agent, thinner, dispersion agent and disintegrating agent.
Tablet can be by randomly with one or more ancillary components or vehicle compresses or mold pressing forms.General every of tablet contains about 10-1000mg (about usually 100-600mg) TDF (mainly being the TDF of crystal form A or B usually), every TDF that contains about 100mg or 300mg crystal form A for example, wherein, the only crystallization of the crystal form B of finite quantity (usually less than about 20%), other crystallization type or amorphous TDF exist.Compressed tablets can form by the TDF of unrestricted flow form (as powder or particle) (optionally, can with tackiness agent, disintegrating agent, lubricant, inert diluent, sanitas, tensio-active agent or dispersant) is compressed on suitable machine.The mold pressing tablet can form by mixture mold pressing on suitable machine of the powdered compounds that common liquid dilution agent is wetting, optionally, can carry out dressing and seal is coated with, embossing or indentation to tablet, and can be mixed with and to make contained activeconstituents slowly-releasing or controlled release.Example comprises the product that makes in order to the below method: the mixture compression of the vehicle that will contain crystallization TDF (the normally crystallization of crystal form A or crystal form B) and meet the requirements (for example dry wet granular of crossing, these dry wet granulars of crossing contain for example lactose, pregelatinized Starch, croscarmellose sodium, talcum powder and Magnesium Stearate).
The typical formulation composition that is used for tablet or relevant formulation comprises one or more tackiness agents, thinner, disintegrating agent or lubricant.These vehicle can increase stability of formulation, help the tablet compression in the manufacturing processed or help the disintegration of preparation after being ingested.Tablet is normally in order to below method preparation: one or more vehicle are mixed also wet granulation with TDF, then with the wet-milling of gained particle and carry out drying, make weight loss on drying about below 3%.Optionally, can the have an appointment tackiness agent (if can improve the pregelatinized Starch or the Povidone of the processing characteristics of tablet) of 1-10%.Optionally, can have an appointment the disintegrating agent (as cross-linked celluloses such as Microcrystalline Cellulose or croscarmellose sodiums) of 0.5-5% to promote tablet dissolved.Optionally, can have an appointment the thinner (as monose or disaccharides) of 30-50% with the physicals of covering up TDF or promote tablet dissolved.Optionally, can have an appointment the lubricant (as Magnesium Stearate, talcum powder or silicon-dioxide) of 0.25-10% so that in manufacturing processed, promote tablet to take out.
Optionally, the water of creme for example can comprise weight at least be 30% polyvalent alcohol [promptly, alcohol with two or more hydroxyls is as propylene glycol, 1,3 butylene glycol, N.F,USP MANNITOL, Sorbitol Powder, glycerol and polyoxyethylene glycol (comprising PEG400) and their mixture].Topical preparation can contain the compound that can promote activeconstituents to absorb or see through skin or other site of action aptly.The example of these transdermal enhancers comprises methyl-sulphoxide and relevant analogue.
The oil phase of emulsion of the present invention can be made of known composition.Though oil phase can only be made of emulsifying agent, should constitute by at least a emulsifying agent and fat or oil or their both mixture.Be preferably, oil phase contains hydrophilic emulsifier and as the lipophilic emulsifier of stablizer, both also are preferable for oil-containing and fat.Simultaneously, be with or without the emulsifying agent formation emulsive wax of stablizer.The wax that has oil ﹠ fat simultaneously constitutes emulsive ointment base, and emulsive ointment base forms the oiliness disperse phase of creme.
The emulsifying agent and the emulsion stabilizer that are applicable to preparation of the present invention comprise Tween
60, Span
80, stearyl alcohol mixture, benzylalcohol, tetradecyl alcohol, Zerol and Sodium Lauryl Sulphate BP/USP.
Be applicable to whether the oily of preparation or fat basis can obtain required cosmetic properties and select.Therefore, be preferably, creme answers right and wrong greasy, non-staining and can wash product, and has suitable denseness, to avoid seepage from pencil or other container.Can use straight or branched, monobasic or binary alkyl ester, as di-isoadipate, iso-spermaceti ester alcohol stearic acid, the propylene glycol diesters of coconut fatty acid, Isopropyl myristate, decyl oleate, Wickenol 111, butyl stearate, palmitinic acid 2-ethylhexyl or be called the adulterant of the branched ester of Crodamol CAP.They can use separately or share, and depend on required performance.Perhaps, can use dystectic grease, as paraffinum molle alba and/or whiteruss or other mineral oil.
Be applicable to that the preparation to the eyes topical also comprises eye drops, wherein, activeconstituents is dissolved or suspended in the suitable carriers (aqueous solvent that especially is fit to activeconstituents).The concentration of activeconstituents in these preparations is preferably 0.01-20%, in some instances, is 0.1-10%, and in other examples, about weight is 1.0%.
Be adapted at the lozenge that the preparation of topical in the mouth comprises the activeconstituents in the base-material (normally sucrose and Sudan Gum-arabic or xanthan gum) that is contained in seasoning; Be contained in the lozenge of the activeconstituents in the inertia base-material (as gelatin and glycerine, or sucrose and Sudan Gum-arabic); With the mouth wash shua that is contained in the activeconstituents in the suitable liquid vehicle.
The preparation that is used for rectal administration can be made suppository with the suitable base-material that contains cocoa ester for example or salicylate.Carrier is that solid, the preparation that is fit to intranasal or inhalation comprise that particle diameter is for example at the pulvis that (comprises that particle diameter between 20-500 μ m, is an increment with 5 μ m, as 25 μ m, 30 μ m etc.) between the 1-500 μ m.Carrier is liquid, be fit to comprise with the preparation of the form administration of for example nasal spray or nasal drop the water-based or the oily solution of activeconstituents.The preparation that is fit to aerosol drug delivery can prepare with traditional method, can be with other therapeutical agent administration.The induction type therapeutical agent can easily carry out administration by the metered dose sucker.
The preparation that is fit to vagina administration can be the form of the vaginal suppository, stopper, creme, gel, paste, foaming agent or the sprays that contain activeconstituents and suitable carrier known in the art.
But the preparation that is fit to the intestines external administration should be aseptic, comprises that water-based and nonaqueous injection liquid, injection liquid can contain antioxidant, damping fluid, bacteriostatic agent and make preparation and the recipient's who intends usefulness the isoosmotic solute of blood; Water-based and nonaqueous sterile suspensions, but these suspension suspending agent-containing and thickening materials.Preparation can be the form of unitary dose or multi-dose container, and for example the bottle of Mi Feng ampoule and flexible stopper can be stored under the lyophilisation condition, only need face with before add sterile liquid carrier (for example water for injection).Interim injection liquid and suspension can be with sterile powder, granule and the tablet preparation of previous described kind.Preferable unit dose formulations is those preparations that contain the per daily dose or divided dose every day (front was described) of activeconstituents or contain its suitable part.
Except that the composition that preceding mask body is addressed, preparation of the present invention can comprise other this area relevant medicament of the type with the preparation of just discussing commonly used, for example, is fit to oral preparation and can comprises seasonings.The present invention also provides and contains a kind of top activeconstituents that defined and the animal medicinal composition of veterinary carriers at least.
Compound of the present invention can be used to provide and contains matrix or absorber material and as the controlled-release pharmaceutical formulation of one or more compounds of the present invention of activeconstituents.Wherein, the release of activeconstituents is may command and adjusting, to reduce medicine frequency or pharmacological kinetics or toxicity characteristic in order to improve compound.Be fit to the available traditional method preparation of oral controlled release preparation (wherein, dispersive unit contains one or more compounds of the present invention).All literature contents of quoting herein are incorporated by reference in this article.
All herein citing documents are incorporated the part of this paper as this specification sheets at this.
The following example is illustrated the present invention in more detail, but does not limit the scope of the invention.
Embodiment
The physical properties of TDF crystal form A has been measured the X-ray diffracting spectrum of TDF with Rigaku D/MAX-rA type x-ray diffractometer, carries out according to disclosed method with the sweep velocity at per minute 2 degree 2 θ angles..Under 40KV and 60mA, operate x-ray generator, shine with 4-35 ° 2 θ angles and scan the TDF crystal.The TDF of crystal form A shows the X-ray diffraction peak character, is expressed in about 5.1,7.0,10.7,11.9,12.9,13.7,15.2,15.6,16.4,19.0,20.3,21.5,22.3,25.5,26.0,27.4,30.7 and 31.1 places with 2 θ angles.
Can also analyze the TDF crystal by dsc, use differential scanning calorimeter (Perkin-ElmerDSC7 type) and carry out calorimetric scanning.Use about 5mg TDF crystal and obtain thermogram, under nitrogen, obtain thermogram with the sweep velocity of 10 ℃ of per minutes.TDF crystal form A crystalline thermogram has been located about 109.9 ℃ of characteristic peak and section start at about 113.1 ℃.
Use Switzerland Bruker Tensor 27 type FT-IR spectrographs and analyze the TDF crystal by infrared spectrometer according to the explanation of manufacturers.Contain the TDF crystal (about 5mg) of 1.0% weight of having an appointment and the transparent small pieces of about 90% weight (about 50mg) exsiccant KBr by grinding KBr and TDF powder to obtain the fine powder preparation.TDF crystal form A crystal is presented at the characteristic peak absorption spectrum in the Potassium Bromide, with cm
-1, be expressed as approximately: 3219 (O-H), 2986-2940 (fatty C-H), 1760 (alkyl ester C=O), 1692 (aryl C=N), 1620 (aryl C=C), 1270 (phosphonic acid ester P=O) and 1101 (C-O-C).
Embodiment 2
The physical properties of TDF crystal form B has been measured the X-ray diffracting spectrum of TDF with Rigaku D/MAX-rA type x-ray diffractometer, carries out according to disclosed method with the sweep velocity at per minute 2 degree 2 θ angles..Under 40KV and 60mA, operate x-ray generator, shine with 4-35 ° 2 θ angles and scan the TDF crystal.The TDF of crystal form B shows the X-ray diffraction peak character, is expressed in about 5.1,7.0,10.3,11.4,14.2,15.4,16.2,18.2,19.0,20.6,25.8 and 31.0 places with 2 θ angles.
Can also analyze the TDF crystal by dsc, use differential scanning calorimeter (Perkin-Elmer DSC7 type) and carry out calorimetric scanning.Use about 5mg TDF crystal and obtain thermogram, under nitrogen, obtain thermogram with the sweep velocity of 10 ℃ of per minutes.TDF crystal form B crystalline thermogram has been located about 111.6 ℃ of characteristic peak and section start at about 115.5 ℃.
Use Switzerland Bruker Tensor 27 type FT-IR spectrographs and analyze the TDF crystal by infrared spectrometer according to the explanation of manufacturers.Contain the TDF crystal (about 5mg) of 1.0% weight of having an appointment and the transparent small pieces of about 90% weight (about 50mg) exsiccant KBr by grinding KBr and TDF powder to obtain the fine powder preparation.TDF crystal form B crystal is presented at the characteristic peak absorption spectrum in the Potassium Bromide, with cm
-1Be expressed as approximately: 3225 (O-H), 2987 (fatty C-H), 1760 (alkyl ester C=O), 1685 (aryl C=N), 1269 (phosphonic acid ester P=O) and 1102 (C-O-C).
Embodiment 3
The preparation of TDF crystal form A is dissolved in about 300 grams TDF rough or other crystal formation in 5000 milliliters the dehydrated alcohol of warm (about 34-50 ℃ is typically 40 ℃), makes saturated solution, needs the stirring of minimum degree in order to obtain homogeneous phase solution.Under the stirring of minimum degree, add 20000 milliliters ether, be cooled to about 12-18 ℃, typical about 15 ℃, stop when beginning to form crystal stirring.Under 15 ℃, allow mixture leave standstill at least about 12 hours, typically about 12-30 hour.The pulpous state liquid that obtains is filtered.With premixed dehydrated alcohol and diethyl ether solution (1: 9 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature the about 1-10 of vacuum-drying days.If desired, the exsiccant product can be chosen grinding wantonly, obtains the white fine powder powder crystal of required granular size.Improve product purity if desired, randomly recrystallization TDF.Embodiment comprises the composition of instantaneous generation when carrying out method steps or operation.
Embodiment 4
The preparation of TDF crystal form B is dissolved in warm (about 34-50 ℃ to about 320 grams TDF rough or other crystal formation, be typically 40 ℃) 3000 milliliters methyl alcohol in, make saturated solution, need the stirring of minimum degree in order to obtain homogeneous phase solution, under the stirring of minimum degree, add 18000 milliliters hexane, be cooled to about 12-18 ℃, typical about 15 ℃, stop when beginning to form crystal stirring.Under 15 ℃, allow mixture leave standstill at least about 12 hours, typically about 12-30 hour.The pulpous state liquid that obtains is filtered, with premixed methyl alcohol and hexane solution (1: 9 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature the about 1-10 of vacuum-drying days.If desired, the exsiccant product can be chosen grinding wantonly, obtains the white fine powder powder crystal of required granular size.Improve product purity if desired, randomly recrystallization TDF.Embodiment comprises the composition of instantaneous generation when carrying out method steps or operation.
Embodiment 5
The preparation of several auxiliary material preparation crystal crystal form As that TDF pharmaceutical formulation 1 usefulness is following or the TDF300mg of crystal form B.
The preparation of being prepared contains TDF, pregelatinized Starch, croscarmellose sodium, Spherolac 100 and Magnesium Stearate.
| Component | Weight percent | Per unit content (mg/ sheet) |
| TDF | 50.0 | 300 |
| | 40.0 | 240 |
| Pregelatinized Starch | 5.0 | 30 |
| Croscarmellose sodium | 4.0 | 24 |
| Magnesium Stearate | 1.0 | 6 |
In said preparation, tackiness agent and disintegrating agent when pregelatinized Starch is used as compressing tablet.Croscarmellose sodium, inside is croscarmellose sodium, helps the disintegration and the dissolving of tablet.Spherolac 100 is used as thinner so that prepare and help tablet dissolved, and Magnesium Stearate helps tablet to take out from tabletting machine as lubricant.
The tablet preparation that contains TDF is as follows: pregelatinized Starch, croscarmellose sodium and Spherolac 100 are mixed in mixing tank, add entry until forming suitable wet granular.Grind this wet granular, drying is not higher than 3% until water capacity in fluidized-bed, dried particle grinds, and the outer auxiliary material of particle after will grinding then and particle, croscarmellose sodium and Spherolac 100 combination mix obtaining powdered mixture in mixing tank.This powdered mixture mixes with Magnesium Stearate then, is pressed into tablet again.Tablet is packed in high-density polyethylene bottle or the vial, and use polyester packaging material and optional silica-gel drier.
Embodiment 6
The preparation of several auxiliary material preparation crystal crystal form As that TDF pharmaceutical formulation 2 usefulness are following or the TDF 300mg of crystal form B.
The preparation of being prepared contains TDF, pregelatinized Starch, croscarmellose sodium, Spherolac 100 and Magnesium Stearate.
| Component | Weight percent | Per unit content (mg/ sheet) |
| TDF | 67.0 | 300 |
| | 23.0 | 103.1 |
| Pregelatinized Starch | 5.0 | 22.4 |
| Croscarmellose sodium | 4.0 | 18.0 |
| Magnesium Stearate | 1.0 | 4.5 |
In said preparation, tackiness agent and disintegrating agent when pregelatinized Starch is used as compressing tablet.Croscarmellose sodium, inside is croscarmellose sodium, helps the disintegration and the dissolving of tablet.Spherolac 100 is convenient to preparation and is helped tablet dissolved as thinner.Magnesium Stearate helps tablet to take out from tabletting machine as lubricant.
The tablet preparation that contains TDF is as follows: pregelatinized Starch, croscarmellose sodium and Spherolac 100 are mixed in mixing tank, add entry until forming suitable wet granular.Grind this wet granular, drying is not higher than 3% until water capacity in fluidized-bed, dried particle grinds, and the outer auxiliary material of particle after will grinding then and particle, croscarmellose sodium and Spherolac 100 combination mix obtaining powdered mixture in mixing tank.This powdered mixture mixes with Magnesium Stearate then, is pressed into tablet again.Tablet is packed in high-density polyethylene bottle or the vial, and use polyester packaging material and optional silica-gel drier.
Accompanying drawing of the present invention:
● the crystalline XRD figure of Fig. 1 crystal form A.
● Fig. 2 carries out the differential scanning calorimetry to the crystallization of crystal form A and the differential thermogram that obtains.
● Fig. 3 carries out that infrared absorption is measured and the infrared absorption spectrum that obtains to the crystallization of crystal form A.
● the crystalline XRD figure of Fig. 4 crystal form B.
● Fig. 5 carries out the differential scanning calorimetry to the crystallization of crystal form B and the differential thermogram that obtains.
● Fig. 6 carries out that infrared absorption is measured and the infrared absorption spectrum that obtains to the crystallization of crystal form B.
Claims (6)
1. the method for preparation fumaric acid tenofovir disoproxil (tenofovir disoproxil fumarate is called for short " TDF ") new crystal is characterized in that the crystallization of described new crystal for not moisture and other recrystallisation solvent, is referred to as crystal form A and B.
2. various crystal formations as claimed in claim 1, can be with characteristic the characterizing property evaluation of several method [normally using Cu-Ka radiation X-ray powder diffraction (XRD) and dsc analysis (DSC)] to them: (1) crystal form A: the XRD characteristic peak be expressed in about 5.1,7.0,10.7,11.9,12.9,13.7,15.2,15.6,16.4,19.0,20.3,21.5,22.3,25.5,26.0,27.4,30.7 and 31.1 places and DSC endotherm(ic)peak at about 113.1 ℃ with 2 θ angles; (2) crystal form B: the XRD characteristic peak is expressed in about 5.1,7.0,10.3,11.4,14.2,15.4,16.2,18.2,19.0,20.6,25.8 and 31.0 places and DSC endotherm(ic)peak at about 115.5 ℃ with 2 θ angles.
One kind from the solution of crystallization solvent crystallization go out the as claimed in claim 1 various crystal formation methods of fumaric acid tenofovir disoproxil, wherein, described crystallization solvent is selected from following (I) or (I) and (II) mixed solvent.As the need mixed solution, about 1: 1 of its volume ratio is to 1: 10:(I) the first crystallization solvent, TDF has high-dissolvability therein, is selected from (a) C
1-4Alkyl formamides, (b) C
1-4Alkyl ethanamide, (c) C
1-6Alkanol, (d) formic acid C
1-4Alkyl ester, (e) acetate C
1-4Alkyl ester, (f) C
1-4Alkyl ketone (example is known acetone and methyl ethyl ketone), (g) methyl-sulphoxide, (h) tetrahydrofuran (THF), (i) acetonitrile and (j) slightly acidic (pH 3-4) aqueous solution; (II) the second crystallization solvent, TDF has low solubility therein, by (1) formula R
1-O-R
2First dialkyl ether form, wherein, R
1Be the alkyl of 1,2,3,4,5 or 6 carbon atom, R
2Be the alkyl of 2,3,4,5 or 6 carbon atoms, wherein, R
1And R
2Identical or different, perhaps R
1And R
2Both link together, and form 5,6,7 or 8 yuan of rings, (2) hexane, (3) methylene dichloride, (4) 1,2-ethylene dichloride or chloroforms.
4. contain any defined TDF crystal form A of claim 1-3 and B, and be mixed with the composition of one or more medicinal tax row agent.
5. composition as claimed in claim 4 contains the made various types of tablets of composition of per daily dose 10-1000mg TDF crystal form A and B, capsule (containing soft capsule) and other pharmaceutical dosage form.
6. any defined TDF crystal form A of claim 1-3 and B are applied to prepare the treatment and the prophylactic agent of Type B viral hepatitis and human immunodeficiency virus (HIV/AIDS) infection as single or compound active composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710014625 CN101066980A (en) | 2007-05-08 | 2007-05-08 | Crystalline tenofovir fumarate and its medicine prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710014625 CN101066980A (en) | 2007-05-08 | 2007-05-08 | Crystalline tenofovir fumarate and its medicine prepn |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101066980A true CN101066980A (en) | 2007-11-07 |
Family
ID=38879693
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710014625 Pending CN101066980A (en) | 2007-05-08 | 2007-05-08 | Crystalline tenofovir fumarate and its medicine prepn |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101066980A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| CN101948485A (en) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | Alpha crystal form of tenofovir disoproxil fumarate, and preparation method and application thereof |
| JP2011518815A (en) * | 2008-04-25 | 2011-06-30 | シプラ・リミテッド | Crystalline form of tenofovir disoproxil and process for producing the same |
| CN103127028A (en) * | 2013-03-14 | 2013-06-05 | 南京恒道医药科技有限公司 | Capsule containing tenofovir disoproxil fumarate |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| CN105106227A (en) * | 2015-08-14 | 2015-12-02 | 正大天晴药业集团股份有限公司 | Drug combination of tenofovir dipivoxil disoproxil |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
-
2007
- 2007-05-08 CN CN 200710014625 patent/CN101066980A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| JP2011518815A (en) * | 2008-04-25 | 2011-06-30 | シプラ・リミテッド | Crystalline form of tenofovir disoproxil and process for producing the same |
| CN101948485A (en) * | 2010-08-30 | 2011-01-19 | 杭州和素化学技术有限公司 | Alpha crystal form of tenofovir disoproxil fumarate, and preparation method and application thereof |
| WO2012027972A1 (en) * | 2010-08-30 | 2012-03-08 | 杭州和素化学技术有限公司 | TENOFOVIR DISOPROXIL FUMARATE α-CRYSTAL FORM, PREPARATION METHOD AND APPLICATION THEREOF |
| CN101948485B (en) * | 2010-08-30 | 2012-07-25 | 杭州和素化学技术有限公司 | Alpha crystal form of tenofovir disoproxil fumarate, and preparation method and application thereof |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| CN103127028A (en) * | 2013-03-14 | 2013-06-05 | 南京恒道医药科技有限公司 | Capsule containing tenofovir disoproxil fumarate |
| CN105106227A (en) * | 2015-08-14 | 2015-12-02 | 正大天晴药业集团股份有限公司 | Drug combination of tenofovir dipivoxil disoproxil |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101066980A (en) | Crystalline tenofovir fumarate and its medicine prepn | |
| CN1131026C (en) | Valaciclovir bablets containing colloidal silicon dioxide | |
| CN1970547B (en) | Novel febuxostat crystal form and its preparation method | |
| CN1103593C (en) | Synergistic combination of zidovudine | |
| TWI224103B (en) | Nucleotide analog and pharmaceutical composition containing the same | |
| ES2229342T3 (en) | MESILATE SALTS OF 5- (2- (4- (1,2-BENZOISOTIAZOL-3-IL) -1-PIPERAZINIL) ETIL) -6-CHLORINE-1,3-DIHYDRO-2H-INDOL-2-ONA (= ZIPRASIDONA), YOUR PREPARATION AND USE AS A DOPAMINE D2 ANTAGONIST. | |
| JP2009263389A (en) | Nucleotide analog compound | |
| CN104507902A (en) | Anthraquinone analogs and methods of making and using thereofanthraquinone analogs and methods of making and using thereof | |
| CN101830896A (en) | Organic acid salt of optical isomer of penehyclidine | |
| CN110041326A (en) | Berberine hydrochloride and fumaric acid eutectic object and preparation method and its composition and purposes | |
| CN1051550C (en) | 4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl ] -2-cyclopentene-1-methanol succinate as antiviral agent | |
| CN1263529A (en) | Carbocyclic nucleoside hemisulfate and its use in treating viral infectiosn | |
| CN109232293A (en) | Fragrant happy amine crystalline substance G type, preparation method and its composition and purposes | |
| CN101993417A (en) | Stable novel crystal form of dimemorfan phosphate | |
| CN103288832A (en) | Pyrrolopyridazine compounds with antiviral properties | |
| CN115124420B (en) | Rhein and matrine eutectic hydrate, preparation method, composition and application thereof | |
| CN1925860A (en) | Methods for the production of sildenafil base and citrate salt | |
| CN102093309A (en) | Novel crystal forms of Febuxostat and preparation method of novel crystal forms | |
| CN103159815A (en) | Monophosphate vidarabine crystalline compound, medical composition and preparation method thereof | |
| CN100341495C (en) | Solid dispersion and preoral combination of glibenclamide and preparation method | |
| CN1742723A (en) | Medicine composition containing temozolomide-8-carboxylic ether and use of such compound for preparing anti-tumor medicine | |
| CN105753869B (en) | A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor | |
| CN107200720B (en) | A kind of brilliant II type substance, its preparation method and its pharmaceutical composition and purposes | |
| CN105732642B (en) | A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor | |
| CN102675346A (en) | Levamisole organic acid salt, synthetic method for levamisole organic acid salt and medicinal composition of levamisole organic acid salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20071107 |