CN101574356A - Tenofovir disoproxil pharmaceutical salt and preparations thereof - Google Patents
Tenofovir disoproxil pharmaceutical salt and preparations thereof Download PDFInfo
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- CN101574356A CN101574356A CNA2008100157801A CN200810015780A CN101574356A CN 101574356 A CN101574356 A CN 101574356A CN A2008100157801 A CNA2008100157801 A CN A2008100157801A CN 200810015780 A CN200810015780 A CN 200810015780A CN 101574356 A CN101574356 A CN 101574356A
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Abstract
The invention relates to an adenine (tenofovir disoproxil) salt containing 9-[(R)-2-[[double[[(isopropoxy carbonyl) oxyl] methoxy] phosphinyl] methoxy] propyl] or medicaments of pharmacological activated derivatives thereof. The invention provides a tenofovir disoproxil pharmaceutical salt and a synthesis technology of the pharmacological activated derivatives of the tenofovir disoproxil pharmaceutical salt and also relates to a preparation technology of the pharmaceutical preparations containing the tenofovir disoproxil pharmaceutical salt and the rmacological activated derivatives thereof. The preparations can be used for administration on patients for curing or preventing Type B viral hepatitis or human immunodeficiency virus (HIV/AIDS) infection and HBV or HIV mutant infection with drug tolerance to nucleoside inhibitors and non-nucleoside inhibitors.
Description
The invention technical field
The present invention relates to the pharmaceutical salts of tenofovir disoproxil (English name " tenofovir disoproxil ") and the method for pharmacologically active derivant and synthetic these chemical compounds thereof.In addition, the invention still further relates to the preparation technology of the preparation that contains tenofovir disoproxil salt or its pharmacologically active derivant.The preparation that is provided can be used for being administered to treatment or the prevention that the patient carries out Type B viral hepatitis or HIV (human immunodeficiency virus) (HIV/AIDS) infection.
The invention technical background
The tenofovir disoproxil fumarate chemical name 9-[2-(R)-[[two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyl] methoxyl group] propyl group] the adenine fumarate, common name tenofovir disoproxilfumarate, american goods name Viread} is a kind of acyclic bunch of ucleotides reverse transcriptase inhibitors, 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 HIV (human immunodeficiency virus) (HIV/AIDS) infection.
The synthetic of tenofovir (tenofovir) can be referring to following known references: (1) " Phosphonylmethoxyalkyl and Phosphoneylalkyl Derivatives of Adenine ", I.Rosenberg etc., Czech's chemical communication collection (Collection Czechoslovak Chem.Commun.) 1988,53 volumes, 2753 pages; (2) " Synthesis of EnantiomericN-(2-phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases; I:the Stepwise Approach ", A.Holy etc., Czech's chemical communication collection (CollectionCzechoslovak Chem.Commun.) nineteen ninety-five, 60 volumes, 1196 pages; (3) " Synthesis ofEnantiomeric N-(2-phosphonomethoxypropyl) Derivatives of Purine andPyrimidine Bases; II:the Synthon Approach ", A.Holy etc., Czech's chemical communication collection (Collection Czechoslovak Chem.Commun.) nineteen ninety-five, 60 volumes, 1391 pages; And (4) " Practical Synthesis of the Anti-HIV Drug:PMPA ", L.M.Shultze etc., Dutch tetrahedron wall bulletin (Tetrahedron Letters) 1998,39 volumes, 1853 pages.
The synthetic of tenofovir disoproxil fumarate (tenofovir disoproxil fumarate) can be referring to following known references: Chinese patent 97197460.8 (application number), 98807435.4 (application numbers), ZL200410046290.X (patent No.) and 200510099916.8 (application numbers).The intimate identical synthetic method and the preparation process thereof that contain tenofovir disoproxil and fumaric acid (1: 1) addition salts of the invention of U.S. Gilead Sciences Inc have been reported in these in state's patent application.
It is reported that heavy dose of fumaric acid alkyl ester finds to have nephrotoxicity { (1) J.I.Roodnat etc., Switzerland's medical science weekly (Scheweiz.Med.Wochenschr.),, 119,826-830 in 1989 to the psoriatic; (2) K.Dalhoff etc., German medical science weekly (Dtsch.Med.Wochenschr.), nineteen ninety, 115,1014-1017; (3) W.Stuhlinger etc., German medical science weekly (Dtsch.Med.Wochenschr.), nineteen ninety, 115,1712-1715}.Should its renal function of careful observation when therefore, the someone advises that the bad patient of renal function taken heavy dose of fumarate.
The invention provides the technology that contains various tenofovir disoproxil pharmaceutical salts and pharmacologically active derivant and synthetic these chemical compounds.Lay the foundation for from these numerous tenofovir disoproxil pharmaceutical salts, filtering out low further exploitation of toxicity with the high medicine of drug effect.Synthesis technique provided by the present invention is different from that known references reports, and has simple synthetic method and economic dispatch advantage.
In addition, the invention still further relates to preparation and the preparation technology thereof that exploitation has higher bioavailability and low food effect.Its unit formulation contains daily dose 10-1000mg tenofovir disoproxil salt or its pharmacologically active derivant.This kind new medicine can provide the treatment safety and the effectiveness of reinforcement, produce lower drug resistance simultaneously, and expection has higher patient's compliance.
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 or HIV (human immunodeficiency virus) (HIV/AIDS) infection.The preparation that is provided can be united with other medicines and taken, and also can make compound medicines with other medicines.These combination medicines will further be strengthened the safety and the effectiveness for the treatment of, and produce lower drug resistance simultaneously, and expection have higher patient's compliance.
Summary of the invention
The present invention relates to contain 9-[(R)-two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyls of 2-[[] methoxyl group] propyl group] pharmaceutical salts and the pharmacologically active derivant thereof of adenine (tenofovir disoproxil), its structure is as follows.
Wherein a is and the molal quantity of the salifiable chemical compound of tenofovir disoproxil, and its span is 0.0 to 10.0; B be with tenofovir disoproxil or its salt the molal quantity of bonded compositions, its span is 0.0 to 10.0.
Term as used herein " pharmacologically active derivant " comprises that following any one contains the chemical compound of tenofovir disoproxil: pharmaceutical salts, hydrate, solvate (solvates), eutectic thing (co-crystals), stereoisomer comprise enantiomer, diastereomer or stereoisomerism enrichment or racemic mixture and can provide (directly or indirectly) above-claimed cpd or any one other chemical compound of its antiviral activity metabolite or residue after the patient takes.
The chemical name of tenofovir disoproxil of the present invention comprises: [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester (CAS registration number 201341-05-1); 9-[(R)-and two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyls of 2-[[] methoxyl group] propyl group] adenine (based on the tenofovir disoproxil fumarate of CAS registration number 202138-50-9); And 2,4,6,8-four oxa-s-5-phosphorus nonane diacid-5-[[(1R)-2-(the fast cry of certain animals of 6-amino-9H--9-yl)-1-methyl ethoxy] methyl-two (1-first and second bases) ester-5-oxide (based on the tenofovir monohydrate of CAS registration number 206184-49-8).
The invention provides the synthesis technique of the pharmaceutical salts and the pharmacologically active derivant thereof of tenofovir disoproxil, but advantages such as that its synthetic method has is easy, economic and industrialization.
One aspect of the present invention is to contain the pharmaceutical unit dosage forms of tenofovir disoproxil salt or its pharmacologically active derivant.The suitable type that unit dosage forms contained and the surfactant of content or emulsifying agent have the special efficacy that can improve its bioavailability and reduce food effect.Can prepare this unit dosage forms for oral or other administration, and with regard to the characteristic of component that this class has different structure, described unit dosage forms should have beat all chemical stability." chemical stability " herein is meant that when this product is pharmaceutical dosage form the Degradation that tenofovir disoproxil took place is less than about 10% at least greatly, preferably is lower than 1%, further preferably is lower than 0.05% in 24 hours.
Another aspect of the invention provides medicine of the present invention to be used for the treatment of the application of above-mentioned hepatitis B virus or HIV (human immunodeficiency virus) (HIV/AIDS) infection in preparation.Medicine of the present invention can be made compound medicines with other medicines.These compound medicines will further be strengthened the safety and the effectiveness for the treatment of, and produce lower drug resistance simultaneously, and expection have higher patient's compliance.
Tenofovir disoproxil salt and the general introduction of pharmacologically active derivant synthesis technique thereof:
Tenofovir disoproxil of the present invention (tenofovir disoproxil) and pharmaceutical salts synthesis technique step thereof are as follows:
Its synthesis technique with existing ethyl on the market-(R)-lactate (any other alkyl-(R)-lactate) as initiation material; obtain the two methylchlorosilane bases of (R)-2-O-tertiary butyl-1-O-p-toluenesulfonyl-1 through three-step reaction; the 2-propylene glycol; itself and adenine and the reaction of catalyst carbonic acid caesium are obtained (R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group] adenine (step 4a); without separation; itself and sodium alcoholate and tolysulfonyl oxygen methylphosphonic acid diethylester (by behind phosphonous acid diethylester and the polyformaldehyde reaction again toluenesulfonic acidization prepare) (step 5); (the R)-9-[2-diethyl phosphonyl methoxyl base propyl group that obtains] adenine takes off ester with chlorination trimethyl silicane and potassium iodide and obtains the thick product of tenofovir (step 6a), makes it deposition and purification from water by regulating pH value.This product reuse water recrystallization purifying obtains tenofovir monohydrate (step 6b).
This method is used sodium alcoholate in step 5, slight heat release when it joins in the reactant mixture.The high-activity alkali for example application of NaH makes the exothermic reaction that produces hydrogen be difficult to control.Therefore, compare with using sodium alcoholate, the operation of using NaH is more difficult, needs more careful.Compare with using NaH, use sodium alcoholate and also make the product that obtains have the side-product characteristic of improvement, for example: use sodium alcoholate and can cause containing in the product more a spot of initial substance or excessive alkylating product usually.
Except as otherwise noted, described herein " alkoxyl " is meant the hydrocarbon group that contains 1,2,3,4,5 or 6 carbon atom (being " alkane " described herein) that is connected with oxygen atom.Its example has-OCH
3,-OCH
2CH
3,-OCH
2CH
2CH
3,-OCH (CH
3)
2,-OCH
2CH
2CH
2CH
3,-OCH
2CH (CH
3)
2,-OCH
2(CH
3) CH
2CH
3,-OC (CH
3)
3,-OCH
2CH
2CH
2CH
2CH
3,-OCH (CH
3) CH
2CH
2CH
3,-OCH (CH
2CH
3)
2,-OC (CH
3)
2CH
2CH
3,-OCH (CH
3) CH (CH
3)
2,-OCH
2CH
2CH (CH
3)
2,-OCH
2CH (CH
3) CH
2CH
3,-OCH2C (CH3) 3 ,-OCH2CH2CH2CH2CH2CH3 ,-OCH (CH
3) CH
2CH
2CH
2CH
3,-OCH (CH
2CH
3) CH
2CH
2CH
3,-OC (CH
3)
2CH
2CH
2CH
3,-OCH (CH
3) CH (CH
3) CH
2CH
3,-OCH (CH
3) CH
2CH (CH
3)
2,-OC (CH
3) (CH
2CH
3)
2,-OCH (CH
2CH
3) CH (CH
3)
2,-OC (CH
3)
2CH (CH
3)
2,-OCH (CH
3) C (CH
3)
3
The method that is used for preparing tenofovir disoproxil salt is to use the tenofovir disoproxil that contact as reaction and the medicinal acid of suiting with forming.The general solution that contains the 3-430mg/ml tenofovir disoproxil of having an appointment of using, the about 4-100mg/mL of concentration that it is used usually.General mol ratio about 0.6: the 1-1.4 that uses: 1 tenofovir disoproxil: acid, about 0.9: 1.1 or about 1: 1 usually.Usually solutions employed contains organic solvent for example alkyl acetate, 1-Methyl-2-Pyrrolidone, trialkylamine, C
1-6Alkanol, pyridine, dimethyl formamide, dimethyl sulfoxine, acetone, dichloromethane, oxolane, acetonitrile, toluene, dimethylbenzene, methyl ethyl ketone, 1,2-dichloroethanes or chloroform.
The pharmaceutical salts of tenofovir disoproxil comprises suitable alkali for example alkali metal (as sodium), alkaline-earth metal (as magnesium), ammonium and NX
4 -(wherein X is C
1-C
4Alkyl), perhaps for example fumaric acid, acetic acid, benzoic acid, lactic acid, tartaric acid, maleic acid, malonic acid, malic acid, oxalic acid, newborn diacid and succinic acid of organic carboxyl acid; Also comprise organic sulfonic acid for example sulfamic acid, methanesulfonic acid, ethyl sulfonic acid, hydroxyethylsulfonic acid. and p-methyl benzenesulfonic acid, and mineral acid for example hydrochloric acid, sulphuric acid and phosphoric acid.
For the application of treatment or prevention, the salt of active ingredient of drugs of the present invention should be pharmaceutically acceptable, and promptly they should be derived by pharmaceutical acceptable acid or alkali and obtain.In addition, its all pharmaceutical salts (no matter whether pharmaceutically acceptable acid or alkali derive obtain) all within the scope of the present invention.
The preparation of tenofovir disoproxil salt can also be by the mutual exchange between its salt.Can prepare strong acid salt example hydrochloric acid salt and sulfate by following two kinds of methods from the salt of weak acid such as the fumarate of tenofovir disoproxil: (1) passes through free alkali (embodiment 11) by direct salt exchange (embodiment 10) and (2).Exchange between the salt of weak acid of tenofovir disoproxil then will realize (embodiment 12) by anion exchange resin.
Any one chemical compound that contains following tenofovir disoproxil or its pharmaceutical salts in the medicine of the present invention: hydrate, solvate (solvates), eutectic thing (co-crystals), stereoisomer and after the patient takes, can provide (directly or indirectly) above-claimed cpd or any one other chemical compound of its antiviral activity metabolite or residue.
The formulation components of tenofovir disoproxil salt and pharmacologically active derivant thereof and preparation technology's general introduction:
Pharmaceutical preparation of the present invention contains described medicine and one or more plant pharmaceutically acceptable auxiliaries or excipient and other optional therapeutic agent.The pharmaceutical preparation that contains active component can be with any suitable mode administration.When being used for oral administration, but can be prepared into for example pill, tablet, lozenge, water or oil suspension dispersant or granule, Emulsion, hard or soft capsule, syrup (referring to " pharmaceutics " of Cui Fude chief editor's the professional usefulness of confession pharmacy class (People's Health Publisher, 2003 the 5th edition) and latest edition " the relevant chapter of Chinese pharmacopoeia).Wishing to be used for liquid preparations for oral administration can be according to any one preparation of pharmaceutical compositions method preparation known in the art, in order to obtain good to eat preparation, this based composition can contain one or more adjuvant, comprises antioxidant, sweeting agent, aromatic, coloring agent and antiseptic.These excipient can be, for example inert diluent such as microcrystalline Cellulose, starch, lactose, lactose monohydrate, calcium carbonate or sodium carbonate, calcium phosphate or sodium phosphate; Granulation and disintegrating agent such as cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, corn starch or alginic acid; Binding agent such as cellulose, polyvidone, gelatin or Radix Acaciae senegalis; Lubricant such as sodium stearate, magnesium stearate or Talcum; And surfactant or wetting agent such as sodium lauryl sulphate (SLS), poloxamer 407 (Poloxamer 407, or claim Pluronic F127) and Tween 80 (Tween 80).Tablet is coating not, also can comprise microencapsulation with disintegrate and the absorption of delay in gastrointestinal tract, thereby lasting release action is provided in a long time according to the known method coating.For example can postpone service time material as separately or with blended glyceryl monostearate of wax or glycerol distearate.
Surfactant or emulsifying agent adjuvant have solubilising, effects such as emulsifying and moistening.The surfactant or the emulsifying agent that contain suitable type and content in preparation of the present invention can be used for improving drug bioavailability and reduce food effect.Used surfactant or solubilizing agent can be selected from following kind: high fatty alcohol sulfuric acid ester such as sodium lauryl sulphate (SDS or SLS, claim not only sodium laurylsulfate), sodium hexadecyl sulfate (claim not only spermol sodium sulfate) and sodium stearyl sulfate (but also claiming stearyl alcohol sodium sulfate); Poloxamer or pluoronics (Poloxamer or Pluronic) are as poloxamer 188 ((Poloxamer 188), poloxamer 338 ((Poloxamer 338) and poloxamer 407 ((Poloxamer 407); Tweens (Tween or Polysorbate) polysorbas20, polysorbate40, polysorbate60 and Tween 80; Spans (Span) is as span 20, span 40, sorbester p18, sorbester p38, sorbester p17 and sorbester p37; And VE succinic acid macrogol ester (Vitamin E TPGS).
The preparation that is used for oral administration can also be made into active component and inertia group diluent, the mixed hard gelatin capsule of starch,pregelatinized, calcium phosphate or Kaolin is for example perhaps made the wherein Gelseal of active component and water or oleaginous base such as Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil.
Water suspension of the present invention contains and the blended active substance of excipient that is suitable for making water suspension.This class excipient comprises suspending agent such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, xanthan gum and Radix Acaciae senegalis, disperses or the condensation product (as Tween-81) of the condensation product (as 17 ethylidene oxygen hexadecanols) of condensation product (as Myrj 45), oxirane and the long-chain fatty alcohol of phosphine fat (as lecithin), epoxyalkane and the fatty acid of wetting agent such as native form, oxirane and the ester that obtained by fatty acid and the esterification of hexitol anhydride moiety.Water suspension can also contain one or more plants antiseptic for example ethyl or n-propyl p-hydroxybenzoate, one or more kind coloring agent, one or more aromatic and one or more kind sweeting agent such as raw sugar, Sucralose or glucide.
Making up oil suspensoid can be by being suspended in active component in vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois or mineral oil such as the liquid paraffin.Oral suspensions can contain thickening agent, for example Cera Flava, hard paraffin and hexadecanol.In order to obtain good to eat oral formulations, can add above-mentioned sweeting agent and aromatic.These compound medicines can for example ascorbic acid, BHT etc. store by adding antioxidant.
But, make active component and dispersant or wetting agent, suspending agent and one or more plant antiseptic and form mixture by in the present invention's dispersant that is suitable for preparing water suspension and granule, adding entry.Suitable dispersion or wetting agent and suspending agent are enumerated in front.Can also contain other excipient, for example sweeting agent, aromatic and coloring agent.
Medicine of the present invention can also be oil or aqueous emulsion or Liposomal formulation form.Oil phase can be for example olive oil or an Oleum Arachidis hypogaeae semen of vegetable oil, mineral oil is liquid paraffin for example, the natural gum that perhaps their mixture, examples of suitable emulsifiers comprise native form for example Radix Acaciae senegalis and xanthan gum, native form phosphine fat for example the Semen sojae atricolor lecithin, by fatty acid and hexitol anhydride derive obtain ester or part ester for example dehydrated sorbitol mono-fatty acid ester and these part esters and oxirane combine for example Tween-81 of product.Emulsion can also contain pleasantly sweet and aromatic.Syrup can also for example glycerol, Sorbitol or raw sugar be prepared with sweeting agent.This class preparation can also contain buffer agent, antiseptic, aromatic or coloring agent.
Medicine of the present invention can be the form of sterile injectable preparation, for example sterile injectable water or oiliness suspensoid.Described suspensoid can be according to known method, and suitable dispersion of having mentioned above the use or wetting agent and suspending agent are prepared.Sterile injectable preparation can also be can accept sterile injectable solution agent or suspensoid in diluent or the solvent at the avirulence parenteral, and for example 1, the solution in the 3-butanediol perhaps is prepared into the form of freeze-dried powder.In acceptable media, spendable solvent is water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, aseptic fixedly oil also can be used as solvent or suspension media usually.To achieve these goals, the fixedly oil of any one gentleness be can use, synthetic glycerine monoesters or diester comprised.In addition, similarly fatty acid for example oleic acid also can be used for preparing injection.
Medicine of the present invention can be in parenteral injection, and for example in intravenous, intraperitoneal, the ventricle, intracranial, intramuscular or subcutaneous injection, perhaps they also can pass through the infusion methods administration.They preferably use with the sterile aqueous solutions form that contains other material, and other material for example makes solution and isoosmotic enough salt of blood or glucose.If necessary, aqueous pharmaceutical suitably can be cushioned (preferably its pH is 3-9).The preparation of suitable parenteral formulation under aseptic condition can be finished by standard pharmaceutical technology well-known to those skilled in the art easily.
Medicine of the present invention also can intranasal or inhalation, and Foradil Aerolizer formoterol fumarate or aerosol spray form are sent by propellant from pressurizing vessel or nebulizer easily, propellant is dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, hydrofluoroalkane for example 1 for example, 1,1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas in the situation of pressurised aerosol, are determined dosage unit by the valve that metering is provided.Pressurizing vessel or nebulizer can contain the mixture that for example utilizes ethanol and propellant solution or the suspensoid as the medicine of the present invention of solvent, it can also contain for example sorbitan trioleate of lubricant, can be mixed with for example form of sucrose or starch of the mixture of powders that contains described medicine and suitable powder substrate with being used for the capsule of inhaler or insufflator and cartridge case (for example by gelatin preparation).Preferred aerosol or the dry powder formulations regulated makes when patient's administration each dosing or " once spraying " contain the medicine of 20 μ g to 20mg.The total daily dose of aerosol can be 20 μ g to 20mg, in one day they can with single dose administration or common be with the divided dose administration.
Active component and carrier material merge and obtain unit dosage forms, and its consumption depends on the patient that receives treatment and the concrete model of administration.For example, prepare delivery formulations in time for human oral and can contain about 10-1000mg active substance medicine and suitably and the carrier material of conventional amount used, can account for total composition about 5 to about 95% (weight: weight).Can prepare the medicine that when taking, easily content is detected.For example, in order to realize volume, prepare to contain about 3-500 μ g active component/ml soln agent for the aqueous pharmaceutical of intravenous infusion with about 30mL/ hour speed infusion of suitable.As mentioned above, the preparation of the present invention that is fit to oral administration discrete unit form for example tablet, capsule or cachet, powder or granule, the solution in water or on-aqueous liquid or suspensoid or the oil in water emulsion or the Water-In-Oil liquid emulsion that can be prepared to the active component that contains predetermined content separately.Active component can also with disposablely inject, the form administration of electuary or paste.
Medicine of the present invention can be made the pharmaceutical preparation of unit dosage forms easily.Conventional unit dosage forms preparation contains the active component that content is 10mg to 1000mg (for example but be not limited in 30mg to 600mg) separately, all can obtain the drug effect of tenofovir disoproxil salt or its pharmacologically active derivant under ratio in a big way.For example, unit dosage forms can contain tenofovir disoproxil salt or its pharmacologically active derivant of about 10mg to 1000mg.Better is tenofovir disoproxil salt or its pharmacologically active derivant that unit dosage forms can contain about 30mg to 600mg.Show that the consumption of antiviral activity is used for medicine when in embodiments, medicine can be with independent use.The consumption of employed tenofovir disoproxil mesylate is respectively 200mg to 300mg in the example of formulations.In the described medicine, other dosage is also included within the scope of the invention.
Those skilled in the art should understand that, the required absorption of active ingredient of combination of the present invention in being used for the treatment of depends on various factors, the symptom character, patient age and the situation that comprise the patients receiving treatment, it is finally by the doctor in charge or health care practitioner decision.The factor of need considering comprises administering mode and preparation nature, weight in patients, age and roughly situation and patients receiving treatment's the disease character and the order of severity.For example, be used for the treatment of in the HBV infection research at external (containing the U.S.) II/III phase folk prescription medicament of tenofovir disoproxil fumarate, the dosage once a day that the patient took is 300mg.
Medicine of the present invention can make the patient need not the dosage regimen of multiple dose, alleviates needs of patients and remembers and comply with complicated every day of administration time and the burden of dosage regimen.By with in tenofovir disoproxil or its pharmacologically active derivant unit dosage forms, the form that can take single dose every day is finished ideal every day of dosage regimen.The medicine of the tenofovir disoproxil of being prepared or its pharmacologically active derivant can be used as single pill and takes once every day.
The segregation phenomenon of active component in drug powder and granule is a recognized techniques difficult problem, and it is inhomogeneous that it may cause active component to disperse in final dosage form, and some principal element that causes the segregation phenomenon is little owing to widening, shape and density.When preparation contained the single even tablet of various active composition of different densities and different-grain diameter, the segregation phenomenon was especially thorny.Fluidizer is the material that traditional being used for improves granule and powder flow behavior by reducing the friction between the granule.Referring to " pharmaceutics " of Cui Fude chief editor's the professional usefulness of confession pharmacy class (People's Health Publisher, 2003 the 5th edition) and latest edition " the relevant chapter of Chinese pharmacopoeia is introduced into as a reference at this.Usually before tablet press, in pharmaceutical composition, add fluidizer to promote particulate matter flowing in tablet pelleter fatal weakness.Fluidizer comprises: silica sol, no asbestos Talcum, lagoriolite, calcium silicates, cellulose powder, microcrystalline Cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearate, calcium stearate, magnesium stearate, zinc stearate, starch, starch 1500, Stepanol MG and magnesium oxide.For example, just contain silica sol among the tablet formulation embodiment as fluidizer.For each active component being obtained and keeping uniformity, can contain fluidizer in the novel drugs of the present invention.
The invention provides and contain the enough pharmaceutical preparation uniformly that active component is tenofovir disoproxil or its pharmacologically active derivant, and the method for using this pharmaceutical preparation.In wet preparation method, utilize the aqueous solution that contains binding agent to spray and reach the uniformity of medicine in tablet or capsule.Its wet method preparation process comprises at first tenofovir disoproxil or its pharmacologically active derivant and the adjuvant mix homogeneously in agitator with described amount, again the binding agent of described amount is dissolved in an amount of aqueous solution in 25 ℃ to 80 ℃ temperature ranges and (comprises organic solvent), then with its be sprayed on tenofovir disoproxil or its pharmacologically active derivant and the adjuvant mixture that is being stirred.After the solvent in the wet granular of gained was dried removal, tenofovir disoproxil or its pharmacologically active derivant can be adhered to the adjuvant surface equably.Do the segregation phenomenon that can prevent in the granule like this and the medicine that reduces follow-up preparation process lost.The granule that drying is crossed and other be of the present invention to resemble disintegrating agent and the lubricant adjuvant mixes.The granule of gained can be pressed into tablet then or dress is made capsule.
When stir granulating, the principal element that influences size, compactness and the uniformity has: the kind of (1) binding agent with and solution addition and adding mode; (2) granularity of tenofovir disoproxil or its pharmacologically active derivant and adjuvant mixture; (3) mixing speed; (4) position of the type shape of agitator and angle, cutter etc.Maintain in 25 ℃ to the 80 ℃ temperature ranges, aqueous solution should be sprayed onto tenofovir disoproxil or its pharmacologically active derivant and the adjuvant compositions of mix homogeneously already under suitable flow and pressure.The flow of spraying and state should strict control reduce granule segregation phenomenon.In the spray solution process, the mixture of tenofovir disoproxil or its pharmacologically active derivant and adjuvant should constantly stir by the mode of machinery or air-flow.When using mechanical agitation, the mixture of tenofovir disoproxil or its pharmacologically active derivant and adjuvant can be placed in the high speed agitator and stir.When solvent was the water of pure water or pH regulator, suitable baking temperature should be in 50 ℃ to 80 ℃ scopes.When granulating with fluid bed, can pack tenofovir disoproxil or its pharmacologically active derivant and various adjuvant in the container into, go on foot the air-flow that is blown into preference temperature by sieve plate down from bed, make material mix homogeneously under fluidized state, begin to spray into aqueous solution then, powder begins coalescent granulating, through spraying and drying repeatedly, stop spraying when particulate size meets the requirements, the granule of formation continues to send hot air drying in bed, and next step operation is delivered in discharging.
Compound medicinal formulation
According to conventional method, can prepare the compound medicinal formulation that contains tenofovir disoproxil or its pharmacologically active derivant and other viral infection resisting.The example of known other viral infection resisting medicine has lamivudine (Lamivudine), adefovir ester (Adefovir dipivoxil), Entecavir (Entecavir), Sebivo (Telbivudine), emtricitabine (Emtricitabine), efavirenz (Efavirenz), zidovudine (AZT), stavudine (Stavudine), didanosine (Didanosine), zalcitabine (Zalcitabine), Abacavir (Abacavir), nevirapine (Nevirapine), ritonavir (Norvir), Darunavir, Maraviroc and Raltegravir etc.
The quality examination of preparation
Carry out content analysis by reversed-phase HPLC (high performance liquid chromatography).Active pharmaceutical ingredient tenofovir disoproxil in the tablet or its pharmacologically active derivant and relevant impurity are carried out quantification and measurement.Target is that tenofovir disoproxil or the relevant total impurities of its pharmacologically active derivant should be lower than 5% after being mixed with tablet.
Can referring to " pharmaceutics " of Cui Fude chief editor's the professional usefulness of confession pharmacy class (People's Health Publisher, 2003 the 5th edition) and latest edition " physico-chemical property of preparation measured in the relevant chapter of Chinese pharmacopoeia.
Drug products in the packing sealed container system identical with clinical and commercial sealed container system is carried out stability study.In the stability study process, when packing and storing under the 40 ℃/75%RH with an amount of silica-gel desiccant reach six months after, the formulation content of tenofovir disoproxil or its pharmacologically active derivant does not have and obviously reduces (being reduced to 5% under its content).
Synthetic method embodiment
Two methylchlorosilane bases of embodiment 1, ethyl-2-O-tertiary butyl-(R)-lactate synthetic:
Ethyl-(R)-lactate (73.1g), tertiary butyl dimethylchlorosilane (TBSCl, 90.4g), triethylamine (167.1mL) and 4-dimethylaminopyridine (DMAP, 2.0g) be dissolved in anhydrous tetrahydro furan (THF, 150mL).Stirring reaction under the room temperature nitrogen protection (＞12 hours) promptly gets the ethyl of TBS protection-(R)-lactate.The steaming solvent of sneaking off filters and removes salt, and residue is with ethyl acetate (75mL) washed twice, merges water (100mL) washed twice after the organic facies, and with magnesium sulfate (20g) drying, vacuum distillation falls solvent, both the oily product.
Embodiment 2, (R)-2-O-tertiary butyl dimethylchlorosilane base-1,2-propylene glycol synthetic:
To contain in the reactor of nitrogen protection and calcium chloride tube; the product of embodiment 1 gained was dissolved in ethanol/methylene (1: 1; 250mL); with the ethanol/methylene of sodium borohydride (22.7g) (1: 1; 250mL) drips of solution adds in the above solution; the speed that drips is as the criterion to keep solution to reflux, and finishes until reaction.Add acetone (15mL) then and decompose unnecessary sodium borohydride, heating continues to reflux two hours.Reuse ice-water bath cooling adds dichloromethane (250mL) dilution, and (1M 100mL) and water (100mL) washing, separates and removes the solid catalyst residue, with magnesium sulfate (20g) drying, vacuum concentration solvent, just gets the oily product to use sodium bicarbonate successively.
Embodiment 3, the two methylchlorosilane bases of (R)-2-O-tertiary butyl-1-O-p-toluenesulfonyl-1, the 2-propylene glycol
Synthetic:
To contain in the reactor of calcium chloride tube and nitrogen, add product, the toluene (C of embodiment 2 gained
6H
5CH
3, 200mL) and 4-dimethylaminopyridine (DMAP, 2.0g).Under ice-water bath cooling and stirring, in 1 hour with paratoluensulfonyl chloride (TsCl, triethylamine (Et 95.3g)
3N, 175.0mL) drips of solution adds.After being added dropwise to complete, at room temperature stir at least about 5-14 hour, until with TLC or
1Till H NMR (showing that trace maybe can not detect by paratoluensulfonyl chloride) determines to react when finishing.Solids removed by filtration is with toluene (25mL) washed twice.Liquid water (100mL) washed twice after the merging, with magnesium sulfate (20g) drying, vacuum distillation concentrates organic facies, obtains yellow oil product.
Synthesizing of embodiment 4, (R)-9-(2-hydroxypropyl) adenine:
In the reactor that contains noble gas such as nitrogen, embodiment 3 gained oily compounds, adenine (Adenine, 50.0g), cesium carbonate (65.6g) and N, dinethylformamide (DMF, mixture heated 370mL) is to 80-120 ℃, until reacting completely, show that with the HPLC monitoring remaining adenine is not higher than till about 0.5%.The mixture that obtains is cooled to about 5-30 ℃ in ice-water bath, product (R)-9-(2-O-TBS-2-propoxyl group) adenine can obtain solid precipitation at this moment.
The solid of collecting is dissolved in the solution of warm acetic acid and water (volume ratio is: 2: 1) stirring reaction 3-8 hour.The mixture that obtains is cooled to about 5-30 ℃ in ice-water bath, product (R)-9-(2-hydroxypropyl) adenine is precipitable at this moment to come out, and uses toluene (2x 25mL) and cold ethanol (75mL) washing respectively, is dried to constant weight then, obtains the faint yellow solid product.
Synthesizing of embodiment 5, tolysulfonyl oxygen methylphosphonic acid diethylester:
Containing noble gas for example in the reactor of nitrogen, phosphonous acid the diethylester [(C in toluene (200mL)
2H
5O)
2P (O) H, 56.0g], paraformaldehyde [(CH
2O)
n, 14.0g] and the mixture of triethylamine (5.5mL) 85-90 ℃ of about 2 hours of heating down, refluxed then about 1 hour, represent that when showing that with TLC trace maybe can not detect the phosphonous acid diethylester reaction finishes.Solution is cooled to about 2-8 ℃ in ice-water bath, slowly drip paratoluensulfonyl chloride (p-TsCl, triethylamine (Et 72.0g) then under the ice bath cooling
3N, 75mL) solution (exothermic reaction), and holding temperature is no more than 10 ℃ simultaneously.After being added dropwise to complete, at room temperature stir at least about 5-14 hour, until with TLC or
1Till H NMR (showing that trace maybe can not detect by paratoluensulfonyl chloride) determines to react when finishing.Solids removed by filtration is with toluene (Tolene, 25mL) washed twice.Liquid water (100mL) washed twice after the merging with magnesium sulfate (20g) drying, is filtered, and vacuum distillation concentrates organic facies, obtains yellow oil product.
Embodiment 6, (R)-9-[2-diethyl phosphonyl methoxyl base propyl group] adenine synthetic:
Containing noble gas for example in the reactor of nitrogen, add (R)-9-(2-hydroxypropyl) adenine (50.3g) and N, dinethylformamide (140mL).Suspension is cooled to about 10 ℃ in ice bath, a part of tert-butoxy sodium (43.6g) adding rises to about 30 ℃ up to temperature.Remove ice bath, at room temperature stir about obtained yellow solution in one hour.In the reactor after being cooled to about 5 ℃ in the ice bath, temperature be lower than 10 ℃ and stir under, slowly drip the solution (the tolysulfonyl oxygen methylphosphonic acid of 113.0g is dissolved in the N of 70mL, dinethylformamide) of tolysulfonyl oxygen methylphosphonic acid diethylester.After being added dropwise to complete, remove ice bath, stir about at room temperature a hour, when determining that with HPLC (the intermediate surplus is not more than about 10%) finished in reaction till.Mixture is cooled to about 10 ℃, adds 80% acetic acid (25ml), and reactant at room temperature stirred 30 minutes then, and reaction temperature rises to about 30 ℃ gradually.Vacuum concentration obtains product, need not to be further purified just to can be used for next step reaction.
Synthesizing of embodiment 7a, tenofovir (Tenofovir):
(R)-9-[2-diethyl phosphonyl methoxyl base propyl group with gained among the embodiment 6] the adenine crude product is suspended in (400mL) in the acetonitrile, stirs 30 minutes after-filtration, and filter cake is with twice of acetonitrile (50mL) rinsing.Filtrate and washing liquid are directly used in the next step after merging.
Containing noble gas for example in the reactor of nitrogen, add above-mentioned (R)-9-[2-diethyl phosphonyl methoxyl base propyl group successively] adenine solution, trimethylsilyl chloride (131mL), and potassium iodide (172g).Heat temperature raising is to about 50 ℃, and mixture refluxed about 1 hour down at about 50-55 ℃, and after stopping to heat, moderate agitation is 3 hours again, and temperature is reduced to about 40 ℃ gradually.Analyze the total amount that shows remaining tenofovir mono ethyl ester and two ethyl esters by HPLC and be no more than at about 3% o'clock, expression reacts completely.
In said mixture, slowly drip 3.5M sodium hydrate aqueous solution (400mL), during holding temperature be no more than 45 ℃.After two of mixture is separated, the water ethyl acetate extraction. in extract, slowly drip concentrated hydrochloric acid, regulate pH, at room temperature stirred 6-15 hour to about 2.8-3.2, during product the precipitation appearance should be arranged.The reuse concentrated hydrochloric acid is regulated pH to about 2.8-3.2 if desired, and pulpous state liquid is cooled to about 2-8 ℃ in ice bath.Pulpous state liquid slowly stirs at least about 3 hours in this temperature range.Solid collected by filtration is used the washing of cold water (18mL) and acetone (15mL) successively, obtains wet solid tenofovir crude product, is used to behind the airing be further purified.
Synthesizing of embodiment 7b, tenofovir monohydrate (Tenofovir Hydrate):
Tenofovir crude product (embodiment 7a product) is suspended in the water of 125mL, suspension is heated to about 95-110 ℃, and till extremely high speed stirred when all solids dissolves by middling speed, the solution filtered while hot that obtains obtained settled solution, wash with other hot water (25mL, 95-110 ℃).Filtrate is heated to 100 ℃, cooling then, and at first about 30 ℃ (typically about 20-25 ℃) stir about 3-5 hour at a slow speed, continues to be cooled to about 5-15 ℃ then.Maintain 10 ℃ at least about 3 hours, solid collected by filtration is earlier with cold water (25mL, about 2-10 ℃) reuse acetone (20mL) continuous washing.Wet cake to the about 3.9-7.9% of water content at about 40-60 ℃ in vacuum drying, obtain purified tenofovir monohydrate.Analyze product purity typically about 98% or higher by HPLC.If chemical purity is unsatisfactory, can repeats this step and carry out repurity.
Synthesizing of embodiment 8, tenofovir disoproxil (Tenofovir Disoproxil):
Containing noble gas for example in the reactor of nitrogen, with the mixture stir about of 1-Methyl-2-Pyrrolidone (200mL), tenofovir monohydrate (50g) and triethylamine (68mL) 15-45 minute.As going into carbonic acid chloromethyl-2-propyl diester (125g), mixture heated stir about 3-6 hour, until reacting completely, is monitored (not being higher than 15% tenofovir monoesters existence) with HPLC to about 55-65 ℃ then.Mixture is cooled to room temperature as early as possible with isopropyl acetate (600mL) dilution, at room temperature stirs the mixture about 20-60 minute.Cross and filter out solid, with isopropyl acetate (200mL) washing.Merge organic facies, at room temperature use twice of water extraction (each water 160mL), middling speed stir about 1-10 minute is separated to avoid forming emulsion, to make respectively then during extraction.Merge water, at room temperature with anti-extract twice (the each consumption 160mL) of isopropyl acetate.Merge all organic faciess, at room temperature wash (110mL) with water, middling speed stir about 1-10 minute is to avoid forming emulsion during extraction.Merge organic facies, under about 25-45 ℃ temperature, the initial volume of vacuum concentration (the about 25.5-28 of pressure " Hg) to about 30% is after 1 μ m filter filters; and vacuum under about 20-40 ℃ temperature (about 28 " Hg) concentrated organic facies, until remaining lark oily tenofovir disoproxil.
Synthesizing of embodiment 9, tenofovir disoproxil (Tenofovir Disoproxil) metilsulfate:
The pyrovinic acid (36.0mL, the mol ratio of tenofovir disoproxil and pyrovinic acid is about 1: 1) of aequum is dissolved in the isopropyl alcohol (330mL).Then, the oily tenofovir disoproxil of embodiment 8 gained is dissolved in the aqueous isopropanol of pyrovinic acid of heating (about 45-55 ℃), vigorous stirring is dissolved until solid.Use 1 μ m filter filtering mixt while hot.Under about 34-50 ℃ temperature, stir filtrate, need the stirring of minimum degree in order to obtain homogeneous phase solution.Under the stirring of minimum degree, be cooled to about 12-18 ℃.If no crystal formation after about 1-2 hour, then to add small amount of seeds.Along with the cooling of solution, under about 12-18 ℃ temperature, form crystal.Stop when beginning to form crystal stirring, and allow mixture leave standstill at least 12 hours.The pulpous state liquid that obtains is filtered. with premixed isopropyl alcohol (40mL)/butyl ether (200mL) solution (1: 5 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature, and the about 1-10 of vacuum drying days until constant weight.Exsiccant product can optionally grind, and obtains white fine powder powder crystal tenofovir disoproxil metilsulfate, and purity should be greater than 97.0.Improve product purity if desired, can randomly carry out recrystallization.
Embodiment 10, exchange by salt from the tenofovir disoproxil fumarate and to prepare the tenofovir ester hydrochloride:
Crude product or pure product tenofovir disoproxil fumarate (about 50-100mg/mL) are suspended in an amount of isopropyl alcohol, and heating (about 45-55 ℃) and stirring are all dissolved up to the tenofovir disoproxil fumarate.Under heating (about 45-55 ℃) is stirred, drip the hydrochloric acid (mol ratio of tenofovir disoproxil and hydrochloric acid is 1: 1) that is dissolved in the isopropyl alcohol.After being added dropwise to complete, under stirring at low speed, be cooled to about 12-18 ℃.Stop when beginning to form crystal stirring, and allow mixture leave standstill at least about 12 hours.The pulpous state liquid that obtains is filtered.With premixed isopropyl alcohol/diethyl ether solution (1: 6 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature, and the about 1-10 of vacuum drying days until constant weight.Exsiccant product can optionally grind, and obtains white fine powder powder crystal tenofovir ester hydrochloride, and purity should be greater than 97.0.Improve product purity if desired, can randomly carry out recrystallization.
Embodiment 11, prepare tenofovir disoproxil sulfate by free alkali from the tenofovir disoproxil fumarate:
Crude product or pure product tenofovir disoproxil fumarate (about 10-100mg/mL) are suspended in the ethanol that contains equimolar amounts sodium bicarbonate (mol ratio of tenofovir disoproxil and sodium bicarbonate is 1: 1), and heating (about 45-55 ℃) and stirring are all dissolved up to the tenofovir disoproxil fumarate.Under heating (about 45-55 ℃) is stirred, drip the sulphuric acid (tenofovir disoproxil and vitriolic mol ratio are 1: 1) that is dissolved in the ethanol.After being added dropwise to complete, under stirring at low speed, be cooled to about 12-18 ℃.Stop when beginning to form crystal stirring, and make mixture static at least about 12 hours. the pulpous state liquid that obtains is filtered. with premixed ethanol/diethyl ether solution (1: 6 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature, and the about 1-10 of vacuum drying days until constant weight.Exsiccant product can optionally grind, and obtains white fine powder powder crystal tenofovir disoproxil sulfate, and purity should be greater than 97.0.Improve product purity if desired, can randomly carry out recrystallization.
Embodiment 12, prepare the tenofovir disoproxil winestone by anion exchange resin from the tenofovir disoproxil fumarate
Hydrochlorate:
Crude product or pure product tenofovir disoproxil fumarate (about 10-100mg/mL) are suspended in the isopropyl alcohol, and heating (about 45-55 ℃) and stirring are all dissolved up to the tenofovir disoproxil fumarate.The gained mixture solution is removed fumaric acid through anion exchange resin.Containing the tenofovir disoproxil free base solution under heating (about 45-55 ℃) is stirred, drip the tartaric acid (tenofovir disoproxil and tartaric mol ratio are 1: 1) that is dissolved in the isopropyl alcohol again.After being added dropwise to complete, under stirring at low speed, be cooled to about 12-18 ℃.Stop when beginning to form crystal stirring, and make mixture static at least about 12 hours.The pulpous state liquid that obtains is filtered.With premixed isopropyl alcohol/diethyl ether solution (1: 6 volume ratio) washing leaching cake.This filter cake be not higher than under 40 ℃ the temperature, and the about 1-10 of vacuum drying days until constant weight.Exsiccant product can optionally grind, and obtains white fine powder powder crystal tenofovir disoproxil tartrate, and purity should be greater than 97.0.Improve product purity if desired, can randomly carry out recrystallization.
Pharmaceutical formulation embodiment
The following examples have further described and have explained the concrete preparation production embodiment that enters within the scope of the invention.Correlation technique and preparation usually can be referring to " the relevant chapters of Chinese pharmacopoeia of " pharmaceutics " of Cui Fude chief editor's the professional usefulness of confession pharmacy class (People's Health Publisher, 2003 the 5th edition) and latest edition.Therefore cited embodiment only is for exemplary purposes, it should be interpreted as to be construed as limiting, and this is that it is fully possible carrying out various conversion because only otherwise depart from the spirit and scope of the invention.The following examples are only used for explaining, and and do not mean that by any way and limit the scope of the invention." active component " is representative with the tenofovir disoproxil metilsulfate.And any suitable tenofovir disoproxil pharmaceutical salt or the medicine and the preparation thereof of its pharmacologically active derivant comprise within the scope of the invention equally in them.
The granule of tablet or capsule can be by carrying out each composition wet method (embodiment 13) or dry method (embodiment 14) makes, and then granule is pressed into tablet or incapsulates.The component of tablet, capsule and oral suspensions and content are listed in respectively in embodiment 15-20,21-22 and 23.
Embodiment 13-wet granulation:
Wet-granulation process comprises: tenofovir disoproxil or its pharmacologically active derivant and adjuvant mix homogeneously in granulator with described amount are sprayed on the said mixture that is being stirred with aqueous solution, and further mix.Acceptable granule contains 40% to 60%w/w moisture content respectively.Its process optimization comprise research granulation water content level (40% to 60%w/w) but and the wet-mixed time for the physico-chemical property of final mixture of powders with and to the influence of mixing homogeneity and briquettability (tablet mouldability).
In order to improve the uniformity of drying steps, each wet method shot-like particle is used the blender depolymerization that is equipped with sieve and impeller.The wet granular that will pulverize charging at once after wet milling is gone in the fluidisation bed dryer.The wet granular that will pulverize is to be approximately 25 ℃ to 80 ℃, an amount of dry air air-flow to come dry with the intake air design temperature.Target loss on drying (LOD) is approximately 1.5%, and scope is no more than (NMT) 3.0%.
All dried particles pulverizes by perforated screen.The crusher side of being equipped with row impeller also enters operation.Each batch milled, and the back is manual to be transferred in the V blender.Adjuvant such as microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose outside dried milled powder and the granule are mixed at the V blender.And then and magnesium stearate remove Powder samples after mixing.
Embodiment 14-dry granulation:
The dry granulation process comprises: with the tenofovir disoproxil salt of described amount or its pharmacologically active derivant and adjuvant in granulator mix homogeneously, be compressed into big lamellar or tabular after; be ground into required big granule down, but with itself and mix lubricant even after just tabletting or incapsulate.
Embodiment 15-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 42.86 | 300.0 |
| Microcrystalline Cellulose | 28.57 | 200.0 |
| Lactose monohydrate | 14.29 | 100.0 |
| Cross-linking sodium carboxymethyl cellulose | 7.14 | 50.0 |
| Starch,pregelatinized | 5.71 | 40.0 |
| Silica sol | 0.71 | 5.0 |
| Magnesium stearate | 0.71 | 5.0 |
| Total amount | 100.00 | 700.0 |
Embodiment 16-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 37.50 | 300.0 |
| Microcrystalline Cellulose | 25.00 | 200.0 |
| Lactose monohydrate | 12.50 | 100.0 |
| Cross-linking sodium carboxymethyl cellulose | 6.25 | 50.0 |
| Starch,pregelatinized | 5.00 | 40.0 |
| Poloxamer 407 | 12.50 | 100.0 |
| Silica sol | 0.63 | 5.0 |
| Magnesium stearate | 0.63 | 5.0 |
| Total amount | 100.00 | 800.0 |
Embodiment 17-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 28.57 | 200.0 |
| Microcrystalline Cellulose | 28.57 | 200.0 |
| Lactose monohydrate | 14.29 | 100.0 |
| Cross-linking sodium carboxymethyl cellulose | 11.43 | 80.0 |
| Starch,pregelatinized | 5.71 | 40.0 |
| The VE succinic acid macrogol ester | 10.00 | 70.0 |
| Silica sol | 0.71 | 5.0 |
| Magnesium stearate | 0.71 | 5.0 |
| Total amount | 100.00 | 700.0 |
Embodiment 18-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 25.00 | 200.0 |
| Microcrystalline Cellulose | 37.50 | 300.0 |
| Cross-linking sodium carboxymethyl cellulose | 11.25 | 90.0 |
| Starch,pregelatinized | 5.00 | 40.0 |
| Poloxamer 407 | 10.00 | 80.0 |
| Vitamin E succinum enzyme macrogol ester | 10.00 | 80.0 |
| Silica sol | 0.63 | 5.0 |
| Magnesium stearate | 0.63 | 5.0 |
| Total amount | 100.00 | 800.0 |
Embodiment 19-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 33.33 | 200.0 |
| Microcrystalline Cellulose | 33.33 | 200.0 |
| Lactose monohydrate | 25.83 | 155.0 |
| Polyvinylpolypyrrolidone | 4.17 | 25.0 |
| Hydroxypropyl cellulose | 2.50 | 15.0 |
| Magnesium stearate | 0.83 | 5.0 |
| Total amount | 100.00 | 600.0 |
Embodiment 20-tablet:
| Component | ％W/W | The mg/ tablet |
| The tenofovir disoproxil metilsulfate | 50.00 | 300.0 |
| Microcrystalline Cellulose | 25.00 | 150.0 |
| Lactose monohydrate | 13.33 | 80.0 |
| Polyvinylpolypyrrolidone | 4.17 | 25.0 |
| Polyvidone | 6.67 | 40.0 |
| Magnesium stearate | 0.83 | 5.0 |
| Total amount | 100.00 | 600.0 |
Embodiment 21-capsule:
| Component | ％W/W | The mg/ capsule |
| The tenofovir disoproxil metilsulfate | 52.63 | 300.0 |
| Microcrystalline Cellulose | 42.11 | 240.0 |
| Primojel | 4.39 | 25.0 |
| Magnesium stearate | 0.88 | 5.0 |
| Total amount | 100.00 | 570.0 |
Embodiment 22-capsule:
| Component | ％W/W | The mg/ capsule |
| The tenofovir disoproxil metilsulfate | 35.09 | 200.0 |
| Microcrystalline Cellulose | 44.74 | 255.0 |
| Poloxamer 407 | 8.77 | 50.0 |
| The VE succinic acid macrogol ester | 8.77 | 50.0 |
| Ethyl cellulose | 2.63 | 15.0 |
| Total amount | 100.00 | 570.0 |
Embodiment 23-oral suspensions:
The various compositions of active component and other are mixed, then it is filled as dried powder.Adding purified water before using fully mixes.
| Component | ％W/W | The mg/ suspensoid |
| The tenofovir disoproxil metilsulfate | 4.00 | 200.0 |
| Sugar,confectioner's | 40.00 | 2000.0 |
| Dimethicone | 6.00 | 300.0 |
| The VE succinic acid macrogol ester | 4.00 | 200.0 |
| Peach spice | 10.00 | 500.0 |
| Purified water | 36.00 | 1800.0 |
| Total amount | 100.00 | 5000.0 |
Claims (10)
1. treat or prevention HBV or HIV medicine for treating viral infections, this medicine contains 9-[(R)-two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyls of 2-[[] methoxyl group] propyl group] adenine (tenofovir disoproxil, English name: pharmaceutical salts tcnofovirdisoproxil) or its pharmacologically active derivant, its structure is as follows:
Wherein a is and the molal quantity of the salifiable chemical compound of tenofovir disoproxil, and its span is 0.0 to 10.0; B be with tenofovir disoproxil or its salt the molal quantity of bonded compositions, its span is 0.0 to 10.0.
2. according to the process of claim 1 wherein any one pharmaceutical salts that contains tenofovir disoproxil in this medicine, its example has: suitable alkali comprises alkali metal (as sodium and potassium), alkaline-earth metal (as magnesium and barium), ammonium and NX
4 -(wherein X is C
1-C
4Alkyl), organic carboxyl acid such as fumaric acid, maleic acid, malic acid, tartaric acid, valine, acetic acid, benzoic acid, lactic acid, malonic acid, oxalic acid, newborn diacid and succinic acid, organic sulfonic acid such as sulfamic acid, methanesulfonic acid, ethyl sulfonic acid, hydroxyethylsulfonic acid. and p-methyl benzenesulfonic acid, and mineral acid example hydrochloric acid, sulphuric acid and phosphoric acid etc.
3. according to the method for claim 1, wherein contain any one compositions of tenofovir disoproxil or its salt in this medicine, its example has: hydrate, solvate (solvates), eutectic thing (co-crystals), stereoisomer and can provide (directly or indirectly) above-claimed cpd or any one other chemical compound of its antiviral activity metabolite or residue after the patient takes.
4. according to the method for claim 1 to 3, its synthesis technique comprises makes tenofovir disoproxil contact in liquid state or solid-state environment with salt-forming compound and/or other compositions.
5. according to the method for claim 1, its synthesis technique comprises and contains catalyst sodium alcoholate and intermediate (R)-9 (2-hydroxypropyl) adenine.
6. according to the process of claim 1 wherein that described medicine contains tenofovir disoproxil salt or its pharmacologically active derivant of about 10mg to 1000mg.
7. according to the pharmaceutical preparation of claim 1, it is to be suitable for oral tablet, capsule (containing soft capsule) agent and other preparation.
8. according to the pharmaceutical preparation of claim 7, wherein contain tenofovir disoproxil salt or its pharmacologically active derivant and the pharmaceutic adjuvant of described amount, the example of adjuvant has: microcrystalline Cellulose, lactose monohydrate, dextrin, glucose, mannitol, sorbitol, calcium phosphate, methylcellulose, hydroxypropyl emthylcellulose, polyvidone, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, primojel, stearic acid and magnesium stearate etc.
9. according to the pharmaceutical preparation of claim 7, the surfactant or the solubilizing agent adjuvant that wherein contain described amount are used for improving drug bioavailability and reduce food effect. and the example of described surfactant or solubilizing agent has: high fatty alcohol sulfuric acid ester, poloxamer class (Poloxamer), Tweens (Tween), spans (Span) and VE succinic acid macrogol ester (Vitamin E TPGS) etc.
10. according to the pharmaceutical preparation of claim 7, dosage that can be suitable is to being administered once every day by the patient of HBV or HIV infection or repeatedly, being used for treating or prevention HBV or HIV viral infection.
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| US20110009368A1 (en) * | 2007-12-12 | 2011-01-13 | Ultimorphix Technologies B.V. | Solid forms of tenofovir disoproxil |
| CN102232923A (en) * | 2010-05-07 | 2011-11-09 | 沈阳双鼎制药有限公司 | Low-dose Tenofovir compound by injection delivery 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 |
| CN103917550A (en) * | 2011-11-16 | 2014-07-09 | 劳拉斯实验室私人有限公司 | Process for preparation of tenofovir |
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