WO2012027972A1 - TENOFOVIR DISOPROXIL FUMARATE α-CRYSTAL FORM, PREPARATION METHOD AND APPLICATION THEREOF - Google Patents
TENOFOVIR DISOPROXIL FUMARATE α-CRYSTAL FORM, PREPARATION METHOD AND APPLICATION THEREOF Download PDFInfo
- Publication number
- WO2012027972A1 WO2012027972A1 PCT/CN2011/070142 CN2011070142W WO2012027972A1 WO 2012027972 A1 WO2012027972 A1 WO 2012027972A1 CN 2011070142 W CN2011070142 W CN 2011070142W WO 2012027972 A1 WO2012027972 A1 WO 2012027972A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tenofovir disoproxil
- disoproxil fumarate
- crystalline form
- solvent
- tenofovir
- Prior art date
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- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- GMMXJVUYXPXLPY-UHFFFAOYSA-N decyl 4-hydroxybenzoate Chemical compound CCCCCCCCCCOC(=O)C1=CC=C(O)C=C1 GMMXJVUYXPXLPY-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- JMPVESVJOFYWTB-UHFFFAOYSA-N dipropan-2-yl carbonate Chemical group CC(C)OC(=O)OC(C)C JMPVESVJOFYWTB-UHFFFAOYSA-N 0.000 description 1
- XMVQMLUXHIIYLN-UHFFFAOYSA-L disodium dicarbamate Chemical compound [Na+].[Na+].C(N)([O-])=O.C(N)([O-])=O XMVQMLUXHIIYLN-UHFFFAOYSA-L 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- OQQTZLSEKBDXRS-UHFFFAOYSA-N propan-2-yl propan-2-yloxycarbonyl carbonate Chemical group CC(C)OC(=O)OC(=O)OC(C)C OQQTZLSEKBDXRS-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Definitions
- the present invention relates to an antiviral drug tenofovir disoproxil fumarate ((R)-[[2-(6-amino-9 ⁇ - ⁇ -9-yl)-1-indolylethoxy]indolyl] A new crystalline form of diisopropoxycarbonyl oxime ester fumarate) and a process for the preparation of the novel crystalline form and its use in pharmaceutical formulations.
- Tenofovir disoproxil fumarate (TDF), chemical name (R)-[[2-(6-amino-9H- ⁇ -9-yl)-1-indolylethoxy] ⁇ Phosphonic acid diisopropoxycarbonyloxy oxime fumarate, which has the structure shown in formula (I), was developed by Glead Sciences, USA, and was first marketed in the United States in October 2001. It is now in Europe. Listed in countries such as Australia and Canada. At the 58th Annual Meeting of the American Association for the Study of Liver Diseases in November 2007 and the 43rd European Conference on Liver Diseases in 2008-04, reports on the treatment of chronic hepatitis B CHB with tenofovir have attracted widespread attention.
- Tenofovir fumarate is a novel nucleoside (acid) analog that was approved by the US Food and Drug Administration (FDA) in 2001 for HIV infection. It is hydrolyzed in vivo to give tenofovir, a medicinal ingredient (structure is shown in formula (III)). It is able to significantly inhibit the activity of HBV replication in vitro, so it is hopeful to become a member of HAART therapy for HIV/HBV co-infection.
- TDF is a prodrug of tenofovir and is a novel acyclic nucleoside (acid) analog that has anti-HIV-1 and HIV-2 activity in vitro.
- TDF is one of the widely used nucleoside (acid) reverse enzyme inhibitors for the treatment of HIV. Its outstanding effect, good applicability and proper dosage make him the most popular therapeutic drug in the first line, and have been recommended by the 4 ⁇ multi-guideline as a better nucleoside (acid) reversal enzyme inhibition for first-line antiviral therapy. Use of the agent.
- Viread tenofovir disoproxil fumarate
- Viread tenofovir disoproxil fumarate
- tenofovir is significantly more effective than adefovir in the treatment of chronic hepatitis B.
- Form A XRD characteristic peaks are expressed at about 2,, 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 and
- the DSC differential heat absorption peak is about 113.1 °C;
- Form B XRD characteristic peaks are expressed at about 2, 3, 3, 11.3, 11.2, 14.2, 15.4, 16.2, 18.2, 19.0, 20.6, 25.8, and 31.0 and the DSC differential heat absorption peak is about 115.5 °C.
- the invention content is expressed at about 2, 3, 3, 11.3, 11.2, 14.2, 15.4, 16.2, 18.2, 19.0, 20.6, 25.8, and 31.0 and the DSC differential heat absorption peak is about 115.5 °C.
- the first technical problem to be solved by the present invention is to provide a novel crystalline form of tenofovir disoproxil fumarate which we have named as the alpha crystalline form.
- the new crystalline form is substantially free of water and crystalline forms of other solvents, and this crystalline form can satisfy the performance required for large scale synthesis or formulation into therapeutic formulations.
- the tenofovir fumarate alpha form of the present invention using Cu-Ka radiation, has an X-ray powder diffraction spectrum expressed at a angle of 2 ⁇ of about 7.1, about 7.8, about 8.1, about 9.8, about 10.5, About 10.9, about
- differential thermal analysis pattern of the ⁇ crystal form has an endothermic peak at about 117.4 °C.
- the infrared spectrum of the ⁇ crystal form is about 3198 cm- 1 at about SSS cm- 1 .
- a second technical problem to be solved by the present invention is to provide a method for preparing a crystalline form of tenofovir disoproxil fumarate which can be used for large-scale industrial production.
- a method for preparing a crystalline form of tenofovir disoproxil fumarate comprises the following steps:
- the first solvent is selected from the group consisting of one or any combination of the following: a C1-C6 alcohol solvent (including a linear alkane alcohol and a Side chain alkane alcohol),
- the step (1) of the present invention in consideration of the need for solvent recovery in production, it is preferred to use a single solvent for dissolution, and in particular, a common solvent such as decyl alcohol, ethanol, isopropanol, ethyl acetate or acetone may be used.
- a common solvent such as decyl alcohol, ethanol, isopropanol, ethyl acetate or acetone may be used.
- the crystal form is dissolved.
- the volume of the first solvent is 10 to 50 mL/g, preferably 20 to 30 mL/g, based on the mass of tenofovir fumarate.
- the dissolution temperature in the step (1) is generally from room temperature to the reflux temperature of the solvent.
- the present invention selects a solvent having a polarity of 0.1 or less as a crystallization solvent, and the second solvent is preferably one of the following: petroleum ether, n-hexane, Cyclohexane, isopentane, n-pentane, tridecylpentane.
- the volume of the second solvent is generally from 10 to 50 mL/g based on the mass of tenofovir fumarate.
- the drying is generally carried out at a temperature of 20 to 40 °C.
- the crystalline form of tenofovir fumarate of the present invention can be used for the preparation of a medicament for the treatment of viral hepatitis B or AIDS (HIV/AIDS).
- the preparation process of the formulation containing the crystalline form of tenofovir disoproxil fumarate and the preparation of the preparation will be specifically described below: Although tenofovir may be administered as a pure compound, it is preferably administered in the form of a pharmaceutical preparation.
- the preparation of the present invention comprises a formulation of a crystalline form of tenofovir disoproxil fumarate and a pharmaceutically acceptable carrier.
- Formulations suitable for oral administration of the present invention can be provided in the form of tablets, capsules/soft gelatin, granules, pills, and oral preparations.
- the oral preparation containing the crystal form of tenofovir disoproxil fumarate according to the invention is prepared by mixing alpha crystal form of tenofovir disoproxil fumarate with one or several suitable excipients.
- Uniform, round or shaped solid preparations prepared by formulation techniques can be prepared into oral tablets, dispersible tablets, film coated tablets, sublingual tablets, orally disintegrating tablets, enteric coated tablets, sustained release tablets, controlled release Tablets, instant release tablets, etc.
- the oral preparation containing the crystal form of tenofovir fumarate of the present invention is prepared by the method of ⁇
- the crystalline form of tenofovir disoproxil fumarate and one or more suitable adjuvants such as diluents, glidants, disintegrants, etc., are uniformly powdered or granulated in hollow capsules, which can be made into a hard Plastic bottles.
- the formulation of the present invention comprises a formulation of a crystalline form of tenofovir disoproxil fumarate alpha and a pharmaceutically acceptable carrier.
- Pharmaceutical carriers include diluents, disintegrants, preservatives, binders, glidants, and lubricants. These compositions may, if necessary, be a compound containing about 10 to 1000 mg of tenofovir disoproxil alpha form, preferably in the range of 100 to 300 mg.
- the diluent in the pharmaceutical preparation of the present invention includes, but is not limited to, microcrystalline cellulose, lactose, pregelatinized starch, starch, dextrin, phosphoric acid 4 bow, carbonic acid 4 bow, mannitol, sorbitol, glucose, dextran and cyclodextrin. Fine
- the binder in the pharmaceutical preparation of the present invention includes, but is not limited to, for example, starch syrup, povidone, hydroxypropyl hydrazine cellulose, hydroxypropyl cellulose, decyl cellulose, hydroxyethyl cellulose, gelatin, xanthan gum, and the like;
- the lubricant in the pharmaceutical preparation of the present invention includes, but is not limited to, magnesium stearate, stearic acid, sodium stearate, sodium talc, sodium lauryl sulfate, and the like;
- the disintegrant in the pharmaceutical preparation of the present invention includes, but is not limited to, carboxymethyl starch, sodium sulfonate, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and Sodium carbamate sodium starch and pregelatinized starch;
- the preservatives in the pharmaceutical preparation of the present invention include, but are not limited to, sodium benzoate, potassium sorbate, decyl p-hydroxybenzoate and ethyl p-hydroxybenzoate;
- the buffering agent in the pharmaceutical preparation of the present invention includes, but is not limited to, phosphate buffer solution, citric acid, sodium citrate, acetate buffer solution, sodium phosphate and sodium hydroxide;
- the antioxidant in the pharmaceutical preparation of the present invention includes, but is not limited to, sodium edetate, sodium sulfite, sodium metabisulfite, cystine and vitamins;
- the taste regulating agent in the pharmaceutical preparation of the present invention includes, but is not limited to, fructose, sucrose, sodium saccharin, maltitol, orange flavor and strawberry flavor; Further, the pharmaceutical preparation of the present invention may further comprise other conventional and appropriate additives.
- the pharmaceutically acceptable carrier in the above-mentioned preparation means that it may or may not be used as needed.
- the same carrier such as a filler may be selected one or more.
- the pharmaceutically acceptable carrier is a matrix or excipient that maintains the pharmaceutical dosage form, usually in accordance with different dosage forms or in combination, optionally including excipients or diluents, such as microcrystalline cellulose, in accordance with methods well known in the art.
- lactose pregelatinized starch, starch, dextrin, phosphoric acid 4 bow, carbonic acid 4 bow, mannitol, sorbitol, glucose, dextran and cyclodextrin
- a binder such as starch
- a lubricant such as magnesium stearate , one or more of stearic acid, sodium stearate, talc and sodium lauryl sulfate
- a disintegrant such as carboxymethyl starch, sodium methylcellulose, low substituted hydroxyl
- preservatives such as sodium benzoate, sorbic acid Potassium,
- the invention can be prepared by the following methods: (e.g., ordinary tablets)
- the tenofovir disoproxil is separately mixed with the pharmaceutical ingredient to obtain preferred handling and processing properties, and the pharmaceutical ingredients which can be used include fillers, lubricants, disintegrating agents and other pharmaceutically acceptable excipients.
- the pharmaceutical ingredients which can be used include fillers, lubricants, disintegrating agents and other pharmaceutically acceptable excipients.
- a certain amount of the binder solution is added, wet granulation, the obtained granules are dried to a certain extent, a lubricant is added, and the tablets are pressed into a certain size and size to obtain a common tablet of tenofovir.
- the invention can be prepared by the following methods: (e.g., an anthraquinone)
- the tenofovir disoproxil is separately mixed with the pharmaceutical ingredient to obtain a preferred treatment and processing property, sieved, and directly placed in a hollow capsule to obtain a capsule.
- a certain amount of the binder solution is added to the mixed components, wet granulation, and the obtained granules are dried to a certain extent, and the whole granules are placed in a hollow capsule to obtain a capsule.
- the tenofovir disoproxil fumarate 0 crystal form prepared by the invention is superior to the conventional crystal form in terms of dissolution, and can be better absorbed by the human body. Moreover, the preparation method of the invention is simple and suitable for industrial production. Fourth, the description of the drawings
- Figure 1 is a powder X-ray diffraction spectrum of tenofovir disoproxil fumarate ⁇ crystal form.
- Figure 2 is a differential thermal analysis of the crystalline form of tenofovir disoproxil fumarate.
- Figure 3 is an infrared spectrum of the crystalline form of tenofovir disoproxil fumarate. V. Specific implementation methods
- the XRD characteristic peaks of the obtained crystal form are expressed at about 2, 11, 7.8, 8.1, 9.8, 10.5, 10.9, 11.6, 11.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4.
- Infrared spectroscopy (IR) absorption bands are approximately 3337, 3198, 2986 ⁇ 2935, 1764, 1661, and 1621 cm" 1
- the DSC has an endothermic peak at about 117.4, starting at about 115.5 °C.
- the mixture was slowly stirred at room temperature for 30 minutes, and then slightly cooled to about 15 ° C, and after 1 hour of incubation, suction filtration was carried out, and vacuum drying was carried out for 10 hours at room temperature to obtain about 47 g of the final product.
- the yield is 94% and the purity is over 99%.
- the XRD characteristic peaks of the obtained crystal form are expressed at about 2, 11, 7.8, 8.1, 9.8, 10.5, 10.9, 11.6, 11.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4.
- Infrared spectroscopy (IR) absorption bands are approximately 3337, 3198, 2986 ⁇ 2935, 1764, 1661, and 1621 cm" 1
- the DSC has an endothermic peak at about 117.4, starting at about 115.5 °C.
- Example 4 and Example 5 The raw materials of the crystal form of tenofovir disoproxil fumarate from the United States Gilead Science were respectively prepared according to the methods of Example 4 and Example 5 (labeled as tablet b and capsule b), and the same as the ⁇ crystal form.
- the method is as follows: 900ml water as dissolution medium, rotary dissolution, rotation speed is 75r/min, according to the Chinese Pharmacopoeia 2005 edition two appendix XC first method, sampling at 30min, filtering through 0. 45 ⁇ ⁇ microporous membrane The filtrate was used as a test solution.
- the appropriate amount of the tenofovir disoproxil reference substance was accurately weighed, dissolved in water, and then diluted to a lmg/ml with a mobile phase, and filtered through a 0.54 m microporous membrane to obtain a reference solution.
- Peak area of the test sample X Concentration of the reference substance X 900
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- General Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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Abstract
Tenofovir disoproxil fumarate α-crystal form, preparation method and application thereof are disclosed. By Cu-Ka radiation, an X-ray powder diffraction spectrum of tenofovir disoproxil fumarate α-crystal form, expressed in degrees 2Θ, shows characteristic peaks at about 7.1, 7.8, 8.1, 9.8, 10.5, 10.9, 1 1.6, 1 1.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4. The prepared tenofovir disoproxil fumarate a-crystal form gets a visibly ad vantage over the former crystal form on the aspect of dissolution rate and has better absorption into the body. The preparation method is simple and adaptive for industrialized production.
Description
富马酸替诺福韦酯 α晶型及其制备方法和应用 Tenofovir fumarate alpha crystal form and preparation method and application thereof
一、 技术领域 First, the field of technology
本发明涉及一种抗病毒药物富马酸替诺福韦酯 （（R)-[[2-(6-氨基 -9Η-嘌呤 -9- 基) -1-曱基乙氧基]曱基]膦酸二异丙氧羰氧基曱酯富马酸盐 ) 的新晶型以及此新 晶型的制备方法和其在药用制剂方面的应用。 二、 背景技术 The present invention relates to an antiviral drug tenofovir disoproxil fumarate ((R)-[[2-(6-amino-9Η-嘌呤-9-yl)-1-indolylethoxy]indolyl] A new crystalline form of diisopropoxycarbonyl oxime ester fumarate) and a process for the preparation of the novel crystalline form and its use in pharmaceutical formulations. Second, the background technology
富马酸替诺福韦酯 (tenofovir disoproxil fumarate , TDF) , 化学名为（R)-[[2-(6- 氨基 -9H-嘌呤 -9-基) -1-曱基乙氧基]曱基]膦酸二异丙氧羰氧基曱酯富马酸盐， 其 结构如式（I )所示， 是由美国 Glead Sciences公司研发， 2001年 10月首次在美 国上市， 现已在欧洲、 澳大利亚和加拿大等国家和地区上市。 在 2007年 11 月 第 58届美国肝病研究协会年会和 2008-04第 43届欧洲肝病年会上，关于替诺福 韦酯治疗慢性乙型肝炎 CHB的报道引起了广泛的关注。 Tenofovir disoproxil fumarate (TDF), chemical name (R)-[[2-(6-amino-9H-嘌呤-9-yl)-1-indolylethoxy]曱Phosphonic acid diisopropoxycarbonyloxy oxime fumarate, which has the structure shown in formula (I), was developed by Glead Sciences, USA, and was first marketed in the United States in October 2001. It is now in Europe. Listed in countries such as Australia and Canada. At the 58th Annual Meeting of the American Association for the Study of Liver Diseases in November 2007 and the 43rd European Conference on Liver Diseases in 2008-04, reports on the treatment of chronic hepatitis B CHB with tenofovir have attracted widespread attention.
富马酸替诺福韦酯是新型核苷 (酸)类似物， 于 2001年被美国食品与药品管 理局 (FDA)批准治疗 HIV感染。 它在体内水解后得到药用成分替诺福韦 （结构 如式（III )所示）。 它在体外能够显著抑制 HBV复制的活性， 因此 4艮有希望成 为 HIV/HBV合并感染 HAART疗法一员。 TDF是替诺福韦（tenofovir)的前药， 是一个新型的无环核苷 (酸)类似物， 在体外有抗 HIV-1和 HIV-2的活性。
Tenofovir fumarate is a novel nucleoside (acid) analog that was approved by the US Food and Drug Administration (FDA) in 2001 for HIV infection. It is hydrolyzed in vivo to give tenofovir, a medicinal ingredient (structure is shown in formula (III)). It is able to significantly inhibit the activity of HBV replication in vitro, so it is hopeful to become a member of HAART therapy for HIV/HBV co-infection. TDF is a prodrug of tenofovir and is a novel acyclic nucleoside (acid) analog that has anti-HIV-1 and HIV-2 activity in vitro.
(ΠΙ) (ΠΙ)
目前 TDF已经是广泛使用的治疗 HIV的核苷 (酸)类逆转酶抑制剂之一。 其 突出的效果、 良好的适用性和合适的剂量都使他成为一线最流行的治疗药物， 并且目前已经被 4艮多指南推荐为一线抗病毒治疗的较好核苷 (酸)类逆转酶抑制 剂使用。 目前 Viread (富马酸泰诺福韦二吡呋酯）已获得中国上市， 用于治疗慢 性乙肝。 研究证实泰诺福韦治疗慢性乙肝的疗效明显高于阿德福韦。 Currently, TDF is one of the widely used nucleoside (acid) reverse enzyme inhibitors for the treatment of HIV. Its outstanding effect, good applicability and proper dosage make him the most popular therapeutic drug in the first line, and have been recommended by the 4艮 multi-guideline as a better nucleoside (acid) reversal enzyme inhibition for first-line antiviral therapy. Use of the agent. Currently, Viread (tenofovir disoproxil fumarate) has been marketed in China for the treatment of chronic hepatitis B. Studies have shown that tenofovir is significantly more effective than adefovir in the treatment of chronic hepatitis B.
根据中国专利 CN98807435.4 (美国吉里德科学公司） 的报道中提到， 双 ( POC ) PMPA和富马酸 1 : 1的组合物， 并且在专利中特别阐述了发明的晶型， 此晶型的特征是用 X-RAY和 DSC以及红外光谱共同来表征。它的 X-ray的特征 峰通常在约 4.9、 10.2 , 10.5 , 18.2, 20.0, 21.9, 24、 25.0, 25.5 , 27.8, 30.1和 30.4处。 吉里德科学的 DSC吸收峰在约 118°C , 起始处约 116°C。 吉里德科学晶 型的 IR红外光谱吸收带在约 3224、 3107-3052、 2986-2939、 1759、 1678、 1620、 1269和 1102cm 。 According to the report of Chinese patent CN98807435.4 (Girard Science, USA), a combination of bis(POC)PMPA and fumaric acid 1:1, and the crystal form of the invention is specifically described in the patent, this crystal form It is characterized by X-ray and DSC and infrared spectroscopy. Its X-ray characteristic peaks are usually around 4.9, 10.2, 10.5, 18.2, 20.0, 21.9, 24, 25.0, 25.5, 27.8, 30.1 and 30.4. Gilead Science has a DSC absorption peak at about 118 ° C and a start at about 116 ° C. The IR infrared spectral absorption bands of the Gilead Scientific Crystal are at approximately 3224, 3107-3052, 2986-2939, 1759, 1678, 1620, 1269 and 1102 cm.
另外， 黑龙江加州国际投资咨询有限公司也申请了富马酸替诺福韦酯的两 个晶型，其分别命名为 A晶型和 B晶型。详细数据在中国专利 CN200710014625.3 中有描述。 其 A\B晶型的特征参数主要如下： In addition, Heilongjiang California International Investment Consulting Co., Ltd. also applied for two crystal forms of tenofovir fumarate, which were named as A crystal form and B crystal form. Detailed data is described in Chinese patent CN200710014625.3. The characteristic parameters of its A\B crystal form are as follows:
晶型 A: XRD特征峰以 2Θ角表达在约 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和 31.1处以 及 DSC差热吸收峰在约 113.1 °C ; Form A: XRD characteristic peaks are expressed at about 2,, 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 and The DSC differential heat absorption peak is about 113.1 °C;
晶型 B: XRD特征峰以 2Θ角表达在约 5.1、 7.0、 10.3、 11.4、 14.2、 15.4、 16.2、 18.2、 19.0、 20.6、 25.8和 31.0处以及 DSC差热吸收峰在约 115.5°C。
三、 发明内容 Form B: XRD characteristic peaks are expressed at about 2, 3, 3, 11.3, 11.2, 14.2, 15.4, 16.2, 18.2, 19.0, 20.6, 25.8, and 31.0 and the DSC differential heat absorption peak is about 115.5 °C. Third, the invention content
本发明要解决的第一个技术问题是提供一种全新的富马酸替诺福韦酯晶 型， 我们将之命名为 α 晶型。 新晶型基本不含水以及其他溶剂的结晶型态， 并 且此晶型可满足大规模合成或配置成治疗用制剂所需的性能。 The first technical problem to be solved by the present invention is to provide a novel crystalline form of tenofovir disoproxil fumarate which we have named as the alpha crystalline form. The new crystalline form is substantially free of water and crystalline forms of other solvents, and this crystalline form can satisfy the performance required for large scale synthesis or formulation into therapeutic formulations.
本发明所述的富马酸替诺福韦酯 α晶型， 使用 Cu-Ka辐射， 以 2Θ角度表示 的 X-射线粉末衍射光谱在约 7.1、 约 7.8、 约 8.1、 约 9.8、 约 10.5、 约 10.9、 约 The tenofovir fumarate alpha form of the present invention, using Cu-Ka radiation, has an X-ray powder diffraction spectrum expressed at a angle of 2 在 of about 7.1, about 7.8, about 8.1, about 9.8, about 10.5, About 10.9, about
11.6、 约 11.9、 约 13.7、 约 14.3、 约 14.7、 约 15.6、 约 16.1、 约 16.6、 约 16.8、 约 17.9、 约 18.4、 约 19.2、 约 20.4、 约 21.2、 约 21.6、 约 22.5、 约 22.7、 约 23.4、 约 24.3、 约 25.4和约 26.4处有特征峰， 偏差在士 0.01以内。 11.6, about 11.9, about 13.7, about 14.3, about 14.7, about 15.6, about 16.1, about 16.6, about 16.8, about 17.9, about 18.4, about 19.2, about 20.4, about 2.12, about 21.6, about 22.5, about 22.7, There are characteristic peaks at about 23.4, about 24.3, about 25.4, and about 26.4, and the deviation is within ±0.01.
进一步， 所述的 α晶型的差热分析图谱在约 117.4°C有吸热峰。 Further, the differential thermal analysis pattern of the α crystal form has an endothermic peak at about 117.4 °C.
进一步， 所述的 α 晶型的红外光谱在约 SSS cm-1 约 3198cm-1、Further, the infrared spectrum of the α crystal form is about 3198 cm- 1 at about SSS cm- 1 ,
2986~2935cm 、 约 1764cm 、 约 1661cm 和约 1621cm 有吸收峰。 There are absorption peaks at 2986~2935cm, about 1764cm, about 1661cm and about 1621cm.
本发明要解决的第二个技术问题是提供一种操作筒单、 可满足大规模工业 化生产的富马酸替诺福韦酯 α晶型的制备方法。 A second technical problem to be solved by the present invention is to provide a method for preparing a crystalline form of tenofovir disoproxil fumarate which can be used for large-scale industrial production.
为解决上述技术问题， 本发明采用如下技术方案： In order to solve the above technical problem, the present invention adopts the following technical solutions:
一种富马酸替诺福韦酯 α晶型的制备方法， 包括如下步骤： A method for preparing a crystalline form of tenofovir disoproxil fumarate comprises the following steps:
( 1 )将富马酸替诺福韦酯用第一溶剂溶解； 所述的第一溶剂选自下列一种 或任意几种的组合： C1~C6的醇类溶剂（包括直链烷烃醇和含有侧链的烷烃醇）、 (1) dissolving tenofovir fumarate in a first solvent; the first solvent is selected from the group consisting of one or any combination of the following: a C1-C6 alcohol solvent (including a linear alkane alcohol and a Side chain alkane alcohol),
C2~C6的烷基酯类、 C2~C6的酮类； C2~C6 alkyl esters, C2~C6 ketones;
( 2 )加入第二溶剂析晶； 所述的第二溶剂极性在 0.1以下； (2) adding a second solvent to crystallization; the second solvent has a polarity of 0.1 or less;
( 3 )干燥， 收集得到所述的富马酸替诺福韦酯 α晶型。 (3) Drying, collecting the crystalline form of tenofovir disoproxil fumarate.
进一步， 本发明步骤（1 ) 中， 考虑到在生产上溶剂回收套用的需要， 建议 使用单一溶剂进行溶解为佳， 尤其可采用曱醇、 乙醇、 异丙醇、 乙酸乙酯、 丙 酮等常用溶剂使晶型溶解。
进一步， 所述第一溶剂的体积用量以富马酸替诺福韦酯的质量计为 10~50 mL/ g, 优选为 20-30 mL/ g。 Further, in the step (1) of the present invention, in consideration of the need for solvent recovery in production, it is preferred to use a single solvent for dissolution, and in particular, a common solvent such as decyl alcohol, ethanol, isopropanol, ethyl acetate or acetone may be used. The crystal form is dissolved. Further, the volume of the first solvent is 10 to 50 mL/g, preferably 20 to 30 mL/g, based on the mass of tenofovir fumarate.
进一步， 步骤（1 ) 中的溶解温度一般在室温至溶剂回流温度。 Further, the dissolution temperature in the step (1) is generally from room temperature to the reflux temperature of the solvent.
进一步， 本发明步骤（2 ) 中， 为了保证产品结晶的晶型纯度， 本发明选择 极性在 0.1以下的溶剂作为析晶溶剂， 所述第二溶剂优选下列之一： 石油醚、 正 己烷、 环己烷、 异戊烷、 正戊烷、 三曱基戊烷。 所述第二溶剂的体积用量以富 马酸替诺福韦酯的质量计一般在 10~50 mL/ g。 Further, in the step (2) of the present invention, in order to ensure the crystal purity of the product crystal, the present invention selects a solvent having a polarity of 0.1 or less as a crystallization solvent, and the second solvent is preferably one of the following: petroleum ether, n-hexane, Cyclohexane, isopentane, n-pentane, tridecylpentane. The volume of the second solvent is generally from 10 to 50 mL/g based on the mass of tenofovir fumarate.
在一般的操作中， 我们通常是将析晶的第二溶剂滴加到步骤（ 1 )得到的溶 液中， 析晶采取的温度在 -5°C〜室温。 In a typical operation, we usually add a second solvent for crystallization to the solution obtained in the step (1), and the temperature of the crystallization is from -5 ° C to room temperature.
进一步， 本发明步骤（3 ) 中， 所述的干燥一般在 20~40°C的温度条件下进 行。 Further, in the step (3) of the present invention, the drying is generally carried out at a temperature of 20 to 40 °C.
在本发明中， 如不作特别说明， 我们将室温设置在 20~35°C。 In the present invention, we set the room temperature at 20 to 35 ° C unless otherwise specified.
本发明所述的富马酸替诺福韦酯晶型可用于制备治疗病毒性乙型肝炎或艾 滋病 （HIV/AIDS ) 的药物。 The crystalline form of tenofovir fumarate of the present invention can be used for the preparation of a medicament for the treatment of viral hepatitis B or AIDS (HIV/AIDS).
下面对含富马酸替诺福韦酯 α晶型的制剂和制剂制备工艺做具体说明： 虽然泰诺福韦酯可以以纯化合物的形式给药，但是以药物制剂的形式给药为 佳。 本发明的制剂包含富马酸替诺福韦酯 α晶型的制剂和药用载体， The preparation process of the formulation containing the crystalline form of tenofovir disoproxil fumarate and the preparation of the preparation will be specifically described below: Although tenofovir may be administered as a pure compound, it is preferably administered in the form of a pharmaceutical preparation. The preparation of the present invention comprises a formulation of a crystalline form of tenofovir disoproxil fumarate and a pharmaceutically acceptable carrier.
本发明适合口服的制剂可以以以下形式提供： 片剂、 胶嚢剂 /软胶嚢剂、 颗 粒剂、 丸剂和口 良液制剂。 Formulations suitable for oral administration of the present invention can be provided in the form of tablets, capsules/soft gelatin, granules, pills, and oral preparations.
本发明所述的含有富马酸泰诺福韦酯 α晶型的口服制剂，其制备方法是将 α 晶型的富马酸泰诺福韦酯与一种或几种适宜的赋形剂混合均匀， 通过制剂技术 压制而成的圓形或异形的固体制剂， 可以制成口服片、 分散片、 薄膜包衣片、 舌下片、 口腔崩解片、 肠溶片、 緩释片、 控释片、 速释片等。 The oral preparation containing the crystal form of tenofovir disoproxil fumarate according to the invention is prepared by mixing alpha crystal form of tenofovir disoproxil fumarate with one or several suitable excipients. Uniform, round or shaped solid preparations prepared by formulation techniques can be prepared into oral tablets, dispersible tablets, film coated tablets, sublingual tablets, orally disintegrating tablets, enteric coated tablets, sustained release tablets, controlled release Tablets, instant release tablets, etc.
本发明所述的含有富马酸泰诺福韦酯 α晶型的口服制剂，其制备方法是将 α
晶型的富马酸泰诺福韦酯与一种或几种适宜的辅料如稀释剂、 助流剂、 崩解剂 等制成均匀的粉末或颗粒填充于空心胶嚢中， 可以制成硬胶嚢。 The oral preparation containing the crystal form of tenofovir fumarate of the present invention is prepared by the method of α The crystalline form of tenofovir disoproxil fumarate and one or more suitable adjuvants such as diluents, glidants, disintegrants, etc., are uniformly powdered or granulated in hollow capsules, which can be made into a hard Plastic bottles.
本发明的制剂包含富马酸替诺福韦酯 α晶型的制剂和药用载体的组合物。药 用载体包括稀释剂、 崩解剂、 防腐剂、 粘合剂、 助流剂和润滑剂等。 视需要， 这些组合物可以是包含约 10 ~ lOOOmg的富马酸替诺福韦酯 α晶型的化合物，优 选 100 ~ 300mg范围。 The formulation of the present invention comprises a formulation of a crystalline form of tenofovir disoproxil fumarate alpha and a pharmaceutically acceptable carrier. Pharmaceutical carriers include diluents, disintegrants, preservatives, binders, glidants, and lubricants. These compositions may, if necessary, be a compound containing about 10 to 1000 mg of tenofovir disoproxil alpha form, preferably in the range of 100 to 300 mg.
本发明药物制剂中的稀释剂包括但不限定于微晶纤维素、乳糖、预胶化淀粉、 淀粉、 糊精、 磷酸 4弓、 碳酸 4弓、 甘露醇、 山梨醇、 葡萄糖、 右旋糖酐和环糊精 等； The diluent in the pharmaceutical preparation of the present invention includes, but is not limited to, microcrystalline cellulose, lactose, pregelatinized starch, starch, dextrin, phosphoric acid 4 bow, carbonic acid 4 bow, mannitol, sorbitol, glucose, dextran and cyclodextrin. Fine
本发明药物制剂中的粘合剂包括但不限定于例如淀粉浆、 聚维酮、 羟丙曱纤 维素、 羟丙纤维素、 曱基纤维素、 羟乙纤维素、 明胶和黄原胶等； The binder in the pharmaceutical preparation of the present invention includes, but is not limited to, for example, starch syrup, povidone, hydroxypropyl hydrazine cellulose, hydroxypropyl cellulose, decyl cellulose, hydroxyethyl cellulose, gelatin, xanthan gum, and the like;
本发明药物制剂中的润滑剂包括但不限定于硬脂酸镁、硬脂酸、硬脂酸富马 酸钠、 滑石粉和月桂硫酸钠等； The lubricant in the pharmaceutical preparation of the present invention includes, but is not limited to, magnesium stearate, stearic acid, sodium stearate, sodium talc, sodium lauryl sulfate, and the like;
本发明药物制剂中的崩解剂包括但不限定于羧曱基淀粉那、 所曱基纤维素 钠、 低取代羟丙纤维素、 交联聚维酮、 交联羧曱基纤维素钠、 交联羧曱基淀粉 钠和预胶化淀粉等； The disintegrant in the pharmaceutical preparation of the present invention includes, but is not limited to, carboxymethyl starch, sodium sulfonate, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, and Sodium carbamate sodium starch and pregelatinized starch;
本发明药物制剂中的防腐剂包括但不限定于苯曱酸钠、 山梨酸钾、 对羟基苯 曱酸曱酯和对羟基苯曱酸乙酯等； The preservatives in the pharmaceutical preparation of the present invention include, but are not limited to, sodium benzoate, potassium sorbate, decyl p-hydroxybenzoate and ethyl p-hydroxybenzoate;
本发明药物制剂中的緩沖剂包括但不限定于磷酸盐緩沖液、柠檬酸、柠檬酸 钠、 醋酸盐緩沖液、 磷酸钠和氢氧化钠等； The buffering agent in the pharmaceutical preparation of the present invention includes, but is not limited to, phosphate buffer solution, citric acid, sodium citrate, acetate buffer solution, sodium phosphate and sodium hydroxide;
本发明药物制剂中的抗氧剂包括但不限定于依地酸 4弓钠、 亚硫酸钠、 焦亚硫 酸钠、 胱氨酸和维生素等； The antioxidant in the pharmaceutical preparation of the present invention includes, but is not limited to, sodium edetate, sodium sulfite, sodium metabisulfite, cystine and vitamins;
本发明药物制剂中的口味调节剂包括但不限定于果糖、 蔗糖、 糖精钠、 麦芽 糖醇、 橘子香精和草莓香精等；
另外本发明药物制剂还可包括其它常规的、 恰当的添加剂。 The taste regulating agent in the pharmaceutical preparation of the present invention includes, but is not limited to, fructose, sucrose, sodium saccharin, maltitol, orange flavor and strawberry flavor; Further, the pharmaceutical preparation of the present invention may further comprise other conventional and appropriate additives.
应当理解的是上述本制剂中的药用载体是指视需要选择使用， 也可以不使 用。 同一种载体如填充剂可以选择一种， 也可以选择几种。 It should be understood that the pharmaceutically acceptable carrier in the above-mentioned preparation means that it may or may not be used as needed. The same carrier such as a filler may be selected one or more.
应当理解，按照本领域熟知的方法，药用载体是保持药用剂型的基质或辅料， 通常根据不同剂型来选用或组合使用， 可选择的包括赋形剂或稀释剂， 例如微 晶纤维素、 乳糖、 预胶化淀粉、 淀粉、 糊精、 磷酸 4弓、 碳酸 4弓、 甘露醇、 山梨 醇、 葡萄糖、 右旋糖酐和环糊精中的一种或几种； 还可包括粘合剂， 例如淀粉 浆、 聚维酮、 羟丙甲纤维素、 羟丙纤维素、 甲基纤维素、 羟乙纤维素、 明胶和 黄原胶中的一种或几种； 还包括润滑剂， 例如硬脂酸镁、 硬脂酸、 硬脂酸富马 酸钠、 滑石粉和月桂硫酸钠中的一种或几种； 还包括崩解剂， 例如羧甲基淀粉 那、 所甲基纤维素钠、 低取代羟丙纤维素、 交联聚维酮、 交联羧甲基纤维素钠、 交联羧甲基淀粉钠和预胶化淀粉中的一种或几种； 还包括防腐剂， 例如苯甲酸 钠、 山梨酸钾、 对羟基苯甲酸甲酯和对羟基苯甲酸乙酯中的一种或几种； 还包 括緩沖剂， 例如磷酸盐緩沖液、 柠檬酸、 柠檬酸钠、 醋酸盐緩沖液、 磷酸钠和 氢氧化钠中的一种或几种； 还包括抗氧剂， 例如依地酸 4弓钠、 亚^ £酸钠、 焦亚 硫酸钠、 胱氨酸和维生素中的一种或几种； 还包括口味调节剂， 例如果糖、 蔗 糖、 糖精钠、 麦芽糖醇、 橘子香精和草莓香精中的一种或几种； 另外还可包括 其它常规的、 恰当的添加剂。 It will be understood that the pharmaceutically acceptable carrier is a matrix or excipient that maintains the pharmaceutical dosage form, usually in accordance with different dosage forms or in combination, optionally including excipients or diluents, such as microcrystalline cellulose, in accordance with methods well known in the art. One or more of lactose, pregelatinized starch, starch, dextrin, phosphoric acid 4 bow, carbonic acid 4 bow, mannitol, sorbitol, glucose, dextran and cyclodextrin; may also include a binder such as starch One or more of pulp, povidone, hypromellose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, gelatin, and xanthan gum; also includes a lubricant such as magnesium stearate , one or more of stearic acid, sodium stearate, talc and sodium lauryl sulfate; further comprising a disintegrant such as carboxymethyl starch, sodium methylcellulose, low substituted hydroxyl One or more of propyl cellulose, crospovidone, croscarmellose sodium, croscarmellose sodium, and pregelatinized starch; also includes preservatives such as sodium benzoate, sorbic acid Potassium, p-hydroxy One or more of methyl formate and ethyl p-hydroxybenzoate; also including buffers such as phosphate buffer, citric acid, sodium citrate, acetate buffer, sodium phosphate, and sodium hydroxide One or more; further comprising an antioxidant, such as one or more of sodium edetate, sodium sulphate, sodium metabisulfite, cystine and vitamins; and a taste regulating agent such as fructose One or more of sucrose, sodium saccharin, maltitol, orange flavor and strawberry flavor; other conventional and appropriate additives may also be included.
本发明可以通过以下方法制备： （例如普通片） The invention can be prepared by the following methods: (e.g., ordinary tablets)
将泰诺福韦酯分别和制药成分混合， 从而获得优选的处理及加工性能， 可 以使用的药用成分包括填充剂、 润滑剂、 崩解剂及其它药用辅料。 加入一定量 的粘合剂溶液， 湿法制粒， 将所得的颗粒烘干至一定程度， 加入润滑剂， 压制 成一定规格和大小的片剂， 得到泰诺福韦酯的普通片。 The tenofovir disoproxil is separately mixed with the pharmaceutical ingredient to obtain preferred handling and processing properties, and the pharmaceutical ingredients which can be used include fillers, lubricants, disintegrating agents and other pharmaceutically acceptable excipients. A certain amount of the binder solution is added, wet granulation, the obtained granules are dried to a certain extent, a lubricant is added, and the tablets are pressed into a certain size and size to obtain a common tablet of tenofovir.
本发明可以通过以下方法制备： （例如胶嚢剂）
将泰诺福韦酯分别和制药成分混合，从而获得优选的处理及加工性能，过筛， 直接装入空心胶嚢中， 得到胶嚢剂。 或者将一定量的粘合剂溶液加入混合成分 中， 湿法制粒， 将所得的颗粒烘干至一定程度， 整粒装入空心胶嚢中， 得到胶 嚢剂。 The invention can be prepared by the following methods: (e.g., an anthraquinone) The tenofovir disoproxil is separately mixed with the pharmaceutical ingredient to obtain a preferred treatment and processing property, sieved, and directly placed in a hollow capsule to obtain a capsule. Alternatively, a certain amount of the binder solution is added to the mixed components, wet granulation, and the obtained granules are dried to a certain extent, and the whole granules are placed in a hollow capsule to obtain a capsule.
应当理解的是上述 "可选择的包括"是指视需要选择使用， 也可以不使用。 与现有技术相比， 本发明的有益效果在于： It should be understood that the above "optional inclusion" means that it may or may not be used as needed. Compared with the prior art, the beneficial effects of the invention are:
本发明制得的富马酸替诺福韦酯 0晶型， 在溶出度方面要明显优于以往晶 型， 能够更好的被人体吸收。 并且， 本发明制备方法筒单， 适于工业化生产。 四、 附图说明 The tenofovir disoproxil fumarate 0 crystal form prepared by the invention is superior to the conventional crystal form in terms of dissolution, and can be better absorbed by the human body. Moreover, the preparation method of the invention is simple and suitable for industrial production. Fourth, the description of the drawings
图 1是富马酸替诺福韦酯 α晶型的粉末 X-射线衍射光谱图。 Figure 1 is a powder X-ray diffraction spectrum of tenofovir disoproxil fumarate α crystal form.
图 2是富马酸替诺福韦酯 α晶型的差热分析图谱。 Figure 2 is a differential thermal analysis of the crystalline form of tenofovir disoproxil fumarate.
图 3是富马酸替诺福韦酯 α晶型的红外光谱图。 五、 具体实施方式 Figure 3 is an infrared spectrum of the crystalline form of tenofovir disoproxil fumarate. V. Specific implementation methods
我们以下面的实例来阐述本发明， 但并不限制本发明的范围。 The invention is illustrated by the following examples, without limiting the scope of the invention.
实施例 1 Example 1
将 50g的富马酸替诺福韦酯溶解至 1250ml的乙醇中， 略升温至溶清， 然后 将之室温， 应无晶体析出， 在室温下滴加 1000ml 的石油醚， 然后慢慢冷却至 0~5 °C , 緩慢搅拌， 有大量白色结晶析出。 保温 1 小时后， 抽滤， 将滤饼置于 30~35°C真空干燥箱内干燥至干燥失重小于 0.5%,约得到 45g的产品，收率 90% 左右， 纯度在 99%左右。 如需要提高纯度， 可重复上面操作重结晶。 50 g of tenofovir disoproxil fumarate was dissolved in 1250 ml of ethanol, slightly warmed to dissolve, and then room temperature, no crystals were precipitated, 1000 ml of petroleum ether was added dropwise at room temperature, and then slowly cooled to 0. ~5 °C, stirring slowly, a large amount of white crystals precipitated. After 1 hour of heat preservation, the filter cake was dried in a vacuum oven at 30-35 ° C until the weight loss was less than 0.5%, about 45 g of product was obtained, the yield was about 90%, and the purity was about 99%. If you need to increase the purity, repeat the above operation and recrystallize.
富马酸替诺福韦酯 α晶形的物理性质： 我们选用日本理学电机株式会社生 产的 Rigaku D/max 2550PC全自动多晶 X射线衍射仪测定我们上步所得的产品
X-ray图谱。 α晶形的 XRD特征峰以 2Θ角表达在约 7.1、 7.8、 8.1、 9.8、 10.5、 10.9 , 11.6, 11.9, 13.7, 14.3 , 14.7, 15.6, 16.1 , 16.6, 16.8, 17.9 , 18.4, 19.2, 20.4、 21.2、 21.6、 22.5、 22.7、 23.4、 24.3、 25.4和 26.4处。 如附图 1所示。 Physical properties of the crystalline form of tenofovir disoproxil fumarate: We selected the Rigaku D/max 2550PC fully automated polycrystalline X-ray diffractometer from Rigaku Corporation of Japan to determine the products we obtained in the previous step. X-ray map. The XRD characteristic peaks of the α crystal form are expressed at 2 Θ angles at about 7.1, 7.8, 8.1, 9.8, 10.5, 10.9, 11.6, 11.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4. As shown in Figure 1.
我们也可通过差热分析我们所得到产品的晶形，我们采用美国 ΤΑ公司生产 的 Q200差示扫描量热仪进行量热扫描， 如附图 2所示， 在 117.40处有吸热峰， 起 始处在 115.52 °C。 We can also analyze the crystal form of the product we obtained by differential thermal analysis. We use the Q200 differential scanning calorimeter produced by American Corporation for calorimetric scanning. As shown in Figure 2, there is an endothermic peak at 117.40. At 115.52 °C.
另外， 我们用 IR红外光谱对我们的产品进行分析， 采用的是美国 nicolet 公司生产的 Nexus670型傅里叶红外光谱变换仪测试我们上步得到的晶形。 通过 研磨 KBr和 TDF粉末以得到精细粉末制备含有约 1.0%重量的富马酸替诺福韦酯 晶体和干燥的 KBr的透明小片。 红外光谱（IR )吸收带约在 3337 (芳烃）、 3198 In addition, we analyzed our products by IR spectroscopy, and used the Nexus 670 Fourier infrared spectrum converter from Nicolet to test the crystal form we obtained in the previous step. A transparent tablet containing about 1.0% by weight of tenofovir disoproxil fumarate crystals and dried KBr was prepared by grinding KBr and TDF powders to obtain a fine powder. Infrared spectroscopy (IR) absorption band is approximately 3337 (aromatics), 3198
(羟基）、 2986-2935 (饱和脂肪烃）、 1764 (羰基）、 1661 (芳烃氰基 )和 1621cm-1 (hydroxyl), 2986-2935 (saturated aliphatic hydrocarbon), 1764 (carbonyl), 1661 (aromatic cyano) and 1621 cm- 1
(不饱和烃）。 如附图 3所示。 实施例 2 (unsaturated hydrocarbons). As shown in Figure 3. Example 2
将 50g的富马酸替诺福韦酯溶解至 1000ml的曱醇中， 室温搅拌至溶清， 用 一微孔滤膜滤除微量不溶物， 滤液转至三口瓶中， 机械搅拌， 慢速搅拌下慢慢 滴加 1000ml的正己烷， 水浴保温， 随着滴加， 有白色晶体慢慢析出。 正己烷滴 加完毕之后， 室温慢速搅拌 30分钟， 然后稍冷却至 15°C左右， 保温 1小时后抽 滤， 室温下真空干燥 10小时， 得到最终产品约 40g。 收率 80%, 纯度 99%以上。 50 g of tenofovir disoproxil fumarate was dissolved in 1000 ml of methanol, stirred at room temperature until dissolved, and a small amount of insoluble matter was filtered off with a microporous membrane. The filtrate was transferred to a three-necked flask, mechanically stirred, and slowly stirred. 1000 ml of n-hexane was slowly added dropwise, and the mixture was incubated with a water bath. As the drop was added, white crystals gradually precipitated. After the completion of the dropwise addition of n-hexane, the mixture was slowly stirred at room temperature for 30 minutes, and then slightly cooled to about 15 ° C. After 1 hour of incubation, the mixture was filtered, and vacuum dried at room temperature for 10 hours to obtain about 40 g of the final product. The yield is 80%, and the purity is over 99%.
制得晶型的 XRD特征峰以 2Θ角表达在约 7.1、 7.8、 8.1、 9.8、 10.5、 10.9、 11.6, 11.9, 13.7, 14.3 , 14.7, 15.6, 16.1 , 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2 , 21.6, 22.5 , 22.7, 23.4, 24.3 , 25.4和 26.4处。 The XRD characteristic peaks of the obtained crystal form are expressed at about 2, 11, 7.8, 8.1, 9.8, 10.5, 10.9, 11.6, 11.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4.
红外光谱（IR )吸收带约在 3337、 3198、2986~2935、 1764、 1661和 1621cm"1„Infrared spectroscopy (IR) absorption bands are approximately 3337, 3198, 2986~2935, 1764, 1661, and 1621 cm" 1 „
DSC在约 117.4处有吸热峰， 起始处在约 115.5 °C。
实施例 3 The DSC has an endothermic peak at about 117.4, starting at about 115.5 °C. Example 3
将 50g的富马酸替诺福韦酯溶解至 1500ml的异丙醇中， 室温搅拌至溶清， 用一微孔滤膜滤除微量不溶物， 滤液转至三口瓶中， 机械搅拌， 慢速搅拌下慢 慢滴加 500ml的环己烷， 水浴保温， 随着滴加， 有白色晶体慢慢析出。 正己烷 滴加完毕之后， 室温慢速搅拌 30分钟， 然后稍冷却至 15°C左右， 保温 1小时后 抽滤， 室温下真空干燥 10小时， 得到最终产品约 47g。 收率 94%, 纯度 99%以 上。 50 g of tenofovir disoproxil fumarate was dissolved in 1500 ml of isopropanol, stirred at room temperature until dissolved, and a trace of insoluble matter was filtered off with a microporous membrane. The filtrate was transferred to a three-necked flask, mechanically stirred, slow. 500 ml of cyclohexane was slowly added dropwise with stirring, and the mixture was incubated with a water bath. As the dropwise addition, white crystals gradually precipitated. After the completion of the dropwise addition of n-hexane, the mixture was slowly stirred at room temperature for 30 minutes, and then slightly cooled to about 15 ° C, and after 1 hour of incubation, suction filtration was carried out, and vacuum drying was carried out for 10 hours at room temperature to obtain about 47 g of the final product. The yield is 94% and the purity is over 99%.
制得晶型的 XRD特征峰以 2Θ角表达在约 7.1、 7.8、 8.1、 9.8、 10.5、 10.9、 11.6, 11.9, 13.7, 14.3 , 14.7, 15.6, 16.1 , 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2 , 21.6, 22.5 , 22.7, 23.4, 24.3 , 25.4和 26.4处。 The XRD characteristic peaks of the obtained crystal form are expressed at about 2, 11, 7.8, 8.1, 9.8, 10.5, 10.9, 11.6, 11.9, 13.7, 14.3, 14.7, 15.6, 16.1, 16.6, 16.8, 17.9, 18.4, 19.2, 20.4, 21.2, 21.6, 22.5, 22.7, 23.4, 24.3, 25.4 and 26.4.
红外光谱（IR )吸收带约在 3337、 3198、 2986~2935、 1764、 1661和 1621cm"1„Infrared spectroscopy (IR) absorption bands are approximately 3337, 3198, 2986~2935, 1764, 1661, and 1621 cm" 1 „
DSC在约 117.4处有吸热峰， 起始处在约 115.5 °C。 实施例 4 The DSC has an endothermic peak at about 117.4, starting at about 115.5 °C. Example 4
富马酸泰诺福韦酯片剂及其制备（ 1000片 ): Tenofovir fumarate tablets and their preparation (1000 tablets):
富马酸泰诺福韦酯 150.0g Tenofovir fumarate 150.0g
乳糖 60.0g Lactose 60.0g
微晶纤维素 20.0g Microcrystalline cellulose 20.0g
交联聚维酮 4.0g Cross-linked povidone 4.0g
硬脂酸镁 2.0g Magnesium stearate 2.0g
取上述配方， 用常规方法， 将富马酸泰诺福韦酯、 乳糖、 微晶纤维素混合 均匀后， 以交联聚维酮的水溶液湿法制粒， 烘干， 整粒后加入硬脂酸镁， 混匀， 压制制成片剂， 每片含富马酸泰诺福韦酯 150mg。
实施例 富马酸泰诺福韦酯胶嚢及其制备（ 1000粒）: 富马酸泰诺福韦酉; 150.0g
Take the above formula, mix the tenofovir fumarate fucrose, lactose and microcrystalline cellulose in a conventional manner, then wet granulate with an aqueous solution of crospovidone, dry, and add stearic acid after the whole grain. Magnesium, mixed, compressed into tablets, each containing 150 mg of tenofovir fumarate. EXAMPLES Tenofovir Fumarate Fumarate and Its Preparation (1000 Capsules): Tenofovir Fumarate; 150.0g
微晶纤维素 20.0g 硬脂酸镁 Microcrystalline cellulose 20.0g magnesium stearate
实施例 6 溶出度实验 Example 6 Dissolution test
取美国吉里德科学的富马酸泰诺福韦酯晶型的原料分别按实施例 4和实施 例 5的方法制成样品 （标注为片剂 b和胶嚢 b ), 同 α晶型的富马酸泰诺福韦酯 制成的实施例 4样品和实施例 5样品（标注为片剂 a和胶嚢 a )进行溶出度实验 比较。 方法如下： 以 900ml水为溶出介质， 旋转溶解， 转速为 75r/min, 按中国 药典 2005版二部附录 X C第一法操作，于 30min取样，经 0. 45 μ ηι微孔滤膜过滤 取续滤液作为供试品溶液。 另外精密称取泰诺福韦酯对照品适量， 用水溶解后 再用流动相稀释至 lmg/ml , 经 0. 45m微孔滤膜过滤取续滤液作为对照品溶液。 分别取对照品溶液和供试品溶液 20 μ 1注入 HPLC色语仪中， 于 260nm波长处分 别进行测定， 以外标法计算每片的溶出量， 再与每片的标识量对比， 计算每片 的溶出度。 The raw materials of the crystal form of tenofovir disoproxil fumarate from the United States Gilead Science were respectively prepared according to the methods of Example 4 and Example 5 (labeled as tablet b and capsule b), and the same as the α crystal form. A sample of Example 4 made with tenofovir tartrate and a sample of Example 5 (labeled tablet a and capsule a) were compared for dissolution experiments. The method is as follows: 900ml water as dissolution medium, rotary dissolution, rotation speed is 75r/min, according to the Chinese Pharmacopoeia 2005 edition two appendix XC first method, sampling at 30min, filtering through 0. 45 μ ηι microporous membrane The filtrate was used as a test solution. In addition, the appropriate amount of the tenofovir disoproxil reference substance was accurately weighed, dissolved in water, and then diluted to a lmg/ml with a mobile phase, and filtered through a 0.54 m microporous membrane to obtain a reference solution. Take the reference solution and the test solution 20 μl into the HPLC colorimeter, measure them at the wavelength of 260 nm, calculate the dissolution amount of each piece by external standard method, and compare each sample with the amount of each piece to calculate each piece. Dissolution.
计算公式 Calculation formula
供试品峰面积 X对照品浓度 X 900 Peak area of the test sample X Concentration of the reference substance X 900
溶出度：
Dissolution:
对照品峰面积 X每片标识含量
溶出度测定结果如下表 1 : Reference product peak area X per tablet identification content The dissolution test results are shown in Table 1 below:
表 1 样品的溶出度测定结果（溶出度 /% ) Table 1 Dissolution test results of samples (dissolution /%)
样品 1 2 3 4 5 6 均值 RSD(%) 片剂 a样品 90.53% 93.23% 92.64% 93.53% 96.57% 92.52% 93.17% 0.020 片剂 b样品 88.95% 90.67% 92.54% 87.64% 91 .64% 86.95% 89.73% 0.022 胶嚢 a样品 85.62% 87.65% 89.61 % 85.96% 89.24% 85.12% 87.20% 0.019 胶嚢 b样品 83.23% 85.64% 87.23% 83.86% 81 .23% 81 .58% 83.80% 0.023 Sample 1 2 3 4 5 6 Mean RSD (%) Tablet a sample 90.53% 93.23% 92.64% 93.53% 96.57% 92.52% 93.17% 0.020 Tablet b sample 88.95% 90.67% 92.54% 87.64% 91 .64% 86.95% 89.73 % 0.022 嚢 a sample 85.62% 87.65% 89.61 % 85.96% 89.24% 85.12% 87.20% 0.019 嚢 b sample 83.23% 85.64% 87.23% 83.86% 81 .23% 81 .58% 83.80% 0.023
上述结果表明： 富马酸泰诺福韦酯 (X晶型的样品在此条件下的溶出明显优 于美国吉里德科学的富马酸泰诺福韦酯晶型的样品。
The above results indicate that the dissolution of tenofovir disoproxil fumarate (X-form sample) under these conditions is superior to that of the Gilead Science of tenofovir disoproxil crystal form.
Claims
1、 一种富马酸替诺福韦酯 α晶型， 其特征在于所述的富马酸替诺福韦酯 α晶型 使用 Cu-Ka辐射， 以 2Θ角度表示的 X-射线粉末衍射光谱在约 7.1、 约 7.8、 约 8.1、 约 9.8、 约 10.5、 约 10.9、 约 11.6、 约 11.9、 约 13.7、 约 14.3、 约 14.7、 约 15.6、 约 16.1、 约 16.6、 约 16.8、 约 17.9、 约 18.4、 约 19.2、 约 20.4、 约 21.2、 约 21.6、 约 22.5、 约 22.7、 约 23.4、 约 24.3、 约 25.4和约 26.4处有特征峰。 1. A crystalline form of tenofovir disoproxil fumarate, characterized in that the crystalline form of tenofovir disoproxil fumarate alpha uses Cu-Ka radiation, X-ray powder diffraction spectrum expressed in terms of 2 Θ angle At about 7.1, about 7.8, about 8.1, about 9.8, about 10.5, about 10.9, about 11.6, about 11.9, about 13.7, about 14.3, about 14.7, about 15.6, about 16.1, about 16.6, about 16.8, about 17.9, about 18.4. Characteristic peaks at about 19.2, about 20.4, about 2.12, about 21.6, about 22.5, about 22.7, about 23.4, about 24.3, about 25.4, and about 26.4.
2、 如权利要求 1所述的富马酸替诺福韦酯 α晶型， 其特征在于所述的富马酸替 诺福韦酯 晶型的差热分析图谱在约 117.4 °C有吸热峰。 2. The crystalline form of tenofovir disoproxil fumarate according to claim 1, characterized in that the differential thermal analysis pattern of the crystalline form of tenofovir disoproxil fumarate has an endotherm at about 117.4 °C. peak.
3、 如权利要求 1所述的富马酸替诺福韦酯 α晶型， 其特征在于所述的富马酸替 诺福韦酯 α晶型的红外光谱在约 SSS cm-1 约 S WScm-1 2986~2935cm"1 , 约 1764cm"1 , 约 1661cm 和约 1621cm 处有吸收峰。 3. The crystalline form of tenofovir disoproxil fumarate according to claim 1, characterized in that the infrared spectrum of the crystalline form of tenofovir disoproxil fumarate is about SSS cm- 1 about S WScm. - 1 2986~2935cm" 1 , about 1764cm" 1 , there are absorption peaks at about 1661cm and about 1621cm.
4、 一种如权利要求 1所述的富马酸替诺福韦酯 α晶型的制备方法， 包括如下步 骤： 4. A method of preparing a crystalline form of tenofovir disoproxil fumarate according to claim 1, comprising the steps of:
( 1 )将富马酸替诺福韦酯用第一溶剂溶解； 所述的第一溶剂选自下列一种 或任意几种的组合： C1~C6的醇类溶剂、 C2~C6的烷基酯类、 C2~C6的酮类； (1) dissolving tenofovir fumarate in a first solvent; the first solvent is selected from the group consisting of one or any combination of the following: a C1-C6 alcohol solvent, a C2-C6 alkyl group Esters, ketones of C2~C6;
( 2 )加入第二溶剂析晶； 所述的第二溶剂极性在 0.1以下； (2) adding a second solvent to crystallization; the second solvent has a polarity of 0.1 or less;
( 3 )干燥， 收集得到所述的富马酸替诺福韦酯 α晶型。 (3) Drying, collecting the crystalline form of tenofovir disoproxil fumarate.
5、 如权利要求 4所述的富马酸替诺福韦酯 α晶型的制备方法， 其特征在于所述 的第一溶剂选自下列之一： 曱醇、 乙醇、 异丙醇、 乙酸乙酯、 丙酮。 5. The method for preparing a crystalline form of tenofovir disoproxil fumarate according to claim 4, wherein the first solvent is selected from the group consisting of: sterol, ethanol, isopropanol, acetic acid Ester, acetone.
6、 如权利要求 4所述的富马酸替诺福韦酯 α晶型的制备方法， 其特征在于所述 第一溶剂的体积用量以富马酸替诺福韦酯的质量计为 10~50mL/g。 6. The method for preparing a crystalline form of tenofovir disoproxil fumarate according to claim 4, wherein the volume of the first solvent is 10% by mass of tenofovir fumarate. 50 mL / g.
7、 如权利要求 4所述的富马酸替诺福韦酯 α晶型的制备方法， 其特征在于步骤 ( 1 ) 中溶解温度在室温至溶剂回流温度。 7. A process for the preparation of a crystalline form of tenofovir disoproxil fumarate according to claim 4, wherein the dissolution temperature in the step (1) is from room temperature to the reflux temperature of the solvent.
8、 如权利要求 4所述的富马酸替诺福韦酯 α晶型的制备方法， 其特征在于所述 第二溶剂选自下列之一： 石油醚、 正己烷、 环己烷、 异戊烷、 正戊烷、 三曱基 戊烷。 8. The method for preparing a crystalline form of tenofovir disoproxil fumarate according to claim 4, wherein the second solvent is selected from the group consisting of petroleum ether, n-hexane, cyclohexane, and isopenic acid. Alkane, n-pentane, tridecyl Pentane.
9、 如权利要求 4所述的富马酸替诺福韦酯 o晶型的制备方法， 其特征在于步骤 (2) 中析晶温度在 -5°C〜室温。 The method for preparing a crystalline form of tenofovir disoproxil fumarate according to claim 4, wherein the crystallization temperature in the step (2) is from -5 ° C to room temperature.
10、 如权利要求 1 所述的富马酸替诺福韦酯 α晶型在制备治疗病毒性乙型肝炎 或艾滋病药物中的应用。 10. Use of tenofovir disoproxil fumarate alpha form according to claim 1 for the manufacture of a medicament for the treatment of viral hepatitis B or AIDS.
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| CN103626803B (en) * | 2012-08-23 | 2017-12-15 | 四川海思科制药有限公司 | Solid of tenofovir dipivoxil and its production and use |
| CN107312039B (en) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | A kind of preparation method of tenofovir prodrug |
| CN103705478B (en) * | 2013-12-23 | 2020-02-07 | 浙江华海药业股份有限公司 | Oral tablet containing tenofovir disoproxil fumarate |
| KR101677433B1 (en) * | 2014-10-29 | 2016-11-21 | 주식회사 퍼슨 | Ion exchanging process method for Tenofovir disoproxil fumarate in manufacturing synthesis and a preparation method of the Fast Dissolving Films for Oral Dosage of Tenofovir disoproxil fumarate |
| CN106008603B (en) * | 2016-06-03 | 2018-12-11 | 东北制药集团股份有限公司 | A kind of preparation method of tenofovir dipivoxil and its fumarate |
| CN107998094A (en) * | 2016-10-31 | 2018-05-08 | 顾世海 | A kind of tenofovir disoproxil fumarate sustained release tablets and preparation method thereof |
| KR101805684B1 (en) * | 2016-11-11 | 2018-01-11 | 주식회사 퍼슨 | A fast dissolving film-formulation for oral dosage of tenofovir disoproxil fumarate and the manufacturing method thereof |
| CN108948083A (en) * | 2017-05-17 | 2018-12-07 | 上海科胜药物研发有限公司 | A kind of tenofovir disoproxil fumarate novel crystal forms and preparation method thereof |
| CN109942634A (en) * | 2019-01-24 | 2019-06-28 | 深圳科兴药业有限公司 | A kind of the crystal form I and preparation method and application of tenofovir disoproxil fumarate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013086A1 (en) * | 2005-07-26 | 2007-02-01 | Hetero Drugs Limited | Novel polymorphs of tenofovir disoproxil fumarate |
| CN101066980A (en) * | 2007-05-08 | 2007-11-07 | 黑龙江加州国际投资咨询有限公司 | Crystalline tenofovir fumarate and its medicine prepn |
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| WO2009130437A1 (en) * | 2008-04-25 | 2009-10-29 | Cipla Limited | Crystalline form of tenofovir disoproxil and a process for its preparation |
| CN101781335A (en) * | 2010-03-04 | 2010-07-21 | 福建广生堂药业有限公司 | New tenofovir disoproxil fumarate crystal and preparation method thereof |
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| WO2010026603A2 (en) * | 2008-09-05 | 2010-03-11 | Matrix Laboratories Limited | Novel amine salts of tenofovir, process for producing the same and use thereof in production of tenofovir dioproxil |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007013086A1 (en) * | 2005-07-26 | 2007-02-01 | Hetero Drugs Limited | Novel polymorphs of tenofovir disoproxil fumarate |
| CN101066980A (en) * | 2007-05-08 | 2007-11-07 | 黑龙江加州国际投资咨询有限公司 | Crystalline tenofovir fumarate and its medicine prepn |
| WO2009064174A1 (en) * | 2007-11-14 | 2009-05-22 | Ultimorphix Technologies B.V. | Polymorphic form of tenofovir disoproxil fumarate, method for its preparation and use |
| WO2009130437A1 (en) * | 2008-04-25 | 2009-10-29 | Cipla Limited | Crystalline form of tenofovir disoproxil and a process for its preparation |
| CN101781335A (en) * | 2010-03-04 | 2010-07-21 | 福建广生堂药业有限公司 | New tenofovir disoproxil fumarate crystal and preparation method thereof |
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