CN103626803B - Solid of tenofovir dipivoxil and its production and use - Google Patents
Solid of tenofovir dipivoxil and its production and use Download PDFInfo
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- CN103626803B CN103626803B CN201310346710.5A CN201310346710A CN103626803B CN 103626803 B CN103626803 B CN 103626803B CN 201310346710 A CN201310346710 A CN 201310346710A CN 103626803 B CN103626803 B CN 103626803B
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- Prior art keywords
- tenofovir disoproxil
- degrees
- acid
- eutectic
- tartrate
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 110
- 239000007787 solid Substances 0.000 title claims abstract description 104
- 229960004556 tenofovir Drugs 0.000 title abstract description 15
- 238000004519 manufacturing process Methods 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 163
- 150000003839 salts Chemical class 0.000 claims abstract description 153
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 63
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 21
- 230000009385 viral infection Effects 0.000 claims abstract description 7
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- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 897
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 613
- 239000013078 crystal Substances 0.000 claims description 266
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 231
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 43
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical group OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 claims description 42
- 229960001627 lamivudine Drugs 0.000 claims description 37
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 37
- -1 tenofovir disoproxil compound Chemical class 0.000 claims description 37
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- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 claims description 35
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Abstract
The present invention relates to the solid of tenofovir dipivoxil.The solid is:(1) the tenofovir dipivoxil compound shown in formula IV;Or tenofovir dipivoxil eutectic or salt shown in (2) Formula V.The invention further relates to the preparation method of the solid of the tenofovir dipivoxil, pharmaceutical composition containing these solids, and these solids are preparing prevention and/or are treating virus infection, the application in the medicine of special hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection.
Description
Technical Field
The invention relates to a solid of tenofovir disoproxil for preventing and/or treating virus infection, a preparation method thereof, application of the solid in preparing medicaments for preventing and/or treating virus infection, in particular Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection, and a pharmaceutical composition containing the solid.
Background
Tenofovir disoproxil (Tenofovir disoproxil), chemical name: 9- [2- (R) - [ [ bis [ [ (isopropoxycarbonyl) oxy ] methoxy ] phosphono ] methoxy ] propyl ] adenine having the molecular structure shown in formula I:
the tenofovir disoproxil is ester precursor medicine of tenofovir, is one kind of acyclic nucleotide reverse transcriptase inhibitor, has broad spectrum antiviral effect, and can inhibit the reverse transcriptase of HIV-1 and HIV-2 and HBV polymerase to inhibit virus replication. After being taken orally, the tenofovir disoproxil is hydrolyzed into tenofovir, the tenofovir is phosphorylated into a metabolite tenofovir diphosphate with pharmacological activity by cell kinase, the tenofovir diphosphate competes with 5 '-triphosphate deoxyadenosine monophosphate to participate in synthesis of virus DNA, and after entering the virus DNA, the DNA elongation is blocked due to the lack of 3' -hydroxyl, so that the virus replication is inhibited. Compared with the similar medicines, the tenofovir disoproxil is used for preventing and/or treating Hepatitis B Virus (HBV) and human immunodeficiency virus (HIV/AIDS) infection, and has higher safety and lower drug resistance. Currently, single formulations of Tenofovir disoproxil fumarate (Tenofovir disoproxil fumarate) are on the market at home and abroad.
The antiviral prevention or/and treatment by using nucleoside drugs alone often causes poor drug resistance and response, and one of the important strategies for solving the problem is combined medication, so that the development of safer, more effective and low-drug-resistance anti-hepatitis B and anti-AIDS compound drugs becomes the development direction in the future. Currently, there are several compound formulations containing tenofovir disoproxil fumarate in different stages of development, such as: tenofovir disoproxil fumarate/Emtricitabine (Emtricitabine), Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz (Efavirenz), Tenofovir disoproxil fumarate/Emtricitabine/rilpivirine hydrochloride (Rilpivrine HCl), Tenofovir disoproxil fumarate/Emtricitabine/Eltiravir (Elvitegravir)/Cobicistat and other compound preparations are marketed in the United states, European Union, Canada, Australia, etc.; the compound of tenofovir disoproxil fumarate/Lamivudine (Lamivudine), tenofovir disoproxil fumarate/Lamivudine/efavirenz and the like is in the registration or pre-registration stage abroad.
In the above compound formulation, emtricitabine or lamivudine is another important active ingredient in addition to tenofovir disoproxil. Lamivudine and emtricitabine are structural analogs (the 5-position of pyrimidine ring in the lamivudine structure is substituted by fluorine to form emtricitabine), and also are nucleoside reverse transcriptase inhibitors, which have antiviral activity to HIV-1, HIV-2 and HBV, and are on the market at home and abroad. They can be prepared according to the methods disclosed in patent documents CN1132073A, CN1563002A, CN1149871A, CN1563003A and the like. The structural formulas of lamivudine and emtricitabine are shown in formula II and formula III, respectively:
because the solid melting point of the tenofovir disoproxil is lower, the solubility in water is lower, and the preparation of a medicinal preparation and the dissolution in the medicinal preparation are not facilitated, the tenofovir disoproxil is developed into a fumarate form and is used for single preparations and compound preparations. Although the tenofovir disoproxil fumarate is greatly improved in water solubility, physical properties and the like compared with tenofovir disoproxil fumarate, the tenofovir disoproxil fumarate has a complex polymorphism, for example, patent documents CN101066980A, CN101781335A, CN101948485A, WO2007013086, WO2008140302, WO2009064174 and the like disclose multiple crystal forms (including amorphous forms) of the tenofovir disoproxil fumarate, for example, CN101778855A shows that analysis on a plurality of commercially available tenofovir disoproxil fumarate shows that the products are all mixtures of different crystal forms, which may cause crystal form conversion of the tenofovir disoproxil fumarate in preparation and storage, and further cause unstable quality and drug effect.
In addition, when the tenofovir disoproxil fumarate is used in a compound preparation, the chemical stability of the tenofovir disoproxil fumarate is greatly influenced by other active ingredients or auxiliary materials, for example, in WO2006135932, tenofovir disoproxil fumarate, emtricitabine, efavirenz and other auxiliary materials are mixed together, so that the tenofovir disoproxil fumarate is rapidly degraded.
Therefore, in order to overcome the above-mentioned deficiencies in the prior art, it is necessary to develop a new solid form of tenofovir disoproxil (including cocrystals, salts or compounds) so as to further improve the chemical stability, process controllability and the like of tenofovir disoproxil or a preparation containing tenofovir disoproxil, thereby enhancing the safety and effectiveness of the product and providing better drug selection for patients.
Disclosure of Invention
It is an object of the present invention to provide novel solids of tenofovir disoproxil. The solid is superior to the prior art in the aspects of physical properties, process controllability and the like.
The invention also aims to provide a preparation method of the solid tenofovir disoproxil.
It is a further object of the present invention to provide a solid pharmaceutical composition comprising a therapeutically effective amount of the above tenofovir disoproxil.
The invention also aims to provide application of the solid tenofovir disoproxil in preparation of a medicament for preventing and/or treating virus infection.
According to the purpose of the invention, the invention provides a solid of tenofovir disoproxil, which is:
(1) a tenofovir disoproxil compound shown in a formula IV,
wherein m is 0.5-1; x is selected from: DL-tartaric acid, D-tartaric acid, L-tartaric acid, DL-malic acid or D-malic acid;
or,
(2) a tenofovir disoproxil co-crystal or salt shown in formula V;
wherein n =1, 2 or 3, B is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (also known as DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic, Stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid (also known as DL-tartaric acid), meso-tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (also known as DL-mandelic acid), 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, tartaric acid, adipic acid, sebacic, Glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactaric acid (also known as mucic acid), tannic acid (also known as tannic acid), alginic acid, hydroxynaphthoic acid (also known as 3-hydroxy-2-naphthoic acid), pamoic acid (also known as 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), amino acids or acylated amino acids (such as acetoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine, etc.).
In the above formula IV, the "complex" refers to a compound in which tenofovir disoproxil and a corresponding acid coexist by binding through a non-covalent bond such as a hydrogen bond or an ionic bond, and includes salts, co-crystals, or a mixed form thereof, which are well known in the art. The composite further includes its polymorphic forms, solvates, solvate polymorphs, hydrates, hydrate polymorphs, and the like.
In the formula IV, the value of m is 0.5-1, for example, m is 0.5, 0.75 or 1, wherein m is preferably 0.5 or 1, which means the molar composition ratio of tenofovir disoproxil and corresponding acid in the compound structure can be determined through1H-NMR, elemental analysis, HPLC, X-ray diffraction (e.g., single crystal X-ray diffraction), and the like.
In a specific embodiment, in formula IV: m is 1, X is DL-tartaric acid, namely DL-tartaric acid tenofovir disoproxil fumarate; or m is 1, X is D-tartaric acid, namely tenofovir disoproxil D-tartrate; or m is 1, X is DL-malic acid, namely DL-malic acid tenofovir disoproxil fumarate; or m is 1, X is D-malic acid, namely the D-malic acid tenofovir disoproxil fumarate; or m is 1, and X is L-tartaric acid, namely tenofovir disoproxil L-tartrate.
In the formula V, the tenofovir disoproxil eutectic refers to a solid formed by tenofovir disoproxil and acid in a form of eutectic. "eutectic" (Co-Crystals) refers to a multi-component crystal of fixed stoichiometric proportions in which the components coexist at the molecular level, bonded by hydrogen bonding or other non-covalent, non-ionic bonding. In pharmaceutical Co-crystals, typically comprising a pharmaceutically active ingredient and another Co-crystal former (Co-crystal former) or more, such as the "tenofovir disoproxil Co-crystal", tenofovir disoproxil is the pharmaceutically active ingredient and the acid is the Co-crystal former. When the pure co-crystal former alone is present in the liquid state at room temperature, the co-crystal is also referred to as a "solvate", wherein the solvent is water, is referred to as a "hydrate", such as a co-crystal of tenofovir disoproxil with acetic acid, which may be referred to as an acetic acid solvate of tenofovir disoproxil.
The "pharmaceutical co-crystals" also include multi-component crystals having a fixed stoichiometric ratio in which the pharmaceutically active ingredient is bound to the other components, in part by hydrogen bonding or other non-covalent bonding, and in part by ionic bonding or by forces between hydrogen bonding and ionic bonding. For example, a complex of tenofovir disoproxil and a dicarboxylic acid, wherein one carboxyl group of the carboxylic acid is ionically bound to tenofovir disoproxil and the other carboxyl group is hydrogen bound to tenofovir disoproxil, is also considered to form a co-crystal with the dicarboxylic acid.
The definition of "salt" in "tenofovir disoproxil salt" in the above formula V is well known to those skilled in the art, and refers to a compound formed by a cation and an anion through the action of an ionic bond. "tenofovir disoproxil" refers to that in a solid composed of tenofovir disoproxil and acid, protons in the acid are transferred to the tenofovir disoproxil, and the protonated positive ions and negative ions of the tenofovir disoproxil are combined with each other through ionic bond.
In the formula V, the "tenofovir disoproxil eutectic crystal or salt" also includes the solvate, hydrate and other forms of the tenofovir disoproxil eutectic crystal or salt. When the tenofovir disoproxil eutectic is prepared, slurried or crystallized in a certain solvent, the solvent possibly enters the tenofovir disoproxil eutectic or salt crystals to form a solvate; when the solvent is water, hydrates may be formed.
Methods for determining "co-crystals" or "salts" are well known to those skilled in the art, such as analysis by X-ray diffraction (e.g., single crystal or X-ray powder diffraction), and the like.
In the above formula V, "tenofovir disoproxil co-crystal or salt" is generally expressed as "tenofovir disoproxil B (n:1) co-crystal" or "tenofovir disoproxil B (n:1) salt" according to the stoichiometric numbers of tenofovir disoproxil and acid B in the structure and the solid form thereof, wherein B and n are defined as in the formula V. It is understood that "n: 1" is the molar composition ratio of tenofovir disoproxil to acid B in the tenofovir disoproxil co-crystal or salt, and can be determined by1H-NMR, elemental analysis, HPLC, X-ray diffraction (e.g., single crystal or X-ray powder diffraction), and the like.
In a specific embodiment, in formula V, n =3, B is selected from: phosphoric acid, citric acid, tannic acid (also known as tannic acid) or alginic acid. In the present embodiment, the "tenofovir disoproxil co-crystal" is preferably a tenofovir disoproxil phosphate (3:1) co-crystal, a tenofovir disoproxil citrate (3:1) co-crystal.
In a specific embodiment, in formula V, n =2, B is selected from: sulfuric acid, persulfuric acid, thiocyanic acid, phosphoric acid, carbonic acid, glycerophosphoric acid, ethanedisulfonic acid, butanedisulfonic acid, naphthalene-1, 5-disulfonic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid (also known as DL-tartaric acid), meso-tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, camphoric acid, galactaric acid (also known as mucic acid), tannic acid (also known as tannic acid), alginic acid, pamoic acid (also known as 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), aspartic acid, glutamic acid. In the present embodiment, the "tenofovir disoproxil co-crystal" is preferably a tenofovir disoproxil phosphate (2:1) co-crystal, tenofovir disoproxil carbonate (2:1) co-crystal, tenofovir disoproxil oxalate (2:1) co-crystal, tenofovir disoproxil malonate (2:1) co-crystal, tenofovir disoproxil succinate (2:1) co-crystal, tenofovir disoproxil L-malic acid (2:1) co-crystal, tenofovir disoproxil D-malic acid (2:1) co-crystal, tenofovir disoproxil racemic malic acid (2:1) co-crystal, tenofovir disoproxil L-tartaric acid (2:1) co-crystal, tenofovir disoproxil D-tartaric acid (2:1) co-crystal, tenofovir disoproxil racemic disoproxil (2:1) co-crystal, tenofovir disoproxil tartrate co-1 co-crystal, tenofovir disoproxil D-tartaric acid (2:1) co-crystal, tenofovir disoproxil tartrate co-1 co-crystal, or a tenofovir disoproxil succinate co-1 co-crystal, The composition comprises a tenofovir disoproxil fumarate (2:1) eutectic, a tenofovir disoproxil maleate (2:1) eutectic, a tenofovir disoproxil (2:1) citric acid eutectic and a tenofovir disoproxil pamoate (2:1) eutectic. In the present embodiment, "tenofovir disoproxil" is preferably a tenofovir disoproxil sulfate (2:1) salt, tenofovir disoproxil edisulfonic acid (2:1) salt, tenofovir disoproxil butanedisulfonic acid (2:1) salt, tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt.
In a specific embodiment, in formula V, n =1, B is selected from: hydrochloric acid, sulfuric acid, persulfuric acid, thiocyanic acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, carbonic acid, dodecylsulfuric acid, glycerophosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, taurine, camphorsulfonic acid, cyclamic acid, sulfamic acid, ethanedisulfonic acid, butanedisulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-hydroxyphenylsulfonic acid, o-hydroxybenzenesulfonic acid, 2, 5-dihydroxybenzenesulfonic acid, sulfanilic acid, saccharin, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, formic acid, acetic acid, glycolic acid, 2-dichloroacetic acid, propionic acid, L-lactic acid, D-lactic acid, racemic lactic acid (also known as DL-lactic acid), cyclopentanepropionic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, capric acid, undecylenic acid, lauric acid, palmitic, Stearic acid, oleic acid, oxalic acid, malonic acid, succinic acid, L-malic acid, D-malic acid, racemic malic acid (also known as DL-malic acid), L-tartaric acid, D-tartaric acid, racemic tartaric acid (also known as DL-tartaric acid), meso-tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, glutaric acid, 2-oxoglutaric acid, adipic acid, sebacic acid, citric acid, benzoic acid, p-methoxybenzoic acid, 4-acetamidobenzoic acid, salicylic acid, acetylsalicylic acid, gentisic acid, 4-aminosalicylic acid, phenylacetic acid, L-mandelic acid, D-mandelic acid, racemic mandelic acid (also known as DL-mandelic acid), 3-phenylpropionic acid, cinnamic acid, caffeic acid, phenylbutyric acid, picric acid, nicotinic acid, orotic acid, quinic acid, ascorbic acid, tartaric acid, adipic acid, sebacic, Glucuronic acid, gluconic acid, galacturonic acid, glucoheptonic acid, lactobionic acid, camphoric acid, galactaric acid (aka mucic acid), tannic acid (aka tannic acid), alginic acid, hydroxynaphthoic acid (aka 3-hydroxy-2-naphthoic acid), pamoic acid (aka 4,4' -methylenebis (3-hydroxy-2-naphthoic acid) or prussic acid), acetamidoacetic acid, hippuric acid, aspartic acid, glutamic acid, pyroglutamic acid, glutamine, asparagine. In the present embodiment, the "tenofovir disoproxil co-crystal" is preferably tenofovir disoproxil phosphate (1:1) co-crystal, tenofovir disoproxil carbonate (1:1) co-crystal, tenofovir disoproxil acetate (1:1) co-crystal, tenofovir disoproxil (1:1) co-crystal propionate, tenofovir disoproxil L-lactic acid (1:1) co-crystal, tenofovir disoproxil D-lactic acid (1:1) co-crystal, tenofovir disoproxil racemic lactic acid (1:1) co-crystal, tenofovir disoproxil palmitate (1:1) co-crystal, tenofovir disoproxil stearate (1:1) co-crystal, tenofovir disoproxil malate (1:1) co-crystal, tenofovir disoproxil malonate (1:1) co-crystal, tenofovir disoproxil succinate co-crystal, tenofovir succinate co-crystal (1:1) co-crystal, tenofovir disoproxil malate, tenofovir disoproxil fumarate (1) co-crystal, or tenofovir disoproxil fumarate (1) co-crystal, A preparation method of the eutectic crystal comprises the following steps of (1:1) eutectic crystal of tenofovir disoproxil D-malic acid, 1:1 eutectic crystal of tenofovir disoproxil racemic malic acid, 1:1 eutectic crystal of tenofovir disoproxil L-tartaric acid, 1:1 eutectic crystal of tenofovir disoproxil D-tartaric acid, 1:1 eutectic crystal of tenofovir disoproxil racemic tartaric acid, 1:1 eutectic crystal of tenofovir disoproxil meso-tartaric acid, 1:1 eutectic crystal of tenofovir disoproxil fumarate, 1:1 eutectic crystal of tenofovir disoproxil maleate, 1:1 eutectic crystal of tenofovir disoproxil citrate, 1:1 eutectic crystal of tenofovir disoproxil benzoate, 1:1 eutectic crystal of tenofovir disoproxil L-mandelic acid, 1:1 eutectic crystal of tenofovir disoproxil D-malic acid, 1:1 eutectic crystal of tenofovir disoproxil fumarate, The composition comprises tenofovir disoproxil nicotinate (1:1) eutectic, tenofovir disoproxil hydroxynaphthoic acid (1:1) eutectic, tenofovir disoproxil pamoate (1:1) eutectic and tenofovir disoproxil hippuric acid (1:1) eutectic. In the present embodiment, the "tenofovir disoproxil" is preferably tenofovir disoproxil hydrochloride (1:1) salt, tenofovir disoproxil sulfate (1:1) salt, tenofovir disoproxil thiocyanate (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitrate (1:1) salt, tenofovir disoproxil methanesulfonate (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil edisulfonic acid (1:1) salt, Tenofovir disoproxil butanedisulfonic acid (1:1) salt, Tenofovir disoproxil benzenesulfonic acid (1:1) salt, Tenofovir disoproxil p-toluenesulfonic acid (1:1) salt, Tenofovir disoproxil 2, 5-dihydroxy benzenesulfonic acid (1:1) salt, Tenofovir disoproxil naphthalene-2-sulfonic acid (1:1) salt.
According to an object of the present invention, there is provided a preparation method of the solid of tenofovir disoproxil, the preparation method being selected from the following methods:
the method comprises the following steps: a preparation method of a tenofovir disoproxil compound shown in a formula IV comprises the following steps:
(1) dissolving tenofovir disoproxil fumarate and DL-tartaric acid, D-tartaric acid, L-tartaric acid, DL-malic acid or D-malic acid in a solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, drying the isolated solid, or further purifying the isolated solid prior to drying;
or,
the second method comprises the following steps: a preparation method of tenofovir disoproxil co-crystal or salt shown in a formula V comprises the following steps:
(1) forming a solution comprising tenofovir disoproxil and an acid in a solvent;
(2) crystallizing;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or the isolated solid is further purified and then dried.
In the step (1) of the first preparation method, the tenofovir disoproxil can be prepared according to the methods disclosed in patent documents CN1264387A, WO2008007392, CN101574356A and the like. These documents are incorporated by reference into the present application. The tenofovir disoproxil can exist in any form, such as crystalline forms, amorphous forms or mixtures thereof. "DL-tartaric acid" refers to racemic tartaric acid composed of L-tartaric acid and D-tartaric acid in equal proportion; "DL-malic acid" refers to racemic malic acid composed of L-malic acid and D-malic acid in equal proportion.
In the step (1) of the first method, the "solvent" is a solvent having a certain solubility for tenofovir disoproxil and acid, and capable of forming the tenofovir disoproxil complex therein. These solvents are selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, acetone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, and the like or mixtures thereof. The weight ratio of the solvent to tenofovir disoproxil is generally 3: 1-100: 1.
In the step (1) of the first method, the feeding molar ratio of tenofovir disoproxil to DL-tartaric acid, D-tartaric acid, L-tartaric acid, DL-malic acid or D-malic acid is generally 0.5: 1-2: 1.
In step (2) of the first method, the "solid precipitation" method is a method conventional in the art, such as cooling, adding an anti-solvent, concentrating a part of the solvent, adding seed crystals, and the like, and can be used alone or in combination. The "antisolvent" refers to a solvent which has poor solubility to the formed tenofovir disoproxil compound at normal temperature and is miscible with the solvent for dissolving tenofovir disoproxil and acid, such as n-hexane, cyclohexane, petroleum ether, diethyl ether, ethyl acetate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, and the like, or a mixture thereof. The volume ratio of the antisolvent to the solvent for dissolving the tenofovir disoproxil and the acid is generally 0.2: 1-5: 1.
In step (3) of the first method, the "separation" may be performed by a conventional method in the art, such as filtration, and optionally, the separated solid may be washed with the solvent in step (1).
In step (4) of the first method, the drying manner includes drying under normal pressure, drying under reduced pressure or a combination thereof. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
In step (1) of the second process, tenofovir disoproxil can be prepared according to the methods disclosed in patent documents CN1264387A, WO2008007392, CN101574356A and the like. These documents are incorporated by reference into the present application. Tenofovir disoproxil can exist in any form, such as crystalline forms, amorphous forms or mixtures thereof.
In step (1) of the second method, the "solvent" is a solvent having a certain solubility for tenofovir disoproxil and acid, and capable of forming a tenofovir disoproxil eutectic crystal or salt therein. These solvents are selected from the group consisting of water, ethanol, methanol, propanol, isopropanol, butanol, ethylene glycol, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, diethyl ether, isopropyl ether, n-butyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, t-butyl methyl ether, tetrahydrofuran, petroleum ether, acetonitrile, dichloromethane, chloroform, n-hexane, cyclohexane, acetone, butanone, pentanone, cyclohexanone, toluene, xylene, dimethylacetamide, dimethylformamide and the like or mixtures thereof. The weight ratio of the solvent to tenofovir disoproxil is generally 3: 1-100: 1.
In step (1) of the second process, the "acid" is selected from the group consisting of acids represented by B in formula V. The feeding molar ratio of tenofovir disoproxil to acid is generally 4: 1-0.5: 1, and when a tenofovir disoproxil acid (3:1) eutectic or salt is prepared, the feeding molar ratio of tenofovir disoproxil to acid is generally 3.5: 1-2.7: 1; when preparing a tenofovir disoproxil acid (2:1) eutectic or salt, the feeding molar ratio of tenofovir disoproxil to acid is generally 2.5: 1-1.7: 1; when the tenofovir disoproxil acid (1:1) eutectic or salt is prepared, the feeding molar ratio of tenofovir disoproxil to acid is generally 1.5: 1-0.5: 1.
In the step (2) of the second method, the "crystallization" method comprises cooling crystallization, adding an anti-solvent for crystallization, concentrating a part of the solvent for crystallization, adding a seed crystal for crystallization, and the like, and the methods can be used alone or in combination. The antisolvent is a solvent which has poor solubility to formed tenofovir disoproxil eutectic or salt at normal temperature and can be miscible with a proper solvent for dissolving tenofovir disoproxil and acid, such as n-hexane, cyclohexane, petroleum ether and the like. The volume ratio of the antisolvent to a suitable solvent for dissolving tenofovir disoproxil and the acid is generally 0.2: 1-5: 1.
In step (3) of the second method, the "separation" method includes filtration, centrifugation, or the like. Optionally, the collected solid may be washed with a suitable solvent.
In the step (4) of the second method, the drying manner includes drying under normal pressure, drying under reduced pressure or a combination thereof. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
DL-Tenofovir disoproxil tartrate
In one embodiment, in formula IV, m is selected to be 1 and X is selected to be DL-tartaric acid, i.e., a complex of tenofovir disoproxil and DL-tartaric acid in a 1:1 molar ratio is provided, referred to as "DL-tartaric acid tenofovir disoproxil".
In one embodiment, the present invention provides a method for preparing DL-tenofovir disoproxil tartrate, the method comprising:
(1) dissolving tenofovir disoproxil and DL-tartaric acid in a suitable solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
In the above-mentioned production process step (1), the "suitable solvent" is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, dichloromethane, chloroform, dimethylacetamide, dimethylformamide, dimethylsulfoxide and the like or a mixture thereof, and preferably methanol, ethanol, isopropanol or a mixture thereof. The weight ratio of the suitable solvent to tenofovir disoproxil is generally 7: 1-80: 1.
In the step (1) of the preparation method, the dissolving temperature is generally 20 ℃ to the boiling point of the solvent, and preferably 35 to 50 ℃.
In the step (1) of the preparation method, the feeding molar ratio of tenofovir disoproxil to DL-tartaric acid is generally 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1.
In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. The "antisolvent" is selected from diethyl ether, ethyl acetate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, etc. or mixtures thereof, preferably isopropyl ether. The volume ratio of the antisolvent to a suitable solvent for dissolving tenofovir disoproxil and DL-tartaric acid is generally 0.3: 1-3: 1. The solid precipitation process can be static or stirring.
In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).
In the step (4) of the preparation method, the drying temperature is generally 20-60 ℃, and preferably 25-40 ℃; drying under normal pressure or reduced pressure is also possible. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
This embodiment produces a crystalline form of DL-tenofovir disoproxil tartrate.
Accordingly, the present invention provides a crystalline form of DL-tenofovir disoproxil tartrate (for convenience of description, this crystalline form is referred to as "crystalline form a of DL-tenofovir disoproxil tartrate"). The X-ray powder diffraction pattern (using Cu-Ka radiation) of the crystal form is characterized in that: characteristic diffraction peaks are mapped at positions with 2 theta values of 7.7 +/-0.2 degrees, 10.1 +/-0.2 degrees, 10.8 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.6 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.5 +/-0.2 degrees and 23.6 +/-0.2 degrees.
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: characteristic diffraction peaks are corresponded at positions of 7.7 DEG + -0.2 DEG, 10.1 DEG + -0.2 DEG, 10.8 DEG + -0.2 DEG, 13.4 DEG + -0.2 DEG, 16.3 DEG + -0.2 DEG, 16.8 DEG + -0.2 DEG, 17.6 DEG + -0.2 DEG, 17.9 DEG + -0.2 DEG, 19.2 DEG + -0.2 DEG, 20.6 DEG + -0.2 DEG, 21.4 DEG + -0.2 DEG, 22.5 DEG + -0.2 DEG, 23.6 DEG + -0.2 DEG, 26.1 DEG + -0.2 DEG, 29.1 DEG + -0.2 DEG and 30.5 DEG + -0.2 DEG in terms of 2 theta.
Further, the X-ray powder diffraction pattern of the DL-tenofovir disoproxil tartrate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
7.7±0.2° | 9 |
10.1±0.2° | 100 |
10.8±0.2° | 9 |
13.4±0.2° | 14 |
16.3±0.2° | 8 |
16.8±0.2° | 18 |
17.6±0.2° | 16 |
17.9±0.2° | 5 |
19.2±0.2° | 10 |
20.6±0.2° | 7 |
21.4±0.2° | 9 |
22.5±0.2° | 10 |
23.6±0.2° | 17 |
26.1±0.2° | 5 |
29.1±0.2° | 7 |
30.5±0.2° | 7 |
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: diffraction peaks at the 2 theta values of 6.7 +/-0.2 degrees, 7.7 +/-0.2 degrees, 8.0 +/-0.2 degrees, 10.1 +/-0.2 degrees, 10.8 +/-0.2 degrees, 11.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.7 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.6 +/-0.2 degrees, 17.9 +/-0.2 degrees, 19.2 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.1 +/-0.2 degrees, 22.5 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 26.9 +/-0.8 degrees, 27.2 degrees, 1.2 degrees, 2 degrees, 33.9 +/-0.2 degrees, 33 degrees, 2 degrees, 33.3 +/-0.2 degrees, 3 +/-0.2 degrees and 29.2 degrees are correspondingly.
Further, the X-ray powder diffraction pattern of the DL-tenofovir disoproxil tartrate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
6.7±0.2° | 4 |
7.7±0.2° | 9 |
8.0±0.2° | 3 |
10.1±0.2° | 100 |
10.8±0.2° | 9 |
11.9±0.2° | 3 |
13.4±0.2° | 14 |
14.7±0.2° | 4 |
15.3±0.2° | 3 |
16.3±0.2° | 8 |
16.8±0.2° | 18 |
17.6±0.2° | 16 |
17.9±0.2° | 5 |
19.2±0.2° | 10 |
20.0±0.2° | 4 |
20.6±0.2° | 7 |
21.4±0.2° | 9 |
22.1±0.2° | 4 |
22.5±0.2° | 10 |
22.9±0.2° | 3 |
23.6±0.2° | 17 |
26.1±0.2° | 5 |
26.9±0.2° | 4 |
27.8±0.2° | 4 |
29.1±0.2° | 7 |
29.8±0.2° | 3 |
30.5±0.2° | 7 |
32.1±0.2° | 3 |
33.9±0.2° | 3 |
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil tartrate provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 1.
In a specific embodiment, the Differential Scanning Calorimetry (DSC) pattern (temperature rise rate: 10 ℃/min) of the crystalline form a of DL-tenofovir disoproxil tartrate provided by the present invention is characterized in that: the peak temperature of the endothermic peak is in the range of 131 ℃ to 141 ℃.
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil tartrate provided by the present invention has the characteristics represented by the DSC profile shown in fig. 6.
In a specific embodiment, the crystal form purity of the DL-tenofovir disoproxil tartrate crystal form a (i.e. the mass percentage of the crystal form a contained in the DL-tenofovir disoproxil tartrate) provided by the present invention is generally more than 70%, preferably more than 80%, and most preferably more than 90%. The content can be measured by an X-ray powder diffraction method, a Differential Scanning Calorimetry (DSC) method, an infrared absorption spectrometry method or the like.
D-Tenofovir disoproxil tartrate
In one embodiment, in formula IV, m is selected to be 1 and X is selected to be D-tartaric acid, i.e., a complex of tenofovir disoproxil and D-tartaric acid in a 1:1 molar ratio is provided, referred to as "tenofovir disoproxil D-tartrate".
In one embodiment, the present invention provides a method for preparing tenofovir disoproxil D-tartrate, the method comprising:
(1) dissolving tenofovir disoproxil and D-tartaric acid in a suitable solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
In step (1) of the above preparation method, the "suitable solvent" is selected from isopropanol, tetrahydrofuran, acetone and the like or a mixture thereof, and is preferably isopropanol. The weight ratio of the suitable solvent to tenofovir disoproxil is generally 10: 1-30: 1.
In the step (1) of the preparation method, the dissolving temperature is generally 20 ℃ to the boiling point of the solvent, and preferably 35 to 50 ℃.
In the step (1) of the preparation method, the feeding molar ratio of tenofovir disoproxil to D-tartaric acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.
In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. The "antisolvent" is selected from diethyl ether, ethyl acetate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, etc. or mixtures thereof, preferably isopropyl ether. The volume ratio of the antisolvent to a suitable solvent for dissolving tenofovir disoproxil and D-tartaric acid is generally 0.2: 1-3: 1. The solid precipitation process can be static or stirring.
In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).
In the step (4) of the preparation method, the drying temperature is generally 20-60 ℃, and preferably 25-40 ℃; drying under normal pressure or reduced pressure is also possible. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
This embodiment produces tenofovir disoproxil D-tartrate as a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir disoproxil D-tartrate (for convenience of description, this crystalline form is referred to as "crystalline form A of tenofovir disoproxil D-tartrate"). The X-ray powder diffraction pattern (using Cu-Ka radiation) of the crystal form is characterized in that: characteristic diffraction peaks are corresponded to positions with 2 theta values of 4.7 DEG +/-0.2 DEG, 10.4 DEG +/-0.2 DEG, 16.5 DEG +/-0.2 DEG, 17.1 DEG +/-0.2 DEG, 20.5 DEG +/-0.2 DEG, 24.7 DEG +/-0.2 DEG and 28.1 DEG +/-0.2 deg.
In a specific embodiment, the crystalline form a of D-tenofovir disoproxil tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: characteristic diffraction peaks are corresponded at the positions of 4.7 DEG +/-0.2 DEG, 10.4 DEG +/-0.2 DEG, 11.8 DEG +/-0.2 DEG, 14.4 DEG +/-0.2 DEG, 16.5 DEG +/-0.2 DEG, 17.1 DEG +/-0.2 DEG, 17.7 DEG +/-0.2 DEG, 18.9 DEG +/-0.2 DEG, 20.5 DEG +/-0.2 DEG, 20.9 DEG +/-0.2 DEG, 21.7 DEG +/-0.2 DEG, 24.7 DEG +/-0.2 DEG and 28.1 DEG +/-0.2 DEG in the 2 theta value.
Further, the X-ray powder diffraction pattern of the D-tenofovir disoproxil tartrate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
4.7±0.2° | 100 |
10.4±0.2° | 7 |
11.8±0.2° | 5 |
14.4±0.2° | 5 |
16.5±0.2° | 24 |
17.1±0.2° | 12 |
17.7±0.2° | 8 |
18.9±0.2° | 6 |
20.5±0.2° | 39 |
20.9±0.2° | 9 |
21.7±0.2° | 7 |
24.7±0.2° | 17 |
28.1±0.2° | 7 |
In a specific embodiment, the crystalline form a of D-tenofovir disoproxil tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: corresponding diffraction peaks should be found at the 2 theta values of 4.7 DEG + -0.2 DEG, 10.4 DEG + -0.2 DEG, 11.0 DEG + -0.2 DEG, 11.8 DEG + -0.2 DEG, 13.3 DEG + -0.2 DEG, 14.4 DEG + -0.2 DEG, 14.6 DEG + -0.2 DEG, 15.3 DEG + -0.2 DEG, 16.5 DEG + -0.2 DEG, 17.1 DEG + -0.2 DEG, 17.7 DEG + -0.2 DEG, 18.9 DEG + -0.2 DEG, 20.5 DEG + -0.2 DEG, 20.9 DEG + -0.2 DEG, 21.7 DEG + -0.2 DEG, 24.7 DEG + -0.2 DEG, 28.1 DEG + -0.2 DEG, 29.1 DEG + -0.2 DEG and 33.5 DEG + -0.2 deg.
Further, the X-ray powder diffraction pattern of the D-tenofovir disoproxil tartrate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
4.7±0.2° | 100 |
10.4±0.2° | 7 |
11.0±0.2° | 3 |
11.8±0.2° | 5 |
13.3±0.2° | 3 |
14.4±0.2° | 5 |
14.6±0.2° | 4 |
15.3±0.2° | 2 |
16.5±0.2° | 24 |
17.1±0.2° | 12 |
17.7±0.2° | 8 |
18.9±0.2° | 6 |
20.5±0.2° | 39 |
20.9±0.2° | 9 |
21.7±0.2° | 7 |
24.7±0.2° | 17 |
28.1±0.2° | 7 |
29.1±0.2° | 2 |
33.5±0.2° | 2 |
In a specific embodiment, the crystalline form a of tenofovir disoproxil D-tartrate provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 2.
In a specific embodiment, the crystal form purity of the crystal form a of the D-tenofovir disoproxil tartrate provided by the present invention (i.e. the mass percentage of the crystal form a contained in the D-tenofovir disoproxil tartrate) is generally more than 70%, preferably more than 80%, and most preferably more than 90%. The content can be measured by an X-ray powder diffraction method, a Differential Scanning Calorimetry (DSC) method, an infrared absorption spectrometry method or the like.
DL-tenofovir disoproxil malate
In one embodiment, in formula IV, m is selected to be 1 and X is selected to be DL-malic acid, i.e. a complex of tenofovir disoproxil and DL-malic acid in a 1:1 molar ratio is provided, referred to as "tenofovir disoproxil DL-malate".
In one embodiment, the present invention provides a method for preparing tenofovir disoproxil DL-malate, comprising:
(1) dissolving tenofovir disoproxil and DL-malic acid in a suitable solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
In step (1) of the above preparation process, the "suitable solvent" is selected from isopropanol, tetrahydrofuran, acetone, acetonitrile, etc., or a mixture thereof, preferably isopropanol. The weight ratio of the suitable solvent to tenofovir disoproxil is generally 3: 1-10: 1.
In the step (1) of the preparation method, the dissolving temperature is generally 20 ℃ to the boiling point of the solvent, preferably 35 to 50 ℃.
In the step (1) of the preparation method, the feeding molar ratio of tenofovir disoproxil to DL-malic acid is generally 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1.
In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. The "antisolvent" is selected from the group consisting of diethyl ether, ethyl acetate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, and the like, or mixtures thereof, preferably isopropyl ether, methyl tert-butyl ether, and the like, or mixtures thereof. The volume ratio of the antisolvent to a suitable solvent for dissolving tenofovir disoproxil and DL-malic acid is generally 0.5: 1-5: 1. The solid precipitation process can be static or stirring.
In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).
In the step (4) of the preparation method, the drying temperature is generally 20-60 ℃, and preferably 25-40 ℃; drying under normal pressure or reduced pressure is also possible. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
The DL-tenofovir disoproxil malate prepared by this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of DL-tenofovir disoproxil malate (for convenience of description, this crystalline form is referred to as "crystalline form a of DL-tenofovir disoproxil malate"). The X-ray powder diffraction pattern (using Cu-Ka radiation) of the crystal form is characterized in that: characteristic diffraction peaks are corresponded to positions with 2 theta values of 5.0 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees, 10.1 degrees +/-0.2 degrees, 13.1 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees, 17.2 degrees +/-0.2 degrees, 19.4 degrees +/-0.2 degrees, 20.1 degrees +/-0.2 degrees and 25.2 degrees +/-0.2 degrees.
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil malate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: diffraction patterns corresponding to the 2 theta values of 5.0 +/-0.2 degrees, 5.9 +/-0.2 degrees, 7.4 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.1 +/-0.2 degrees, 10.1 +/-0.2 degrees, 10.8 +/-0.2 degrees, 11.6 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.1 +/-0.2 degrees, 13.8 +/-0.2 degrees, 14.5 +/-0.2 degrees, 14.8 +/-0.2 degrees, 16.1 +/-0.2 degrees, 17.2 +/-0.2 degrees, 18.4 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.1 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.4 +/-0.2 degrees, 25.2 degrees, 2 degrees, 27.2 degrees, 2 degrees and the angles of the 2 degree are correspondingly.
Further, the X-ray powder diffraction pattern of the DL-tenofovir disoproxil malate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
5.0±0.2° | 100 |
5.9±0.2° | 34 |
7.4±0.2° | 31 |
8.1±0.2° | 48 |
9.1±0.2° | 39 |
10.1±0.2° | 96 |
10.8±0.2° | 26 |
11.6±0.2° | 28 |
12.6±0.2° | 24 |
13.1±0.2° | 40 |
13.8±0.2° | 55 |
14.5±0.2° | 23 |
14.8±0.2° | 20 |
16.1±0.2° | 28 |
17.2±0.2° | 98 |
18.4±0.2° | 33 |
19.4±0.2° | 48 |
20.1±0.2° | 82 |
21.3±0.2° | 36 |
21.7±0.2° | 21 |
22.9±0.2° | 27 |
23.4±0.2° | 31 |
24.4±0.2° | 31 |
25.2±0.2° | 86 |
26.2±0.2° | 14 |
27.7±0.2° | 15 |
30.4±0.2° | 22 |
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil malate provided by the present invention has the characteristics represented by the X-ray powder diffraction pattern shown in fig. 3.
In a specific embodiment, the Differential Scanning Calorimetry (DSC) pattern (temperature rise rate: 10 ℃/min) of the DL-tenofovir disoproxil malate crystal form a provided by the present invention is characterized in that: the peak temperature of the endothermic peak is in the range of 69 ℃ to 79 ℃.
In a specific embodiment, the crystalline form a of DL-tenofovir disoproxil malate provided by the present invention has the characteristics represented by the DSC pattern shown in fig. 7.
In a specific embodiment, the crystal form purity of the DL-tenofovir disoproxil malate crystal form a (i.e. the mass percentage of the DL-tenofovir disoproxil malate containing crystal form a)) is generally more than 70%, preferably more than 80%, and most preferably more than 90%. The content can be measured by an X-ray powder diffraction method, a Differential Scanning Calorimetry (DSC) method, an infrared absorption spectrometry method or the like.
D-tenofovir disoproxil malate
In one embodiment, in formula IV, m is selected to be 1, and X is selected to be D-malic acid, i.e., a compound formed by tenofovir disoproxil and D-malic acid in a molar ratio of 1:1 is provided, and is called 'tenofovir disoproxil D-malate'.
In one embodiment, the present invention provides a method for preparing tenofovir disoproxil D-malate, comprising:
(1) dissolving tenofovir disoproxil and D-malic acid in a suitable solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
In step (1) of the above preparation process, the "suitable solvent" is selected from isopropanol, tetrahydrofuran, acetone, acetonitrile, etc., or a mixture thereof, preferably isopropanol. The weight ratio of the suitable solvent to tenofovir disoproxil is generally 3: 1-10: 1.
In the step (1) of the preparation method, the dissolving temperature is generally 20 ℃ to the boiling point of the solvent, and preferably 35 to 50 ℃.
In the step (1) of the preparation method, the feeding molar ratio of tenofovir disoproxil to D-malic acid is generally 0.5: 1-1.5: 1, and preferably 0.8: 1-1.2: 1.
In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, and the method includes cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used singly or in combination. The "antisolvent" is selected from diethyl ether, ethyl acetate, n-heptane, ethylene glycol dimethyl ether, isopropyl ether, methyl tert-butyl ether, etc. or mixtures thereof, preferably isopropyl ether. The volume ratio of the antisolvent to a suitable solvent for dissolving tenofovir disoproxil and D-malic acid is generally 0.5: 1-3: 1. The solid precipitation process can be static or stirring.
In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).
In the step (4) of the preparation method, the drying temperature is generally 20-60 ℃, and preferably 25-40 ℃; drying under normal pressure or reduced pressure is also possible. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
The tenofovir disoproxil D-malate prepared by this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir disoproxil D-malate (for convenience of description, this crystalline form is referred to as "crystalline form a tenofovir disoproxil D-malate"). The X-ray powder diffraction pattern (using Cu-Ka radiation) of the crystal form is characterized in that: characteristic diffraction peaks are corresponded to positions with 2 theta values of 7.8 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees, 11.8 degrees +/-0.2 degrees, 14.1 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 21.0 degrees +/-0.2 degrees, 22.6 degrees +/-0.2 degrees and 24.1 degrees +/-0.2 degrees.
In a specific embodiment, the crystalline form a of tenofovir disoproxil D-malate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: characteristic diffraction peaks are corresponding to the positions of 7.8 degrees +/-0.2 degrees, 8.1 degrees +/-0.2 degrees, 9.9 degrees +/-0.2 degrees, 11.8 degrees +/-0.2 degrees, 12.0 degrees +/-0.2 degrees, 12.4 degrees +/-0.2 degrees, 13.6 degrees +/-0.2 degrees, 14.1 degrees +/-0.2 degrees, 16.1 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 16.8 degrees +/-0.2 degrees, 18.1 degrees +/-0.2 degrees, 18.9 degrees +/-0.2 degrees, 19.5 degrees +/-0.2 degrees, 20.3 degrees +/-0.2 degrees, 21.0 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 22.6 degrees +/-0.2 degrees, 24.1 degrees +/-0.2 degrees, 25.0 degrees +/-0.2 degrees and 25.5 degrees +/-0.2 degrees.
Further, the X-ray powder diffraction pattern of the tenofovir disoproxil D-malate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
7.8±0.2° | 73 |
8.1±0.2° | 69 |
9.9±0.2° | 12 |
11.8±0.2° | 69 |
12.0±0.2° | 41 |
12.4±0.2° | 10 |
13.6±0.2° | 25 |
14.1±0.2° | 47 |
16.1±0.2° | 30 |
16.6±0.2° | 81 |
16.8±0.2° | 26 |
18.1±0.2° | 15 |
18.9±0.2° | 47 |
19.5±0.2° | 14 |
20.3±0.2° | 22 |
21.0±0.2° | 80 |
21.4±0.2° | 44 |
21.6±0.2° | 16 |
22.6±0.2° | 100 |
24.1±0.2° | 66 |
25.0±0.2° | 34 |
25.5±0.2° | 28 |
In a specific embodiment, the crystalline form a of tenofovir disoproxil D-malate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: the diffraction angles of the diffraction peaks at the 2 theta values of 7.8 +/-0.2 degrees, 8.1 +/-0.2 degrees, 9.9 +/-0.2 degrees, 10.5 +/-0.2 degrees, 11.2 +/-0.2 degrees, 11.8 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.6 +/-0.2 degrees, 14.1 +/-0.2 degrees, 14.7 +/-0.2 degrees, 16.1 +/-0.2 degrees, 16.6 +/-0.2 degrees, 16.8 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.0 +/-0 +/-0.2 degrees, 21.4 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.1 +/-0.24 +/-0.2 degrees, 3 +/-0.2 degrees, 21.0.2 degrees, 2 degrees, 2.2 degrees, 2 degrees, 2.2 degrees, 2 +/-0.2 degrees, 2 degrees and 25.2 degrees.
Further, the X-ray powder diffraction pattern of the tenofovir disoproxil D-malate crystal form A has the following characteristic diffraction peaks and relative intensities:
2θ(°) | relative Strength (%) |
7.8±0.2° | 73 |
8.1±0.2° | 69 |
9.9±0.2° | 12 |
10.5±0.2° | 9 |
11.2±0.2° | 8 |
11.8±0.2° | 69 |
12.0±0.2° | 41 |
12.4±0.2° | 10 |
13.6±0.2° | 25 |
14.1±0.2° | 47 |
14.7±0.2° | 9 |
16.1±0.2° | 30 |
16.6±0.2° | 81 |
16.8±0.2° | 26 |
18.1±0.2° | 15 |
18.9±0.2° | 47 |
19.5±0.2° | 14 |
20.3±0.2° | 22 |
21.0±0.2° | 80 |
21.4±0.2° | 44 |
21.6±0.2° | 16 |
22.6±0.2° | 100 |
24.1±0.2° | 66 |
24.3±0.2° | 8 |
25.0±0.2° | 34 |
25.5±0.2° | 28 |
26.1±0.2° | 5 |
27.4±0.2° | 8 |
28.7±0.2° | 7 |
32.5±0.2° | 8 |
33.5±0.2° | 6 |
In a specific embodiment, the invention provides a crystalline form A of tenofovir disoproxil D-malate having the characteristics represented by the X-ray powder diffraction pattern shown in figure 4.
In a specific embodiment, the Differential Scanning Calorimetry (DSC) pattern (temperature rise rate: 10 ℃/min) of the crystalline form a of D-tenofovir disoproxil malate provided by the present invention is characterized in that: the peak temperature of the endothermic peak is in the range of 80 ℃ to 90 ℃.
In a specific embodiment, the crystalline form a of tenofovir disoproxil D-malate provided by the present invention has the characteristics represented by the DSC pattern shown in fig. 8.
In a specific embodiment, the crystal form purity of the tenofovir disoproxil D-malate crystal form A (i.e. the mass percentage of the crystal form A contained in the tenofovir disoproxil D-malate) is generally more than 70%, preferably more than 80%, and most preferably more than 90%. The content can be measured by an X-ray powder diffraction method, a Differential Scanning Calorimetry (DSC) method, an infrared absorption spectrometry method or the like.
L-tartaric acid saltCrystalline form a of norfovir dipivoxil
In one embodiment, in formula IV, m is selected to be 1 and X is selected to be L-tartaric acid, i.e., a complex of tenofovir disoproxil and L-tartaric acid in a 1:1 molar ratio is provided, referred to as "tenofovir disoproxil L-tartrate".
The tenofovir disoproxil L-tartrate prepared in this embodiment is a crystal.
Accordingly, the present invention provides a crystalline form of tenofovir disoproxil L-tartrate (for convenience of description, this crystalline form is referred to as "crystalline form a tenofovir disoproxil L-tartrate"). The X-ray powder diffraction pattern (using Cu-Kalpha radiation) of the crystal form A of the L-tenofovir disoproxil tartrate is characterized in that: characteristic diffraction peaks are corresponded to positions with 2 theta values of 4.0 degrees +/-0.2 degrees, 6.9 degrees +/-0.2 degrees, 7.5 degrees +/-0.2 degrees, 8.4 degrees +/-0.2 degrees, 17.1 degrees +/-0.2 degrees, 18.7 degrees +/-0.2 degrees, 19.7 degrees +/-0.2 degrees and 22.5 degrees +/-0.2 degrees.
In a specific embodiment, the crystalline form a of tenofovir disoproxil L-tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: diffraction characteristics of the diffraction angles of 4.0 +/-0.2 DEG, 6.3 +/-0.2 DEG, 6.5 +/-0.2 DEG, 6.9 +/-0.2 DEG, 7.5 +/-0.2 DEG, 8.4 +/-0.2 DEG, 9.2 +/-0.2 DEG, 10.3 +/-0.2 DEG, 11.4 +/-0.2 DEG, 12.2 +/-0.2 DEG, 13.0 +/-0.2 DEG, 13.8 +/-0.2 DEG, 15.0 +/-0.2 DEG, 16.0 +/-0.2 DEG, 17.1 +/-0.2 DEG, 18.0 +/-0.2 DEG, 18.7 +/-0.2 DEG, 19.7 +/-0.2 DEG, 20.3 +/-0.2 DEG, 20.7 +/-0.2 DEG, 21.0 +/-0.2 DEG, 21.6 +/-0.2 DEG, 22.5 +/-0.2 DEG +/-23.3 DEG, 23.3 +/-0.2 DEG, 2 DEG, 2.24 +/-2 DEG, 26.2 DEG, 2 DEG, and 25 +/-2 DEG are correspondingly.
Further, the X-ray powder diffraction pattern of the crystal form A of the L-tenofovir disoproxil tartrate has the following characteristic diffraction peaks and relative intensities thereof:
2θ(°) | relative Strength (%) |
4.0±0.2° | 100 |
6.3±0.2° | 31 |
6.5±0.2° | 38 |
6.9±0.2° | 45 |
7.5±0.2° | 37 |
8.4±0.2° | 64 |
9.2±0.2° | 27 |
10.3±0.2° | 23 |
11.4±0.2° | 18 |
12.2±0.2° | 26 |
13.0±0.2° | 23 |
13.8±0.2° | 19 |
15.0±0.2° | 15 |
16.0±0.2° | 28 |
17.1±0.2° | 68 |
18.0±0.2° | 25 |
18.7±0.2° | 53 |
19.7±0.2° | 50 |
20.3±0.2° | 32 |
20.7±0.2° | 30 |
21.0±0.2° | 32 |
21.6±0.2° | 16 |
22.5±0.2° | 52 |
23.3±0.2° | 18 |
23.8±0.2° | 12 |
24.4±0.2° | 15 |
24.9±0.2° | 20 |
25.3±0.2° | 24 |
26.0±0.2° | 18 |
27.5±0.2° | 12 |
28.2±0.2° | 11 |
In a specific embodiment, the crystalline form a of tenofovir disoproxil L-tartrate according to the present invention has an X-ray powder diffraction pattern (using Cu-ka radiation) characterized by: diffraction is characterized by the 20.3 +/-0.2, 9, 2, 24, 2, 3, 2.
Further, the X-ray powder diffraction pattern of the crystal form A of the L-tenofovir disoproxil tartrate has the following characteristic diffraction peaks and relative intensities thereof:
2θ(°) | relative Strength (%) |
4.0±0.2° | 100 |
6.3±0.2° | 31 |
6.5±0.2° | 38 |
6.9±0.2° | 45 |
7.5±0.2° | 37 |
8.4±0.2° | 64 |
9.2±0.2° | 27 |
10.3±0.2° | 23 |
11.4±0.2° | 18 |
12.2±0.2° | 26 |
13.0±0.2° | 23 |
13.8±0.2° | 19 |
15.0±0.2° | 15 |
16.0±0.2° | 28 |
17.1±0.2° | 68 |
18.0±0.2° | 25 |
18.7±0.2° | 53 |
19.7±0.2° | 50 |
20.3±0.2° | 32 |
20.7±0.2° | 30 |
21.0±0.2° | 32 |
21.6±0.2° | 16 |
22.5±0.2° | 52 |
23.3±0.2° | 18 |
23.8±0.2° | 12 |
24.4±0.2° | 15 |
24.9±0.2° | 20 |
25.3±0.2° | 24 |
26.0±0.2° | 18 |
27.5±0.2° | 12 |
28.2±0.2° | 11 |
28.9±0.2° | 7 |
In a specific embodiment, the invention provides crystalline tenofovir disoproxil L-tartrate form a having the characteristics represented by the X-ray powder diffraction pattern shown in fig. 5.
In a specific embodiment, the Differential Scanning Calorimetry (DSC) spectrum (temperature rise rate: 10 ℃/min) of the crystalline form A of the L-tenofovir disoproxil tartrate provided by the invention is characterized in that: the peak temperature of the endothermic peak is in the range of 114 ℃ to 124 ℃.
In a specific embodiment, the crystalline form a of tenofovir disoproxil L-tartrate provided by the present invention has the characteristics represented by the DSC profile shown in figure 9.
In a specific embodiment, the crystal form purity of the L-tenofovir disoproxil tartrate crystal form a (i.e. the mass percentage of the L-tenofovir disoproxil tartrate containing the crystal form a) provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%. The content can be measured by an X-ray powder diffraction method, a Differential Scanning Calorimetry (DSC) method, an infrared absorption spectrometry method or the like.
The invention provides a preparation method of a crystal form A of L-tenofovir disoproxil tartrate, which comprises the following steps:
(1) dissolving tenofovir disoproxil and L-tartaric acid in methanol or ethanol;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or further purified and then dried.
In the step (1) of the preparation method, the dissolving temperature is generally 20 ℃ to the boiling point of the solvent, and preferably 35 to 50 ℃.
In the step (1) of the preparation method, the feeding molar ratio of tenofovir disoproxil to L-tartaric acid is generally 0.5: 1-1.5: 1, preferably 0.8: 1-1.2: 1.
In the step (2) of the preparation method, the method of "precipitating a solid" is a method which is conventional in the art, such as cooling, adding an anti-solvent, concentrating a part of the solvent body, adding a seed crystal and the like, and is used alone or in combination, preferably cooling and crystallizing. The solid precipitation process can be static or stirring.
In the step (3) of the preparation method, the separation may be performed by a conventional method in the art such as filtration. Optionally, the collected solid may be washed with a suitable solvent in step (1).
In the step (4) of the preparation method, the drying temperature is generally 20-60 ℃, preferably 25-40 ℃; drying under normal pressure or reduced pressure is also possible. Methods of "further purification" include recrystallization, slurrying, washing, and the like.
According to the purpose of the invention, the invention provides a pharmaceutical composition containing a therapeutically effective amount of the solid tenofovir disoproxil or the solid tenofovir disoproxil prepared by the preparation method and a pharmaceutical excipient.
Alternatively, the pharmaceutical compositions or formulations described above may further comprise another antiviral agent or antiviral adjuvant, including but not limited to emtricitabine, lamivudine, Abacavir, Acemann, Ainprenavir, Amprenavir, Atazanavir, Clevudine, Cobicistat, Dapivirine, Darunavir, Delavirdine, Didanosine, Dolutegravir, Efavirenz, Elvitegravir, Enfuvirtide, Entecavir, Etravirine, Famciclovir, Fosampravir, Glutathione, Indidnavir, Levamisole, Lopinavir, Maraviroc, Nelfinavir, Nevirapine, Penciclovir, Pentamidine, Phosphazid, Propagermanium, Raltegravir, Ribavirin, Rilpivridine, Ritonavir, Saquinavir, Stavudine, Telbivudine, Tipranavir, Vorinostat, Zalcitabine, Zidovudine, and the like, or pharmaceutically acceptable salts thereof, with Cobicistat, Efavirenz, elvitavir, rilpivavir hydrochloride being preferred.
Preferably, the pharmaceutical composition of the invention is selected from one of the following:
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil and emtricitabine; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine and efavirenz; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine and ropinirole hydrochloride; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine, eltamivir and Cobicistat; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil and lamivudine; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, lamivudine and efavirenz.
In a specific embodiment, the invention provides a pharmaceutical composition or a formulation comprising a therapeutically effective amount of a tenofovir disoproxil compound represented by formula IV (including DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form a or D-tenofovir disoproxil malate crystal form a) and a pharmaceutical excipient.
The above pharmaceutical composition or preparation can be administered orally or parenterally. When the preparation is orally taken, the preparation can be prepared into tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained-release preparations or controlled-release preparations and the like by adopting the conventional preparation technology. When the preparation is administered parenterally, it can be made into transdermal preparation, injection, infusion solution or suppository by conventional preparation technology.
The various dosage forms of the above pharmaceutical composition can be prepared according to conventional methods in the pharmaceutical field. For example, a therapeutically effective amount of the tenofovir disoproxil complex of formula IV, DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form a or D-tenofovir disoproxil malate crystal form a, optionally with another therapeutically effective amount of an active ingredient or ingredients, mixed or contacted with one or more pharmaceutical excipients, and then formulated into the desired dosage form.
The pharmaceutical composition or preparation is preferably an oral dosage form, including tablets, capsules, pills, granules, solutions, syrups, dry suspensions, powders, sustained-release preparations or controlled-release preparations and the like. Among them, solid oral preparations such as tablets, capsules, granules, dry suspensions, sustained-release preparations or controlled-release preparations are preferable, and among them, tablets and capsules are more preferable. Preferred pharmaceutical compositions or formulations of the present invention may be prepared according to any of the conventional methods employed for preparing solid oral formulations. For example, the tablet can be prepared by wet granulation, tabletting and the like, and can be coated in any form according to the needs, for example, the tablet can be prepared into any release form (such as quick release, enteric coating, sustained and controlled release and the like); the capsule can be prepared by wet granulation and capsule filling, and the capsule content can be prepared into any release form (such as quick release preparation, enteric preparation and sustained and controlled release preparation).
In one embodiment, the particle size distribution of the tenofovir disoproxil compound shown in formula IV, DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form A or D-tenofovir disoproxil tartrate crystal form A is controlled to be 95% less than 200 μm, preferably less than 180 μm, more preferably less than 150 μm, and more preferably less than 100 μm. Pharmaceutical excipients which are conventional in the art in oral dosage forms include fillers, disintegrants, binders, dispersants, lubricants or retention aids, and various types of coating materials, and the like.
The filler generally includes pregelatinized starch, lactose, dextrin, calcium hydrogen phosphate, calcium carbonate, mannitol, microcrystalline cellulose, sorbitol, glucose, etc., which may be used alone or in combination, among which pregelatinized starch, lactose, microcrystalline cellulose, mannitol are preferred.
The disintegrant generally includes croscarmellose sodium, carboxymethylcellulose sodium, sodium carboxymethyl starch, crospovidone, starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like, which may be used alone or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose are preferred.
The binder generally comprises microcrystalline cellulose, pre-crosslinked starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, acacia, polyethylene glycol 4000, polyvinyl alcohol, alginate, water, and various concentrations of ethanol solution, which can be used alone or in combination, wherein hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and starch slurry are preferred.
Such lubricants generally include magnesium stearate, stearic acid, calcium stearate, sodium stearate fumarate, potassium stearate fumarate, palmitic acid, microsilica, stearamide, talc, solid polyethylene glycols, glyceryl triacetate, and the like. These may be used alone or in combination, and magnesium stearate, stearic acid, talc, microsilica, and glyceryl triacetate are preferable among them.
If necessary, other adjuvants such as sweetener (such as aspartame, steviosin, etc.), colorant (such as lemon yellow, iron oxide, etc., medicinal or edible pigment), stabilizer (such as calcium carbonate, calcium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.), surfactant (such as Tween 80, sodium dodecyl sulfate, etc.), and coating material (such as Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymer, etc.) can be added into the composition or preparation.
In a specific embodiment, the present invention provides a single composition or formulation wherein the active ingredient is selected from a therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form a or D-tenofovir disoproxil malate crystal form a. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; they are generally present in a unit composition or formulation in an amount of from 1mg to 1g, preferably from 100mg to 400mg, for example about 245mg (as tenofovir disoproxil), where "about" refers to a range of ± 5%.
In a specific embodiment, the present invention provides a combination composition or a formulation, wherein the first active ingredient is selected from therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, crystalline form A, L of DL-tenofovir disoproxil tartrate, crystalline form A, D of tenofovir disoproxil tartrate, crystalline form A, DL of tenofovir disoproxil malate or crystalline form a of D-tenofovir disoproxil tartrate, and the second active ingredient is therapeutically effective amount of emtricitabine. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 400mg, for example containing about 245mg of the first active ingredient (calculated as tenofovir disoproxil) and about 200mg of the second active ingredient (emtricitabine) as described above, wherein "about" means a range of ± 5%.
In a specific embodiment, the present invention provides a combination or formulation wherein the first active ingredient is selected from therapeutically effective amounts of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form a or D-tenofovir disoproxil tartrate crystal form a, the second active ingredient is therapeutically effective amount of emtricitabine, and the third active ingredient is therapeutically effective amount of efavirenz. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 700mg, for example about 245mg (calculated as tenofovir disoproxil), about 200mg of the second active ingredient (emtricitabine) and about 600mg of the third active ingredient (efavirenz) as described above for the first active ingredient, where "about" means a range of ± 5%.
In a particular embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form A or D-tenofovir disoproxil malate crystal form A, the second active ingredient is emtricitabine with a therapeutically effective amount, and the third active ingredient is rilpivirine hydrochloride with a therapeutically effective amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each present in an amount of typically 1mg to 1g, preferably 100mg to 400mg, for example about 245mg (calculated as tenofovir disoproxil), about 200mg of the second active ingredient (emtricitabine) and about 25mg (calculated as rilpivirine) of the third active ingredient (rilpivirine hydrochloride) as described above for the first active ingredient, where "about" means a range of ± 5%.
In a particular embodiment, the present invention provides a combination composition or formulation wherein the first active ingredient is selected from the group consisting of a therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form A or D-tenofovir disoproxil malate crystal form A, a second active ingredient is emtricitabine with a therapeutically effective amount, a third active ingredient is ezetivir with a therapeutically effective amount, and a fourth active ingredient is Cobicistat with a therapeutically effective amount. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 400mg, for example containing about 245mg (calculated as tenofovir disoproxil), about 200mg of the second active ingredient (emtricitabine), about 150mg of the third active ingredient (ezetivir) and about 150mg of the fourth active ingredient (Cobicistat), as described above, wherein "about" means a range of ± 5%.
In a specific embodiment, the present invention provides a combination composition or a formulation, wherein the first active ingredient is selected from therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, crystalline form A, L of DL-tenofovir disoproxil tartrate, crystalline form A, D of tenofovir disoproxil tartrate, crystalline form A, DL of tenofovir disoproxil malate or crystalline form a of D-tenofovir disoproxil tartrate, and the second active ingredient is a therapeutically effective amount of lamivudine. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 400mg, for example containing about 245mg of the first active ingredient (calculated as tenofovir disoproxil) and about 300mg of the second active ingredient (lamivudine) as described above, wherein "about" means a range of ± 5%.
In a specific embodiment, the present invention provides a combination composition or formulation, wherein the first active ingredient is selected from therapeutically effective amount of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, D-tenofovir disoproxil malate, DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form a or D-tenofovir disoproxil tartrate crystal form a, the second active ingredient is therapeutically effective amount of lamivudine crystal form, and the third active ingredient is therapeutically effective amount of efavirenz. The composition or preparation is preferably an oral preparation, more preferably a tablet or capsule; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 700mg, for example containing about 245mg of the first active ingredient (calculated as tenofovir disoproxil), about 300mg of the second active ingredient (lamivudine) and about 600mg of the third active ingredient (efavirenz) as described above, wherein "about" means a range of ± 5%.
The pharmaceutical composition or preparation can be prepared according to conventional production methods in the pharmaceutical field, for example, one or more of DL-tenofovir disoproxil tartrate crystal form A, L-tenofovir disoproxil tartrate crystal form A, D-tenofovir disoproxil tartrate crystal form A, DL-tenofovir disoproxil malate crystal form A or D-tenofovir disoproxil malate crystal form A are mixed with one or more carriers and then prepared into a required dosage form.
The above compositions are not only chemically stable, but also have a synergistic effect and/or can reduce the side effects and resistance of tenofovir disoproxil, emtricitabine or lamivudine, alone or in combination with another active ingredient; while possibly increasing patient compliance.
In conclusion, the DL-tenofovir disoproxil tartrate, the L-tenofovir disoproxil tartrate, the D-tenofovir disoproxil tartrate, the DL-tenofovir disoproxil malate and the D-tenofovir disoproxil malate provided by the invention are obviously different from the existing solid of tenofovir disoproxil, and are new compound solid of tenofovir disoproxil. The preparation methods of the novel compound solids of tenofovir disoproxil are simple and controllable, the physical properties, stability, solubility, preparation adaptability and the like are not lower than or better than those of original tenofovir disoproxil fumarate or other salts of tenofovir disoproxil fumarate, and the preparation method has good industrial practicability.
In a specific embodiment, the invention provides a pharmaceutical composition or preparation containing a therapeutically effective amount of tenofovir disoproxil co-crystal or salt shown in formula V and a pharmaceutical excipient.
In a specific embodiment, the present invention provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of a tenofovir disoproxil co-crystal or salt of formula V and emtricitabine or lamivudine.
Alternatively, the pharmaceutical compositions described above may further comprise another antiviral agent or antiviral adjuvant, including but not limited to Abacavir, Acemann, Ainprenavir, Amprenavir, Atazanavir, Clevudine, Cobicistat, Dapivirine, Darunavir, Delavirdine, Didanosine, Dolutegravir, Efavirenz, Elvitegravir, Enfuvirtide, Entecavir, Etravirine, Famciclovir, Fosampravir, Glutathione, indinavir, Levamisole, Lopinavir, Maraviroc, Nelfinavir, Nevirapine, Penciclovir, Pentamidine, Phosphazid, Propagermanium, Raltegravir, Ribavirin, Rilpivridine, Ritonavir, Saquinavir, Stavudine, Telbivudine, Tipranavir, Vorinostat, Zalcitabine, Zidovudine, and the like or pharmaceutically acceptable salts thereof, with Cobicistat, Efavirenz, elbowavir, rilpivirine hydrochloride being preferred.
The pharmaceutical composition or preparation is preferably: tenofovir disoproxil eutectic or salt shown in formula V/emtricitabine, tenofovir disoproxil eutectic or salt shown in formula V/emtricitabine/efavirenz, tenofovir disoproxil eutectic or salt shown in formula V/emtricitabine/rilpivirine hydrochloride, tenofovir disoproxil eutectic or salt shown in formula V/lamivudine/efavirenz, tenofovir disoproxil eutectic or salt shown in formula V/emtricitabine/ezavir/Cobicistat.
The pharmaceutical composition can be prepared into various dosage forms with pharmaceutical excipients to be administered in various forms, wherein the preferred dosage forms are oral dosage forms, including tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained release preparations or controlled release preparations. Among them, solid oral preparations such as capsules, tablets, granules, and suspensions are preferable, and among them, tablets and capsules are more preferable.
The active ingredients in the pharmaceutical composition or preparation comprise tenofovir disoproxil co-crystal or salt, emtricitabine or lamivudine, and optionally one or more antiviral agents or antiviral auxiliary agents, and the weight content of each of the two in the unit composition or preparation is generally 1mg to 1g, preferably 10mg to 700 mg.
In a particular embodiment, the present invention provides a composition or formulation comprising a therapeutically effective amount of tenofovir disoproxil co-crystal or salt and emtricitabine, or a pharmaceutical composition or formulation comprising a therapeutically effective amount of tenofovir disoproxil co-crystal or salt and lamivudine.
Optionally, the composition provided by this embodiment may further include an active ingredient such as Efavirenz (Efavirenz), Rilpivrine (Rilpivrine), Cobicistat, etiavir (Elvitegravir), or a pharmaceutically acceptable salt thereof.
Preferably, this embodiment provides the following compositions or formulations:
a pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1) eutectic, tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic malic acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, tenofovir disoproxil D-tartaric acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil disulfuric acid (2:1) salt, Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is emtricitabine; preferably oral preparations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 400mg, for example about 245mg (as free base) of the above tenofovir disoproxil cocrystal and about 200mg of emtricitabine, where "about" means a range of ± 5%.
A pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1), tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic eutectic malic acid (2:1), tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil disulfuric acid (2:1) salt, Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is emtricitabine, and the third active component is efavirenz; preferably oral formulations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 100mg to 700mg, for example containing about 245mg (calculated as the free base) of the tenofovir dipivoxil co-crystal in the first active component, about 200mg of emtricitabine and about 600mg of efavirenz, where "about" means the range ± 5%.
A pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1) eutectic, tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic malic acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, tenofovir disoproxil D-tartaric acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil succinate (2:1) salt or Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil 1) 1:1 eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is emtricitabine, and the third active component is hydrochloric acid Lipivirine; preferably oral preparations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1g, preferably from 10mg to 400mg, for example containing about 245mg (as free base) of the tenofovir dipivoxil co-crystal in the first active component, about 200mg of emtricitabine and about 25mg of rilpivirine hydrochloride (as free base), where "about" means a range of ± 5%.
A pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1) eutectic, tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic malic acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, tenofovir disoproxil D-tartaric acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil succinate (2:1) salt or Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil 1) 1:1 eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is emtricitabine, the third active component is ezetivir, and the fourth active component is Cobicistat; preferably oral preparations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1000mg, preferably from 10mg to 400mg, for example containing about 245mg (calculated as the free base) of the tenofovir disoproxil co-crystal in the first active ingredient, about 200mg of emtricitabine, about 150mg of eltamivir and about 150mg of Cobicistat, wherein "about" means a range of ± 5%.
A pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1) eutectic, tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic malic acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, tenofovir disoproxil D-tartaric acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil disulfuric acid (2:1) salt, Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is lamivudine; preferably oral preparations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1000mg, preferably from 100mg to 400mg, for example containing about 245mg (as free base) of the tenofovir disoproxil co-crystal and about 300mg of lamivudine in the first active ingredient, wherein "about" means a range of ± 5%.
A pharmaceutical composition or a preparation comprises a first active component of tenofovir disoproxil phosphate (3:1) eutectic, tenofovir disoproxil citrate (3:1) eutectic, tenofovir disoproxil phosphate (2:1) eutectic, tenofovir disoproxil carbonate (2:1) eutectic, tenofovir disoproxil oxalate (2:1) eutectic, tenofovir disoproxil malonate (2:1) eutectic, tenofovir disoproxil succinate (2:1) eutectic, tenofovir disoproxil L-malic acid (2:1) eutectic, tenofovir disoproxil D-malic acid (2:1) eutectic, tenofovir disoproxil racemic malic acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, tenofovir disoproxil D-tartaric acid (2:1) eutectic, tenofovir disoproxil L-tartaric acid (2:1) eutectic, and tenofovir disoproxil D-tartaric acid (2:1) eutectic, Tenofovir disoproxil racemic tartrate (2:1) eutectic, Tenofovir disoproxil meso-tartaric acid (2:1) eutectic, Tenofovir disoproxil fumarate (2:1) eutectic, Tenofovir disoproxil maleate (2:1) eutectic, Tenofovir disoproxil citrate (2:1) eutectic, Tenofovir disoproxil pamoate (2:1) eutectic, Tenofovir disoproxil sulfate (2:1) salt, Tenofovir disoproxil ediforrestylate ediforresthate (2:1) salt, Tenofovir disoproxil disulfuric acid (2:1) salt, Tenofovir disoproxil naphthalene-1, 5-disulfonic acid (2:1) salt, Tenofovir disoproxil phosphate (1:1) eutectic, Tenofovir disoproxil acetate (1:1) eutectic, The pharmaceutical composition comprises a tenofovir disoproxil (1:1) propionic acid eutectic, a tenofovir disoproxil L-lactic acid (1:1) eutectic, a tenofovir disoproxil D-lactic acid (1:1) eutectic, a tenofovir disoproxil racemic lactic acid (1:1) eutectic, a tenofovir disoproxil palmitate (1:1) eutectic, a tenofovir disoproxil stearic acid (1:1) eutectic, a tenofovir disoproxil oxalic acid (1:1) eutectic, a tenofovir disoproxil malonic acid (1:1) eutectic, a tenofovir disoproxil succinate (1:1) eutectic, a tenofovir disoproxil L-malic acid (1:1) eutectic, a tenofovir disoproxil D-malic acid (1:1) eutectic, a tenofovir disoproxil racemic malate (1:1) eutectic, a tenofovir disoproxil tartrate L-tartaric acid (1:1) eutectic, A tenofovir disoproxil D-tartrate (1:1) eutectic, a tenofovir disoproxil racemic tartrate (1:1) eutectic, a tenofovir disoproxil meso-tartrate (1:1) eutectic, a tenofovir disoproxil fumarate (1:1) eutectic, a tenofovir disoproxil maleate (1:1) eutectic, a tenofovir disoproxil citrate (1:1) eutectic, a tenofovir disoproxil benzoate (1:1) eutectic, a tenofovir disoproxil L-mandelic acid (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil racemic eutectic (1:1), a tenofovir disoproxil (1:1) eutectic, a tenofovir disoproxil D-mandelic acid (1:1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, a tenofovir disoproxil fumarate (1) eutectic, Co-crystals of tenofovir disoproxil hippurate (1:1), tenofovir disoproxil hippurate (1:1) salt, tenofovir disoproxil sulfuric acid (1:1) salt, tenofovir disoproxil thiocyanic acid (1:1) salt, tenofovir disoproxil hydrobromide (1:1) salt, tenofovir disoproxil nitric acid (1:1) salt, tenofovir disoproxil methanesulfonic acid (1:1) salt, tenofovir disoproxil taurine (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, tenofovir disoproxil p-toluenesulfonate (1:1) salt, tenofovir disoproxil disulfate (1:1) salt, 2-5-1-2-1-dihydroxynaphthyrofovir disoproxil disulfate, the second active component is lamivudine, and the third active component is efavirenz; preferably oral preparations, more preferably tablets and capsules; in a unit composition or formulation, they are each generally present in an amount of from 1mg to 1000mg, preferably from 100mg to 700mg, for example containing about 245mg (calculated as the free base) of the tenofovir disoproxil co-crystal in the first active ingredient, about 300mg of lamivudine and about 600mg of efavirenz, wherein "about" means a range of ± 5%.
The pharmaceutical composition is not only chemically stable, but also has a synergistic effect and/or can reduce the side effect and drug resistance of tenofovir disoproxil co-crystal or salt, emtricitabine or lamivudine, or another active ingredient; while possibly increasing patient compliance.
In addition, the present invention provides a method for preparing the above pharmaceutical composition or formulation. For single compositions or formulations, the method generally comprises mixing or contacting a therapeutically effective amount of a tenofovir disoproxil complex of formula IV or a tenofovir disoproxil co-crystal or salt of formula V with one or more pharmaceutical excipients. For a combination composition or formulation, the method generally comprises mixing or contacting a therapeutically effective amount of a tenofovir disoproxil complex of formula IV or a tenofovir disoproxil co-crystal or salt of formula V, emtricitabine (or lamivudine) with one or more pharmaceutical excipients. For a tri-or multi-compound composition or formulation, the method generally comprises mixing or contacting a therapeutically effective amount of a tenofovir disoproxil complex of formula IV or a tenofovir disoproxil co-crystal or salt of formula V, emtricitabine (or lamivudine), and one or more active ingredients with a pharmaceutically acceptable excipient. The pharmaceutical compositions or formulations are prepared in a manner well known in the art. The pharmaceutic adjuvant is a conventional pharmaceutic adjuvant in the field and comprises a filler, a disintegrant, an adhesive, a lubricant and the like.
The filler generally includes pregelatinized starch, lactose, mannitol, microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, etc., which may be used alone or in combination, among which pregelatinized starch, lactose, mannitol, microcrystalline cellulose are preferred.
The disintegrating agent generally includes croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, crospovidone, starch, polyvinylpyrrolidone, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and the like, and they may be used alone or in combination, and among them, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, and crospovidone are preferable.
The binder generally comprises microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, polyethylene glycol 4000, polyvinyl alcohol, alginate, water, and ethanol solution with various concentrations, which can be used alone or in combination, wherein hydroxypropyl methylcellulose, hydroxypropyl cellulose, and povidone are preferred.
Such lubricants typically include magnesium stearate, stearic acid, calcium stearate, palmitic acid, silicon dioxide, stearamide, talc, solid polyethylene glycols and the like. These may be used alone or in combination, and magnesium stearate, silicon dioxide, stearic acid, and talc are preferred.
If necessary, other adjuvants such as sweetener (such as aspartame, steviosin, etc.), colorant (such as lemon yellow, iron oxide, etc., medicinal or edible pigment), stabilizer (such as calcium carbonate, calcium bicarbonate, sodium carbonate, calcium phosphate, calcium hydrogen phosphate, glycine, etc.), surfactant (such as Tween 80, sodium dodecyl sulfate, etc.), and coating material (such as Opadry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin copolymer, etc.) can be added into the composition or preparation.
The pharmaceutical composition or preparation is preferably an oral dosage form comprising: tablets, capsules, pills, granules, solutions, syrups, suspensions, powders, sustained-release preparations or controlled-release preparations, and the like. Among them, solid oral preparations such as tablets, capsules, granules, drinkable suspensions and the like are preferable, and among them, tablets and capsules are more preferable. Preferred pharmaceutical compositions or formulations of the present invention may be prepared according to any of the conventional methods employed for preparing solid oral formulations. For example, the tablet can be prepared by wet granulation and tabletting and the like, and can be coated as required; the capsule can be prepared by wet granulation and capsule filling.
According to the purpose of the invention, the invention provides the application of the solid of tenofovir disoproxil or the solid of tenofovir disoproxil prepared by the preparation method in preparing a medicament for preventing and/or treating virus infection.
Specifically, the invention provides an application of the solid of tenofovir disoproxil in preparation of a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides an application of a tenofovir disoproxil compound shown in formula IV in preparation of a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir disoproxil compound shown in formula IV and a pharmaceutical excipient in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir disoproxil complex shown in formula IV, another antiviral agent or antiviral auxiliary agents and pharmaceutical excipients in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides application of tenofovir disoproxil co-crystal or salt shown in formula V in preparation of a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir disoproxil co-crystal or salt shown in formula V and a pharmaceutical excipient in preparation of a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
In a specific embodiment, the invention provides application of a pharmaceutical composition containing a therapeutically effective amount of tenofovir disoproxil co-crystal or salt shown in formula V, another antiviral agent or antiviral auxiliary agents and pharmaceutical excipients in preparing a medicament for preventing and/or treating Hepatitis B Virus (HBV) and/or Human Immunodeficiency Virus (HIV) infection.
Experiments prove that the DL-tenofovir disoproxil tartrate, the L-tenofovir disoproxil tartrate, the D-tenofovir disoproxil tartrate, the DL-tenofovir disoproxil malate or the D-tenofovir disoproxil malate have the following advantages:
(1) the preparation method is simple and convenient, and the crystal form is easy to control; high purity, such as 98%, 99% or more than 99.5% by HPLC area normalization, can be obtained.
(2) Has good or improved physical properties, chemical stability or preparation adaptability. For example, the melting point of DL-tenofovir disoproxil tartrate is higher than that of the tenofovir disoproxil fumarate on the market in the original research, so that the preparation is more favorable; for example, the solubility of DL-tenofovir disoproxil tartrate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate and D-tenofovir disoproxil malate in different pH media is better than that of tenofovir disoproxil fumarate, so that the preparation can be dissolved out easily; in addition, DL-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate or D-tenofovir disoproxil malate is also superior to salt formed by tenofovir disoproxil succinate and hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid, oxalic acid, citric acid, benzoic acid and the like in the aspects of preparation process amplification, crystal form controllability, solubility, chemical stability, preparation adaptability and the like.
(3) The slow release carrier has no obvious difference with the pharmacokinetics of tenofovir disoproxil fumarate on the market in the original research, and DL-tartaric acid, L-tartaric acid, D-tartaric acid, DL-malic acid and D-malic acid are all conventional medicinal acids or medicinal auxiliary materials with the history of many years of use, so that the compound formed by the slow release carrier and the tenofovir disoproxil fumarate has good safety and effectiveness.
The X-ray powder diffraction analysis of the crystal of the invention is carried out by radiating with Cu-K α of X' Pert PRO type X-ray powder diffractometer of Pasacaceae in the Netherlands under ambient temperature and humidity The assay was complete. The "ambient temperature" is generally 0 to 40 ℃; "ambient humidity" is typically 30% to 80% relative humidity. It is understood that the same crystal type is influenced by various factors (such as the granularity of a test sample, a sample processing method during the test, an instrument, test parameters, test operation and the like) during the test processThe positions or intensities of the characteristic diffraction peaks of the measured X-ray powder diffraction patterns have certain differences. In general, the experimental error of the characteristic diffraction peak 2 theta values in the X-ray powder diffraction pattern may be + -0.2 deg..
The Differential Scanning Calorimetry (DSC) analysis of the crystal is carried out in the temperature range of 40-200 ℃, the temperature rise rate is 10 ℃/min, and the Differential Scanning Calorimetry (DSC) analysis is finished by the American TA DSC Q200 type differential scanning calorimeter.
Experiments show that the tenofovir disoproxil co-crystal or salt, and a composition or preparation containing the same and emtricitabine or lamivudine have good or improved physical properties, chemical stability, process controllability or safety and effectiveness.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of DL-tenofovir disoproxil tartrate form A.
FIG. 2 is an X-ray powder diffraction pattern of crystalline form A of D-tenofovir disoproxil tartrate.
FIG. 3 is an X-ray powder diffraction pattern of DL-tenofovir disoproxil malate form A.
FIG. 4 is an X-ray powder diffraction pattern of crystalline form A of tenofovir disoproxil D-malate.
FIG. 5 is an X-ray powder diffraction pattern of crystalline form A of tenofovir disoproxil L-tartrate.
FIG. 6 is a DSC spectrum of DL-tenofovir disoproxil tartrate crystal form A.
FIG. 7 is a DSC spectrum of DL-tenofovir disoproxil malate crystal form A.
FIG. 8 is a DSC spectrum of tenofovir disoproxil D-malate crystal form A.
FIG. 9 is a DSC spectrum of tenofovir disoproxil L-tartrate form A.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments of examples, but it should not be construed that the present invention is limited to the examples, and the present invention based on the above description is within the scope of the present invention.
In the following examples1The H NMR test is carried out by taking deuterated dimethyl sulfoxide as a test solvent, taking tetramethylsilane as an internal standard and measuring at room temperature by using a Bruke AV-II 300MHz nuclear magnetic resonance instrument.
In the following examples, the optical rotation was measured by a Shanghai precision SGW-3 polarimeter.
The X-ray powder diffraction in the following examples was measured by an X-ray powder diffractometer of the type X' Pert PRO of Pastaceae, the Netherlands under the conditions of theta-theta configuration, a scanning range of 4 DEG to 50 DEG, a step size of 0.0130 DEG, and continuous scanning, the test light source being a copper target K α radiatingA PIXcel detector; the voltage and current were 40kV and 40mA, respectively. The sample preparation method comprises the following steps: under the environment condition, a proper amount of sample is taken by a medicine spoon and placed in the groove of the glass sample slide, the glass slide is properly rolled, the sample is uniformly distributed in the groove of the sample slide, and the surface of the sample is scraped by the glass slide. The sample does not rotate in its own plane during the test.
The Differential Scanning Calorimetry (DSC) analysis in the following examples was carried out at a temperature range of 40 ℃ to 200 ℃ with a temperature rise rate of 10 ℃/min as measured by a TA DSC Q200 differential scanning calorimeter in the United states.
Example 1
Preparation of tenofovir disoproxil fumarate
Adding 41.4g of tenofovir monohydrate (commercially available or prepared according to the method disclosed in CN 1264387A) into 164g of N-methylpyrrolidone at 20-25 ℃, adding 40g of triethylamine under stirring, stirring for 0.5 hour at 20-25 ℃, adding 100g of chloromethyl isopropyl carbonate, heating to 55-65 ℃, and carrying out heat preservation reaction for 5 hours; stopping heating, cooling to 20-30 ℃, adding 320g of ethyl acetate and 180g of purified water, stirring at 0-5 ℃, separating liquid, extracting the lower layer at 0-5 ℃ by using 110g of ethyl acetate, combining ethyl acetate layers, purifying and washing twice at 0-5 ℃, each time using 320g of purified water, and concentrating ethyl acetate at 30-35 ℃; adding 150mL of cyclohexane into the concentrate, stirring for 10 hours at the temperature of 20-25 ℃, filtering, and leaching with 20mL of cyclohexane to obtain tenofovir disoproxil and a white solid.
1H NMR(300MHz,DMSO-d6):8.14(s,1H),8.03(s,1H),7.21(s,2H),5.57-5.51(m,4H),4.82-4.80(m,2H),4.23-4.19(m,2H),4.00-3.96(m,3H),1.25-1.23(d,12H),1.07-1.05(d,3H)。
Melting range: 102 to 105 ℃.
Example 2
Preparation of DL-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 50.0g (96.3mmol) of tenofovir disoproxil and 14.4g (95.9mmol) of DL-tartaric acid in 4.5L of isopropanol at 40-45 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring for crystallization; carrying out suction filtration; and drying the filter cake at 30-35 ℃ under reduced pressure to obtain 57.0g of DL-tenofovir disoproxil tartrate with the yield of 88.5%.
Measured by1H NMR results were:1H NMR(300MHz,DMSO-d6):8.13(s,1H),8.03(s,1H),7.30(s,2H),5.57-5.53(m,4H),4.83-4.79(m,2H),4.33-4.32(d,2H),4.24-4.19(m,2H),4.01-3.96(m,3H),1.24-1.22(d,12H),1.07-1.05(d,3H).
as described above1In the H NMR results, the signal peaks at chemical shifts of 8.13(s, 1H) and 8.03(s, 1H) were assigned to two H on tenofovir disoproxil adenine, the signal peaks at 4.33 to 4.32(d, 2H) were assigned to H of 2 methines on DL-tartaric acid, and the molar composition ratio of tenofovir disoproxil and DL-tartaric acid in the sample was judged to be 1:1 from the integrated area ratio of the two sets of signal peaks.
And (3) optical rotation testing: and (2) preparing a tenofovir disoproxil solution and a DL-tenofovir disoproxil tartrate solution with equal molar concentrations, and testing optical rotation in parallel, wherein the measured optical rotation of the tenofovir disoproxil solution is equal to that of the DL-tenofovir disoproxil tartrate solution, namely when the tenofovir disoproxil solution is used as a blank, the measured optical rotation of the DL-tenofovir disoproxil tartrate solution is 0.
The X-ray powder diffraction pattern is shown in figure 1. The measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
The Differential Scanning Calorimetry (DSC) was shown in FIG. 6.
The obtained crystal form is named as a DL-tenofovir disoproxil tartrate crystal form A.
Experiments show that the pharmacokinetics of DL-tenofovir disoproxil tartrate is not obviously different from that of the tenofovir disoproxil fumarate on the market in the original research.
Example 3
Preparation of DL-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 50.0g (96.3mmol) of tenofovir disoproxil and 15.9g (105.9mmol) of DL-tartaric acid in 1L of methanol/ethanol (volume ratio of 1/1) at 45-50 ℃, after complete dissolution, dropwise adding 500mL of isopropyl ether at 45-50 ℃, stirring and cooling to 15-20 ℃ after dropwise adding, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 35-40 ℃ under reduced pressure to obtain 53.0g of DL-tenofovir disoproxil tartrate crystal form A53.0g, wherein the yield is 82.3%. The X-ray powder diffraction pattern is similar to that of figure 1.
Example 4
Preparation of DL-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 10.0g (19.2mmol) of tenofovir disoproxil and 2.9g (19.3mmol) of DL-tartaric acid in 500mL of ethanol at 50-55 ℃, stirring and cooling to 15-20 ℃ after complete dissolution, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 30-35 ℃ under reduced pressure to obtain DL-tenofovir disoproxil tartrate crystal form A10.1g with the yield of 78.4%. The X-ray powder diffraction pattern is similar to that of figure 1.
Example 5
Preparation of DL-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 5.0g (9.63mmol) of tenofovir disoproxil and 1.6g (10.6mmol) of DL-tartaric acid in 300mL of acetonitrile at 40-45 ℃, stirring and cooling to 15-20 ℃, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 25-30 ℃ under reduced pressure to obtain the DL-tenofovir disoproxil tartrate crystal form A4.9g with the yield of 76.1%. The X-ray powder diffraction pattern is similar to that of figure 1.
Example 6
Preparation of DL-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 5.0g (9.63mmol) of tenofovir disoproxil and 1.6g (10.6mmol) of DL-tartaric acid in 50mL of a solvent at 50-55 ℃, controlling the internal temperature to be 45-50 ℃ after complete dissolution, dropwise adding 50mL of methyl tert-butyl ether, stirring and cooling to 15-20 ℃ after dropwise adding, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 30-35 ℃ under reduced pressure to obtain DL-tenofovir disoproxil tartrate crystal form A5.4g with the yield of 83.9%. The X-ray powder diffraction pattern is similar to that of figure 1.
Example 7
Pharmacokinetic comparison study of DL-tenofovir disoproxil tartrate crystal form A and tenofovir disoproxil fumarate in original ground and market
Multiple batches of the original ground commercial tenofovir disoproxil fumarate crystals (prepared according to the method disclosed in patent document CN 1264387A) and DL-tenofovir disoproxil tartrate crystal form a crystals with comparable crystal sizes were prepared by sieving using a μm sieve. 12 male SD rats (240 plus 270 g) are selected and randomly divided into 2 groups, and tenofovir disoproxil fumarate or DL-tenofovir disoproxil tartrate crystal form A is respectively administrated by intragastric administration, and the dosage is 10mg/kg (calculated according to tenofovir). Blood was collected by jugular vein at about 200. mu.L each time at 5500rpm before and 15 minutes, 30 minutes, 45 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 12 hours, 24 hours and 28 hours after administration, and the supernatant plasma was centrifuged and stored at-40 ℃ for further use.
Plasma samples were further processed to analyze the tenofovir (active metabolite of tenofovir disoproxil fumarate) content therein by LC-MS/MS. A standard curve was prepared by spiking a certain amount of tenofovir into rat blank plasma and the concentration of tenofovir in plasma samples was quantified by LC-MS/MS. The pharmacokinetic parameters were calculated and then subjected to a T test, the results of which are shown in the following table.
The main pharmacokinetic parameters of the DL-tenofovir disoproxil tartrate crystal form A and the original tenofovir disoproxil fumarate crystal on the market have no significant difference (P > 0.05).
Example 8
Recrystallization of DL-tenofovir disoproxil tartrate crystal form A
Taking the DL-tenofovir disoproxil tartrate crystal form A prepared by the method in the embodiment 2, adding the crystal form A into a proper amount of solvent listed in the following table at the temperature of 45-50 ℃, dissolving, cooling and crystallizing; carrying out suction filtration; and drying the filter cake under reduced pressure. The crystal form condition after recrystallization is inspected by measuring an X-ray powder diffraction pattern, and the result is as follows:
recrystallization solvent | Crystal form |
Methanol | Crystal form A |
Ethanol | Crystal form A |
Tetrahydrofuran (THF) | Crystal form A |
Isopropanol (I-propanol) | Crystal form A |
Acetonitrile | Crystal form A |
Acetone (II) | Crystal form A |
Isopropanol/isopropyl ether (volume ratio 7/1) | Crystal form A |
Acetone/isopropyl ether (volume ratio 6/1) | Crystal form A |
Methanol/water/isopropyl ether (volume ratio 10/1/5) | Crystal form A |
ethanol/N, N-dimethylformamide/isopropyl ether (volume ratio 10/1/2.5) | Crystal form A |
The above studies show that: the DL-tenofovir disoproxil tartrate crystal form A provided by the invention can reappear under various recrystallization conditions.
Example 9
Preparation of D-tenofovir disoproxil tartrate and crystal form A thereof
Dissolving 10.0g (19.3mmol) of tenofovir disoproxil and 3.1g (20.6mmol) of D-tartaric acid in 300mL of isopropanol at 35-45 ℃, dropwise adding 100mL of isopropyl ether at 35-45 ℃ after complete dissolution, stirring and cooling to 15-20 ℃ after dropwise addition, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 20-30 ℃ under reduced pressure to obtain 9.7g of D-tenofovir disoproxil tartrate with the yield of 75.3%.
Measured by1H NMR results were:1H NMR(300MHz,DMSO-d6):8.16-8.15(d,1H),8.05-8.04(d,1H),7.33(s,2H),5.57-5.53(m,4H),4.81-4.79(m,2H),4.35-4.33(d,2H),4.25-4.19(m,2H),3.96(s,3H),1.21(s,12H),1.05-1.01(m,3H).
as described above1In the H NMR results, the signal peaks at chemical shifts of 8.16 to 8.15(D, 1H) and 8.05 to 8.04(D, 1H) were assigned to two H groups on tenofovir disoproxil adenine, the signal peaks at 4.35 to 4.33(D, 2H) were assigned to H groups of 2 methines on D-tartaric acid, and the molar composition ratio of tenofovir disoproxil and D-tartaric acid in the sample was determined to be about 1:1 from the integrated area ratio of the two signal peaks.
The X-ray powder diffraction pattern is shown in FIG. 2. The measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 1% or more).
The obtained crystal form is named as a tenofovir disoproxil D-tartrate crystal form A.
Example 10
Preparation of DL-tenofovir disoproxil malate and novel crystal form A thereof
Dissolving 50g (96.3mmol) of tenofovir disoproxil and 12.9g (96.2mmol) of DL-malic acid in 200mL of isopropanol at 40-50 ℃, after complete dissolution, dropwise adding 300mL of isopropyl ether at 40-50 ℃, after dropwise adding, stirring and cooling to 15-20 ℃, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 25-30 ℃ under reduced pressure to obtain 53.5g of DL-tenofovir disoproxil malate, wherein the yield is 85.0%.
Measured by1H NMR results were:1H NMR(300MHz,DMSO-d6):8.16-8.14(d,1H),8.05-8.04(d,1H),7.29(s,2H),5.58-5.50(m,4H),4.83-4.79(m,2H),4.29-4.28(d,1H),4.27-4.15(m,2H),3.99-3.97(d,3H),2.59-2.67(m,1H),2.49-2.41(m,1H),1.25-1.22(t,12H),1.08-1.05(t,3H).
as described above1In the H NMR results, the signal peaks at chemical shifts of 8.16-8.15(d, 1H) and 8.05-8.04(d, 1H) were assigned to two H on tenofovir disoproxil adenine, the signal peaks at 4.29-4.28(d, 1H) were assigned to H of the last methyl group of DL-malic acid, and the molar composition ratio of tenofovir disoproxil and DL-malic acid in the sample was judged to be about 1:1 from the integrated area ratio of the two sets of signal peaks.
And (3) optical rotation testing: preparing a tenofovir disoproxil fumarate solution and a DL-tenofovir disoproxil malate solution with equal molar concentrations, and testing the optical rotation in parallel, wherein the optical rotation of the tested tenofovir disoproxil fumarate solution is equal to that of the DL-tenofovir disoproxil malate solution, namely when the tenofovir disoproxil fumarate solution is used as a blank, the optical rotation of the DL-tenofovir disoproxil malate solution is 0.
The X-ray powder diffraction pattern is shown in FIG. 3. The measurement values are shown in the following table (taking the measurement values corresponding to diffraction peaks having a relative intensity of 10% or more, the measurement values are rounded to three decimal places).
The Differential Scanning Calorimetry (DSC) was shown in FIG. 7.
The obtained crystal form is named as a DL-tenofovir disoproxil malate crystal form A.
The pharmacokinetic comparison research shows that the main pharmacokinetic parameters of the DL-tenofovir disoproxil fumarate crystal form A and the original tenofovir disoproxil fumarate crystal on the market have no significant difference.
Example 11
Preparation of DL-tenofovir disoproxil malate crystal form A
Dissolving 5.0g (9.63mmol) of tenofovir disoproxil and 1.1g (8.5mmol) of DL-malic acid in 20mL of isopropanol at 40-45 ℃, controlling the internal temperature to be 40-45 ℃ after complete dissolution, dropwise adding 30mL of methyl tert-butyl ether, stirring and cooling to 15-20 ℃ after dropwise addition, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 30-35 ℃ under reduced pressure to obtain 5.0g of the DL-tenofovir disoproxil malate crystal form A5.0g, wherein the yield is 90.6%. The X-ray powder diffraction pattern is similar to that of figure 3.
Example 12
Preparation of D-tenofovir disoproxil malate and crystal form A thereof
Dissolving 50g (96.3mmol) of tenofovir disoproxil and 12.9g (96.2mmol) of D-malic acid in 250mL of isopropanol at 40-50 ℃, after complete dissolution, dropwise adding 250mL of isopropyl ether at 40-50 ℃, after dropwise adding, stirring and cooling to 15-20 ℃, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 30-40 ℃ under reduced pressure to obtain 48.2g of D-tenofovir disoproxil malate, wherein the yield is 76.6%.
Measured by1H NMR results were:1H NMR(300MHz,DMSO-d6):8.16-8.14(d,1H),8.05-8.03(d,1H),7.30(s,2H),5.58-5.54(m,4H),4.81-4.80(m,2H),4.26-4.25(d,1H),4.21-4.15(m,2H),3.97(s,3H),2.66-2.61(m,1H),2.49-2.43(m,1H),1.22(s,12H),1.07-1.06(d,3H).
as described above1In the H NMR results, the signal peaks at chemical shifts of 8.16-8.14(D, 1H) and 8.05-8.03(D, 1H) were assigned to two H on tenofovir disoproxil adenine, the signal peaks at 4.26-4.25(D, 1H) were assigned to H of the last methyl group of D-malic acid, and the molar composition ratio of tenofovir disoproxil and D-malic acid in the sample was judged to be about 1:1 from the integrated area ratio of the two sets of signal peaks.
The X-ray powder diffraction is shown in figure 4; the measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 3% or more).
The Differential Scanning Calorimetry (DSC) is shown in figure 8.
The obtained crystal form is named as a tenofovir disoproxil D-malate crystal form A.
Example 13
Preparation of crystal form A of L-tenofovir disoproxil tartrate
Dissolving 50.0g (96.3mmol) of tenofovir disoproxil and 14.4g (95.9mmol) of L-tartaric acid in 500mL of mixed solvent of methanol/ethanol (volume ratio of 3:2) at 40-50 ℃, stirring and cooling to 15-20 ℃, and continuing stirring and crystallizing; carrying out suction filtration; and drying the filter cake at 25-30 ℃ under reduced pressure to obtain the L-tenofovir disoproxil tartrate crystal form A57.8g with the yield of 89.8%.
Measured by1H NMR results were:1H NMR(300MHz,DMSO-d6):8.19-8.15(d,1H),8.08-8.04(d,1H),7.29-7.25(d,2H),5.61-5.55(m,4H),4.86-4.84(m,2H),4.36-4.33(d,2H),4.29-4.24(m,2H),4.01-3.98(m,3H),1.29-1.23(d,12H),1.11-1.06(d,3H).
as described above1In the H NMR results, the signal peaks at chemical shifts of 8.19 to 8.15(d, 1H) and 8.08 to 8.04(d, 1H) were assigned to two H groups on tenofovir disoproxil adenine, the signal peaks at 4.36 to 4.33(d, 2H) were assigned to H groups of 2 methines on L-tartaric acid, and the molar composition ratio of tenofovir disoproxil to L-tartaric acid in the sample was determined to be about 1:1 from the integrated area ratio of the two signal peaks.
The X-ray powder diffraction pattern is shown in FIG. 5. The measured values are shown in the following table (three decimal places are rounded off from the measured values corresponding to diffraction peaks having a relative intensity of 1% or more).
The Differential Scanning Calorimetry (DSC) is shown in figure 9.
Example 14
Stability study
Tenofovir disoproxil fumarate (originally developed as a commercially available salt form, prepared by the method disclosed in patent document CN 1264387A), DL-Tenofovir disoproxil tartrate (prepared by the method of example 2) and DL-Tenofovir disoproxil malate (prepared by the method of example 10) were each subjected to a test under high temperature, high humidity and high light conditions, and the results were as follows after 10 days:
the purity in the table above is detected by HPLC, and the detection conditions are as follows:
mobile phase: acetonitrile: 0.1% triethylamine aqueous solution (pH adjusted with phosphoric acid =6.0) =45:55
A chromatographic column: inertsil ODS-3,5 μm, 4.6X 250mm
Column temperature: 30 deg.C
Wavelength: 262nm
Flow rate: 1.0mL/min
Mobile phase: gradient elution was performed according to the following table
The detection method comprises the following steps: taking a proper amount of sample, precisely weighing, adding methanol to dissolve and dilute to prepare solution containing 0.5mg of sample solution per 1mL, precisely measuring 10 mu L, injecting into a liquid chromatograph, recording chromatogram, and calculating related substance content according to an area normalization method.
The above studies show that: the stability of the DL-tenofovir disoproxil tartrate and the DL-tenofovir disoproxil malate under the conditions of high temperature, high humidity and illumination is equivalent to that of tenofovir disoproxil fumarate. Further studies indicate that the stability of DL-tenofovir disoproxil tartrate or DL-tenofovir disoproxil malate is also superior to other compounds or salts of tenofovir disoproxil.
Example 15
Solubility study
Taking tenofovir disoproxil fumarate (as a commercially available salt form, prepared as disclosed in patent document CN 1264387A), DL-tenofovir disoproxil tartrate (prepared as in example 2), DL-tenofovir disoproxil malate (prepared as in example 10), L-tenofovir disoproxil tartrate (prepared as in example 13), D-tenofovir disoproxil tartrate (prepared as in example 9) and D-tenofovir disoproxil malate (prepared as in example 12), their solubilities in media of different pH were measured at 25 ℃ respectively, and the results were as follows:
the above studies show that: the solubility of DL-tenofovir disoproxil tartrate, DL-tenofovir disoproxil malate, L-tenofovir disoproxil tartrate, D-tenofovir disoproxil tartrate and D-tenofovir disoproxil malate provided by the invention is equivalent to or better than that of tenofovir disoproxil fumarate.
Example 16
DL-tenofovir disoproxil tartrate film coated tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
DL-Tenofovir disoproxil tartrate | 316.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the raw materials and auxiliary materials in the table are weighed, the pregelatinized starch and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate is added for mixing for 10 minutes, and then the DL-tenofovir disoproxil tartrate and the microcrystalline cellulose are added for mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 17
DL-tenofovir disoproxil tartrate capsule and preparation thereof
Components | Content (mg/tablet) |
DL-tenofovir disoproxil tartrate crystal form A | 316.0 |
Microcrystalline cellulose | 70.0 |
Lactose monohydrate | 65.0 |
Sodium carboxymethyl starch | 15.0 |
Magnesium stearate | 1.5 |
The method comprises the following specific operations:
the raw materials and auxiliary materials in the table are weighed, sodium carboxymethyl starch and lactose monohydrate are mixed together for 5 minutes, microcrystalline cellulose is added and mixed for 10 minutes, and then DL-tenofovir disoproxil tartrate crystal form A is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and filling into hypromellose capsule.
Example 18
DL-tenofovir disoproxil malate film-coated tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
DL-tenofovir disoproxil malate | 308.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the pregelatinized starch and croscarmellose sodium are mixed for 5 minutes, lactose monohydrate is added and mixed for 10 minutes, and then DL-tenofovir disoproxil malate and microcrystalline cellulose are added and mixed for 10 minutes according to the weighing of the raw materials and the auxiliary materials in the table. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 50 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 19
D-tenofovir disoproxil malate capsule and preparation method thereof
Components | Content (mg/tablet) |
D-tenofovir disoproxil malate | 308.0 |
Microcrystalline cellulose | 70.0 |
Lactose monohydrate | 65.0 |
Sodium carboxymethyl starch | 15.0 |
Magnesium stearate | 1.5 |
The method comprises the following specific operations:
the raw materials and auxiliary materials are weighed according to the table above, sodium carboxymethyl starch and lactose monohydrate are mixed together for 5 minutes, microcrystalline cellulose is added and mixed for 10 minutes, and then tenofovir disoproxil D-malate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulating machine, drying with fluidized bed at 50 deg.C to water content of less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and making into capsule.
Example 20
D-tenofovir disoproxil malate capsule and preparation method thereof
Components | Content (mg/tablet) |
D-tenofovir disoproxil malate | 308.0 |
Microcrystalline cellulose | 70.0 |
Lactose monohydrate | 65.0 |
Cross-linked polyvidone | 10.0 |
Magnesium stearate | 1.5 |
The method comprises the following specific operations:
drying microcrystalline cellulose, lactose monohydrate and crospovidone for 10 hours at about 85 ℃, weighing the raw materials according to the above table, mixing the crospovidone and the lactose monohydrate for 5 minutes, adding the microcrystalline cellulose for mixing for 10 minutes, adding the tenofovir disoproxil D-malate for mixing for 10 minutes, finally adding the magnesium stearate for mixing for 10 minutes, and filling capsules to obtain the medicament.
Example 21
D-tenofovir disoproxil tartrate film-coated tablet and preparation method thereof
Components | Content (mg/tablet) |
Tablet core: | |
D-Tenofovir disoproxil tartrate | 316.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the raw materials and auxiliary materials in the table are weighed, the pregelatinized starch and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate is added for mixing for 10 minutes, and then the tenofovir disoproxil D-tartrate and the microcrystalline cellulose are added for mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 22
L-tenofovir disoproxil tartrate film-coated tablet and preparation method thereof
Components | Content (mg/tablet) |
Tablet core: | |
crystalline form A of tenofovir disoproxil L-tartrate | 316.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the pregelatinized starch and the croscarmellose sodium are mixed for 5 minutes according to the weighing of the raw materials in the table above, the lactose monohydrate is added for mixing for 10 minutes, and the tenofovir disoproxil L-tartrate crystal form a and the microcrystalline cellulose are added for mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 23
DL-tenofovir disoproxil tartrate, emtricitabine film coated tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
DL-Tenofovir disoproxil tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the raw materials and auxiliary materials in the table are weighed, the pregelatinized starch and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate is added and mixed for 10 minutes, the DL-tenofovir disoproxil tartrate is added and mixed for 10 minutes, and the emtricitabine and the microcrystalline cellulose are added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Experiments show that the preparation is equivalent to a tenofovir disoproxil fumarate/emtricitabine compound tablet which is originally researched and marketed.
Example 24
DL-tenofovir disoproxil malate, emtricitabine film coated tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
DL-tenofovir disoproxil malate | 308.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The method comprises the following specific operations:
the raw materials and auxiliary materials in the table are weighed, pregelatinized starch and croscarmellose sodium are mixed for 5 minutes, lactose monohydrate is added and mixed for 10 minutes, DL-tenofovir disoproxil malate is added and mixed for 10 minutes, and emtricitabine and microcrystalline cellulose are added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 50 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, mixing for 10 min, and tabletting; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 25
DL-tenofovir disoproxil tartrate, emtricitabine capsule and preparation thereof
Components | Content (mg/tablet) |
DL-tenofovir disoproxil tartrate crystal form A | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 145.0 |
Sodium carboxymethyl starch | 30.0 |
Magnesium stearate | 2.0 |
The method comprises the following specific operations:
drying microcrystalline cellulose and sodium carboxymethyl starch at about 85 ℃ for 10 hours, weighing the raw materials and auxiliary materials in the table above, mixing the sodium carboxymethyl starch and the microcrystalline cellulose for 5 minutes, adding emtricitabine for mixing for 10 minutes, adding the crystal form A of DL-tenofovir disoproxil tartrate for mixing for 10 minutes, finally adding magnesium stearate for mixing for 10 minutes, and filling the mixture into a hydroxypropyl methylcellulose capsule to obtain the finished product.
Example 26
DL-tenofovir disoproxil malate, emtricitabine capsule and preparation thereof
Components | Content (mg/tablet) |
DL-tenofovir disoproxil malate crystal form A | 308.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 145.0 |
Sodium carboxymethyl starch | 30.0 |
Magnesium stearate | 2.0 |
The method comprises the following specific operations:
drying microcrystalline cellulose and sodium carboxymethyl starch at about 85 ℃ for 10 hours, weighing the raw materials and auxiliary materials in the table above, mixing the sodium carboxymethyl starch and the microcrystalline cellulose for 5 minutes, adding emtricitabine for mixing for 10 minutes, adding the crystal form A of DL-tenofovir disoproxil malate for mixing for 10 minutes, finally adding magnesium stearate for mixing for 10 minutes, and filling the mixture into a hydroxypropyl methylcellulose capsule to obtain the finished product.
Example 27
DL-tenofovir disoproxil tartrate, emtricitabine and efavirenz film-coated double-layer tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
granule-I: | |
DL-Tenofovir disoproxil tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 80.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 7.5 |
Particle II: | |
efavirenz | 600.0 |
Microcrystalline cellulose | 130.0 |
Croscarmellose sodium | 20.0 |
Sodium lauryl sulfate | 10.0 |
Hydroxypropyl cellulose | 20.0 |
Magnesium stearate | 10.0 |
Film coating material |
Opadry II | 30.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, microcrystalline cellulose and croscarmellose sodium are mixed for 5 minutes, emtricitabine is added and mixed for 10 minutes, and DL-tenofovir disoproxil tartrate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing sodium lauryl sulfate, croscarmellose sodium and hydroxypropyl cellulose for 10 minutes, adding microcrystalline cellulose for mixing for 10 minutes, and adding efavirenz for mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 28
Film-coated double-layer tablet of D-tenofovir disoproxil malate, emtricitabine and efavirenz and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
granule-I: | |
d-tenofovir disoproxil malate | 308.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 80.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 7.5 |
Particle II: |
efavirenz | 600.0 |
Microcrystalline cellulose | 130.0 |
Croscarmellose sodium | 20.0 |
Sodium lauryl sulfate | 10.0 |
Hydroxypropyl cellulose | 20.0 |
Magnesium stearate | 10.0 |
Film coating material | |
Opadry II | 30.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, microcrystalline cellulose and croscarmellose sodium are mixed for 5 minutes, emtricitabine is added and mixed for 10 minutes, and tenofovir disoproxil D-malate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at 50 deg.C to water content of less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing sodium lauryl sulfate, croscarmellose sodium and hydroxypropyl cellulose for 10 minutes, adding microcrystalline cellulose for mixing for 10 minutes, and adding efavirenz for mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 29
DL-tenofovir disoproxil tartrate, emtricitabine, rilpivirine hydrochloride film coating double-layer tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: |
granule-I: | |
DL-Tenofovir disoproxil tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 180.0 |
Lactose monohydrate | 80.0 |
Pregelatinized shore powder | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Particle II: | |
rilpivirine hydrochloride | 27.5 |
Microcrystalline cellulose | 60.0 |
Lactose monohydrate | 200.0 |
Croscarmellose sodium | 15.0 |
Povidone K30 | 3.0 |
Polysorbate 20 | 0.5 |
Magnesium stearate | 3.0 |
Film coating material | |
Opadry II | 25.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, the pre-gelatinized capecitabine powder and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate and the microcrystalline cellulose are added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and then the DL-tenofovir disoproxil tartrate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing microcrystalline cellulose and croscarmellose sodium for 10 minutes, adding lactose monohydrate for mixing for 10 minutes, and then adding hydrochloric acidPivirine was mixed for 10 minutes. With povidone K30And polysorbate 20 aqueous solution, granulating by a high-efficiency wet granulator, drying at about 60 ℃ by a fluidized bed until the water content is less than 1.5%, grading by a 24-mesh porous plate sieve, adding magnesium stearate, and mixing for 10 minutes to obtain the final product.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 30
L-tenofovir disoproxil tartrate, emtricitabine, rilpivirine hydrochloride film-coated double-layer tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
granule-I: | |
crystalline form A of tenofovir disoproxil L-tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 180.0 |
Lactose monohydrate | 80.0 |
Pregelatinized shore powder | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Particle II: | |
rilpivirine hydrochloride | 27.5 |
Microcrystalline cellulose | 60.0 |
Lactose monohydrate | 200.0 |
Croscarmellose sodium | 15.0 |
Povidone K30 | 3.0 |
Polysorbate 20 | 0.5 |
Magnesium stearate | 3.0 |
Film coating material | |
Opadry II | 25.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, the pre-gelatinized capecitabine powder and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate and the microcrystalline cellulose are added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and the L-tenofovir disoproxil tartrate crystal form A is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: the raw materials and auxiliary materials in the table are weighed, microcrystalline cellulose and croscarmellose sodium are mixed for 10 minutes, lactose monohydrate is added and mixed for 10 minutes, and rilpivirine hydrochloride is added and mixed for 10 minutes. With povidone K30And polysorbate 20 aqueous solution, granulating by a high-efficiency wet granulator, drying at about 60 ℃ by a fluidized bed until the water content is less than 1.5%, grading by a 24-mesh porous plate sieve, adding magnesium stearate, and mixing for 10 minutes to obtain the final product.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 31
DL-tenofovir disoproxil tartrate, emtricitabine, ezetivir, Cobicistat double-layer tablet and preparation thereof
Components | Content (mg/tablet) |
granule-I: |
DL-Tenofovir disoproxil tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 150.0 |
Lactose monohydrate | 120.0 |
Pregelatinized shore powder | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Particle II: | |
ettelavir | 150.0 |
Cobicistat | 150.0 |
Microcrystalline cellulose | 200.0 |
Lactose monohydrate | 200.0 |
Croscarmellose sodium | 20.0 |
Hydroxypropyl cellulose | 15.0 |
Magnesium stearate | 6.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, the pre-gelatinized capecitabine powder and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate and the microcrystalline cellulose are added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and then the DL-tenofovir disoproxil tartrate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate for 10 minutes, adding the rest lactose monohydrate for 10 minutes, adding the ezetivir and the Cobicistat for 10 minutes, and finally adding the microcrystalline cellulose for 10 minutes. Granulating with purified water, granulating by high efficiency wet granulating machine, drying at 60 deg.C with fluidized bed until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 32
Double-layer tablet of D-tenofovir disoproxil tartrate, emtricitabine, ezetivir and Cobicistat and preparation thereof
Components | Content (mg/tablet) |
granule-I: | |
D-Tenofovir disoproxil tartrate | 316.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 150.0 |
Lactose monohydrate | 120.0 |
Pregelatinized shore powder | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Particle II: | |
ettelavir | 150.0 |
Cobicistat | 150.0 |
Microcrystalline cellulose | 200.0 |
Lactose monohydrate | 200.0 |
Croscarmellose sodium | 20.0 |
Hydroxypropyl cellulose | 15.0 |
Magnesium stearate | 6.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the raw materials and auxiliary materials in the table are weighed, the pre-gelatinized capecitabine powder and the croscarmellose sodium are mixed for 5 minutes, the lactose monohydrate and the microcrystalline cellulose are added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and the tenofovir disoproxil D-tartrate is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing hydroxypropyl cellulose, croscarmellose sodium and 20% lactose monohydrate for 10 minutes, adding the rest lactose monohydrate for 10 minutes, adding the ezetivir and the Cobicistat for 10 minutes, and finally adding the microcrystalline cellulose for 10 minutes. Granulating with purified water, granulating by high efficiency wet granulating machine, drying at 60 deg.C with fluidized bed until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 33
DL-tenofovir disoproxil tartrate, lamivudine film coated tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
inside the granule: | |
DL-Tenofovir disoproxil tartrate | 316.0 |
Lamivudine | 300.0 |
Microcrystalline cellulose | 220.0 |
Croscarmellose sodium | 15.0 |
Outside the particle: |
microcrystalline cellulose | 140.0 |
Croscarmellose sodium | 15.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 25.0 |
Weighing the raw materials and auxiliary materials in the table above, uniformly mixing the croscarmellose sodium and the microcrystalline cellulose together by adopting an equivalent progressive method, adding lamivudine, mixing for 10 minutes, adding emtricitabine, mixing for 10 minutes, and adding DL-tenofovir disoproxil tartrate, mixing for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, and sieving with 24 mesh porous plate sieve. Adding croscarmellose sodium and microcrystalline cellulose, mixing, adding magnesium stearate, mixing for 10 min, and tabletting. Then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 34
DL-tenofovir disoproxil tartrate, lamivudine and efavirenz film-coated double-layer tablet and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
granule-I: | |
DL-tenofovir disoproxil tartrate crystal form A | 316.0 |
Lamivudine | 300.0 |
Microcrystalline cellulose | 60.0 |
Croscarmellose sodium | 40.0 |
Magnesium stearate | 7.5 |
Particle II: |
efavirenz | 600.0 |
Microcrystalline cellulose | 145.0 |
Croscarmellose sodium | 20.0 |
Sodium lauryl sulfate | 10.0 |
Hydroxypropyl cellulose | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 35.0 |
The method comprises the following specific operations:
(1) preparation of granule-I: the microcrystalline cellulose and the croscarmellose sodium are mixed for 5 minutes, the lamivudine is added and mixed for 10 minutes, and finally the DL-tenofovir disoproxil tartrate crystal form A is added and mixed for 10 minutes according to the weighing of the raw and auxiliary materials in the table. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(1) Preparation of granule-II: weighing the raw materials and auxiliary materials in the table above, mixing hydroxypropyl cellulose, sodium lauryl sulfate and croscarmellose sodium for 10 minutes, adding microcrystalline cellulose, mixing for 10 minutes, adding efavirenz, and mixing for 10 minutes. Granulating with purified water, granulating by high efficiency wet granulating machine, drying at 60 deg.C with fluidized bed until water content is less than 1.5%, sieving with 24 mesh porous plate sieve, adding magnesium stearate, and mixing for 10 min.
(3) Tabletting the core particles-I and the core particles-II by adopting a double-layer tablet machine; then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 35
Preparation of tenofovir disoproxil succinate (2:1) eutectic
Dissolving 2.0g (3.84mmol) of tenofovir disoproxil and 0.24g (2.12mmol) of succinic acid in 10ml of tetrahydrofuran, adding 5ml of n-hexane, stirring, crystallizing, filtering and drying to obtain the tenofovir disoproxil succinate (2:1) eutectic.
Examples 36 to 54
With reference to the procedure of example 35 above, various co-crystals or salts of tenofovir disoproxil with a pharmaceutically acceptable acid were prepared:
example 55
Tenofovir disoproxil succinate (2:1) eutectic, emtricitabine film coated tablets and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
co-crystal of tenofovir disoproxil succinate (2:1) | 273.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 120.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material: | |
opadry II | 20.0 |
The raw materials and auxiliary materials in the table are weighed, the croscarmellose sodium, the pregelatinized starch and the lactose monohydrate are mixed together for 10 minutes, the microcrystalline cellulose is added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and the tenofovir disoproxil succinate (2:1) eutectic is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, and sieving with 24 mesh porous plate sieve. Adding magnesium stearate, mixing for 10 min, and tabletting. Then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
Example 56
Tenofovir disoproxil fumarate (1:1) eutectic, emtricitabine film coated tablets and preparation thereof
Components | Content (mg/tablet) |
Tablet core: | |
co-crystal of tenofovir disoproxil fumarate (1:1) | 300.0 |
Emtricitabine | 200.0 |
Microcrystalline cellulose | 300.0 |
Lactose monohydrate | 150.0 |
Pregelatinized starch | 50.0 |
Croscarmellose sodium | 20.0 |
Magnesium stearate | 10.0 |
Film coating material | |
Opadry II | 20.0 |
The raw materials and auxiliary materials in the table are weighed, the croscarmellose sodium, the pregelatinized starch and the lactose monohydrate are mixed together for 10 minutes, the microcrystalline cellulose is added and mixed for 10 minutes, the emtricitabine is added and mixed for 10 minutes, and the tenofovir disoproxil fumarate (1:1) eutectic is added and mixed for 10 minutes. Adding appropriate amount of purified water, granulating with high efficiency wet granulator, drying with fluidized bed at about 60 deg.C until water content is less than 1.5%, and sieving with 24 mesh porous plate sieve. Adding magnesium stearate, mixing for 10 min, and tabletting. Then stirring the coating material with 75% ethanol to prepare suspension, and coating by using a high-efficiency coating machine at a tablet bed temperature of about 45 ℃.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.
Claims (12)
1. A solid of tenofovir disoproxil, which is:
a tenofovir disoproxil compound shown in a formula IV,
wherein m takes the value of 1; x is DL-tartaric acid, namely DL-tenofovir disoproxil tartrate;
the DL-tenofovir disoproxil tartrate is DL-tenofovir disoproxil tartrate crystal form A, Cu-Kalpha radiation is used, and an X-ray powder diffraction pattern of the DL-tenofovir disoproxil tartrate crystal form A has characteristic diffraction peaks at the following 2 theta positions: 7.7 degrees +/-0.2 degrees, 10.1 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 13.4 degrees +/-0.2 degrees, 16.8 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.5 degrees +/-0.2 degrees and 23.6 degrees +/-0.2 degrees.
2. A solid of tenofovir disoproxil according to claim 1, wherein,
the X-ray powder diffraction pattern of the DL-tenofovir disoproxil tartrate crystal form A has characteristic diffraction peaks at the following 2 theta positions: 7.7 degrees +/-0.2 degrees, 10.1 degrees +/-0.2 degrees, 10.8 degrees +/-0.2 degrees, 13.4 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.8 degrees +/-0.2 degrees, 17.6 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.2 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 21.4 degrees +/-0.2 degrees, 22.5 degrees +/-0.2 degrees, 23.6 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees, 29.1 degrees +/-0.2 degrees and 30.5 degrees +/-0.2 degrees.
3. A solid of tenofovir disoproxil according to claim 2, wherein,
the X-ray powder diffraction pattern of the DL-tenofovir disoproxil tartrate crystal form A has the following characteristic diffraction peaks and relative intensities:
4. a solid of tenofovir disoproxil according to claim 3, wherein the X-ray powder diffraction pattern of crystalline form A of DL-tenofovir disoproxil tartrate is substantially as shown in figure 1.
5. A process for the preparation of a solid of tenofovir disoproxil as claimed in any one of claims 1 to 4, which comprises:
(1) dissolving tenofovir disoproxil and DL-tartaric acid in a solvent;
(2) separating out solids;
(3) separating the precipitated solid;
(4) optionally, the isolated solid is dried, or the isolated solid is further purified and then dried.
6. The method for preparing a solid of tenofovir disoproxil according to claim 5, wherein,
in the step (1), the solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, acetone, dimethylacetamide, dimethylformamide, dimethylsulfoxide or a mixture thereof; the molar ratio of tenofovir disoproxil fumarate to DL-tartaric acid and D-tartaric acid is 0.5: 1-2: 1.
7. A pharmaceutical composition comprising a therapeutically effective amount of a solid of tenofovir disoproxil as claimed in any one of claims 1 to 4 or prepared by a process according to any one of claims 5 to 6, and a pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 7, further comprising another or additional antiviral or antiviral co-agent selected from the group consisting of: emtricitabine, lamivudine, abacavir, acemenan, amprenavir, atazanavir, cladribine, Cobicistat, dapivirine, darunavir, delavirdine, didoglivir, efavirenz, emfuvirdine, entecavir, etravirine, famciclovir, fosamprenavir, glutathione, indinavir, levamisole, lopinavir, maraviroc, nelfinavir, nevirapine, penciclovir, pentamidine, Phosphazid, propiprogagage, raltegravir, ribavirin, rilpivirine, ritonavir, sanavir, stavudine, tipivudine, tipranavir, vorinostat, certavir, zivudine, zidovudine, or pharmaceutically acceptable salts thereof.
9. The pharmaceutical composition according to claim 8, further comprising another or additional antiviral or antiviral co-agent selected from the group consisting of: emtricitabine, lamivudine, Cobicistat, efavirenz, ezetivir or rilpivirine or a pharmaceutically acceptable salt thereof.
10. The pharmaceutical composition according to claim 8 or 9, selected from one of the following:
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil and emtricitabine; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine and efavirenz; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine and ropinirole hydrochloride; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, emtricitabine, eltamivir and Cobicistat; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil and lamivudine; or,
a pharmaceutical composition comprising a therapeutically effective amount of said solid of tenofovir disoproxil, lamivudine and efavirenz.
11. Use of the solid tenofovir disoproxil fumarate of any one of claims 1 to 4 or the solid tenofovir disoproxil prepared by the preparation method of any one of claims 5 to 6 in the preparation of a medicament for preventing and/or treating viral infections.
12. The use according to claim 11, wherein the solid tenofovir disoproxil is used in the preparation of a medicament for the prevention and/or treatment of hepatitis b virus and/or human immunodeficiency virus infection.
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CN105085571A (en) * | 2014-05-20 | 2015-11-25 | 四川海思科制药有限公司 | Tenofovir alafenamide compound, preparation method and purpose thereof |
RU2660438C1 (en) * | 2014-07-18 | 2018-07-06 | Джей ДаблЮ ФАРМАСЬЮТИКАЛ КОРПОРЭЙШН | New salt of tenofovir disoproxil |
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