CN111202744A - Ledipasvir and sofosbuvir compound tablet and preparation method and application thereof - Google Patents
Ledipasvir and sofosbuvir compound tablet and preparation method and application thereof Download PDFInfo
- Publication number
- CN111202744A CN111202744A CN202010065309.4A CN202010065309A CN111202744A CN 111202744 A CN111202744 A CN 111202744A CN 202010065309 A CN202010065309 A CN 202010065309A CN 111202744 A CN111202744 A CN 111202744A
- Authority
- CN
- China
- Prior art keywords
- sofosbuvir
- ledipasvir
- stirring
- amorphous
- filter cake
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960002063 sofosbuvir Drugs 0.000 title claims abstract description 119
- 229960002461 ledipasvir Drugs 0.000 title claims abstract description 115
- VRTWBAAJJOHBQU-KMWAZVGDSA-N ledipasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N([C@@H](C1)C=2NC(=CN=2)C=2C=C3C(F)(F)C4=CC(=CC=C4C3=CC=2)C=2C=C3NC(=NC3=CC=2)[C@H]2N([C@@H]3CC[C@H]2C3)C(=O)[C@@H](NC(=O)OC)C(C)C)CC21CC2 VRTWBAAJJOHBQU-KMWAZVGDSA-N 0.000 title claims abstract description 114
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- -1 sofosbuvir compound Chemical class 0.000 title claims abstract description 22
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- 239000003814 drug Substances 0.000 claims description 65
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
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- 239000002202 Polyethylene glycol Substances 0.000 description 2
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Abstract
The invention discloses a Ledipasvir and Sofosbuvir compound tablet and a preparation method and application thereof. The invention provides a Ledipasvir and Sofosbuvir compound tablet, which comprises the following components: amorphous ledipasvir I and amorphous sofosbuvir II. The preparation method of the ledipasvir and sofosbuvir compound tablet comprises the following steps: mixing amorphous Ledipasvir I, amorphous Sofosbuvir II and pharmaceutical adjuvants, and making into preparation. The crystal combination of the Ledipasvir and Sofosbuvir compound tablet prepared by the invention and the original grinding tablet has highly similar in vitro dissolution behavior, and the synthesis process is simple and convenient, safe to operate, environment-friendly and suitable for industrial production.
Description
Technical Field
The invention relates to a Ledipasvir and Sofosbuvir compound tablet and a preparation method and application thereof.
Background
Viral hepatitis type c, hepatitis c for short, is a viral hepatitis caused by Hepatitis C Virus (HCV). According to the world health organization, the global hepatitis c infection rate is about 3%, and about 1 hundred million and 7 million people are estimated to carry hepatitis c virus. Hepatitis c can cause chronic inflammation, necrosis and fibrosis of the liver, and some patients may develop cirrhosis and even liver cancer, which brings great threat to the health and life of the patients.
The therapeutic goal of chronic hepatitis c is to eliminate the virus and thus limit or prevent the occurrence of complications, while the standard of successful treatment is defined as no RNA of hepatitis c virus being detectable in the patient's serum 24 weeks after cessation of treatment. However, the existing treatment method for hepatitis C is a combined scheme of polyethylene glycol interferon and ribavirin, but the method can cause side effects such as anemia, allergy, depressive psychosis and the like, so that the research on novel anti-chronic hepatitis C virus medicines is always in the hot field of research. On 10 months 10 in 2014, a novel hepatitis c drug (a compound tablet of ledipasvir and sofosbuvir) developed by gillidd science (Gilead Sciences) is approved by the FDA in the united states, and becomes the world first treatment scheme for treating adult hepatitis c with the gene type 1, which is orally taken and does not contain interferon and ribavirin. Ledipasvir, english name: ledipasvir, the chemical structural formula is shown as formula I; sofosbuvir, english name: the chemical structural formula of the Sofosbuvir is shown as a formula II.
According to the report in patent CN201480000286.1, a certain amount of ledipasofbuvir is contained in the ledipasofbuvir compound tablet developed by gillidd science (Gilead Sciences) and is in an amorphous form, and the ledipasofbuvir is in a crystal 6. However, the synthesis process of the compound tablet is complex and is not suitable for industrial production. Therefore, the search for the ledipasofusobuwei compound tablet which has simple synthesis process and low production cost and is suitable for industrial production is a technical problem which needs to be solved urgently at present.
Disclosure of Invention
The invention aims to overcome the defects that in the prior art, a preparation process of a Ledipasvir and Sofosbuvir compound tablet is complex, production cost is high, the compound tablet is not suitable for industrial production and the like, and provides a Ledipasvir and Sofosbuvir compound tablet and a preparation method and application thereof. The crystal combination of the Ledipasvir and Sofosbuvir compound tablets prepared by the invention and the original ground tablets has highly similar dissolution rates, and the synthesis process is simple and convenient, safe to operate, environment-friendly and suitable for industrial production.
The invention provides a Ledipasvir and Sofosbuvir compound tablet, which comprises: amorphous ledipasvir I and amorphous sofosbuvir II. The purity of the amorphous ledipasvir I is more than 99.5 percent (HPLC purity); the purity of the amorphous sofosbuvir II is more than 99.5 percent (HPLC purity).
In the ledipasvir and sofosbuvir compound tablet, the mass ratio of the amorphous ledipasvir I to the amorphous sofosbuvir II is preferably (1:1) - (1:10), more preferably (1:3) - (1:6), for example 9: 40.
The invention also provides a preparation method of the Ledipasvir and Sofosbuvir compound tablet, which comprises the following steps: mixing amorphous Ledipasvir I, amorphous Sofosbuvir II and pharmaceutical adjuvants, and making into preparation.
The pharmaceutical adjuvant can be a pharmaceutical adjuvant commonly used for preparing tablets in the field: including starch, cellulose and derivatives thereof; lubricants, such as polyethylene glycol, talc, stearic acid or magnesium stearate; diluents such as talc, powdered cellulose, lactose, starches such as cornstarch or corn starch, mannitol, sorbitol; glidants, such as silicon dioxide; disintegrants, such as microcrystalline cellulose or crospovidone; ligands such as methylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, alginic acid, alginates; sweetening agents, such as sucrose, glucose, mannitol, saccharin; or flavoring agents, such as natural or synthetic oils.
The mixing and preparation can be the conventional method for the operation in the field.
The invention also provides a preparation method of the amorphous Ledipasvir I, which comprises the following steps: mixing a solution formed by Ledipasvir bulk drug and an organic solvent with water to obtain amorphous Ledipasvir I;
in the preparation method of the amorphous Ledipasvir I, the Ledipasvir bulk drug comprises various Ledipasvir crystal forms and Ledipasvir solvent compounds which are reported at present, such as Ledipasvir acetonide, Ledipasvir crystal form A, Ledipasvir crystal form B and Ledipasvir crystal form C. (the ledipasvir acetonide, the ledipasvir crystal form A, the ledipasvir crystal form B and the ledipasvir crystal form C can be obtained from commercial sources or prepared according to the method of patent CN 201410226164)
In the preparation method of amorphous ledipasvir I, the organic solvent is preferably one or more of ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile, N-dimethylformamide, dimethyl sulfoxide and ethylene glycol, and is further preferably acetonitrile, tetrahydrofuran, isopropanol or N, N-dimethylformamide.
In the preparation method of amorphous ledipasvir I, the volume-to-mass ratio of the organic solvent to the ledipasvir bulk drug is preferably 2mL/g to 12mL/g, more preferably 4mL/g to 8mL/g, for example 6 mL/g.
In the preparation method of the amorphous ledipasvir I, the water is preferably purified water.
In the preparation method of amorphous ledipasvir I, the volume ratio of the water to the organic solvent is preferably 2-10, more preferably 5-7, such as 5.8.
In the preparation method of the amorphous ledipasvir I, the addition mode is preferably dropwise. The dropping rate is preferably 10mL/min to 100mL/min, for example, 10mL/min or 100 mL/min.
The preparation method of the amorphous Ledipasvir I preferably adopts the following steps: and (3) dropwise adding a solution formed by the Ledipasvir bulk drug and the organic solvent into vigorously stirred water, stirring, filtering, washing and drying to obtain amorphous Ledipasvir I. The dropping rate is preferably 10mL/min to 100mL/min, for example, 10mL/min or 100 mL/min. The vigorous stirring is preferably at a stirring speed of 50 to 500rpm, more preferably at 200 to 400rpm, for example 200rpm, 300rpm, 350rpm or 400 rpm. The stirring, filtering, washing and drying may be carried out by methods conventional in the art for such operations. The stirring temperature is preferably 20 ℃ to 30 ℃, and the stirring time is preferably 0.5 hour to 1.5 hours, for example, 0.5 hour to 1 hour or 1 hour to 1.5 hours. The washing is preferably carried out by using purified water, and the volume mass ratio of the purified water for washing to the ledipasvir is preferably 1 mL/g-5 mL/g, such as 2 mL/g. The number of washing is preferably 1 to 3. The drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 50-60 ℃, the time of the vacuum drying is preferably 8-12 hours, and the pressure of the vacuum drying is preferably-0.01 MPa-0.08 MPa.
The invention also provides a preparation method of the amorphous sofosbuvir II, which comprises the following steps: removing the organic solvent from the solution formed by the sofosbuvir bulk drug and the organic solvent, and then adding the solvent to obtain amorphous sofosbuvir II; said organic solvent is different from said solvent;
in the preparation method of amorphous sofosbuvir II, the sofosbuvir bulk drug comprises various reported sofosbuvir crystal forms and solvent compounds, such as sofosbuvir crystal form 1, sofosbuvir crystal form 2, sofosbuvir crystal form 3, sofosbuvir crystal form 4, sofosbuvir crystal form 5, sofosbuvir crystal form 6, sofosbuvir dichloromethide and sofosbuvir chloroform. (the Sofosbuvir crystal form 1, the Sofosbuvir crystal form 2, the Sofosbuvir crystal form 3, the Sofosbuvir crystal form 4, the Sofosbuvir crystal form 5, the Sofosbuvir crystal form 6, the dichloromethide of the Sofosbuvir and the chloroform of the Sofosbuvir can be obtained by commercial purchase or can be prepared by adopting the method of the patent CN 201180017181.3)
In the preparation method of the amorphous sofosbuvir II, the organic solvent is preferably a polar organic solvent; the polar organic solvent is preferably one or more of ethyl acetate, methanol, ethanol, isopropanol, tetrahydrofuran, acetone and acetonitrile, and is further preferably one or more of ethyl acetate, methanol, acetone and acetonitrile.
In the preparation method of the amorphous sofosbuvir II, the volume-to-mass ratio of the organic solvent to the sofosbuvir bulk drug is preferably 2mL/g to 12mL/g, more preferably 5mL/g to 11mL/g, for example 10 mL/g.
In the preparation method of the amorphous sofosbuvir II, the solvent is preferably a non-polar organic solvent; the non-polar organic solvent is preferably one or more of n-heptane, petroleum ether, cyclohexane, n-hexane and toluene, and is further preferably one or more of n-heptane, n-hexane and toluene.
In the preparation method of the amorphous sofosbuvir II, the volume-to-mass ratio of the solvent to the sofosbuvir bulk drug is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 20mL/g, for example 15 mL/g.
In the method for preparing amorphous sofosbuvir II, the organic solvent is preferably removed by vacuum distillation, and the temperature of the vacuum distillation is preferably 10 to 90 ℃, more preferably 40 to 60 ℃, for example 40 to 50 ℃. The pressure of the reduced pressure distillation is preferably 0.01MPa to 0.08 MPa.
In the preparation method of the amorphous sofosbuvir II, the solvent is preferably added dropwise. The dropping rate is preferably 40mL/min to 500mL/min, for example, 40mL/min or 500 mL/min.
The preparation method of the amorphous sofosbuvir II preferably comprises the following steps: and removing the organic solvent from the solution formed by the sofosbuvir bulk drug and the organic solvent, adding the solvent, stirring, filtering, washing and drying to obtain the amorphous sofosbuvir II.
The stirring, filtering, washing and drying may be carried out by methods conventional in the art for such operations. The stirring temperature is preferably 0 to 30 ℃, and more preferably 20 to 30 ℃. The washing preferably adopts a non-polar organic solvent; the non-polar organic solvent is preferably one or more of n-heptane, petroleum ether, cyclohexane, n-hexane and toluene, and more preferably n-heptane. The volume-to-mass ratio of the washing solvent to the sofosbuvir is preferably 1mL/g to 5mL/g, for example 2 mL/g. The number of washing is preferably 1 to 3. The drying is preferably vacuum drying, the temperature of the vacuum drying is preferably 40-60 ℃, for example 40 ℃, the time of the vacuum drying is preferably 8-12 hours, and the pressure of the vacuum drying is preferably-0.01 MPa-0.08 MPa.
The invention also provides application of the Ledipasvir and Sofosbuvir compound tablet in preparation of a medicine for treating and/or preventing hepatitis C.
As used in this specification, the following words and phrases generally have the meanings as set forth below, unless the context of their use indicates otherwise.
In the present invention, the term "crystal form" refers to different solid states formed by different arrangement of compound molecules or atoms in lattice space.
In the present invention, the term "amorphous" refers to a structure of some amorphous regions that are not completely crystalline (amorphous regions) or a structure of some amorphous solids (amorphous).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the crystal combination of the ledipasvir and sofosbuvir compound tablet prepared by the invention and the tablet prepared by the original research (patent CN201480000286.1) has similar in-vitro dissolution behavior, and the synthesis process is simple, convenient, safe to operate, environment-friendly and suitable for industrial production.
Drawings
FIG. 1 is an XRPD spectrum of an amorphous solid drug substance of Ledipasvir as employed in examples 1-5;
FIG. 2 is a Differential Scanning Calorimetry (DSC) curve of the ledipasvir amorphous solid drug substance employed in examples 1-5;
FIG. 3 is an XRPD spectrum of a sofosbuvir amorphous solid drug substance employed in examples 6-10;
FIG. 4 is a Differential Scanning Calorimetry (DSC) curve of the sofosbuvir amorphous solid drug substance employed in examples 6-10;
FIG. 5 is a graph showing the dissolution profiles of ledipasvir (400 mg)/ledipasvir (90mg) in four different dissolution media in a compound sofosbuvir tablet prepared in example 11.
Shows the dissolution curve of Ledipasvir in a 0.1mol/L hydrochloric acid medium in a Sofosbuvir (400 mg)/Ledipasvir (90mg) compound tablet
Shows the dissolution curve of ledipasvir (400 mg)/ledipasvir (90mg) in a compound tablet (containing 0.4% SLS) in a pH4.5 acetate buffer;
shows the dissolution curve of ledipasvir (400 mg)/ledipasvir (90mg) in phosphate buffer with pH6.8 (containing 0.4% SLS) in the compound tablet of the sofosbuvir;
shows the dissolution curve of ledipasvir (0.4% SLS) in water in a sofosbuvir (400 mg)/ledipasvir (90mg) compound tablet.
FIG. 6 shows the Sofosbuvir (400 mg)/Ledipasvir (90mg) compound tablet prepared in example 11 and GirdizadA comparison graph of the dissolution curves of the control drug in a hydrochloric acid medium of 0.1mol/L and the sofosbuvir; wherein:
representing the original Gilidde corporationThe dissolution curve of the control drug in a hydrochloric acid medium of 0.1mol/L of sofosbuvir;
shows the dissolution profile of the sofosbuvir (400 mg)/ledipasvir (90mg) compound tablet described in example 11 in a 0.1mol/L hydrochloric acid medium.
FIG. 7 shows a Sofosbuvir (400 mg)/Ledipasvir (90mg) compound tablet prepared in example 11 and GirdizadA comparison graph of the dissolution curves of the control drug in 0.1mol/L hydrochloric acid and the sofosbuvir; wherein:
representing the original Gilidde corporationDissolution koji of sofosbuvir in contrast medicineLine drawing;
shows the dissolution profile of sofosbuvir (400 mg)/ledipasvir (90mg) in the compound tablet described in example 11.
FIG. 8 shows a Sofosbuvir (400 mg)/Ledipasvir (90mg) compound tablet prepared in example 11 and GirdizadThe dissolution curves of the control drug in a 0.1mol/L hydrochloric acid medium and the ledipasvir are compared;
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The XRPD spectrum of the ledipasvir amorphous solid drug substance used in examples 1-5 is shown in fig. 1, with the solid being amorphous as shown by XRPD. The Differential Scanning Calorimetry (DSC) curve of the ledipasvir amorphous solid drug substance used in examples 1-5 is shown in figure 2, and the DSC curve shows that the glass transition temperature of the solid is about 166 ℃. The XRPD spectra of the sofosbuvir amorphous solid drug substance employed in examples 6-10 are shown in fig. 3, which shows that the solid is amorphous according to XRPD. The Differential Scanning Calorimetry (DSC) curve of the sofosbuvir amorphous solid bulk drug adopted in the examples 6-10 is shown in figure 4, and the DSC curve shows that the solid has no obvious endothermic peak and decomposes at about 250 ℃.
Example 1 preparation of Ledipasvir amorphous solid drug substance
Adding Ledipasvir crystal form A raw material medicine (10.0g) into 60ml of acetonitrile at room temperature (10-15 ℃), and stirring to dissolve the raw material medicine. The solution obtained above was added to 350ml of purified water vigorously stirred (stirring speed 200rpm) over 6 minutes, and a large amount of off-white solid precipitated from the system. After the dripping is finished, the mixture is kept at the temperature of between 20 and 30 ℃ and stirred for 0.5 to 1 hour. Filtering, leaching the filter cake with 20ml of purified water once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8-12 hours at 50 ℃ to obtain 8.7g of amorphous Ledipasvir, wherein the yield is 87%, the HPLC purity is 99.87%, and the de is more than 99.0%.
Example 2 preparation of Ledipasvir amorphous solid drug substance
Adding Ledipasvir crystal form A raw material medicine (1.0Kg) into 6L acetonitrile at room temperature (15-20 ℃), and stirring to dissolve the raw material medicine. The solution obtained above was added dropwise to 35L of purified water vigorously stirred (rotation speed 200rpm) over 60 minutes, and a large amount of off-white solid precipitated from the system. After the dripping is finished, the mixture is kept at the temperature of between 20 and 30 ℃ and stirred for 1 to 1.5 hours. Filtering, leaching the filter cake with 2L of purified water once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8-12 hours at 50 ℃ to obtain 0.9Kg of amorphous Ledipasvir, wherein the yield is 90%, the HPLC purity is 99.93%, and the de is more than 99.0%.
Example 3 preparation of Ledipasvir amorphous solid drug substance
Adding Ledipasvir crystal form B bulk drug (10.0g) into 60ml tetrahydrofuran at room temperature (20-25 ℃), and stirring to dissolve. The solution obtained above was added to 350ml of purified water vigorously stirred (rotation speed 300rpm) over 6 minutes, and a large amount of off-white solid precipitated from the system. After the dripping is finished, the mixture is kept at the temperature of between 20 and 30 ℃ and stirred for 0.5 to 1 hour. Filtering, leaching the filter cake with 20ml of purified water once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8-12 hours at 50 ℃ to obtain 8.3g of amorphous Ledipasvir, wherein the yield is 83%, the HPLC purity is 99.92%, and the de is more than 99%.
Example 4 preparation of Ledipasvir amorphous solid drug substance
Adding Ledipasvir crystal form C raw material medicine (10.0g) into 60ml of isopropanol at room temperature (25-30 ℃), and stirring to dissolve the raw material medicine clearly. The solution obtained above was added to 350ml of purified water vigorously stirred (rotation speed 400rpm) over 6 minutes, and a large amount of off-white solid precipitated from the system. After the dripping is finished, the mixture is kept at the temperature of between 20 and 30 ℃ and stirred for 0.5 to 1 hour. Filtering, leaching the filter cake with 20ml of purified water once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8 to 12 hours at 50 ℃ to obtain 8.5g of Ledipasvir amorphous bulk drug, wherein the yield is 85%, the HPLC purity is 99.90%, and the de is more than 99.0%.
Example 5 preparation of Ledipasvir amorphous solid drug substance
At room temperature (30-35 ℃), adding Ledipasvir acetonide raw material drug (10.0g) into 60ml of N, N-dimethylformamide, and stirring to dissolve. The solution obtained above was added to 350ml of purified water vigorously stirred (rotation speed 350rpm) over 6 minutes, and a large amount of off-white solid was precipitated from the system. After the dripping is finished, the mixture is kept at the temperature of between 20 and 30 ℃ and stirred for 0.5 to 1 hour. Filtering, leaching the filter cake with 20ml of purified water once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8 to 12 hours at 50 ℃ to obtain 7.6g of Ledipasvir amorphous bulk drug, wherein the yield is 76%, the HPLC purity is 99.94%, and the de is more than 99.0%.
Example 6 preparation of sofosbuvir amorphous solid drug substance
Adding the Sofosbuvir crystal form 1 raw material medicine (8.0g) into 80ml of ethyl acetate at room temperature (10-15 ℃), and stirring to dissolve. And concentrating the obtained solution under reduced pressure until no liquid drops (40-50 ℃ and 0.08Mpa) exist. The system is that 120ml of n-heptane is added within 3 minutes, and stirring is continued for 1-2 hours after the temperature is reduced to 20-30 ℃. Filtering, leaching a filter cake with 16ml of n-heptane once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8-12 hours at 40 ℃ to obtain 7.3g of the sofosbuvir amorphous bulk drug, wherein the yield is 91.3%, the HPLC purity is 99.79%, and the de is more than 99.0%.
Example 7 preparation of sofosbuvir amorphous solid drug substance
Adding the raw material medicine (4Kg) of the Sofosbuvir crystal form 6 into 40L ethyl acetate at room temperature (15-20 ℃), and stirring to dissolve. And concentrating the obtained solution under reduced pressure until no liquid drops (40-50 ℃ and 0.08Mpa) exist. 60L of n-heptane is added into the system within 120 minutes, and the mixture is stirred and cooled to 20-30 ℃ and then is continuously stirred for 1-2 hours. Filtering, leaching the filter cake with 8L of n-heptane once, placing the filter cake in a vacuum oven (the pressure is-0.1 MPa to-0.08 MPa), and drying for 8-12 hours at 40 ℃ to obtain 3.7Kg of the Sofosbuvir amorphous form raw material medicine, wherein the yield is 92.5%, the HPLC purity is 99.83%, and the de is more than 99.0%.
Example 8 preparation of sofosbuvir amorphous solid drug substance
Adding the Sofosbuvir crystal form 6 raw material medicine (8.0g) into 80ml of methanol at room temperature (20-25 ℃), and stirring to dissolve. And concentrating the obtained solution under reduced pressure until no liquid drops (40-50 ℃ and 0.08Mpa) exist. And adding 120ml of normal hexane into the system within 3 minutes, stirring and cooling to 20-30 ℃, and then continuously stirring for 1-2 hours. Filtering, leaching the filter cake with 16ml of n-hexane once, placing the filter cake in a vacuum oven (-0.01MPa to-0.08 MPa), and drying for 8-12 hours at 40 ℃ to obtain 7.1g of the sofosbuvir amorphous bulk drug, wherein the yield is 88.8%, the HPLC purity is 99.86%, and the de is more than 99.0%.
Example 9 preparation of sofosbuvir amorphous solid drug substance
Adding the Sofosbuvir crystal form 1 raw material medicine (8.0g) into 80ml of acetone at room temperature (15-20 ℃), and stirring to dissolve. And concentrating the obtained solution under reduced pressure until no liquid drops (40-50 ℃ and 0.08Mpa) exist. Adding 120ml of toluene in the system within 3 minutes, stirring and cooling to 20-30 ℃, and then continuously stirring for 1-2 hours. Filtering, leaching the filter cake with 16ml of toluene once, placing the filter cake in a vacuum oven (-0.01MPa to-0.08 MPa), and drying for 8-12 hours at 40 ℃ to obtain 6.9g of the sofosbuvir amorphous bulk drug, wherein the yield is 86.3%, the HPLC purity is 99.90%, and the de is more than 99.0%.
Example 10 preparation of amorphous solid drug substance of sofosbuvir
Adding the Sofosbuvir crystal form 6 raw material medicine (8.0g) into 80ml of acetonitrile at room temperature (25-30 ℃), and stirring to dissolve the raw material medicine. And concentrating the obtained solution under reduced pressure until no liquid drops (40-50 ℃ and 0.08Mpa) exist. And adding 120ml of n-heptane into the system within 3 minutes, stirring and cooling to 20-30 ℃, and then continuously stirring for 1-2 hours. Filtering, leaching the filter cake with 16ml of n-heptane once, placing the filter cake in a vacuum oven (-0.01MPa to-0.08 MPa), and drying for 8-12 hours at 40 ℃ to obtain 7.2g of the sofosbuvir amorphous bulk drug, wherein the yield is 90.0%, the HPLC purity is 99.85%, and the de is more than 99.0%.
EXAMPLE 11 preparation of Ledipasvir and Sofosbuvir Compound tablets
400mg of the amorphous bulk drug of the sofosbuvir prepared in the example 7 is mixed with 90mg of the amorphous bulk drug of the ledipasvir prepared in the example 2, 360mg of mannitol, 296mg of microcrystalline cellulose, 30mg of croscarmellose sodium, 5.4mg of silicon dioxide and 9.0mg of magnesium stearate to prepare the ledipasvir and sofosbuvir compound tablet.
The dissolution curves of ledipasvir (90mg) and sofosbuvir (400mg) in the prepared ledipasvir compound tablets under four different dissolution media are shown in figure 5. The prepared Ledipasvir (90mg) and Sofosbuvir (400mg) compound tablet is mixed with original GilidaeThe comparative graph of the dissolution curve of the control drug in the 0.1mol/L hydrochloric acid medium of the sofosbuvir is shown in figure 6. The prepared sofosbuvir (400 mg)/ledipasvir (90mg) compound tablet is prepared with the original Gilidae companyThe comparative graph of the dissolution curve of the control drug in 0.1mol/L hydrochloric acid and the sofosbuvir is shown in figure 7. The prepared sofosbuvir (400 mg)/ledipasvir (90mg) compound tablet is prepared with the original Gilidae companyThe comparative graph of the dissolution curve of ledipasvir of the control drug in 0.1mol/L hydrochloric acid medium is shown in figure 8.
Claims (2)
1. A Ledipasvir and Sofosbuvir compound tablet is characterized by comprising: amorphous ledipasvir I and amorphous sofosbuvir II, wherein the purity of the amorphous ledipasvir I is more than 99.5 percent, and the purity of the amorphous sofosbuvir II is more than 99.5 percent;
the preparation method of the amorphous Ledipasvir I is method 1, method 2, method 3, method 4 or method 5;
the method comprises the following steps: adding 10.0g of Ledipasvir crystal form A raw material medicine into 60ml of acetonitrile at room temperature of 10-15 ℃, stirring for dissolving, adding 350ml of purified water with stirring speed of 200rpm into the obtained solution within 6 minutes, stirring for 0.5-1 hour at 20-30 ℃ after dropwise addition, filtering, leaching a filter cake once with 20ml of purified water, placing the filter cake into a vacuum oven, drying for 8-12 hours at 50 ℃ under the pressure of-0.1 MPa to-0.08 MPa, and obtaining 8.7g of amorphous Ledipasvir with the yield of 87%, the HPLC purity of 99.87% and the de of more than 99.0%;
the method 2 comprises the following steps: adding 1.0Kg of Ledipasvir crystal form A raw material medicine into 6L of acetonitrile at room temperature of 15-20 ℃, stirring for dissolving, dropwise adding 35L of purified water with the rotation speed of 200rpm into the obtained solution within 60 minutes, stirring for 1-1.5 hours at 20-30 ℃, filtering, leaching a filter cake once with 2L of purified water, placing in a vacuum oven, drying for 8-12 hours at 50 ℃, obtaining 0.9Kg of amorphous Ledipasvir, the yield being 90%, the HPLC purity being 99.93%, and the de being more than 99.0%;
the method 3 comprises the following steps: adding 10.0g of Ledipasvir crystal form B raw material medicine into 60ml of tetrahydrofuran at the room temperature of 20-25 ℃, stirring for dissolving, adding 350ml of purified water with the rotation speed of 300rpm into the obtained solution within 6 minutes, stirring for 0.5-1 hour at the temperature of 20-30 ℃ after dropwise adding, filtering, leaching a filter cake once with 20ml of purified water, placing the filter cake into a vacuum oven, drying for 8-12 hours at the temperature of 50 ℃, and obtaining 8.3g of amorphous Ledipasvir, wherein the yield is 83%, the HPLC purity is 99.92%, and the de is more than 99%;
the method 4 comprises the following steps: adding 10.0g of Ledipasvir crystal form C raw material medicine into 60ml of isopropanol at the room temperature of 25-30 ℃, stirring for dissolving, adding 350ml of purified water with the rotation speed of 400rpm into the obtained solution within 6 minutes, violently stirring to separate out a large amount of white-like solids from the system, after dropwise adding, keeping the temperature of 20-30 ℃, stirring for 0.5-1 hour, filtering, leaching a filter cake once with 20ml of purified water, then placing the filter cake into a vacuum oven, drying for 8-12 hours at the temperature of 50 ℃, and obtaining 8.5g of Ledipasvir amorphous raw material medicine, wherein the yield is 85%, the HPLC purity is 99.90%, and the de is more than 99.0%;
the method 5 comprises the following steps: adding 10.0g of ledipasvir acetonide bulk drug into 60ml of N, N-dimethylformamide at room temperature of 30-35 ℃, stirring for dissolving, adding 350ml of purified water with the rotation speed of 350rpm into the obtained solution within 6 minutes, separating out a large amount of white-like solids from the system, after dropwise addition, keeping the temperature of 20-30 ℃, stirring for 0.5-1 hour, filtering, leaching a filter cake with 20ml of purified water once, then placing the filter cake into a vacuum oven, drying for 8-12 hours at 50 ℃ under the pressure of-0.1 MPa to-0.08 MPa, and obtaining 7.6g of ledipasvir amorphous bulk drug with the yield of 76%, the HPLC purity of 99.94% and the de of more than 99.0%;
the preparation method of the amorphous sofosbuvir II comprises the steps of ①, ②, ③, ④ or ⑤;
①, adding 8.0g of Sofosbuvir crystal form 1 raw material medicine into 80ml of ethyl acetate at room temperature of 10-15 ℃, stirring for dissolving, concentrating the obtained solution under reduced pressure until no liquid drops are formed, wherein the temperature is 0.08MPa, adding 120ml of n-heptane into the system within 3 minutes, stirring for cooling to 20-30 ℃, then continuing stirring for 1-2 hours, filtering, leaching the filter cake once with 16ml of n-heptane, then placing the filter cake into a vacuum oven, drying for 8-12 hours at 40 ℃ under the pressure of-0.1 MPa to-0.08 MPa, and obtaining 7.3g of Sofosbuvir amorphous raw material medicine, wherein the yield is 91.3%, the HPLC purity is 99.79%, and de is more than 99.0%;
②, adding 4Kg of bulk drug of Sofosbuvir crystal form 6 into 40L of ethyl acetate at room temperature of 15-20 ℃, stirring for dissolving, concentrating the obtained solution under reduced pressure until no liquid drops are formed at 40-50 ℃ and 0.08MPa, adding 60L of n-heptane in the system within 120 minutes, stirring for cooling to 20-30 ℃, then continuing stirring for 1-2 hours, filtering, leaching the filter cake once with 8L of n-heptane, then placing the filter cake in a vacuum oven, drying for 8-12 hours at 40 ℃ under the pressure of-0.1 MPa to-0.08 MPa, and obtaining 3.7Kg of bulk drug of Sofosbuvir in amorphous form, wherein the yield is 92.5%, the HPLC purity is 99.83%, and de is more than 99.0%;
③, adding 8.0g of Sofosbuvir crystal form 6 raw material medicine into 80ml of methanol at room temperature of 20-25 ℃, stirring for dissolving, concentrating the obtained solution under reduced pressure until no liquid drops are formed, wherein the temperature is 0.08MPa, 120ml of n-hexane is added into the system within 3 minutes, stirring and cooling to 20-30 ℃, then continuously stirring for 1-2 hours, filtering, leaching the filter cake with 16ml of n-hexane once, then placing the filter cake into a vacuum oven, drying for 8-12 hours at the temperature of 40 ℃, and obtaining 7.1g of Sofosbuvir amorphous raw material medicine, wherein the yield is 88.8%, the HPLC purity is 99.86%, and the de is more than 99.0%;
④, adding 8.0g of Sofosbuvir crystal form 1 raw material medicine into 80ml of acetone at room temperature of 15-20 ℃, stirring for dissolving, concentrating the obtained solution under reduced pressure until no liquid drops exist, adding 120ml of toluene within 3 minutes in a system at 40-50 ℃, stirring for cooling to 20-30 ℃, then continuously stirring for 1-2 hours, filtering, leaching a filter cake once with 16ml of toluene, then placing in a vacuum oven, drying for 8-12 hours at 40 ℃, and obtaining 6.9g of Sofosbuvir amorphous raw material medicine, wherein the yield is 86.3%, the HPLC purity is 99.90%, and the de is more than 99.0%;
⑤, adding 8.0g of Sofosbuvir crystal form 6 raw material medicine into 80ml of acetonitrile at room temperature of 25-30 ℃, stirring for dissolving, concentrating the obtained solution under reduced pressure until no liquid drops exist, adding 120ml of n-heptane within 3 minutes in the system at 40-50 ℃, stirring for cooling to 20-30 ℃, then continuously stirring for 1-2 hours, filtering, leaching a filter cake with 16ml of n-heptane once, then placing the filter cake into a vacuum oven, drying for 8-12 hours at 40 ℃, and obtaining 7.2g of Sofosbuvir amorphous raw material medicine, wherein the yield is 90.0%, the HPLC purity is 99.85%, and de is more than 99.0%;
the preparation method of the ledipasvir and sofosbuvir compound tablet comprises the following steps: mixing 400mg of the Sofosbuvir amorphous bulk drug, 90mg of the Ledipasvir amorphous bulk drug, 360mg of mannitol, 296mg of microcrystalline cellulose, 30mg of croscarmellose sodium, 5.4mg of silicon dioxide and 9.0mg of magnesium stearate, and preparing into the Ledipasvir and Sofosbuvir compound tablet.
2. Use of the ledipasvir and sofosbuvir compound tablet as claimed in claim 1 in the preparation of a medicament for treating and/or preventing hepatitis c.
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WO2011123645A2 (en) * | 2010-03-31 | 2011-10-06 | Pharmasset, Inc. | Nucleoside phosphoramidates |
CN104144682A (en) * | 2013-01-31 | 2014-11-12 | 吉利德法莫赛特有限责任公司 | Combination formulation of two antiviral compounds |
CN104379584A (en) * | 2012-06-05 | 2015-02-25 | 吉利德法莫赛特有限责任公司 | Solid forms of antiviral compound |
WO2015132321A1 (en) * | 2014-03-05 | 2015-09-11 | Galenicum Health S.L. | Stable pharmaceutical compositions of sofosbuvir |
WO2016128453A1 (en) * | 2015-02-13 | 2016-08-18 | Sandoz Ag | Pharmaceutical compositions comprising ledipasvir and sofosbuvir |
WO2016156330A1 (en) * | 2015-03-30 | 2016-10-06 | Ratiopharm Gmbh | Solid pharmaceutical composition comprising amorphous sofosbuvir and a phospholipid |
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WO2011123645A2 (en) * | 2010-03-31 | 2011-10-06 | Pharmasset, Inc. | Nucleoside phosphoramidates |
CN104379584A (en) * | 2012-06-05 | 2015-02-25 | 吉利德法莫赛特有限责任公司 | Solid forms of antiviral compound |
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WO2015132321A1 (en) * | 2014-03-05 | 2015-09-11 | Galenicum Health S.L. | Stable pharmaceutical compositions of sofosbuvir |
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