CN108904496A - For treating the pharmaceutical composition of hepatitis C infection - Google Patents
For treating the pharmaceutical composition of hepatitis C infection Download PDFInfo
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- CN108904496A CN108904496A CN201810694874.XA CN201810694874A CN108904496A CN 108904496 A CN108904496 A CN 108904496A CN 201810694874 A CN201810694874 A CN 201810694874A CN 108904496 A CN108904496 A CN 108904496A
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- 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
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
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- 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
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Abstract
The present invention relates to a kind of for treating the pharmaceutical composition and unit dosage forms of infection with hepatitis C virus, the composition and unit dosage forms include KW136 (N- [(2S) -1- [(2S) -2- { 4- [7- (4- { 2- [(2S) -1- [(2S) -2- [(methoxycarbonyl) amino] -3- methylbutyryl] pyrrolidin-2-yl] -1H- imidazol-4 yl } phenyl) -2H-1 of therapeutically effective amount, 3- benzo two dislikes cyclopentadienyl-4- base]-1H- imidazoles-2- base } pyrrolidin-1-yl]-3- methyl-1-oxo-butanes-2- base] methyl carbamate dihydrochloride, Formula II) and at least one pharmaceutically acceptable excipient, and the method for being used to prepare described pharmaceutical composition and unit dosage forms.
Description
Technical field
The present invention relates to pharmaceutical preparations, specifically disclose a kind of for treating the pharmaceutical composition of infection with hepatitis C virus
And unit dosage forms, and the method for being used to prepare described pharmaceutical composition and unit dosage forms.
Background technique
Hepatitis C virus (HCV) infection is the most common chronic Hematogenous infection in the U.S..Although new infection quantity is
Decline, but the burden of chronic infection is still largely, to estimate according to Center for Disease Control, there are 3,900,000 infection in the U.S.
Person's (1.8%).Chronic liver disease ranked tenth position in U.S. adults causality of death, and cause about 25 every year, and 000 people is dead, or
It is about the 1% of all death.Research shows that 40% chronic liver disease is related with HCV, estimation leads to 8,000-10,000 people every year
It is dead.The relevant end-stage liver disease of HCV- is the most common liver transfer operation indication in adult.
In past ten years, the antiviral therapy of chronic c-type hepatopathy is fast-developing, has found out from therapeutic effect
It is significantly improved.However, even if adding triazole nucleoside combine controlling using polyethyleneglycol modified (pegylated) IFN-α
It treats, also has 40% to 50% patient's treatment failure, that is, they are nonresponder or recidivist.These patients are currently without having
The treatment alternative of effect.Particularly, the patient with late stage fibrosis or cirrhosis in liver biopsy is in development
In the danger dramatically increased in the great risk of end-stage liver disease complication, and in hepatocellular carcinoma, wherein the complication
Including ascites, jaundice, variceal bleeding, cerebral lesion and gradual hepatic failure.
The high prevalence of chronic HCV infection there is important publilc health to influence the following burden of U.S.'s chronic liver disease.
It is from national health and nutrition survey (NHANES III) statistics indicate that, from late 1960s phase to the 1980s
In early days, new HCV infection occurrence rate is significantly increased, especially in 20 to 40 years old crowds.Estimation has 20 years or longer
The number of long-standing HCV infection will increase four times or more from 1990 to 2015, i.e., increased to over 3,000,000 from 750,000.Infection
The proportionate increase of 30 or 40 years patients even will be bigger.When continuing due to the danger of the relevant chronic liver disease of HCV with infection
Between it is related, and the cirrhosis danger for infecting the patient more than 20 years gradually increases, therefore this will lead in 1965-1985 sense
In the patient of dye, the relevant morbidity and mortality of cirrhosis are increased considerably.
HCV is the envelope positive chain RNA virus of flaviviridae.Think that single-stranded HCV rna gene group length is about 9500 cores
Thuja acid, and there is single open reading frame (ORF), the single open reading frame coding has the list of about 3000 amino acid
A big polyprotein.In the cell of infection, it is believed that cell and virus protease multiple sites crack this polyprotein with
Generate viral structure and non-structural (NS) albumen.For HCV, it is believed that two kinds of virus proteases influence mature non-structural protein
The generation of (NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B).Think the first virus protease in the NS2- of polyprotein
The cracking of the junction NS3.Think serine protease that the second virus protease is included in the N- petiolarea of NS3 (herein referred as
" NS3 protease ").Think that NS3 protease (is located at the end C- of NS3 in the site in the position the NS3 downstream relative to polyprotein
Site between the end C- of polyprotein) at mediate all subsequent cracking events.NS3 protease cracks position in NS3-NS4
Point shows Cis activity, and on the contrary, shows in the remaining site NS4A-NS4B, NS4B-NS5A and NS5A-NS5B
Trans- activity.NS4A albumen is thought to provide multiple functions, serves as the co-factor of NS3 protease, and may promote NS3 and its
The film of his viral replicase components positions.It is apparent that the complex formation between NS3 and NS4A may be the processing that NS3- is mediated
Necessary to event, and improve the proteolytic efficiency in all sites of NS3 identification.NS3 protease may also show
Nucleoside-triphosphatase and RNA helicase activity out.Think that NS5B is the RNA- Dependent RNA polymerization for participating in HCV rna replicon
Enzyme.In addition, the compound for inhibiting NS5A effect in virus replication may be useful to treatment HCV.
Summary of the invention
The composition and unit dosage forms and be used to prepare institute that the invention discloses a kind of for treating hepatitis c virus infection
The method for stating composition and unit dosage forms, the composition and unit dosage forms include KW136 (N- [(2S) -1- of therapeutically effective amount
[(2S) -2- { 4- [7- (4- { 2- [(2S) -1- [(2S) -2- [(methoxycarbonyl) amino] -3- methylbutyryl] pyrrolidines -2-
Base] -1H- imidazol-4 yl } phenyl) -2H-1,3- benzo two dislikes cyclopentadienyl -4- base] -1H- imidazoles -2- base } pyrrolidin-1-yl] -3- first
Base -1- oxo-butanes -2- base] methyl carbamate dihydrochloride, Formula II) and at least one pharmaceutically acceptable excipient.
Term " therapeutically effective amount " used herein treats the third type liver when Medicine-feeding type II structural compounds alone or in combination
When scorching, it is the content for being enough to mitigate hepatitis patient's infection symptoms which, which is effective,.
Term " prepared product " or " dosage form " are used to the active agent preparations including solid and liquid, and art technology
Personnel recognize that, according to required dosage and pharmacokinetic parameter, active constituent can reside in different prepared products.
What term " unit dosage forms " referred to the reactive compound containing predetermined content is physically separated unit.It is preferred single
Position dosage form is containing daily dose or unit daily dose.
Term " pharmaceutically acceptable " refer to corresponding to those of reasonable benefit/Hazard ratio compound, composition and/or
Dosage form is suitble to contact with the tissue of human and animal in the range of correct medical judgment, without excessive toxicity, thorn
Sharp, allergic reaction or other problem complications.
Term " pharmaceutically acceptable excipient " refers to being used to prepare pharmaceutical composition and usually safe and nontoxic
And on biology or other aspects do not have undesirable compound.
KW136 can be crystal form or unbodied, and the method for prepare compound KW136 is in Chinese patent
It is disclosed in CN102791687B, is referred to this text herein.KW136 is a kind of NS5A inhibition for anti-hepatitis C virus
Agent, referred to herein as formula (II) compound, therefore the present invention provides a kind of formula (II) structure comprising therapeutically effective amount
Compound and at least one pharmaceutically acceptable excipient composition, wherein formula (II) compound is a kind of
Crystal type object, referred to herein as crystal form H.
There is greatly difficulty in the crystal form of acquisition formula (II) compound, invention technician is in the compound to formula (II)
When carrying out crystal form screening, is attempted by using a large amount of solvent and its solvent combination and different method for crystallising, all may be used
To obtain formula (II) compound of amorphous forms, but fail to obtain effective crystallization.
Unexpectedly, invention technician is heated to reflux to the methanol solution dissolved with formula (II) compound
When, discovery has a large amount of solid to be precipitated in reflux course, and this solid is separated, and refines, has obtained formula
(II) crystal form of compound, i.e. crystal form H.
Therefore in one aspect of the invention, the method for the crystal form H of preparation formula II compound a kind of, the method packet are provided
It includes, by the substantially pure compound (referred to herein as compound (I)) with formula (I) structure,
Solvent is added to make it dissolve, filters, knot is precipitated in filtrate added drop-wise hydrochloric acid or hydrochloric coordinative solvent, temperature rising reflux
Crystalline substance, it is cooling, it filters, washing is dry that crystal form H, the solvent are preferably methanol, ethyl alcohol, isopropanol, ethyl acetate or dimethyl
Acetamide.
Specifically, the method for preparing formula (II) compound crystal form of the present invention, can be：Take the pure chemical combination with structure I
Object, the methanol that 2~4 times of amounts (g/g) are added make it dissolve, and filter, and filtrate drop is slowly plus hydrochloric acid or methanol hydrochloride solution, stirring are equal
It is even, it is warming up to 60-65 DEG C, crystallization is precipitated in return stirring, and reaction solution Temperature fall continues that crystallization, filtering, filter cake second is precipitated
Acetoacetic ester mashing, is filtered, filtration cakes torrefaction obtains crystal form H.
The crystal form H of formula (II) compound of the present invention, is capable of providing lower hygroscopicity, and in terms of Control of Impurities it is excellent
Performance.
Compound (II).
The crystal form H of various characterized by techniques formula (II) compounds can be used, the example of characterizing method includes but is not limited to single
Brilliant X-ray diffraction, powder x-ray diffraction, simulation powder X-ray diffraction pattern, differential scanning calorimetry hair, solid-state13C-NMR, Raman light
Spectrum, infrared spectroscopy, moisture sorption isotherm, thermogravimetry and thermal station technology.
A kind of method characterizing crystal structure is powder x-ray diffraction analysis, wherein Diffraction fringe distribution figure and pure powder will be represented
The simulation drawing of powder material compares, and both carries out at a temperature of same analysis, and by the measurement of target crystal form with a series of 2 θ
Value characterization.
Formula (II) compound crystal form H of the present invention, following characteristic peak that the crystal form powder x-ray diffraction includes (±
0.2 degree)：8.527,9.650,13.942,15.498,19.305,22.337,23.115,24.452,24.952 and 31.354
At 2 θ values.
Further, the crystal form H of formula (II) compound of the present invention, have substantially with X-ray diffraction powder described in Fig. 1
The identical absorption map in end.
Further, the crystal form H of formula (II) compound of the present invention, starts to absorb heat within the scope of 232-279 DEG C
The molten mass of decomposition (shown in Fig. 2).
In the present invention, formula (II) compound of H crystal form, crystal form H content has at least purity of 95 weight %, preferably
With at least purity of 96 weight %, more preferably for at least purity of 97 weight %, or even there are at least 98 weight %
Purity, more preferably there is at least purity of 99 weight %, such as purity of 99.5 weight %.
In the present invention, the composition for treating HCV includes the KW136 of weight percentage about 1%-50%, it is preferable that
The composition includes the KW136 that weight percentage is about 5%-50%, it is further preferable that including 15%-30%'s
KW136, such as the composition include about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%,
25%, 26%, 27%, 28%, 29% or 30% KW136, the KW136 are crystal form H.
In the present invention, the pharmaceutically acceptable excipient includes：Filler, disintegrating agent, lubricant and help stream
At least one of agent.
In one embodiment, filler is selected from sucrose, lactose, microcrystalline cellulose, mannitol, dextrin, pregelatinated and forms sediment
Powder, PVP, cross-linked pvp,Soludexl5 orAny one or more；Disintegrating agent
Selected from croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, povidone, pre-gelatinized starch or
Any one or more in sodium starch glycollate；Lubricant is selected from calcium stearate, magnesium stearate, polyethylene glycol, stearic richness
Any one or more of horse acid sodium, stearic acid or talcum powder；Glidant is selected from silica, talcum powder, starch or starch derivatives
Any one or more in biology.
In a specific embodiment, pharmaceutical composition of the present invention includes：(1) formula of 15%-30% (w/w)
(II) compound of structure；(2) filler of 60%-70% (w/w)；(3) disintegrating agent of 1%-5% (w/w)；(4) 1%-5%
(w/w) lubricant, and the glidant of (5) 1%-5% (w/w).The composition includes (1) 20%- in the preferred scheme
The compound of 30% formula (II) structure；(2) filler of 60%-70% (w/w)；(3) disintegrating agent of 1%-5% (w/w)；
(4) lubricant of 1%-5% (w/w), and the glidant of (5) 1%-5% (w/w).In a more preferably embodiment,
The compound of (1) 24% formula (II) structure；The filler of (2) 67.5% (w/w)；The disintegrating agent of (3) 3% (w/w)；(4)
The lubricant of 1.5% (w/w), and the glidant of (5) 4% (w/w).The composition includes：Wherein, the change of the Formula II structure
Conjunction object is crystal form H.
In another specific embodiment, the present invention provides the unit doses comprising compound K W136 of the present invention
Type, the unit dosage forms include：
(1) compound of formula (II) structure of about 10-80mg, such as 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg
Or 80mg；With
(2) at least one pharmaceutically acceptable excipient；
Wherein the compound of the Formula II structure is crystal form H.
In a preferred embodiment, the unit dosage forms, including：：(1) compound of the Formula II structure of 60mg；(2)
168.75mg(3) crospovidone of 7.5mg；(4) magnesium stearate of 3.75mg；(5) dioxy of 10mg
SiClx；
Wherein the compound of Formula II structure is crystal form H.
As the concrete mode of unit dosage forms of the present invention, such as it can be capsule, tablet, granule, dispersing agent and take orally
Dosage form, preferably capsule.
In another of the invention specific embodiment, it is related to a kind of preparing the list of the present invention comprising formula (II) compound
The method of position dosage form (capsule), the method includes：(1) the first particle and the second particle are mixed, to obtain mixed group
Close object；(2) by the filling capsule of mixed composition；
Wherein, in the particle composition include the compound of formula (II) of recipe quantity, recipe quantity filler, recipe quantity
Glidant, and the lubricant of about recipe quantity about 1/3 is uniformly mixed, the first particle of pelletizing to obtain；Second particle is prescription
Measure remaining lubricant.
The invention further relates to the compositions comprising formula (II) described compound for the use in hepatitis c virus infection drug
On the way, the composition can be used as individual unit dosage forms treatment hepatitis C patients, can also be with the anti-hepatitis disease of other units
Malicious unit dosage form combination is such as used with sofosbuvir or ribavirin combination using to treat hepatitis patient.
On the other hand, the present invention relates to a kind of product or medicine boxs, include container and package insert, wherein the container transfer
The compound for the Formula II structure of the present invention with crystal form of swinging, or the Formula II structural compounds comprising crystal form
Composition, the package insert are loaded with the operation instructions of drug.In a preferred embodiment, the product or medicine box
One or more containers are further included, other the resisting in the container equipped with one or more preventions or treatment HCV virus infection
Virus drugs.In a preferred embodiment, the other medicines are NS3 serpin, NS5A polymerization
The suppression of enzyme inhibitor, NS5B polymerase inhibitors, ucleosides anti-virus formulation, interferon, thymosin extrasin, more preferably NS5B polymerase
Preparation, most preferably sofosbuvir, such as sofosbuvir unit formulation or Ribavirin unit formulation.
Detailed description of the invention
Fig. 1 is formula (II) compound crystal form H powder x-ray diffraction map.
Fig. 2 is formula (II) compound DSC map.
Specific embodiment
1 compound N of embodiment-[(2S) -1- [(2S) -2- { 4- [7- (4- { 2- [(2S) -1- [(2S) -2- [(methoxyl group carbonyl
Base) amino] -3- methylbutyryl] pyrrolidin-2-yl] -1H- imidazol-4 yl } phenyl) -2H-1,3- benzo two dislikes cyclopentadienyl -4-
Base]-1H- imidazoles-2- base } pyrrolidin-1-yl]-3- methyl-1-oxo-butanes-2- base] methyl carbamate (according to
Method disclosed in CN102791687B is prepared) preparation of dihydrochloride
At room temperature, to sequentially adding the sterling (800g, 1.0eq) of structural formula I and the solution of ethyl acetate (8L) in 20L bottles
Stirring.The HCl/ ethyl acetate solution (839g) of dropwise addition concentration about 11.2% into system, 15 DEG C~25 DEG C of control system temperature,
It is more than hour to stir 3, stops reaction, filters, filter cake is washed with ethyl acetate (2L), baking material at 40~60 DEG C of filter cake temperature control,
For sample detection until ethyl acetate remains < 0.5%, (about baking material 73 hours or so) obtain the compound of structure formula (II), class is white
Color solid powder or particle, 774g, HPLC purity：98.65%, yield：88.5%, test XRPD is unformed.
Embodiment 2 carries out crystal form screening with different method for crystallising to formula (II) compound
1, slowly volatilization crystallization
Respectively weighing about 10mg has the sterling of formula II into 3mL vial, is separately added under about 0.5-1.25mL
State solvent, it is ensured that sample is completely dissolved to obtain clear solution, and acquired solution is slowly volatilized at room temperature, after solvent volatilization
The solid test XRPD arrived, the results are shown in Table 1, and obtained solid is unformed in the crystallization experiment that volatilizees, and not obtain new other
Crystal form.
| Test serial number | Solvent for use | Temperature | Obtain solid |
| 805301-14-A1 | H2O | RT | It is amorphous |
| 805301-14-A2 | MeoH | RT | It is amorphous |
| 805301-14-A3 | EtOH | RT | It is amorphous |
| 805301-14-A4 | IPA | RT | N/A* |
| 805301-14-A5 | Acetic acid | RT | It is amorphous |
| 805301-14-A6 | DMSO | RT | It is amorphous |
| 805301-14-A7 | DMAc | RT | It is amorphous |
| 805301-14-A8 | NMP | RT | It is amorphous |
| 805301-14-A9 | ACN/H2O 1/1 | RT | It is amorphous |
| 805301-14-A10 | Acetone/H2O 1/1 | RT | It is amorphous |
| 805301-14-A11 | THF/MeOH 1/1 | RT | It is amorphous |
| 805301-14-A12 | EtOAc/MeOH 1/1 | RT | It is amorphous |
| 805301-14-A13 | MTBE/Acetic acid 1/1 | RT | It is amorphous |
| 805301-14-A14 | Heptane/Acetic acid 1/1 | RT | It is amorphous |
| 805301-14-A15 | 1’4-Dioxane/DMAc 1/1 | RT | It is amorphous |
| 805301-14-A16 | Toluene/DMAc 1/1 | RT | It is amorphous |
N/A*：No solid is precipitated
2, suspension stirring test
The sterling of about 10mg structure formula (II) is weighed into 1.5mL vial, is separately added into 0.5mL following solvents, room temperature
(RT) and under the conditions of 50 DEG C it stirs one day, be centrifugated solid and test XRPD, have found 3 kinds of crystalline substances in suspension stirring test altogether
Type names crystal form A, crystal form B, crystal form C respectively.
| Test serial number | Solvent for use | Temperature | Obtain solid |
| 805301-12-A11 | DCM | RT | It is amorphous |
| 805301-12-A13 | Anisole | RT | It is amorphous |
| 805301-12-A15 | CAN/H2O 19/1 | RT | It is amorphous |
| 805301-12-A16 | Acetone/H2O 19/1 | RT | It is amorphous |
| 805301-12-A17 | THF/Acetic acid 19/1 | RT | It is amorphous |
| 805301-12-A18 | Toluene/Acetic acid 19/1 | RT | It is amorphous |
| 805301-12-A19 | EtOAc/DMSO 19/1 | RT | It is amorphous |
| 805301-12-A20 | Heptane/EtOH 19/1 | RT | It is amorphous |
| 805301-29-B4 | IPA/IPE 2/1 | RT-50℃ | It is amorphous |
| 805301-13-A1 | ACN | 50℃ | It is amorphous |
| 805301-13-A2 | Acetone | 50℃ | It is amorphous |
| 805301-13-A3 | THF | 50℃ | It is amorphous |
| 805301-13-A4 | EtOAc | 50℃ | It is amorphous |
| 805301-13-A8 | 1’4-Dioxane | 50℃ | It is amorphous |
| 805301-13-A11 | DCM | 50℃ | It is amorphous |
| 805301-13-A15 | CAN/H2O 19/1 | 50℃ | It is amorphous |
| 805301-13-A16 | Acetone/H2O 19/1 | 50℃ | It is amorphous |
| 805301-13-A17 | THF/Acetic acid 19/1 | 50℃ | It is amorphous |
| 805301-13-A18 | Toluene/Acetic acid 19/1 | 50℃ | It is amorphous |
| 805301-13-A19 | EtOAc/DMSO 19/1 | 50℃ | It is amorphous |
| 805301-13-A20 | Heptane/EtOH 19/1 | 50℃ | It is amorphous |
| 805301-27-A3 | IPA/MTBE 2/1 | 50℃ | It is amorphous |
| 805301-27-A4 | IPA/IPE 2/1 | 50℃ | It is amorphous |
| 805301-27-A5 | IPA/IPE 1/1 | 50℃ | It is amorphous |
| 805301-27-A6 | IPA/IPE 2/1 | 50℃ | It is amorphous |
RT-50℃*：The clarification of change in 1 day is stirred at room temperature, and continues to stir 1 day at 50 DEG C and obtain
3, slow cooling is tested
The sterling of about 15mg structure formula (II) is weighed into 1.5mL vial, the following dissolutions of 0.5mL are separately added into, 50
DEG C balance cool down 3 days to 5 DEG C after 30 minutes, then slowly volatilizees obtain solid at room temperature, and tests XRPD, does not find in experiment
New crystal form is unformed product.
| Test serial number | Solvent for use | Temperature | Obtain solid |
| 805301-16-A1 | DCM | 50℃-5℃ | It is amorphous |
| 805301-16-A2 | Cyclohexanol/MeOH 10/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A3 | CAN/H2O 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A4 | Acetone/H2O 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A5 | IPAc/DMSO 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A6 | 2-MeTHF/DMSO 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A7 | THF/Acetic acid 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A8 | Toluene/Acetic acid 9/1 | 50℃-5℃ | N/A* |
| 805301-16-A9 | 1’4-Dioxane/MeOH 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A10 | MIBK/MeOH 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A11 | EtOAc/DMSO 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A12 | Heptane/EtOH 9/1 | 50℃-5℃ | It is amorphous |
| 805301-16-A13 | MeOH | R50℃-5℃ | It is amorphous |
N/A*：No solid is precipitated
4, humidity Induction experiments
The sterling of about 15mg structure formula (II) is weighed into 3mL vial, being placed in constant humidity, (humidity is set separately
32%, 57%, 75%, 97%) in container, room temperature storage 6 days, obtained solid tested XRPD, does not find new crystal form, obtains
It is unformed solid.
| Test serial number | Damp condition | Storage time | Obtain solid |
| 805301-15-A1 | 32.8%RH | 6 days | It is amorphous |
| 805301-15-A2 | 57.6%RH | 6 days | It is amorphous |
| 805301-15-A3 | 75.3%RH | 6 days | It is amorphous |
| 805301-15-A4 | 97.3%RH | 6 days | It is amorphous |
5, anti-solvent adds crystallization experiment
The sterling of about 15mg structure formula (II) is weighed into 3mL vial, is separately added into 0.2mL positive solvent as follows：Methanol,
Ethyl alcohol, isopropanol make the complete solvent of solid, then following anti-solvent 0.2-2ML are accordingly added dropwise respectively：Acetone, acetone, acetic acid second
Ester, if there is Precipitation, precipitation and separation simultaneously tests XRPD, if precipitating is not precipitated, quickly volatilization at room temperature, and experiment
Middle gained is unformed solid, does not find new crystal form.
N/A*：No solid is precipitated
6, positive anti-solvent addition experiment
The sterling of 15mg structure formula (II) is weighed into 3mL vial, is separately added into 0.2mL positive solvent as follows,
It is completely dissolved solid, the above clear solution is added dropwise to and is pre-placed in 1-2 hours anti-solvents of 5 DEG C of refrigerators, if there is heavy
Precipitation goes out, and by precipitation and separation and tests XRPD, if not there is Precipitation, quickly volatilizees at room temperature, in experiment not
To crystal form.
| Test serial number | Positive solvent | Anti-solvent | Obtain solid |
| 805301-18-A1 | H2O | Acetone | It is amorphous |
| 805301-18-A2 | NMP | EtOAc | It is amorphous |
| 805301-18-A3 | MeOH | EtOAc | It is amorphous |
| 805301-18-A4 | EtOH | Heptane | It is amorphous |
| 805301-18-A5 | IPA | Heptane | It is amorphous |
| 805301-18-A6 | Acetic acid | ACN | It is amorphous |
| 805301-18-A7 | DMSO | ACN | It is amorphous |
| 805301-18-A8 | DMAc | Acetone | It is amorphous |
| 805301-28-B1 | IPA | MTBE | It is amorphous |
| 805301-28-B2 | IPA | IPE | It is amorphous |
7, slow cooling single crystal cultivation is tested
The sterling of 5mg structure formula (II) is weighed into 3mL vial, is separately added into 0.5-1.25mL different solvents, it is ensured that
Sample, which is completely dissolved to obtain clear solution, to be filled into 4mL vial, and resulting solution cools down 3 days after balancing 30 minutes at 50 DEG C
5 DEG C are down to, what no solid was precipitated is slowly volatilizing at room temperature, the experimental results showed that：MeOH/THF(1:5),MeOH/
IPAc(1:5),EtOH/THF(1：5),MeOH/Tolene(1:5),Etoh/Tolueen(1:5),IPA/Toluene(1:2),
IPA/Heptane(1:2),IPA/IPAc(1:2),IPA/DCM(1:2),EtOH/Heptane(1：8 or 1:9) it is not obtained in
Crystalline solid.
3 formula of embodiment (II) compound crystal form H preparation
(1) into 100mL there-necked flask, the sterling of about 7g structural formula I is added, 16.8g methanol filters, mistake after stirring dissolved clarification
Filtrate is transferred in 100mL there-necked flask after the completion of filter, and nitrogen is replaced 3 times, and (the control time about 10 minutes or so) is then slowly added dropwise
2.8g methanol hydrochloride solution (methanol hydrochloride solution concentration is 32%-38%) is added dropwise, without controlling temperature, dripping rear solution is
Clear solution.
(2) after methanol hydrochloride solution is added dropwise, solution temperature is risen into 60-65 DEG C of reflux, return time is about the left side 2h
The right side has in solution a large amount of white solids to be precipitated.
(3) solution being precipitated with white solid after reflux is closed into heating, ethyl acetate is slowly added dropwise, is added dropwise
Afterwards, first Temperature fall stirring, until being cooled to 10 ± 5 DEG C, stir about 20min, filtering, filter cake is transferred to 100mL tri- after room temperature
In mouth bottle, 20 ± 5 DEG C of stirring to pulp about 30min of ethyl acetate (about 24.5g) are repeated to be beaten once, are filtered, obtain white solid.
Or step (3) may be：The solution being precipitated with white solid after reflux is closed into heating, is naturally cooling to
Solution temperature is 10-20 DEG C, and filtering, filter cake twice (about 24.5g every time), obtains white solid with ethyl acetate foam washing.
(4) white solid 35 ± 5 DEG C of temperature, vacuum degree be≤- 0.080MPa under be dried under reduced pressure for 24 hours, obtain white or class
White powder solid, as crystal form H.
According to different disposal condition, the yield spectra of final crystal form H is about in 65.0%%-85.0%.
4 capsule prescription of embodiment and preparation process
1 KW-136 composition of table and proportion
Using dry granulation process, 1.5 ten thousand (specifications are produced in batches：60mg, raw material are crystal form H) and 0.3 ten thousand (rule
Lattice：10mg, raw material are crystal form H), 0.3 ten thousand (specifications：60mg, raw material are unformed powder) operating procedure mainly includes：It is former auxiliary
Material burden process (sieving claims to match), premix process, granulation process, total mix process, capsule filling work procedure, inner packing process.
Supplementary material burden process
Bulk pharmaceutical chemicals need to feed intake according to content is pure, claim to match after crossing 40 meshes；
Silica, magnesium stearate cross 60 meshes, claim to match, be individually placed in polybag, spare；
Crospovidone, Ludipress are claimed to match by recipe quantity, are individually placed in polybag, spare；
It is stored in polybag after magnesium stearate (additional, unit formulation additional amount is 2mg) sieving, good particle to be prepared
Afterwards, claim to match again after converting additional dosage by particle yield.
Premix process
Successively by Ludipress (half), silica, crospovidone, bulk pharmaceutical chemicals (remaining Ludipress rinses bag) and
Magnesium stearate (interior to add, unit formulation additional amount is 1.5mg) and microcrystalline cellulose PH102 are added in single column mixing machine feed bin,
Setting speed is 12rpm, mixes 10min.
Granulation process
Dry granulating machine hopper is added in mixed material, confirms level-one sieve 5.0mm, second level sieve 0.8mm, setting
Feeding frequency range is 6~10Hz, and tabletting frequency range is 14~20Hz, and granulation frequency range is 8~12Hz, is pelletized.
Check that particle size distribution will sieve if 60 mesh oversizes sieve 60 meshes of particle obtained less than 50% with 60 meshes
Lower fine powder carries out secondary granulation, and grain made parameter is the same.
Total mix process
The particle made is added in single column mixing machine feed bin, adds magnesium stearate (additional), setting speed is
12rpm mixes 5min.
Capsule filling work procedure
Calculate capsule loading according to granule content after total mix, if the average content of total mix particle 97.0%~
103.0%, it is filled according to theoretical loading amount.10mg specification capsule is loaded by hand using 3# capsule；60mg specification uses 1# capsule glue
The filling of capsule filling machine.
Inner packing process
With polyvinyl chloride (PVC) solids+Key works Drug packing aluminium foil, housing polyester/aluminium/polyethylene Medicinal composite film bag packet
Dress, every plate 10 are sealed.
The stability test of 5 crystal form of embodiment and amorphous powder capsule preparations is studied
Standard stability trials：High temperature (60 DEG C), high humidity (92.5% ± 5%), illumination (4500 ± 500) are investigated respectively
Lx detected at the 5th day, the 10th day and the 30th day respectively, the results are shown in Table 2.
Accelerated test：Investigation condition is 40 DEG C ± 2 DEG C of temperature, and relative humidity RH75% ± 5% time 6 months, is as a result shown in
Table 3.
Long term test：Investigation condition is 25 DEG C ± 2 DEG C of temperature, relative humidity RH60% ± 10%, the time 12 months, as a result
It is shown in Table 4.
Testing index：Detect the capsule preparations shape of crystal form H and unformed powder, moisture, related substance (including impurity A,
Impurity B, impurity C and total miscellaneous) and content.
Standard stability trials are the result shows that (table 2)：Under high temperature, high humidity and strong illumination, character and 0 day data result
Compare, crystal form H and unformed is showed no significant change.And for impurity A, crystal form H also base under high temperature, high humidity and strong illumination
This stabilization has no the raising of Impurity A content after 30 days, it is total it is miscellaneous also have no raising, it is amorphous in high temperature, high humidity and strong illumination
Under, impurity A shows a increasing trend, and especially at 60 DEG C of high temperature in Related substances separation, impurity A has that growth trend is obvious, from
The 0.8% of 0th day was increased by 3.15% by the 30th day, reaches 4 times of initial amount, and total miscellaneous content is in high temperature, high humidity and strong light
It also all shows a increasing trend under irradiation.In terms of hygroscopicity, crystal form H to be also substantially better than it is amorphous, especially under conditions of high humidity,
Unbodied hygroscopicity becomes apparent.
Long term test and accelerated test result also indicate that (table 3, table 4), and crystal form H is capsule made of raw material, effectively at
Point content has no significant change substantially, and impurity A also all maintains a maintenance level, using amorphous powder as glue made of raw material
Capsule, impurity A have the tendency that obviously rising, and correspondingly, KW136 content is on a declining curve.
2 standard stability experimental result of table
ND expression is not detected.
3 Acceleration study stability result of table
ND：It is not detected, refers to less than integral threshold.
4 long term test data stability result of table
ND：It is not detected, refers to less than integral threshold.
Claims (14)
1. a kind of pharmaceutical composition, it includes：
(1) compound with Formula II structure of about 15%-30% (w/w), and
(2) at least one pharmaceutically acceptable excipient,
Wherein the compound of the Formula II structure is crystal form H；The compound preferably from about 5%-25% (w/w) of the Formula II structure.
2. composition according to claim 1, wherein the crystal form powder x-ray diffraction packet of the Formula II structural compounds
The following characteristic peak (± 0.2 degree) contained：8.527,9.650,13.942,15.498,19.305,22.337,23.115,
24.452, at 24.952 and 31.354 2 θ values.
3. composition according to claim 3, wherein the Formula II structural compounds its penetrated with powder X-ray-shown in FIG. 1
Ray diffraction diagram spectrum.
4. composition according to claim 1, wherein at least one materia medica be subjected to excipient include filler,
At least one of disintegrating agent, glidant and lubricant.
5. composition according to claim 1, the composition include：
(1) compound of the Formula II structure of 15%-30% (w/w), preferably 20%-30%；
(2) filler of 60%-70% (w/w)；
(3) disintegrating agent of 1%-5% (w/w)；
(4) lubricant of 1%-5% (w/w)；With
(5) glidant of 1%-5% (w/w)；
Wherein the compound of the Formula II structure is crystal form H.
6. composition according to claim 4 or 5, wherein filler choosing selected from sucrose, lactose, microcrystalline cellulose,
Mannitol, dextrin, pregelatinized starch, PVP, cross-linked pvp,Di-Soludexl5 orAppoint
It anticipates one or more, preferablyThe disintegrating agent is selected from croscarmellose sodium, crospovidone, crystallite
Any one or more in cellulose, modified corn starch, povidone, pre-gelatinized starch or sodium starch glycollate, preferably
For crospovidone；The glidant in colloidal silicon dioxide, talcum powder, starch or starch derivatives any one or
It is a variety of, preferably silica；The lubricant is selected from calcium stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate, hard
Any one or more of resin acid or talcum powder, preferably magnesium stearate.
7. composition according to claim 6, the composition include：
The compound of the Formula II structure of (1) 24% (w/w)；
(2) 67.5% (w/w's)
The crospovidone of (3) 3% (w/w)；
The magnesium stearate of (4) 1.5% (w/w)；With
The silica of (5) 4% (w/w)；
Wherein the compound of the Formula II structure is crystal form H.
8. a kind of unit dosage forms, it includes：
(1) compound of the Formula II structure of about 10-80mg, such as 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg or
80mg；With
(2) at least one pharmaceutically acceptable excipient；
Wherein the compound of the Formula II structure is crystal form H.
9. unit dosage forms according to claim 8, it includes：
(1) compound of the Formula II structure of 60mg；
(2) 168.75mg
(3) crospovidone of 7.5mg；
(4) magnesium stearate of 3.75mg；With
(5) silica of 10mg；
Wherein the compound of Formula II structure is crystal form H.
10. unit dosage forms according to claim 8 are capsule or tablet.
11. a kind of method being used to prepare comprising 10-80mg Formula II compound capsule formulation comprising：
First particle and the second particle are mixed, to obtain mixed composition；
By the filling capsule of mixed composition；
Wherein, composition includes that the compound of Formula II of recipe quantity, the filler of recipe quantity, recipe quantity help stream in the particle
Agent, and the lubricant of about recipe quantity about 1/3 are uniformly mixed, the first particle of pelletizing to obtain；Second particle is that recipe quantity is remaining
Lubricant.
12. composition described in claim 1 is for the purposes in hepatitis c virus infection drug.
13. a kind of product or medicine box include container and package insert, wherein equipped with any in claim 1-7 in the container
Unit dosage forms described in composition described in one claim or claim 8-10, the package insert are loaded with making for drug
Use specification.
14. product described in claim 13 or medicine box further include one or more containers, in the container equipped with a kind of or
The other medicines of a variety of preventions or treatment HCV infection, the other medicines are preferably NS3 serpin, NS5A
Polymerase inhibitors, NS5B polymerase inhibitors, ucleosides anti-virus formulation, interferon, thymosin extrasin, more preferably NS5B polymerization
Enzyme inhibitor, most preferably sofosbuvir or Ribavirin, such as sofosbuvir unit formulation or Ribavirin unit formulation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020117966A1 (en) * | 2018-12-05 | 2020-06-11 | Atea Pharmaceuticals, Inc. | Highly active drug combination for treatment of hepatitis c virus |
| CN113480512A (en) * | 2021-07-23 | 2021-10-08 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
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|---|---|---|---|---|
| CN102791687A (en) * | 2009-12-18 | 2012-11-21 | 英特穆恩公司 | Novel inhibitors of hepatitis C virus replication |
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2018
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102791687A (en) * | 2009-12-18 | 2012-11-21 | 英特穆恩公司 | Novel inhibitors of hepatitis C virus replication |
| CN104341401A (en) * | 2009-12-18 | 2015-02-11 | 北京凯因科技股份有限公司 | Novel inhibitors of hepatitis c virus replication |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020117966A1 (en) * | 2018-12-05 | 2020-06-11 | Atea Pharmaceuticals, Inc. | Highly active drug combination for treatment of hepatitis c virus |
| CN113164505A (en) * | 2018-12-05 | 2021-07-23 | 阿堤亚制药公司 | High activity pharmaceutical combination for treating hepatitis C virus |
| CN113480512A (en) * | 2021-07-23 | 2021-10-08 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
| CN113480512B (en) * | 2021-07-23 | 2022-07-29 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
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