CN109568328A - It is a kind of for preventing and treating the pharmaceutical composition of HIV infection - Google Patents

Abstract

It ends the present invention relates to a kind of tenofovir and draws the pharmaceutical composition of phenol amine (tenofovir alafenamide) and cabotegravir (CAB), with collaboration HIV-resistant activity, it can be used for preventing and treating HIV infection, composition has the advantages of inhibiting HIV effect strong, being not likely to produce drug resistance.

Description

It is a kind of for preventing and treating the pharmaceutical composition of HIV infection

Technical field

It ends the present invention relates to a kind of tenofovir and draws phenol amine (tenofovir alafenamide) and cabotegravir The pharmaceutical composition and the composition of (CAB, GSK744, GSK1265744), which are used to prepare, prevents and treats HIV infection Purposes in drug, belongs to pharmaceutical technology field.

Background technique

Human immunodeficiency virus (Human Immunodeficiency Virus, HIV) is a kind of retrovirus, can To cause acquired immunodeficiency syndrome (Acquired Immune Deficiency Syndrome, AIDS) also known as AIDS Disease.Since discovery Patient With Aids patient in 1981, the mankind, which pass through, was up to difficult exploration in 36 years, and functionality may be implemented at present It cures, but there is the risk of recurrence.Inhibition of HIV has high variability and infectiousness, and it is resistance to be easy to produce acquisition over the course for the treatment of Pharmacological property (acquired drug resistance), acquired resistance Strain can be broadcast to non-antiretroviral therapy Patient, so as to cause HIV spread drug resistance (transmitted drug resistance).HIV obtains drug resistance and propagates resistance to The main reason for medicine is the decline or failure for leading to antiretroviral treatment (HAART) curative effect, seriously limits and uses for the first time The therapeutic choice of medicine patient.Propagation of the drug resistance HIV in crowd has become public health problem very serious, in part Area, does not receive HIV medicament-resistant mutation detected in the HIV infection person for the treatment of, and most (84.8%) has derived from other By the HIV infection person for the treatment of.

Highly effective antiretroviral therapy (highly active anti-retroviral therapy, HAART) is A kind of new methods show synergistic effect in terms of inhibiting HIV duplication, can be obviously improved the prognosis (Ann of HIV infection person Intern Med. 2001;135:17-26).Clinical most common antiretroviral drugs are more than 25 kinds at present, according to work With the difference of mechanism, antiretroviral drugs can be divided into reverse transcriptase inhibitor, hiv protease inhibitor, integrase and inhibit Agent, fusion inhibitor etc.；However, inhibition of HIV is to nucleotide reverse transcriptase inhibitors (NtTRIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitor (NNRTIs), protease inhibitors even modern fusion inhibitor it is resistance to Medicine is an important factor for influencing HAART final result.Therapeutic scheme not enough optimizes or the reasons such as patient compliance is poor are easy to cause Acquired resistance (acquired drug resistance), acquired resistance Strain can be broadcast to the trouble for not receiving HAART Person, so as to cause HIV spread drug resistance (transmitted drug resistance), HIV spread drug resistance can lead to HAART treatment The decline or failure of effect seriously limit therapeutic choice (the J Infect Dis. 2015 of medication patient for the first time; 212: 5- 7).Clinically, the mode for improving active medicine blood plasma level is often taken for the treatment of drug resistance patient, makes antiretroviral Drug reaches the effective concentration of the different inhibition of HIV of resistance, as a result causes dose burden bigger, the not compliance of prescribed treatment and secondary work With further increasing.Therefore, for the first-line treatment of HIV, need to design that a kind of dose load is lower, and curative effect is better, Toxicity is lower and the more simplified therapeutic combination of dosage regimen, and the composition is to wild type HIV virus and more and more common Drug-resistant HIV has remarkable result, can inhibit the reproduction of drug-resistant virus, and can be permanently effective.

Tenofovir (tenofovir) is a kind of novel nucleoside acids reverse transcriptase inhibitor, dipivoxil fumaric acid Salt (TDF) is the first-line treatment drug of AIDS, can effectively inhibit the duplication and transfection of retrovirus, but still be will appear resistance to Medicine problem is published in " Lancet Infectious Diseases " according in Mays, 2016 such as The TenoRes Study Group The result of study of page 572 is shown, in South Africa, TDF joint efavirenz and cytimidine treat 1 year resistant rate be about 7.5 ~ 17.5%.It is another prodrug of tenofovir that tenofovir Chinese mugwort, which draws phenol amine, and in clinical test, which has been found be lower than When ten/dose of TDF, just there is extraordinary antiviral effect, while renal function and bone parameters can be significantly improved.Often It give half fumaric acid tenofovir of single dose (about 5mg) Chinese mugwort draw phenol amine (tenofovir Chinese mugwort draw phenol amine a kind of acceptable salt, Abbreviation TAF) HIV can be significantly inhibited, greatly reduce administration frequency.In terms of clinical resistance, some document emphasis ratios The drug resistance sex differernce for relatively having studied TDF and TAF is published in " Antimicrobial Agents according to Nicolas etc. in October, 2015 And Chemotherapy " data are shown in the 5921st page table 2, the EC of TAF and TDF in each drug resistance site₅₀The basic phase of FC value Together, thus it is speculated that TAF and TDF has comparable drug resistance.With the passage of clinical use time, the drug resistance of TAF will become one Unavoidable problem.

Cabotegravir(CAB, GSK744, GSK1265744) it is a kind of integrase inhibitor, it can take orally, it can also With muscle or subcutaneous injection.The CAB that oral dose is 30mg daily, can effectively inhibit HIV.

Tenofovir Chinese mugwort draws phenol amine Cabotegravir

It is anti-can to obtain significant collaboration the study found that by drawing phenol amine and CAB to be applied in combination tenofovir Chinese mugwort by the present inventor HIV effect can play good AntiHIV1 RT activity effect at lower levels, and virus, limitation drug resistance HIV can be inhibited to longer-term to become Allogeneic appearance, and there is lower toxic side effect.

Summary of the invention

An object of the present invention is to provide a kind of end comprising tenofovir and draws the pharmaceutical composition of phenol amine and CAB, the group Close the long-term treatment that object can be used for HIV patient for the first time.

An object of the present invention is to provide a kind of end comprising tenofovir and draws the pharmaceutical composition of phenol amine and CAB, daily It only needs to be administered once and can reach preferable HIV therapy effect.The compound of composition can be administered in the following manner: (1) Each compound in composition is administered simultaneously；(2) each compound in composition is separately administered.

Based on therapeutically effective amount, therapeutically effective amount is meant to be taken in active constituent dosage in product of the present invention every time It is enough to apply the amount of abundant HIV inhibitory effect in time between preparation.

An object of the present invention is to provide a kind of end comprising tenofovir and draws the pharmaceutical composition of phenol amine and CAB, the group Closing object is not only stable in chemistry, and also there is synergistic effect and/or independent active medicine can be reduced or both Side effect.

An object of the present invention be to provide it is a kind of draw phenol amine and CAB pharmaceutical composition comprising tenofovir Chinese mugwort, have with The completely different drug resistance curve of presently commercially available HIV-resistant activity drug more long-term can inhibit virus, and limitation drug resistance HIV becomes Allogeneic appearance.

An object of the present invention is to provide a kind of end comprising tenofovir and draws the pharmaceutical composition of phenol amine and CAB, wherein Each active medicine in combination can be used alone or the unit formulation by co-formulated at composition.The composition unit style Agent is for the administration of oral or other approach, and the unit formulation has good chemical stability.

One of the object of the invention is to provide a kind of end comprising tenofovir and draws the pharmaceutical composition and its system of phenol amine and CAB Agent can be used for wild type HIV virus and drug-resistant HIV is propagated and treatment of infection.

One of the object of the invention is to provide a kind of method for preparing aforementioned composition and preparation, including tenofovir is ended and is drawn Phenol amine and CAB are combined into pharmaceutical composition or are prepared into preparation, to obtain better antiviral effect.

In inverase composition provided by the invention, it further comprises tenofovir that the tenofovir Chinese mugwort, which draws phenol amine, Chinese mugwort draws the pharmaceutically acceptable salt, such as fumarate, hemifumarate, fumarate, sodium salt etc. of phenol amine, and preferably half is rich Horse hydrochlorate, i.e. TAF.

In inverase composition provided by the invention, the CAB further comprises the pharmaceutically acceptable salt of CAB, Such as sodium salt, sylvite etc., particular certain cancers；The CAB further comprises enantiomer, diastereomer, the diastereomer mixing of CAB The mixture and its pharmaceutically acceptable salt of object, mixture of enantiomers and its enantiomer and diastereomer.

Inverase composition product provided by the invention, which can be to end comprising tenofovir, draws the unit of phenol amine and CAB Preparation can also further include one or more other inverase active constituent or therapeutic agent.

Wherein, other inverase active constituents include hiv protease inhibitor, HIV non-nucleotide inhibitor or HIV Reverse transcriptase non-nucleotide inhibitor, HIV nucleotide inhibitor or HIV reverse transcriptase nucleotide inhibitor, hiv integrase inhibit Agent, the non-catalytic position HIV (or allosteric) integrase inhibitor, HIV entry inhibitor (such as CCR5 inhibitor, gp41 inhibitor, CD4 connection inhibitor etc.), CXCR4 inhibitor, gp120 inhibitor, G6PD and NADH oxidation retarder, HIV vaccine, HIV maturation Inhibitor, potential reversing drug (such as histon deacetylase (HDAC) inhibitor, proteasome inhibitor, protein kinase C activation Agent and BRD4 inhibitor), target the drug (capsid inhibitor, such as capsid polymerization inhibitor or destruction capsid of HIV capsid Drug, HIV nucleocapsid protein p7 inhibitor, HIV p24 capsid protein inhibitor), pharmacokinetics promotor, immune correlation is controlled It treats drug (such as Pd-1 regulator, Pd-L1 regulator etc.), CTLA4 regulator, Toll-like receptor adjustment agent, IL-15 adjustment agent, HIV gene, HIV antibody, bispecific antibody, antibody sample treatment albumen (such as DARTs, Duobodies, Bites, XmAbs, TandAbs, Fab derivatives etc.), HIV p17 stromatin inhibitor, IL-13 solves anti-agent, peptidyl-prolyl cis-trans Structure enzyme A regulator, protein disulfide-isomerase, c5a receptors complement antagonist, dnmt rna inhibitor, HIV Vif gene regulation agent, Vif dimer solution anti-agent, HIV-1 viral infective agent inhibitor, TAT protein inhibitor, HIV-1 nef Regulator, hematopoietic cell kinases tyrosine kinase modulators mix serial protein kinase -3(MLK-3) inhibitor, HIV-1 shearing Inhibitor, Rev protein inhibitor, integrin solution anti-agent, nucleoprotein inhibitor, shear factor regulator, COMM structural domain include 1 regulator of albumen, HIV ribonuclease H inhibitor, tetracycline regulator, CDK-9 inhibitor, surface of dendritic cells are special Non- 1 inhibitor of integrin of property, HIV GAG protein inhibitor, HIV POL protein inhibitor, complement factor H regulator, ubiquitin Connect enzyme inhibitor, deoxycytidine kinase enzyme inhibitor, cyclin dependent kinase inhibitor, former convertase PC9 thorn Swash agent, the RNA helicase DDX3X inhibitor that ATP is relied on, reverse transcriptase starts complex inhibitor, P13K inhibitor, Yi Ji The drug mentioned in following patent: WO 2013/006738(Gilid Science Co.), US 2013/0165489(guest sunset method Buddhist nun Sub- university), WO 2013/091096A1(Boehringer Ingelheim company), WO2009/062285(Boehringer Ingelheim company), Industry companies, US20140221380(Japan Tobacco), industry companies, US20140221378(Japan Tobacco), WO2010/130034 (Boehringer Ingelheim company), there are also the drugs of other treatment HIV and their any combination.

Preferably hiv protease inhibitor, HIV non-nucleotide or reverse transcriptase non-nucleotide inhibitor, HIV nucleotide or Reverse transcriptase nucleoside acid inhibitor, hiv integrase inhibitor, the non-catalytic site HIV (or Isoforms) integrase inhibitor, medicine generation Dynamics promotor and their any combination.

Other HIV therapy drugs include: efavirenz+emtricitabine, rilpivirine+emtricitabine, angstrom for lattice Wei+ Cobicistat+emtricitabine, Lamivudine+nevirapine+Zidovudine, sulfuric acid atazanavir+cobicistat, ground are auspicious Na Wei+cobicistat, efavirenz+Lamivudine, Vacc-4x vaccine+romidepsin, APH-0812, Merck+drawing Meter Fu Ding, KALETRA(ALUVIA, Lopinavir+Ritonavir), sulfuric acid atazanavir+Ritonavir, COMBIVIR(is more together Husband determines+Lamivudine, AZT+3TC), EPZICOM(Livexa, sulfuric acid atazanavir+Lamivudine, ABC+3TC), TRIZIVIR(sulfuric acid atazanavir+Zidovudine+Lamivudine, ABC+AZT+3TC), emtricitabine, Lamivudine, A Zhana Wei+cobicistat, doravirine+ Lamivudine.

Above-mentioned hiv protease inhibitor includes anpunave, atazanavir, fosamprenavir, fosamprenavir calcium, indenes ground that Wei, indinavir sulfate, Lopinavir, Ritonavir, Nai Feinawei, nelfinavir mesilate, inverase, methanesulfonic acid sand Kui That Wei, tipranavir, brecanavir, darunavir, DG-17, TMB-657(PPL-100), TMC-310911 and TMB-657；

Above-mentioned HIV non-nucleotide or reverse transcriptase non-nucleotide inhibitor include delavirdine, U-90152S, Nai Weila Flat (+), etravirine, dapivirine, doravirine, rilpivirine, efavirenz, KM023, VM-1500, mushroom are more Sugar, AIC-292；

The screening of above-mentioned HIV nucleotide or reverse transcriptase nucleoside acid inhibitor includes VIDEX and VIDEX EC(Didanosine, Ddl), Zidovudine, emtricitabine, Didanosine, stavudine, zalcitabine, Lamivudine, censavudine, A Baka Wei, abacavir sulfate, amdoxovir, elvucitabine, Aovudine, phosphazid, fozivudine tidoxil, A Pu The shore Rui Xita, amdoxovir, KP-1461, fosalvudine tidoxil, adefovirdipivoxil, Aldoforwe ester, festinavir；

Above-mentioned hiv integrase inhibitor (removing Du Lutewei) includes curcumin, curcumin derivate, Cichoric acid, Cichoric acid derivative Object, 3,5-diCQA, 3,5-diCQA derivative, aurin tricarboxyli acid (ATA), aurin tricarboxyli acid (ATA) derivative, coffee Coffee acid phenenyl ester, Caffeic acid phenethyl ester derivative, tyrphostin, tyrphostin derivative, quercitrin are yellow Ketone, quercetin derivative, Merck and angstrom replace lattice Wei；

The non-catalytic site above-mentioned HIV or allosteric integrin enzyme inhibitor (NCINI) include CX-05168 and CX-1442；

Above-mentioned HIV gp41 inhibitor includes enfuirtide, sifuvirtide and Ai Boweitai；

Above-mentioned HIV entry inhibitor includes cenicriviroc；

Above-mentioned HIV gp120 inhibitor includes Radha-108(Receptol) and BMS-663068；

Above-mentioned CCR5 inhibitor includes aplaviroc, Vicriviroc, maraviro, Cenicriviroc, PRO-140, Adaptavir(RAP-101), nifeviroc (TD-0232), TD-0680, TBR-220(TAK-220) and vMI(Haimipu)；

Above-mentioned CD4 attachment inhibitor includes Ibalizumab；

Above-mentioned CXCR4 inhibitor includes Plerixafor, ALT-1188, vMIP and Haimipu；

Above-mentioned pharmacokinetics promotor includes cobicistat and Ritonavir；

Above-mentioned Immune-dependence drug includes derma Vir, IL-7, lexgenleucel-T(VRX-496), hydroxychloroquine (hydroxychloroquine), Aldesleukin (Aldesleukin, IL-2), alpha interferon, alpha interferon -2b, alpha interferon-n3, polyethylene glycol Alpha interferon, interferon, hydroxycarbamide, mycophenolate (MPA) and its derivative mycophenolate mofetil (MMF), WF-10, triazole core Glycosides, IL-2, IL-2 XL, IL-12, polymer/polyethyleneimine (PEI), Corvic, VGV-1, MOR-22, toll sample Receptor modulators (TLRl, TLR2, TLR3, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, TLR13), BMS-936559, rintatolimod and IR-103；

Above-mentioned HIV gene includes polypeptide vaccine, recombinant subunit protein vaccine, live vector vaccine, DNA vaccination, virus like particle Vaccine (pseudo- viral vaccine), derived from the vaccine of CD4 peptide, recombinant vaccine, rgp120(AIDSVAX), ALVAC HIV (Vcp1521)/AIDSVAXB/E(gp120) (RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax- 001(CDX-2401), PEP-6409, vacc-4x, Vacc-C5, VAC-3S, multistage DNA recombined adhenovirus -5(rAd5), Pennvax-G, VRC-HIV, MAB060-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly- ICLC vaccine adjuvant, TatImmune, GTU-multiHIV(FIT-06), AGS-004, pg140 [delta] V2.TV1+MF-59, rVSVIN HIV-1, HIV-1 blank vaccine, SeV-Gag vaccine, AT- 20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, monomer gp120 HIV subtype C vaccine (Novartis), MVA-CMDR, MVATG-17401, ETV-01, CDX-1401, rcAd26 MOS1, HIV-Env and DNA-Ad5 Gap/pol/nef/nev(HVTN505)；

Above-mentioned HIV antibody, bispecific antibody and class Antybody therapy albumen (such as DARTs, Duobodies, Bites, XmAbs, TandAbs, Fab derivative) it include BMS-936559, TMB-360 and those drugs for targeting HIV gp120 or gp41 include Ba Wei former times monoclonal antibody, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10,3-BNC-117, KD-247, PGT145, PGT121, MDX010(Ipilimumab), VRC01, A32,7B2,10E8, VRC-07-523 and VRC07；

Above-mentioned potential reversing drug includes that deacetylase inhibits such as sieve miaow ester peptide, Vorinostat, pabishta；Protease is small Body inhibitor such as Bortezomib；Protein kinase C activators (PKC) such as Indolactam, Prostratin, ingenol B and DAG- class Ester, ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitor, IL-15, JQ1, amphotericin B and disulfram；

Above-mentioned HIV nucleocapsid p7(NCp7) inhibitor includes azodicarbonamide；

Above-mentioned HIV maturation inhibitor includes BMS-955176 and GSK-2838232；

Above-mentioned PI3K inhibitor includes idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, comes that For Buddhist nun, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotic acid, perifosine, RG-7666, GSK- 2636772, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB- 040093, Pilaralisib, BY-1082439, puquitinib methanesulfonic acid, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401；

Other treatment active pharmaceutical ingredient further includes WO 2004/096286(Gilid Science Co.), WO2006/110157(is lucky Sharp moral scientific company)；WO2006/015261(Gilid Science Co.), WO 2013/006738(Gilid Science Co.)； US2013/0165489(Bin Xifani presses university), US20140221380(Japan Tobacco Inc (JTI)), US20140221378 Japan Tobacco company), WO2013/006792(Pharma Resources), WO2009,062285(Boehringer Ingelheim company), WO2010/130034 Boehringer Ingelheim company), WO2013/091096A1(Boehringer Ingelheim company), WO2012/ 003497(Gilid Science Co.), WO2014/100323(Boehringer Ingelheim company), WO2012/145728(Bo Linge Yin Ge Han company), WO2012/003497(Boehringer Ingelheim company), WO2014/100323(Boehringer Ingelheim company), WO2012/145728(Boehringer Ingelheim company), WO2013/159064(Boehringer Ingelheim company) and WO2012/ 003498(Boehringer Ingelheim company) in the drug that has disclosed；

The drug of other treatment HIV further includes REP 9, Cytolin, CYT-107, Debiopharm, agglutinin, MK-9507, AG- 1105, TR-452, MK-8591, REP 9, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, lactogen, 1,5-Dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO- 3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TRA-CCR5RZ, MzaF gene are controlled It treats, blockAaide, ABX-464, SCY-635, naltrexone, AAV-eCD4-Ig gene therapy, TEV-90110, TEV- 90112, Deferiprone and PA-1050040(PA-040).

Tenofovir Chinese mugwort draws being optionally combined for phenol amine and CAB or they and one or more drugs, these one kind or more Kind drug can be same class drug, be also possible to inhomogeneity drug.

Tenofovir Chinese mugwort draws phenol amine and CAB or the combination such as Merck of they and one or more other drugs, grace His bent shore, Maraviroc, enfuirtide, abacavir sulfate+Lamivudine (ABC+3TC), Trizivir(abacavir sulfate + Zidovudine+Lamivudine, ABC+ACT+3TC), adefovirdipivoxil, Aldoforwe ester, angstrom replace lattice Wei+cobicistat+grace His bent shore), rilpivirine, hydrochloric acid rilpivirine, Merck+Lamivudine, Eviplera+ ripivirine+grace it is bent he Shore), Cobicisstat, efavirenz+emtricitabine, sulfuric acid atazanavir+cobicistat, atazanavir+ Cobicistat, darunavir+cobicistat, atazanavir, sulfuric acid atazanavir, angstrom replace lattice Wei, Aluvia/Kaletra (Lopinavir+Ritonavir), Ritonavir, sulfuric acid atazanavir+Ritonavir, darunavir, lactogen, phosphine it is husky that Wei, fosamprenavir calcium, efavirenz, Combivir(Zidovudine+Lamivudine, AZT+3TC), etravirine, Nai Feinawei, Nelfinavir mesilate, interferon, Didanosine, stavudine, indinavir, indinavir sulfate, Zidovudine, Nai Weila It is flat, inverase, methanesulfonic acid Sha Kuilawei, Aldesleukin, zalcitabine, tipranavir, anpunave, delavirdine, first Sulfonic acid delavirdine, Radha-108(Receptol), efavirenz+Lamivudine, phosphazid, Lamivudine+Nai Weila Flat+Zidovudine, Abacavir, abacavir sulfate.

Tenofovir Chinese mugwort draw phenol amine and CAB can be administered simultaneously or separate with above-mentioned active constituent or therapeutic agent/gradually to Medicine.When being gradually administered, which can be with 1 time, 2 times or multiple dosing.

The suitable amount of each compound used in the composition are as follows: show antiviral activity when used alone Amount, as inverase composition, required tenofovir Chinese mugwort draw the amount of phenol amine and CAB composition be it is variable, need to examine The factor of worry includes the property of the property of administration route and preparation, weight, age and ordinary circumstance and treated disease and tight Principal characteristic.

In general, tenofovir is ended when phenol amine being drawn to give the mankind and be used to treat HIV infection, in the case where oral administration, Each adult dosage of giving daily is the mg of 1 mg ~ 50, can give 1 time, 2 times or 3 times, preferred dose 5 ~ 25mg/ days, one day 1-2 It is secondary.

In general, in the case where oral administration, CAB suitable dosage be it is each it is adult give daily dosage be 0.05 ~ 3000 mg, about 0.1 ~ 1000 mg of preferred dose, it is furthermore preferred that dosage is 0.05 ~ 500 mg.

CAB can also be used for intramuscular administration, and the dosage of adult HIV infection treatment is 50-3000mg, preferably 100-1000mg.

Except other explanation, the weight of all active components is all calculated according to drug prototype, using TAF and CAB or its When derivative and other pharmaceutically acceptable salts, active component weight should be scaled.

In conventional method, the ingredient of composition, also referred to as active component can be given to animal, such as mammal, Including people, for treating disease.

Although active component in composition can be given in the form of former chemicals, preferably deposited with pharmaceutical preparation form ?.Pharmaceutical preparation of the present invention includes the present composition and one or more pharmaceutical acceptable carrier or excipient.Carrier must be with Other components are compatible in preparation and are harmless to subject.

Pharmaceutical preparation of the invention can be formulated into the various forms for different dosing type.Drug system of the invention Agent is preferably formulated as being suitable for, and is especially suitable for taking orally, rectum, percutaneous, intranasal or inhalation or is administered to by non-gastrointestinal The unit dosage forms of medicine.Preferably it is administered orally.

In the preparation for preparing peroral dosage form, any conventional pharmaceutical media can be used, such as with regard to liquid oral For preparation (such as suspension, syrup, elixir, emulsion and solution), solvent includes water, oil, alcohol etc.；With regard to powder, pill, capsule For tablet, solid carrier includes starch, sugar, kaolin, diluent, lubricant, adhesive, disintegrating agent etc..Since it is given Prescription just, therefore tablet and the best oral dosage unit form of Capsules representative, preferably tablet.For parenteral compositions Object, carrier will generally comprise sterile water, and at least account for major part, although may include other ingredients, such as the ingredient for hydrotropy. Such as the solution of injectable can be prepared, wherein carrier includes that physiological saline, glucose solution or physiological saline and glucose are molten The mixture of liquid.Suitable liquid carrier, suspension etc. can be used in the suspension that injectable can also be prepared for it. Long-acting injection can also be prepared into long-acting slow-release carrier.

Composition of the invention can be made into the form of oral tablet, further include pharmaceutically acceptable figuration Agent, weight is between 150mg to 600mg, appropriately 200mg to 400mg.It is suitable for comprising active constituent according to the present invention Oral tablet slice weight is 200mg to 1500mg, appropriately 500mg to 1250mg, more appropriately 600mg to 1100mg.

Doctor is for example every according to the severity of conditions of patients and the weight of patient, gender or possible other parameters The absorption of a drug, bio distribution, the individual difference of metabolism and discharge rate and it is well known by persons skilled in the art it is other because Element determines the precise dosage of administration.

Invention benefit

Joint anti-HIV composition of the invention has collaboration AntiHIV1 RT activity effect, has bent with the completely different drug resistance in commercial composite Line, effect are more preferable；Application dose is lower, takes once day effectively, can significantly reduce patient's dose load；It can be more long-term Inhibit virus, limits the appearance of drug resistance HIV variant, and there is lower toxic side effect relevant to drug；It can use for a long time Make the first-line treatment of medication patient for the first time；It can be used as unit formulation, one or more can also be added with co-formulated Other inverase active constituents or therapeutic agent；A variety of dosage forms can be prepared into, different sick Man's Demands are met.

Specific embodiment

The following examples are further illustrations of the invention, it but does not limit the scope of the present invention, art technology The preparation method that personnel should be appreciated that invention is not limited to these embodiments and use.Those skilled in the art are according to this The description of invention can be equivalently replaced the present invention, combines, improves or modify, but these are intended to be included in model of the invention In enclosing.

Embodiment 1: tablet formulation

By the way that by the solution wet granulation of component and polyvinylpyrrolidone, magnesium stearate and tabletting is then added to prepare A, B And C, it is 1000 prescription dosages below.

Preparation A:

TAF 5 g

CAB 45 g

378 g of lactose B.P.

27 g of polyvinyl pyrrolidone B.P.

36 g of carboxylic amylcose acetate sodium

9 g of magnesium stearate

500 g

Preparation B:

TAF 30 g

CAB 20 g

270 g of lactose B.P.

108 g of microcrystalline cellulose PH101

27 g of polyvinyl pyrrolidone B.P.

36 g of carboxylic amylcose acetate sodium

9 g of magnesium stearate

500 g

Formulation C:

TAF 25g

CAB 25g

Lactose B.P. 270g

Starch 90g

Polyvinyl pyrrolidone B.P. 9g

Magnesium stearate 8g

427g

By the way that mixed component direct tablet compressing to be prepared to lower series preparation D and E.Lactose in preparation E belongs to direct tablet compressing type (Dairy Crest " Zeparox "), is 2000 recipe quantities below.

Preparation D:

TAF 40g

CAB 60g

Pregelatinized starch 300g

400g

Preparation E:

TAF 20g

CAB 80g

Lactose B.P. 300g

Microcrystalline cellulose 200g

600g

Preparation F: sustained release preparation

By by component and polyvinylpyrrolidonesolution solution wet granulation, magnesium stearate and tabletting being then added to prepare preparation, It is 2000 recipe quantities below

Preparation FTAF 30g

CAB 70g

Hydroxypropyl methyl cellulose (Methocel K4M Premium) 224g

Lactose B.P. 106g

Polyvinyl pyrrolidone B.P. 56g

Magnesium stearate 14g

500g

Drug is by starting release in about 6 ~ 8 hours and discharging in end in 12 hours.

Embodiment 2: capsule formulation

Capsule preparations are prepared by mixing and being filled into two parts hard gelatin capsule by the component of preparation D in above-described embodiment 1. Preparation G is prepared with similar approach, is the recipe quantity of 2000 capsules below；

Preparation G:

TAF 50g

CAB 50g

Lactose B.P. 286g

Sodium starch glycolate 50g

Magnesium stearate 4g

440g

Embodiment 3: injectable formulation

It is the recipe quantity of 1000 injections below

TAF 15g

CAB 25g

Hydrochloric acid solution 0.1M or sodium hydroxide solution 0.1M is in right amount to pH 4.0 ~ 7.0

Water for injection is in right amount to 10 L

Embodiment 4: intramuscular injection preparation

It is the recipe quantity of 1000 injections below

TAF 10g

CAB 5g

Benzyl alcohol 1g

Glycofurol 75 1.45 g

Water for injection is in right amount to 3L

Active component is dissolved in Glycofurol, benzyl alcohol is added and is dissolved, 3L is injected water to.Then, it will mix Object passes through sterile filtering with microporous membrane and encapsulates.

Embodiment 5: syrup is 50 recipe quantities below

TAF 40 g

CAB 60 g

1.5 g of sorbitol solution

2.0 g of glycerol

5 g of sodium benzoate

Fragrance, 12.5 mL of Peach 17.42.3169

Appropriate amount of water is purified to 5.00 L

Active component is dissolved in the mixture of glycerol and most of purified water, after the aqueous solution of sodium benzoate is added, then Sorbitol solution, last perfuming is added.The volume of needs is added to purified water and is sufficiently mixed.

Embodiment 6: vaginal plug

It is 200 recipe quantities below

TAF 6g

CAB 4g

Tallow B.P.(Witepsol H15-Dynamit Nobel) 394g

404g

Fusing is heated in steam-jacketed kettle at being 45 DEG C in maximum temperature by 1/5 Witepsol H15, active component is led to It crosses 200 μm of sieves to screen and be added in the matrix of fusing, while being mixed by using the Siverson for being equipped with cutting head, until Even dispersion.Remaining matrix is added to stir to uniformly mixed.Stirring is cooled to 40 DEG C.At 38 ~ 40 DEG C, mixture is filled into suitable In suitable 2mL plastic mould.Suppository is cooled to room temperature.

Embodiment 7: in vitro test research

In order to study the difference of TAF+CAB composition with independent medication and the AntiHIV1 RT activity effect of other commercially available compositions, the present invention is set Comparative experiments group has been set, tenofovir disoproxil+emtricitabine (TDF+FTC) and Zidovudine+Lamivudine (AZT+3TC) group is chosen Object is closed as control experiment group, probes into the different pharmaceutical under same experiment condition to the function and effect of HIV, wherein composition TDF+ The mass ratio of FTC(TDF and FTC is 3:2) and the mass ratio of AZT+3TC(AZT and 3TC be 2:1) proportion and commercial product one It causes, the weight ratio of TAF and CAB are 5:6.

Experimental example 1: HIV-resistant activity research

Antiviral measurement, unless otherwise indicated, cause under 50% reduction MT4 cell growth institute's necessary amounts at 10 times (10 × TCID₅₀, 2×10⁴A plaque forming unit/cell), so that I type human T-cell's lymphotropic virus transformation cell lines MT4 is grown and is felt Contaminate HIV-1 bacterial strain 3B or bacterial strain MN(Advanced biotechnologies Inc. Columbia, Maryland), simultaneously Prepare Mock infection cell.After 1h is cultivated, by cell with 1 × 10⁴The amount of cells/well is transferred in 96 orifice plates.Experimental group It is separately added into TAF, CAB, TAF+CAB of debita spissitudo, TDF+FTC, AZT+3TC of debita spissitudo is added in control group.It will be felt The T lymphocyte constant temperature incubation of dye 5 days, to realize the growth inhibition of HIV-1 mediation.Then, by culture plate with 28 μ L The phosphate buffer (PBS) of Nonidet P-40 (sigma) is handled, and 60 μ L samples are transferred in 96 orifice plates, is added Propidium iodide measures fluorescent value (E) with Chemiluminescence Apparatus after washing.The size of fluorescent value and the number of cell quantity It is directly related, the cytopathy effect (CPE) of HIV-1 mediation is measured with this.The CPE of measured non-infected cells is 0%, and Infected but untreated cell CPE is 100%, and the suppression percentage of the CPE of measurement HIV-1 induction determines drug for CPE Half amount of suppression (IC₅₀).As a result as shown in the table.

The result shows that the composition of TAF+CAB is substantially better than exclusive use to the inhibitory effect of CPE in vitro in test TAF or CAB, and it is more stronger than the inhibitory effect of TDF+FTC and AZT+3TC, there is better HIV-resistant activity.

The measurement of experimental example 2:HIV integrase inhibiting activities

(1) preparation of DNA solution

Using method described in patent WO2004/024693 EXPERIMENTAL EXAMPLE 1, prepare Substrate DNA solution (2pmol/ μ l) and Target dna solution (5pmol/ μ l).

(2) inhibiting rate (IC₅₀) measurement

Streptomysin is dissolved in 0.1M carbonate buffer solution (composition: 90mM Na₂CO₃、10mM NaHCO₃), being configured to concentration is The Streptomycin Solution of 40 μ g/ml.The Streptomycin Solution of 50 μ l is added in immunization test board, 4 DEG C stand overnight to adsorb. With phosphate buffer (composition: 13.7mM NaCl, 0.27mM KCl, 0.43mM Na₂HPO₄、0.14mM KH₂PO₄) washing Twice, with the 300 μ l phosphate buffers containing 1% skimmed milk 30min is closed in each hole.Each hole is washed twice with phosphate buffer, In room temperature, oscillation 50 μ l Substrate DNA solution (2pmol/ μ l) of lower addition, 30min is adsorbed, is washed twice with phosphate buffer, It is washed with distilled water again primary.

Then, 12 μ l buffers (composition: 150mM MOPS(pH7.2), 75mM are added into each hole prepared as described above MnCl₂, 50mM 2 mercapto ethanol, 25% glycerol, 500 μ g/ml bovine serum albumin(BSA)s-ingredient V), and by 39 μ l distilled water prepare 51 μ l reaction solutions.Then, be added the 9 diluted solution of μ l (composition: 20mM MOPS(pH7.2), 400mM or potassium glutamate, 1mM EDTA, 0.1%NP-40,20% glycerol, 1mM DTT, 4M urea), it is sufficiently mixed with plate mixer.

The plate is incubated into 60min at 30 DEG C, abandons reaction solution, then with 250 μ l washing buffers (composition: 150mM MOPS(pH7.2), 50mM 2 mercapto ethanol, 25% glycerol, 500 μ g/ml bovine serum albumin(BSA)s-ingredient V) washing 3 times.To each hole 12 μ l buffers of middle addition (composition: 150mM MOPS(pH7.2), 75mM MgCl₂, 50mM 2 mercapto ethanol, 25% glycerol, 500 μ g/ml bovine serum albumin(BSA)s-ingredient V) and 41 μ l distilled water preparation 53 μ l reaction solutions.

In addition, the DMSO solution of TAF, CAB and TAF+CAB mixture of 6 μ l debita spissitudos is separately added into each hole, It is added in the DMSO solution adding hole of debita spissitudo TDF+FTC, AZT+3TC and does control group, 6 μ l DMSO are added as negative In the hole of control, then it is sufficiently mixed with plate mixer.

After each plate is incubated for 10min at 30 DEG C, reaction solution is abandoned, is then washed twice with phosphate buffer.With anti- The anti-digoxigenin antibody of alkali phosphatase enzyme mark is diluted 2000 times by body dilution, this for being added 100 μ l at 30 DEG C is dilute Liquid is released, in conjunction with 1h, it is washed twice with the phosphate buffer containing 0.05% Tween20, then uses phosphate buffer Washing 1 time.Then, be added at 30 DEG C 150 μ l alkaline phosphatase staining buffers (composition: 10mM p-nitrophenyl phosphate, 5mM MgCl₂, 100mM NaCl, 100mM Tris-HCl(pH9.5)), react 2h, be added 50 μ l 1N NaOH solution to stop The only reaction measures the absorbance (OD405nm) in each hole, calculates inhibiting rate and its inhibits IC₅₀:

Inhibiting rate (%)=100 [1- [(A_sample-A^-)/( A⁺- A^-)]]

A_sample: the absorbance of sample to be tested

A^-: the absorbance of negative control

A⁺: the absorbance of positive control

As a result as shown in the table.

The result shows that the composition of TAF+CAB is stronger than TAF or CAB is used alone to the inhibiting effect of hiv integrase, and Combination of the integrase inhibitory effect of TAF+CAB also superior to TDF+FTC and AZT+3TC, TAF+CAB composition have better HIV Integrase inhibitory effect.

Experimental example 3: external AntiHIV1 RT activity drug resistance Journal of Sex Research

(1) foundation of the MT4-CNHN24 culture systems of drug containing solution

It is (5-8) × 10 with 1640 cell culture fluid of the RPMI adjustment MT4 cell concentration containing 10% fetal calf serum⁴/ ml, each The 10ml concentrations of cells suspension is added in 50ml Tissue Culture Flask.It is respectively inoculated in the cell bottle of culture persister final concentration of 100 TCID₅₀Virus.By the concentration for TAF, CAB and the TAF+CAB composition that table 3 in result is set, drug solution is distinguished It is added in MT4-HIV-1CNHN24 culture systems.Drug initial concentration is 0.008 μm of ol/L, and the TDF+ of debita spissitudo is added FTC and AZT+3TC is incremented by as positive control, later per generation concentration with 2 times, altogether 10 generation of secondary culture, the 10th generation drug concentration It is 512 times of 1st generation for 4.096 μm of ol/L.Cell bottle is put into 37 °C, 5%CO₂It is cultivated in incubator, the 4th day suction 5ml Culture supernatant supplements 5ml fresh medium.Cytopathy is observed under inverted microscope daily after 4th day.Per generation incubation time As shown in table 3.Packing freezes in -80 °C of refrigerators later.And it is the virus inoculation after freeze thawing is next after drug concentration raising For in culture systems.Virus control and cell controls are set simultaneously.Virus control is the MT4-CNHN24 culture of not drug containing. Cell controls are that virus but the MT4-3TC culture added with respective concentration drug is not added.Virus control and cell controls and drug resistance The parallel secondary culture of strain culture systems.Per generation persister culture systems set 2 parallel samples.

(2) phenotypic resistance measures

By 5 × 10⁴The MT4 cell inoculation of/ml is in 96 orifice plates, every 50 μ l of hole；By drug solution with RPMI 1640 culture medium according to Totally 12 concentration add in 96 orifice plates for secondary 2 times of dilutions, 4 repeating holes of every concentration, every 50 μ l of hole；By final concentration of 100 TCID₅₀ Virus to be measured cell hole is added, every 100 μ l of hole is put into 37 °C, 5%CO₂It is cultivated in incubator.It is seen daily with inverted microscope Cytopathy (CPE) is examined, cytopathy degree is recorded after 7 days, the IC of virus is calculated with Reed-Muench method₅₀.As a result such as following table It is shown.

The result shows that in the incubation of entire Drug-resistant strain, viral IC₅₀In the trend being increased generation after generation.From TAF, The IC of CAB administration group₅₀Data can be seen that IC before 5 generations₅₀It increases speed relatively gentle, the 6th generation had suddenly to be greatly improved, Show that it has produced height drug resistance to TAF, CAB；And the IC of the virus of TAF+CAB group₅₀Significantly lower than exclusive use TAF Or CAB, and just there is obvious drug resistance in the 9th generation.The data for comparing TAF+CAB, TDF+FTC and AZT+3TC, no matter TAF+CAB TDF+FTC and AZT+3TC are better than in drug resistance time or drug-resistant intensity.TAF+CAB has the drug resistant energy of outstanding AntiHIV1 RT activity Power.

Experimental example 4: safety evaluatio

Composition is being greater than/is being equal in human body under the blood plasma level of target plasma level, and is greater than in vitro/is equal to and is external anti- Under the concentration of virus concentration, to major organs, the parameter of especially cardiovascular, kidney and bone is had little effect.

Experimental example 5: the measurement that composition prevention passes through related intimate contact infected by HIV ability between sexual intercourse or companion

In a model, the Dendritic Cells (MO-DC) from monocyte is by monotropic HIV bacterial strain Ba-L with 10^-3Infection is multiple Number (MOI) infects 2h.After infection, cell is washed 6 times and with every milliliter 4 × 10⁵A cell concentration is resuspended in 10% BCS. Homologous CD4 (+) T cell is isolated and purified out, and from the lymphocyte of eluent identical as MO-DC with 2 × 10⁶Cell/ml Concentration uses (ratio of MO-DC/CD4 (+) T is 1/5).

TAF, CAB and TAF+CAB of the debita spissitudo of serial dilution, TDF+FTC, AZT+3TC composition are added to MO- In the Combined culture object of DC/CD4 (+) T cell.Each experiment carries out on 96 orifice plates, wherein each hole includes 50ul MO- DC, 50ul CD4 (+) T cell and 100ul experimental drug.Culture medium twice containing drug is replaced weekly.Culture 14 days after Supernatant is analyzed in ELISA.In order to determine antiviral activity, measurement can inhibit the reality of 50% virus replication at originally culture end Test drug concentration (EC₅₀).As a result as shown in the table.

The result shows that the anti-infection ability of the composition of TAF and CAB, which is substantially better than, is used alone TAF or CAB, and TAF+ The prevention ability of CAB is better than commercially available composition TDF+FTC, and the ability of the pre- preventing HIV infection of TAF+CAB is stronger.

Claims (9)

1. a kind of pharmaceutical composition, it includes

1) the tenofovir Chinese mugwort of therapeutically effective amount draws phenol amine or its pharmaceutically acceptable salt；

2) Cabotegravir of therapeutically effective amount or its pharmaceutically acceptable salt；

And pharmaceutically acceptable carrier.

2. pharmaceutical composition according to claim 1, wherein tenofovir Chinese mugwort draws phenol amine pharmaceutically acceptable salt to be selected from Fumarate, sodium salt, hemifumarate and fumarate.

3. pharmaceutical composition according to claim 1, it is half that wherein tenofovir Chinese mugwort, which draws phenol amine pharmaceutically acceptable salt, Fumarate.

4. pharmaceutical composition according to claim 1, wherein Cabotegravir pharmaceutically acceptable salt is sodium salt, potassium Salt.

5. pharmaceutical composition according to claim 1, wherein tenofovir Chinese mugwort draws phenol amine and Cabotegravir that can divide It opens or is administered simultaneously.

6. claim 1 described pharmaceutical composition can also wrap the third active constituent.

7. pharmaceutical composition according to claim 7, wherein the third active constituent is emtricitabine.

8. pharmaceutical composition according to claim 7, wherein the third active constituent is rilpivirine.

9. composition described in claim 1-9 is used to prepare the purposes in the drug for preventing and treating HIV infection.