CN114903891B - Application of saquinavir in treatment or prevention of hepatitis B - Google Patents
Application of saquinavir in treatment or prevention of hepatitis B Download PDFInfo
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- CN114903891B CN114903891B CN202110176785.8A CN202110176785A CN114903891B CN 114903891 B CN114903891 B CN 114903891B CN 202110176785 A CN202110176785 A CN 202110176785A CN 114903891 B CN114903891 B CN 114903891B
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- saquinavir
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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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
- A61P31/20—Antivirals for DNA viruses
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- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides application of saquinavir, deuterated product thereof or pharmaceutically acceptable salt thereof in preparing a medicament for treating or preventing hepatitis B. The present application also provides a pharmaceutical composition for treating or preventing hepatitis b comprising saquinavir, deuterated thereof or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier.
Description
Technical Field
The application relates to the field of anti-hepatitis B medicines, in particular to application of saquinavir, deuterated products thereof, pharmaceutically acceptable salts thereof and derivatives thereof in treating or preventing hepatitis B.
Background
Human Hepatitis B Virus (HBV) infection is a significant public health problem worldwide. After acute hepatitis B virus infection, about 8% of the hepatitis B virus infection still develops into chronic hepatitis B infection, and persistent HBV infection can lead to liver cirrhosis and even liver cancer. The hepatitis B transmission path mainly comprises vertical transmission and horizontal transmission. Vertical transmission refers to maternal and infant transmission; horizontal transmission is primarily through the blood.
Hepatitis B is also a long-term course of treatment, with the goal of maximally inhibiting or eliminating HBV, reducing hepatocyte inflammatory necrosis and hepatic fibrosis, slowing and preventing disease progression, reducing and preventing liver decompensation, cirrhosis, HCC and complications thereof, thereby improving quality of life and prolonging survival time.
There are many hepatitis b therapeutic drugs on the market at present, and antiviral treatment is mainly performed by using interferon or nucleoside analogues. For interferon, recombinant DNA leukocyte interferon (IFN-. Alpha.) can inhibit HBV replication. However, when interferon is used for treating hepatitis B, serious adverse reactions, including myelosuppression, influence on thyroid function, depression and the like are often accompanied.
Nucleoside analogs inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, clinically useful drugs include the following classes: lamivudine, famciclovir, such as acyclovir, adefovir, entecavir, tenofovir, sodium phosphonate and the like, and all have certain HBV inhibiting effect.
Although these reverse transcriptase inhibitors can effectively reduce HBV DNA level and control HBV level, the action target is the process of reverse transcription of RNA into DNA, and has no direct effect on the elimination of HBeAg and HBsAg. Therefore, the single-drug treatment of nucleoside analogues has extremely low probability of serological conversion of HBeAg and HBsAg, and can not truly cure hepatitis B, and patients need to take medicines for a long time or even for life.
For interferon, recombinant DNA leukocyte interferon (IFN-. Alpha.) can inhibit HBV replication. Whereas nucleoside analogues inhibit HBV production primarily by inhibiting reverse transcriptase activity during HBV replication, clinically useful drugs include the following classes: 1) Lamivudine is a synthetic dideoxy cytosine nuclear medicine with anti-HBV effect. The serum HBV-DNA level can be obviously reduced by orally taking lamivudine, and the negative conversion rate of HBV-DNA can reach more than 90% after 12 weeks of taking the lamivudine. The ALT can be reduced and the liver inflammation can be improved after long-term administration; 2) Famciclovir, a guanosine drug, has long half-life and high intracellular concentration, can inhibit HBV-DNA replication, has light side effects, and can be used with lamivudine interferon and the like to improve curative effects; 3) Other antiviral drugs: such as acyclovir, adefovir, entecavir, sodium phosphonoformate and the like, has a certain HBV inhibiting effect.
Although the above-mentioned reverse transcriptase inhibitors can control the level of hepatitis B virus in patients, the problems of drug resistance, huge medical cost, serious side effects of drugs and the like which are caused by the reverse transcriptase inhibitors are not quite small. Accordingly, there is a great need in the art to provide a new medicament for the treatment of hepatitis b. The key point is that at present, no medicine can completely remove viruses to cure hepatitis B. Therefore, there is an urgent need in the art to provide a new drug for treating hepatitis b, capable of eliminating HBsAg, and achieving a functional cure.
Saquinavir (Saquinavir) is a protease inhibitor that specifically cleaves viral precursor proteins in HIV-infected cells, allowing the final formation of infectious viral particles. These viral precursor proteins present a cleavage site that can only be recognized by the proteases of HIV and its closely related viruses. Saquinavir is a peptide-like, structurally mimicking this type of cleavage site. Thus, saquinavir is tightly bound to the active sites of HIV-1 and 2 proteases, exhibiting reversible and selective inhibition of protease activity in vitro, with about 50,000 times less affinity than human protease.
The current research on saquinavir indications mainly aims at the application of the saquinavir indications in treating or preventing diseases such as HIV and the like, and no research on the application of the saquinavir indications in treating or preventing hepatitis B has been reported.
Disclosure of Invention
The present application provides a novel hepatitis b treatment option by applying saquinavir or a pharmaceutically acceptable salt thereof to treat or prevent hepatitis b.
In one aspect, the present application provides the use of saquinavir (compound 2) or a pharmaceutically acceptable salt thereof, a deuterated compound thereof or a derivative thereof in the manufacture of a medicament for the treatment or prevention of hepatitis b.
In one embodiment, the derivative of saquinavir is a compound with a protecting group as described in formula 1,
wherein in said formula 1, R is selected from the group consisting of C1-C10 alkyl (e.g., C1-C6 alkyl) and C3-C10 cycloalkyl (e.g., C3-C6 cycloalkyl).
In one embodiment, wherein the derivative of saquinavir is selected from the following compounds:
in one embodiment, the pharmaceutically acceptable salt of saquinavir is saquinavir mesylate or saquinavir hemisuccinate.
In one embodiment, the agent is capable of reducing Hepatitis B Virus (HBV) loading, HBsAg, and/or HBeAg levels.
In one embodiment, the medicament further comprises one or more additional therapeutic or prophylactic agents.
In one embodiment, the additional therapeutic or prophylactic agent is selected from at least one of an interferon, a pegylated interferon, nitazoxanide or an analog thereof, a compound of formula A or a nucleoside analog,
a is a kind ofThe nucleoside analogue is preferably selected from entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide.
Analogs of nitazoxanide described above include, but are not limited to, those disclosed in CN102803203B, e.g., compounds of formula I:
wherein R is 1 Is the following group: hydroxy or C 1 -C 3 Alkanoyloxy; r is R 2 To R 5 Is H; r is R 6 Is CF (CF) 3 The method comprises the steps of carrying out a first treatment on the surface of the X is N, W is S, Y is CH.
In one embodiment, the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
In one embodiment, the medicament is administered by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
In one embodiment, the medicament is administered orally, preferably in the form of a tablet or capsule.
In another aspect, the application provides a pharmaceutical composition for treating or preventing hepatitis b comprising a therapeutically effective amount of saquinavir, deuterated thereof or a pharmaceutically acceptable salt thereof and optionally one or more additional therapeutic or prophylactic agents, and a pharmaceutically acceptable carrier.
The technical scheme of the application has the following beneficial effects:
1. saquinavir, its deuterated or its pharmaceutically acceptable salts are used for treating or preventing hepatitis b, thereby providing a novel hepatitis b treatment option.
2. Saquinavir, deuterated product thereof or pharmaceutically acceptable salt thereof can effectively reduce the load of Hepatitis B Virus (HBV) and the level of HBsAg and/or HBeAg, has wide application prospect, and particularly can reduce the technical effect of the level of HBsAg and/or HBeAg, so that functional cure of hepatitis B is possible.
3. Saquinavir, deuterated product thereof or pharmaceutically acceptable salt thereof has excellent clinical safety and pharmacokinetic properties and has good drug forming property.
4. Saquinavir, its deuterated or a pharmaceutically acceptable salt thereof can optionally be combined with one or more additional therapeutic or prophylactic agents, in particular with agents capable of reducing viral titer but not completely eliminating the virus, not reducing HBsAg and/or HBeAg levels, inhibiting or eliminating hepatitis b virus from different aspects and with the potential for synergy.
Drawings
Fig. 1: inhibition of Hepatitis B Virus (HBV) load by combination of saquinavir, 0.1nM entecavir, 10 μm saquinavir and 0.1nM at different concentrations.
Fig. 2: inhibition of HBsAg by combinations of saquinavir, 0.1nM entecavir, 10 μM saquinavir and 0.1nM entecavir at different concentrations.
Fig. 3: inhibition of HBeAg by combinations of saquinavir, 0.1nM entecavir, 10 μM saquinavir and 0.1nM entecavir at different concentrations.
Detailed Description
The application surprisingly discovers that saquinavir, deuterated products thereof, pharmaceutically acceptable salts thereof and derivatives thereof have the effect of inhibiting hepatitis B virus, and particularly has the effect of eliminating HBsAg and HBeAg, can be used for preventing and treating hepatitis B, can be used for functionally curing hepatitis B and can be used for eliminating hepatitis B virus.
In one embodiment, the derivative of saquinavir is a compound with a protecting group as described in formula 1,
wherein in the general formula 1, R is selected from C1-C10 alkyl and C3-C10 cycloalkyl.
In a preferred embodiment, wherein the derivative of saquinavir is selected from the following compounds:
in one aspect, the present application provides the use of saquinavir, its deuterated, its derivatives, or its pharmaceutically acceptable salts for the manufacture of a medicament for the treatment or prevention of hepatitis b.
In one embodiment, the saquinavir is in the deuterated form. Those skilled in the art know that deuterated substances do not change the original properties of the compound, but can slow down the metabolic process, thereby prolonging the half-life and more effectively playing a role of a drug.
In one embodiment, the pharmaceutically acceptable salt is saquinavir hydrochloride. In one embodiment, the agent is capable of reducing Hepatitis B Virus (HBV) loading, HBsAg, and/or HBeAg levels.
Saquinavir (Saquinavir) is a protease inhibitor that specifically cleaves viral precursor proteins in HIV-infected cells, allowing the final formation of infectious viral particles. These viral precursor proteins present a cleavage site that can only be recognized by the proteases of HIV and its closely related viruses. Saquinavir is a peptide-like, structurally mimicking this type of cleavage site. Thus, saquinavir is tightly bound to the active sites of HIV-1 and 2 proteases, exhibiting reversible and selective inhibition of protease activity in vitro, with about 50,000 times less affinity than human protease. However, there have been no reports of its use in the treatment of hepatitis B, and no reports of its ability to reduce HBsAg and/or HBeAg levels.
Viral hepatitis:
the etiology of viral hepatitis is typed, five hepatitis viruses, namely A, B, C, D and E, are currently recognized, and are respectively written as HAV, HBV, HCV, HDV, HEV, and the rest are RNA viruses except that the hepatitis B virus is DNA virus.
Hepatitis b is an infectious disease caused by hepatitis b virus and is mainly a liver lesion. Clinically, it is mainly manifested by anorexia, nausea, epigastric discomfort, pain in liver region and hypodynamia. Some patients may have jaundice fever and liver large with liver function impairment. Some patients may become chronicized, even develop cirrhosis, and a few may develop liver cancer.
The pathogen of viral hepatitis B is hepatitis B virus, abbreviated as HBV, and hepatitis B virus is DNA virus. The genome is double-stranded, circular, incompletely closed DNA. The outermost layer of the virus is the outer membrane or coating of the virus, the inner layer of which is the core, the nucleoprotein is the core antigen (HBcAg) and cannot be detected in serum. The serum of HBsAg positive subjects was seen under an electron microscope as 3 particles, round and filiform particles of 22nm diameter, and also as fewer spherical particles of 42 angstrom diameter, also known as Dane's particles, as whole HBV particles.
The markers for hepatitis b were detected as follows: (1) HBsAg and anti-HBs: HBsAg positivity indicates that HBV is currently in the infectious stage, anti-HBs is immunoprotective antibody positivity indicates that immunity to HBV has developed. The diagnosis basis of the chronic HBsAg carrier is that the chronic HBsAg carrier has no clinical symptoms and signs and normal liver function, and the HBsAg is continuously positive for more than 6 months. (2) HBeAg with anti-HBe: HBeAg positive is an index of active replication and strong infectivity of HBV, and the change of the tested serum from HBeAg positive to anti-HBe positive indicates that the disease has reduced infectivity. (3) HBcAg with anti-HBc: HBcAg positive suggests that there is a direct reaction of intact HBV particles and that HBV active replication is rarely used clinically due to the complex detection method. anti-HBc is a marker of HBV infection, and positive IgM for anti-HBc suggests that there is viral replication in the body at the early stage of infection. Three positive HBsAg, HBeAg and anti-HBc in chronic mild hepatitis B and HBsAg carriers have high infectious index that is difficult to negative.
In a preferred embodiment, the medicament further comprises one or more additional therapeutic or prophylactic agents. In a preferred embodiment, the additional therapeutic or prophylactic agent is selected from interferon, nitazoxanide or an analogue, nucleoside analogue or other drug for the treatment of HBV. In a preferred embodiment, the nucleoside analog is selected from entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
Analogs of nitazoxanide described above include, but are not limited to, those disclosed in CN102803203B, e.g., compounds of formula I:
wherein R is 1 Is the following group: hydroxy or C 1 -C 3 Alkanoyloxy; r is R 2 To R 5 Is H; r is R 6 Is CF (CF) 3 The method comprises the steps of carrying out a first treatment on the surface of the X is N, W is S, Y is CH.
Additional therapeutic or prophylactic agents:
in some embodiments, the additional therapeutic or prophylactic agent is selected from one or more of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, for example, from one of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide, or from at least two of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide.
Entecavir (Entecavir) is known by the chemical name 2-amino-1, 9-dihydro-9- [ (1S, 3R, 4S) -4-hydroxy-3- (hydroxymethyl) -2-methylenecyclopentane ] -6H-purin-6-one, and has the following structural formula:
US patent US5206244 discloses entecavir and its use for the treatment of hepatitis b virus; a novel method of entecavir synthesis is disclosed in WO 9809964; WO0164421 discloses low dose entecavir solid formulations.
Entecavir is a highly potent antiviral agent, developed by the american schdule company in the 90 th century, with a potent anti-HBV effect. It can be phosphorylated to an active triphosphate, which has a half-life of 15h in the cell. Entecavir triphosphates inhibit all three activities of the viral polymerase (reverse transcriptase) by competing with deoxyguanosine triphosphate, the natural substrate of HBV polymerase: (1) initiation of HBV polymerase; (2) formation of negative strand of pregenomic mRNA reverse transcription; (3) Synthesis of HBV DNA plus strand.
Tenofovir disoproxil fumarate (English name: tenofovir disoproxil fumarate, TDF; chemical name is (R) - [ [2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phosphonic acid diisopropyl oxycarbonyl methyl ester fumarate) is ester precursor of tenofovir, belongs to novel nucleotide reverse transcriptase inhibitors, and has HBV virus inhibiting activity.
TDF is another novel ring-opened nucleoside phosphonate that was successfully developed by the us gilid company following adefovir dipivoxil, and was first marketed in the us 10 months 2001, and has been marketed in europe, australia, canada, and other countries.
TDF inhibits viral polymerase in vivo by competitively binding to natural deoxyribose substrates and terminates DNA strand synthesis by insertion into DNA. The main action mechanism is that the tenofovir is hydrolyzed into tenofovir after oral administration, the tenofovir is phosphorylated by cell kinase, and a metabolite tenofovir diphosphate with pharmacological activity is generated, the metabolite tenofovir diphosphate competes with 5 '-deoxyadenosine triphosphate to participate in the synthesis of virus DNA, and after entering the virus DNA, the DNA is prolonged and blocked due to the lack of 3' -OH groups, so that the replication of the virus is blocked. Clinical application shows that TDF has obvious anti-HBV virus curative effect and small toxic side effect, thus having great clinical application prospect.
Tenofovir alafenamide (Tenofovir Alafenamide), a prodrug of Tenofovir (Tenofovir), a novel Nucleoside Reverse Transcriptase Inhibitor (NRTI) developed by the american gilid science company. Compared with the previous generation of anti-hepatitis B similar drug tenofovir disoproxil TDF, the antiviral activity of tenofovir alafenamide is 10 times of that of tenofovir alafenamide, the stability in blood plasma is 200 times of that of tenofovir alafenamide, and the half life is 225 times higher than that of tenofovir alafenamide. Compared with TDF, tenofovir alafenamide only needs one tenth of TDF administration dose, and can achieve the same antiviral effect as TDF. Therefore, the tenofovir alafenamide is used for preventing or/and treating Hepatitis B Virus (HBV) infection, and has better curative effect, higher safety and lower drug resistance.
In some embodiments, the additional therapeutic or prophylactic agents further include one or more additional agents for treating HBV, such as, but not limited to, 3-dioxygenase (IDO) inhibitors, antisense oligonucleotides targeting viral mRNA, apolipoprotein A1 modulators, arginase inhibitors, B-and T-lymphocyte antidote inhibitors, bruton Tyrosine Kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytokines, cytotoxic T lymphocyte associated protein 4 (ipi 4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesoid X receptor agonists, gene modifiers or editors, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV antibodies, HBV DNA polymerase inhibitors, HBV replication inhibitors, HBV RNase inhibitors, HBV vaccines, HBV viral entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulators, hepatitis B large envelope protein stimulators, hepatitis B structural protein modulators, hepatitis B surface antigen (HBsAg) inhibitors, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitors, HIV-1 reverse transcriptase inhibitors, hyaluronidase inhibitors, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunoglobulin G modulators, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon alpha 1 ligands, interferon alpha 2 ligands, interferon alpha 5 ligand modulators, interferon alpha ligands, interferon alpha ligand modulators, interferon alpha receptor ligands, interferon beta ligands, interferon receptor modulators, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, microRNA (miRNA) gene therapeutics, axl modulators, B7-H3 modulators, B7-H4 modulator, CD160 modulator, CD161 modulator, CD27 modulator, CD47 modulator, CD70 modulator, GITR modulator, HEVEM modulator, ICOS modulator, mer modulator, NKG2A modulator, NKG2D modulator, OX40 modulator, sirpa modulator, TIGIT modulator, tim-4 modulator, tyro modulator, na+ -taurate cotransporter polypeptide (NTCP) inhibitor, natural killer cell receptor 2B4 inhibitor, NOD2 gene stimulator, nucleoprotein inhibitor, nucleoprotein modulator, PD-1 inhibitor, PD-L1 inhibitor, PEG-interferon lambda, peptidyl prolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI 3K) inhibitor, recombinant Scavenger Receptor A (SRA) protein, recombinant thymosin alpha-1, retinoic acid-induced gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitors, RNA DNA polymerase inhibitors, short interfering RNAs (siRNAs), short synthetic hairpin RNAs (sshRNAs)), SLC10A1 gene inhibitors, SMAC mimetics, src tyrosine kinase inhibitors, interferon gene Stimulators (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, zinc finger nucleases or synthetic nucleases (TALENs) and combinations thereof.
As used herein, "therapeutically effective amount" or "effective amount" refers to an amount that is effective at a dose and for a desired period of time to achieve a desired therapeutic result. The therapeutically effective amount of the therapeutic agent for hepatitis B will depend on the nature of the disorder or condition and on the particular agent and can be determined by standard clinical techniques known to those skilled in the art.
The treatment results may be, for example, alleviation of symptoms, prolongation of survival, improvement of mobility, and the like. The therapeutic outcome need not be "healing". The therapeutic result may also be prophylactic.
In a preferred embodiment, the medicament is formulated for administration by a route selected from the group consisting of: oral, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural.
In a preferred embodiment, the medicament is formulated for oral administration, preferably in the form of a tablet or capsule.
Route of administration:
the medicaments or pharmaceutical compositions of the present disclosure are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In certain embodiments, the medicaments or pharmaceutical compositions disclosed herein are administered by intravenous injection. It will be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. One advantage of the disclosed medicaments or pharmaceutical compositions is that they are orally bioavailable and can be administered orally.
Pharmaceutical composition:
in certain embodiments, the saquinavir drug, derivative thereof, or pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition. The pharmaceutical compositions of the present disclosure may be formulated with conventional carriers and excipients, which will be selected in accordance with common practice. The tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and are generally isotonic when used for delivery by non-oral administration. All formulations will optionally contain excipients, for example those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl celluloses, hydroxyalkyl methylcellulose, stearic acid and the like. The pH of the formulation ranges from about 3 to about 11, but is typically from about 7 to 10. In some embodiments, the pH of the formulation ranges from about 2 to about 5, but is typically from about 3 to 4.
Formulations include those suitable for the aforementioned routes of administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing co., easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which is composed of one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then shaping the product as necessary.
Formulations of the present application suitable for oral administration may exist as: individual dosage forms, such as capsules or tablets, each containing a predetermined amount of the active ingredient; powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by: the active ingredient in free-flowing form, such as a powder or granules, is pressed in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
The pharmaceutical compositions of the present disclosure may also be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol, or as a lyophilized powder. Acceptable carriers and solvents that can be used include water, ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Acceptable carriers and solvents that can be used include water, ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.
Additional objects, advantages and novel features of the present application will become apparent to those of ordinary skill in the art upon examination of the following examples.
Examples
Example 1 evaluation of in vitro anti-HBV Activity of the test Compound saquinavir Using HepG2-NTCP cells
The preparation method of the compound comprises the following steps:
taking the case of preparing a concentration of 10mM, the volume of solvent DMSO (. Mu.l) =sample mass (mg). Times.purity/(molecular weight/(10X 10)) 6
Saquinavir is purchased from Shanghai Tao Shu biotechnology limited. The control compound entecavir (ETV, lot number: P1214012;99.0% purity) was purchased from Shanghai Tao Shu Biochemical Co., ltd. The mother liquor concentration of the above control compound was 20mM and stored at-20 ℃.
1: primary agents and cells, viruses
Experimental protocol
Cell spreading and compound treatment
HepG2-NTCP planks
On day 0, hepG2-NTCP cells were seeded into 48 well cell plates (7.5X104 cells/well).
Infectious virus and compound treatment
On day 2, cells were pretreated with compound for 2 hours and then HepG2-NTCP cells were infected with HBV type D (infection with compound added simultaneously). The tested compound is provided with 3 single drug concentrations and 1 combined drug concentration, wherein the three single drug concentrations of saquinavir drugs are respectively 0.1, 1 and 10 mu M, and the combined drug concentration is 10 mu M+ETV 0.1nM; control compound was ETV, wells containing DMSO alone without compound were set up simultaneously with ETV single drug concentration of 0.1nM, two multiplex well tests. The compound concentrations are shown in Table 2.
The culture medium containing the compound was changed once on days 3, 5 and 7. On day 9, cell supernatants were collected for detection of HBV DNA (qPCR), HBeAg and HBsAg (ELISA). After the cell supernatant was collected, cellTiter-Glo was added to examine the cell viability, and the specific procedure of the experiment is shown in Table 3.
Table 2: concentration of the Compound
Table 3: experimental procedure
Sample detection
1) qPCR method for detecting HBV DNA content in cell culture supernatant
DNA was extracted from the cell culture supernatant by reference to QIAamp 96DNA Blood Kit instructions. The sample volume was 120. Mu.l and the DNA elution volume was 120. Mu.l of supernatant. qPCR detects HBV DNA content.
As shown in Table 4, qPCR reaction mixtures were prepared.
TABLE 4 qPCR reaction composition Table
| PCR reaction solution composition | 1 reaction system required volume |
| FastStart Universal Probe Master(2×) | 5μl |
| Forward primer (10. Mu.M) | 0.4μl |
| Reverse primer (10. Mu.M) | 0.4μl |
| Probe (10 mu M) | 0.2μl |
| AE | 2μl |
The qPCR reaction mixture was added to 384 well reaction plates, and 2. Mu.l of sample or standard (AE) was added to the corresponding wells, with a total volume of 10. Mu.l each. And (3) PCR reaction: 95 ℃ for 10 minutes; 95 ℃,15 seconds, 60 ℃,1 minute, 40 cycles.
2) ELISA method for detecting HBsAg and HBeAg content in cell culture supernatant
Methods referring to the kit instructions, the methods are briefly described as follows: respectively taking 50 μl of standard substance, sample and reference substance, adding 50 μl of enzyme conjugate into each well, incubating at 37deg.C for 60 min, washing the plate with washing solution, blotting, adding 50 μl of premixed luminescent substrate, incubating at room temperature in dark for 10 min, and measuring the luminescence value by enzyme-labeled instrument.
3) Cell viability assay
After the supernatant was collected, an equal volume of medium and CellTiter-Glo were mixed, 50. Mu.l of the mixture was added to the cell plate per well, and the mixture was shaken at room temperature for 10 minutes under light-shielding conditions, and then the luminescence value was measured.
4) Data computation
HBV DNA inhibition ratio (%) = (HBV DNA copy number of 1-compound group sample/HBV DNA copy number of DMSO group) ×100
HBsAg inhibition (%) = (HBsAg value of 1-sample/HBsAg value of DMSO control) ×100
HBeAg inhibition (%) = (HBeAg value of 1-sample/HBeAg value of DMSO control group) ×100
Cytotoxicity% = 100- [ (sample luminescence value-medium control luminescence value)/(DMSO control luminescence value-medium control luminescence value) ]100%
Data analysis
TABLE 5 percent HBV DNA inhibition (%)
TABLE 6 percentage of HBsAg inhibition and percentage of HBeAg inhibition
As shown in figure 1 of the drawings,
saquinavir has an inhibitory effect on HBV DNA. The inhibition rate of 10 mu M saquinavir on HBV DNA in HepG2-NTCP cells reaches 31.39%, and the inhibition rate of 10 mu M saquinavir+0.1 nM ETV on HBV DNA reaches 55.03%.
As shown in the figure 2 of the drawings,
saquinavir has an inhibitory effect on HBsAg. The inhibition rate of 10 mu M saquinavir to HBsAg in HepG2-NTCP cells reaches 45.00%; the inhibition rate of HBsAg by ETV of 10 mu M saquinavir+0.1 nM reaches 47.00%.
Compared with the ETV of 0.1nM without obvious inhibition effect on HBsAg, the inhibition effect of saquinavir on HBsAg is obvious, and the inhibition effect of high-dose saquinavir on HBsAg is better than that of low-dose group; when 10 mu M saquinavir is used in combination with 0.1nM ETV, the inhibition rate of HBsAg is not significantly improved compared with 10 mu M saquinavir.
As shown in the figure 3 of the drawings,
saquinavir has an inhibitory effect on HBeAg. The inhibition rate of 10 mu M saquinavir on HBeAg in HepG2-NTCP cells reaches 68.99%; the inhibition rate of 10 mu M saquinavir+0.1 nM ETV to HBeAg reaches 72.95%.
Compared with the ETV of 0.1nM without obvious inhibition effect on HBeAg, the high-dose saquinavir can better play the inhibition effect on HBeAg; when 10 mu M saquinavir is used in combination with 0.1nM ETV, the inhibition rate of HBeAg is not obviously improved compared with 10 mu M saquinavir.
The test results show that saquinavir has an inhibiting effect on HBV DNA, HBsAg and HBeAg, particularly has an obvious inhibiting effect on HBsAg and HBeAg, so that the saquinavir can be used as a candidate medicament for functionally curing hepatitis B and eliminating hepatitis B virus, and particularly when the saquinavir is combined with a nucleoside analogue medicament capable of reducing HBV titer but incapable of reducing HBsAg and HBeAg, for example, the nucleoside analogue medicament is firstly used for reducing the virus titer, so that when the virus content in a human body is lower, the saquinavir is used for further eliminating the HBsAg and the HBeAg, thereby being hopeful to further cure the virus even completely.
Although the present application has been described with reference to particular embodiments, those skilled in the art will recognize that changes and modifications may be made to the embodiments without departing from the spirit and scope of the application, which is defined by the appended claims.
Claims (6)
1. Use of saquinavir or a pharmaceutically acceptable salt thereof as the sole active ingredient in the manufacture of a medicament for the treatment or prophylaxis of hepatitis b.
2. The use of claim 1, wherein the pharmaceutically acceptable salt of saquinavir is saquinavir mesylate or saquinavir hemisuccinate.
3. The use of claim 1 or 2, wherein the medicament is for reducing Hepatitis B Virus (HBV) load and/or HBsAg level and/or HBeAg level.
4. The use of claim 1 or 2, wherein the medicament is administered by a route selected from the group consisting of: oral and parenteral.
5. The use of claim 4, wherein the medicament is an oral formulation.
6. The use of claim 5, wherein the medicament is a tablet or capsule.
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