CN1738628B - Compositions and methods for combination antiviral therapy - Google Patents
Compositions and methods for combination antiviral therapy Download PDFInfo
- Publication number
- CN1738628B CN1738628B CN200480002190.5A CN200480002190A CN1738628B CN 1738628 B CN1738628 B CN 1738628B CN 200480002190 A CN200480002190 A CN 200480002190A CN 1738628 B CN1738628 B CN 1738628B
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- CN
- China
- Prior art keywords
- emtricitabine
- viread
- preparation
- hiv
- combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
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- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical group N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to therapeutic combinations of [2-(6-amino-purin-9-yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester (tenofovir disoproxil fumarate, Viread <*>) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, Emtriva <TM>, (-)-cis FTC) and their physiologically functional derivatives. The combinations may be useful in the treatment of HIV infections, including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors. The present invention is also concerned with pharmaceutical compositions and formulations of said combinations of tenofovir disoproxil fumarate and emtricitabine, and their physiologically functional derivatives, as well as therapeutic methods of use of those compositions and formulations.
Description
This non-provisional application requires the provisional application 60/440,246 of submission on January 14th, 2003 and 60/440,308 rights and interests, and they are introduced into as a reference at this.
Invention field
Present invention relates in general to contain the combination of the chemical compound of tool antiviral activity (more specifically say so and have anti-HIV characteristic).Especially, the present invention relates to contain the chemically stable combination of the antiviral agent of tool different structure.
Background of invention
HIV (HIV) infects and relevant disease is a public health problem main in the global range.At least three kinds of necessary enzymes of virus replication of human immunodeficiency virus type 1 (HIV-1) coding: reverse transcriptase (RT), protease (Prt) and intergrase (Int).Although being widely used and also having demonstrated, the medicine of targeting reverse transcriptase and protease has curative effect; Particularly when Combined application; But the appearance of toxicity and endurance strain makes its application be restricted (people such as Palella, N.Engl.J.Med. (1998) 338:853-860; Richman, D.D.Nature (2001) 410:995-1001).Human immunodeficiency virus type 1 (HIV-1) protease (Prt) has important function for duplicating of virus, thereby is effective target spot of approved antiviral drugs.HIV Prt lytic virus Gag and Gag-Pol polyprotein obtain virus structural protein (p17, p24, p7 and p6) and three kinds of viral enzymes.Verified, use various RT inhibitor carry out therapeutic alliance can be in the time that continues the virus replication height be suppressed at effectively can't quantized level in.In addition, use RT and Prt inhibitor (PI) to carry out therapeutic alliance and demonstrated cooperative effect aspect duplicating at inhibition HIV.Yet regrettably, owing to drug resistance, the interaction that can not comply with complicated dosage regimen, pharmacokinetics, toxic reaction occur and lack effect causing the patient of present high percentage ratio (being generally 30-50%) can not accept this therapeutic alliance.Therefore, need one type can effectively resist saltant HIV bacterial strain, have distinct drug resistance curve, side effect still less, dosage regimen is simpler, orally active new HIV-1 inhibitor simultaneously.Especially, need a kind of dosage regimen of more oversimplifying, for example every day oral administration once, preferably take the least possible pill.
The Combined application of chemical compound can obtain suitable antiviral effect or obtain enhanced curative effect of medication when reducing toxic reaction.The low more occurrence probability that can reduce HIV drug resistance variant more of total dosage.A variety of distinct methods are used to measure the amalgamation effect (Furman WO 02/068058) of combination in difference mensuration system that contains all cpds.If the pill load reduces, dosage regimen is simplified more; And if also show as synergistic words between the optional all cpds; The low more compliance good more (Loveday, C. " Nucleoside reverse transcriptase inhibitorresistance " (2001) JAIDS Journal of Acquired Immune DeficiencySyndromes 26:S10-S24) that just means the patient of dosage so.According to confirming AZT (zidovudine
TM, 3 '-nitrine, 3 '-AZT) have collaborative antiviral activity when uniting with those medicaments that act on HIV-1 copy step rather than reverse transcription step, this type medicament comprises recombinant soluble CD4 castanospermine and recombinant interferon-α.Yet, it should be noted that the chemical compound combination possibly cause toxic reaction to strengthen.For example, AZT and recombinant interferon-α have enhanced toxic action for normal person's bone marrow blast.
The chemical stability of antiviral agent combination is an importance of combination formulations success, and the present invention just provides the instance of this combination.
In order to treat by some the virus patient that infects of HIV for example; The combination that needs one type of new Orally active medicine; This type combination can provide the treatment safety and the effectiveness of reinforcement, produce lower drug resistance simultaneously, and expection has higher patient's compliance.
Summary of the invention
The invention provides the combination of antiviral compound, specifically be used to suppress compositions and the method for HIV.In illustrative aspects, the present invention includes a kind of compositions that contains Viread (tenofovir disoproxil fumarate) and emtricitabine (emtricitabine) with HIV-resistant activity.The said compositions that contains tenofovir DF and emtricitabine chemically is being stable not only, and has synergism and/or can reduce independent tenofovir DF and emtricitabine or both side effect.Consider the reduction of pill load and the simplification of dosage regimen, such compositions may increase patient's compliance.
The present invention relates to contain [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (Viread, tenofovir DF, TDF, Viread
) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine, Emtriva
TM, (-)-cis FTC) the treatment combination, and the application in comprising the treatment that the HIV that nucleoside and/or non-nucleosidic inhibitors had chemical sproof HIV mutant infection infects.The invention still further relates to the pharmaceutical composition and the preparation of the combination that contains said Viread and emtricitabine.The present invention is to contain the pharmaceutical preparation of physiologic function derivant of physiologic function derivant or the emtricitabine of Viread on the other hand.
Treatment combination of the present invention and pharmaceutical composition and preparation contain PMEA or PMPA (tenofovir) chemical compound and emtricitabine or (2R; 5S, cis)-4-amino-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (3TC; Lamivudine, Epivir
TM) combination, and the application in the treatment that HIV infects.
One aspect of the present invention is the symptom of HIV infection in a kind of treatment or the prevention infected animals or the method for influence; It comprises to what said animal was used (promptly be used for treatment) treatment effective dose contains [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (tenofovir DF; TDF) or its physiologic function derivant and (2R; 5S; Cis)-combination of 4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine) or its physiologic function derivant.
The present invention is to contain the unit dosage forms of the combination of Viread and emtricitabine or its physiologic function derivant on the other hand.Can prepare this unit dosage form and supply oral or other administration, and with regard to the characteristic of component that this type has different structure, said unit dosage forms has beat all chemical stability.
The present invention relates to the chemically stable combination of the antiviral composition that contains Viread and emtricitabine on the other hand.In another aspect of the invention, the said chemically stable combination that contains Viread and emtricitabine further contains the third antiviral agent.In said ternary mixture,, utilized the unique chemical that Viread and emtricitabine had stability in order to guarantee and the third antiviral agent associating.Concrete spendable the third medicine is exemplary and comprise the medicine in the Table A without limitation.Said the 3rd component is preferably the medicine that is applicable to anti-viral uses, more preferably NNRTI or protease inhibitor (PI), further NNRTI more preferably.In a concrete preferred embodiment, the present invention relates to contain the combination of the chemically stable mixture of Viread and emtricitabine and efavirenz.
The present invention is a kind of patient pack on the other hand; It contain be selected from Viread and the emtricitabine at least a, be generally two kinds and optional three kinds of active component and other antiviral agent, and contain relevant for the information inset of uniting the explanation of using Viread and emtricitabine.
The present invention is a kind of method for preparing aforementioned combination on the other hand, and it comprises the mixed medicine that becomes of the tenofovir DF in the combination and emtricitabine to obtain antiviral effect.In another aspect of the invention, provide combination of the present invention to be used for treating the application of the medicine of any one aforementioned viral infection or disease in preparation.
Detailed Description Of The Invention
Although be to combine cited claim the present invention will be described, should be appreciated that this and do not mean that the present invention is limited in these claim.On the contrary, the invention is intended to contain and fall into like all modification, modification within the scope of the invention of claims definition and be equal to replacement.
Definition
Except as otherwise noted, employed following term of this paper and phrase have following implication:
When using trade mark among this paper, the applicant is intended to comprise separately (various) active pharmaceutical ingredient in this branded goods and this branded goods.
Term " chemical stability " is meant that two kinds of main antiviral agent in the combination keep stable basically and chemical degradation does not take place.Preferred their maintenances when physics is mixed are enough stable, thereby allow in the commercial storage life that can utilize this joint product to have.Usually, " chemically stable " is meant that first kind of component can not act on second kind of component and make its degraded when two kinds of components are mixed the formation pharmaceutical dosage form by physics.More typically, " chemically stable " be meant first kind of acidity that component had can catalysis or the acid of quickening second kind of component decompose.(and unrestricted) for instance, in one aspect of the invention, " chemically stable " is meant that Viread can not degrade owing to emtricitabine has acidity basically." basically " in the context is meant when this product is pharmaceutical dosage form; The acid degradation effect that Viread took place in 24 hours is less than about 10% at least greatly; Preferably be lower than 1%, more preferably less than 0.1%, further more preferably less than 0.01%.
Term " is worked in coordination with " and " synergism " is meant that the effect of using chemical compound simultaneously and being obtained is higher than the effect summation that independent these chemical compounds of use are obtained, and just is higher than according to using this two kinds of expectable effects of active component separately.When chemical compound can obtain cooperative effect during for scenarios: (1) is with the form co-formulated and the administration of combination formulations or send; (2) form with independent preparation replaces or parallel sending; Perhaps administration is carried out through some other scheme in (3).When in rotational therapy, sending, if these chemical compounds by for example with independent tablet, pill or capsule, or the form that is contained in the different injections in other syringe of branch carry out administration continuously or send, can obtain cooperative effect.In general, in rotational therapy, the effective dose of various active component is just used continuously successively, and in conjoint therapy, and the effective dose of two kinds or more kinds of active component is used simultaneously.Collaborative antiviral effect is meant than adds merely by each compound effect in the combination and the expect high antiviral effect of effect that obtains.
Term " physiologic function derivant " be meant when with combination of the present invention in other medicines reactive compound when co-administered, have with tenofovir DF or emtricitabine quite or the pharmaceutical active compounds of approximate suitable physiological function.Term as used herein " physiologic function derivant " comprises any one following form: the last acceptable salt of physiology, ether, ester, prodrug, solvate, stereoisomer comprise enantiomer, diastereomer or stereoisomerism enrichment or racemic mixture and (directly or indirectly) above-claimed cpd can be provided or any one other chemical compound of its antiviral activity metabolite or residue after the patient take.
After " bioavailability " is meant and is introduced into medicament in the body, the degree that pharmaceutically active agents is utilized by destination organization.The bioavailability that improves pharmaceutically active agents can provide more effective percentage and more effective treatment for the patient, and this is because for predetermined dose, and more pharmaceutically active agents is obtained to utilize on targeted tissue sites.
Chemical compound in the combination of the present invention can be known as " active component " or " pharmaceutically active agents ".
Term as used herein " prodrug " is meant when system uses to biology, owing to (various) spontaneous chemical reaction, (various) enzyme catalysis chemical reaction and/or the reaction of (various) metabolic chemistry generate any one chemical compound that drug substance is an active component.
" prodrug group " is meant in whole body or endocellular metabolism process through hydrolysis, enzymatic lysis, or the unstable functional group (Bundgaard that separates through some other approach and activity inhibitor chemical compound; Hans; " Design and Application of Prodrugs "
Drug Design and Development(1991), P.Krogsgaard-Larsen and H.Bundgaard, Eds.Harwood Academic Publishers, 113-191 page or leaf).The prodrug group can play and improve dissolubility, absorbability and lipophilic effect, thereby optimizes the sending of medicine, life availability and usefulness.Therefore, " prodrug " is meant the covalent modification analog of therapeutical active compound.
" alkyl " is meant and removes obtain behind the hydrogen atom on the single carbon atom in maternal alkane, alkene or the alkynes saturated or unsaturated, side chain, straight chain, chain or cyclic hydrocarbon group.Common alkyl by 1-18 saturated and/or unsaturated carbon form, for example just, primary, the second month in a season or ring carbon atom.The example comprises but is not restricted to: methyl, Me (CH
3), ethyl, Et (CH
2CH
3), acetenyl (C ≡ CH), vinyl, vinyl (CH=CH
2), the 1-propyl group, just-Pr, n-pro-pyl (CH
2CH
2CH
3), 2-propyl group, different-Pr, isopropyl (CH (CH
3)
2), pi-allyl (CH
2CH=CH
2), propargyl (CH
2C ≡ CH), cyclopropyl (C
3H
5), the 1-butyl, just-Bu, normal-butyl (CH
2CH
2CH
2CH
3), 2-methyl isophthalic acid-propyl group, different-Bu, isobutyl group (CH
2CH (CH
3)
2), 2-butyl, the second month in a season-Bu, sec-butyl (CH (CH
3) CH
2CH
3), 2-methyl-2-propyl group, uncle-Bu, the tert-butyl group (C (CH
3)
3), the 1-amyl group, just-amyl group (CH
2CH
2CH
2CH
2CH
3), 2-amyl group (CH (CH
3) CH
2CH
2CH
3), 3-amyl group (CH (CH
2CH
3)
2), 2-methyl-2-butyl (C (CH
3)
2CH
2CH
3), cyclopenta (C
5H
9), 3-methyl-2-butyl (CH (CH
3) CH (CH
3)
2), 3-methyl isophthalic acid-butyl (CH
2CH
2CH (CH
3)
2), 2-methyl-1-butene base (CH
2CH (CH
3) CH
2CH
3), 1-hexyl (CH
2CH
2CH
2CH
2CH
2CH
3), 5-hexenyl (CH
2CH
2CH
2CH
2CH=CH
2), 1-hexyl (CH (CH
3) CH
2CH
2CH
2CH
3), 3-hexyl (CH (CH
2CH
3) (CH
2CH
2CH
3)), cyclohexyl (C
6H
11), 2-methyl-2-amyl group (C (CH
3)
2CH
2CH
2CH
3), 3-methyl-2-amyl group (CH (CH
3) CH (CH
3) CH
2CH
3), 4-methyl-2-amyl group (CH (CH
3) CH
2CH (CH
3)
2), 3-methyl-3-amyl group (C (CH
3) (CH
2CH
3)
2), 2-methyl-3-amyl group (CH (CH
2CH
3) CH (CH
3)
2), 2,3-dimethyl-2-butyl (C (CH
3)
2CH (CH
3)
2) and 3,3-dimethyl-2-butyl (CH (CH
3) C (CH
3)
3
" aryl " is meant and removes the unit price aromatic hydrocarbyl with 6-20 carbon atom that obtains behind the hydrogen atom on the single carbon atom in the maternal aromatic ring.Common aryl comprises but is not restricted to the group of being derived and being obtained by benzene, substituted benzene, naphthalene, anthracene, biphenyl etc.
" aralkyl " is meant that one of them and carbon atom (are generally end or sp
3Carbon atom) continuous hydrogen atom is by the alternate aliphatic alkyl of aryl.Common aralkyl comprises but is not restricted to benzyl, 2-phenyl second-1-base, 2-phenyl ethylene-1-base, menaphthyl, 2-naphthyl second-1-base, 2-naphthyl ethylene-1-base, naphthyl benzyl, 2-naphthyl phenyl second-1-base etc.Aralkyl for example has 6-20 carbon atom, and the moieties in this aralkyl comprises that alkyl, alkylene or alkynes base have 1-6 carbon atom, and aryl moiety has 5-14 carbon atom.
" substituted alkyl ", " substituted aryl " and " substituted aralkyl " refer to that respectively wherein one or more hydrogen atoms are substituted basic substituted alkyl, aryl and aralkyl independently of one another.Common substituent group comprises but be not restricted to-X ,-R ,-O
-,-OR ,-SR ,-S
-,-NR
2,-NR
3,=NR ,-CX
3,-CN ,-OCN ,-SCN ,-N=C=O ,-NCS ,-NO ,-NO
2,=N
2,-N
3, NC (=O) R ,-C (=O) R ,-C (=O) NRR-S (=O)
2O
-,-S (=O)
2OH ,-S (=O)
2R ,-OS (=O)
2OR ,-S (=O)
2NR ,-S (=O) R ,-OP (=O) O
2RR ,-P (=O) O
2RR-P (=O) (O)
2,-P (=O) (OH)
2,-C (=O) R ,-C (=O) X ,-C (S) R ,-C (O) OR ,-C (O) O
-,-C (S) OR ,-C (O) SR ,-C (S) SR ,-C (O) NRR ,-C (S) NRR ,-C (NR) NRR, wherein each X representes halogen: F, Cl, Br or I independently; And each R representes-H, alkyl, aryl, heterocycle or prodrug group independently.
" heteroaryl " and " heterocycle " is meant that wherein one or more annular atomses are the for example heteroatomic ring system of nitrogen, oxygen and sulfur.Heterocycle is described in: Katritzky, Alan R., Rees, C.W., and Scriven, E.
Comprehensive Heterocyclic Chemistry(1996) Pergamon Press; Paquette, Leo A.;
Principles of Modern Heterocyclic ChemistryW.A.Benjamin, New York, (1968), particularly the 1st, 3,4,6,7 and 9 chapters; " The Chemistry of Heterocyclic Compounds, A series of Monographs " (1950 so far for John Wiley & Sons, New York), especially the 13rd, 14,16,19 and 28 volumes.Exemplary heterocycle comprises but is not restricted to various substituent groups; Promptly by pyrroles, indole, furan, benzofuran, thiophene, benzothiophene, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-imidazoles, 4-imidazoles, 3-pyrazoles, 4-pyrazoles, pyridazine, pyrimidine, pyrazine, purine, cinnolines, pthalazine, quinazoline, quinoxaline, 3-(1,2,4-N)-triazolyl, 5-(1; 2; 4-N)-triazolyl, 5-tetrazole radical, 4-(1-O, 3-N)-oxazoles, 5-(1-O, 3-N)-oxazoles, 4-(1-S; 3-N)-thiazole, 5-(1-S; 3-N)-and thiazole, 2-benzoxazole, 2-[4-morpholinodithio, 4-(1,2,3-N)-group of BTA and benzimidazole derivates:.
McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill BookCompany, New York are normally write in employed spatial chemistry definition of this paper and conversion according to S.P.Parker; And Eliel, E. and Wilen, S., Stereochemistry ofOrganic Compounds (1994) John Wiley & Sons, Inc., New York.There is the optically-active form in a lot of organic compound, that is to say that they have the ability to make the residing plane of linearly polarized light to rotate.When describing optically-active compound, prefix D and L or R and S are used for representing near the absolute configuration of molecule its (a plurality of) chiral centre.Prefix d and l perhaps (+) and (-) are used for representing the direction that the combined thing of linearly polarized light rotates that wherein (-) or l represent that this chemical compound is left-handed.Chemical compound with prefix (+) or d is dextral.For specified chemical constitution, these chemical compounds that are known as stereoisomer are the mirror image except them each other, and all the other are all identical.Specific stereoisomer is known as enantiomer again, and this type mixture of isomers is commonly referred to as diastereomeric mixture.50: 50 mixture of enantiomer are known as racemic mixture or racemic modification.Term " racemic mixture " and " racemic modification " be meant two kinds of enantiomerism materials etc. molar mixture, do not have an optical activity.
Term " chirality " is meant the molecule that its mirror partners (partner) is had non-overlapped characteristic, and " achirality " is meant to its mirror partners it is can eclipsed molecule.
Term " stereoisomer " is meant to have identical chemical constitution, but the spatial arrangements different compounds of atom or group.
" diastereomer " is meant the stereoisomer with two or more chiral centres, and its molecule is not mirror image each other.Diastereomer has different physical propertys, for example fusing point, boiling point, spectral characteristic and reactivity.Diastereomer can through the Analytical high resolution method for example electrophoresis method separate with chromatography.
" enantiomer " is meant two kinds of stereoisomers of chemical compound, they be each other non-can overlapping mirror image.
Active component in the combination
The invention provides the new combination that uses two kinds or more kinds of active component simultaneously.In the part embodiment, obtained collaborative antiviral effect.Obtained chemically stable combination in other embodiments.Said combination comprises the active component of at least a being selected from (1) Viread and physiologic function derivant thereof and the active component of at least a being selected from (2) emtricitabine and physiologic function derivant thereof.Term " collaborative antiviral effect " is meant than adds merely by independent component (a) in the combination and effect (b) and the expect high antiviral effect of effect that obtains.
Viread (also is known as Viread
; Tenofovir DF; Tenofovir disoproxil; TDF; Bis-POC-PMPA (U.S. Patent number 5935946,5922695,5977089,6043230,6069249) is a kind of prodrug of tenofovir, has following structure:
And comprise fumarate (HO
2CCH
2CH
2CO
2 -).
The chemical name of tenofovir disoproxil comprises: [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester; 9-[(R)-and 2-[[two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyl] methoxyl group] propyl group] adenine; With 2,4,6,8-four oxa-s-5-phosphorus nonane diacid, 5-[[(1R)-and 2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl-, two (1-first and second bases) ester, 5-oxide.The CAS registration number comprises: 201341-05-1; 202138-50-9; 206184-49-8.It should be noted that the ethoxyl methyl unit of tenofovir has chiral centre.Here show R (rectus, right hand configuration) enantiomer.Yet the present invention also comprises its S isomer.The present invention includes the stereoisomer mixture of all enantiomers, diastereomer, racemate and the enrichment of tenofovir (PMPA) and physiologic function derivant thereof.
PMPA or tenofovir (U.S. Patent number 4808716,5733788,6057305) have following structure:
PMPA is that the chemical name of tenofovir comprises: (R)-and 9-(2-phosphonyl methoxyl propyl group) adenine; And phosphonic acids, [[(1R)-and 2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl].Its CAS registration number is 147127-20-6.
Viread (DF) is a kind of nucleotide reverse transcriptase inhibitors, goes through to unite with other anti-reverse transcription enzymophathy toxic agent in the U.S. in calendar year 2001 to be used to treat HIV-1 and to infect.(Gilead Science Inc.) is the fumarate of tenofovir disoproxil for Viread or Viread
.Viread
can called after: 9-[(R)-and 2-[[two [[(isopropoxy carbonyl) oxygen base] methoxyl group] phosphinyl] methoxyl group] propyl group] adenine fumarate (1: 1); Perhaps 2,4,6,8-four oxa-s-5-phosphorus Azelaic Acid, 5-[[(1R)-and 2-(6-amino-9H-purine-9-yl)-1-first ethyoxyl] methyl]-, two (1-first and second bases) ester, the 5-oxide, (2E)-2-butylene two acid esters (1: 1).Its CAS registration number is 202138-50-9.
The physiologic function derivant of Viread comprises PMEA (adefovirdipivoxil, 9-((R)-2-(phosphonium mesitoyl methoxy) ethyl) adenine) and PMPA chemical compound.The exemplary joint thing comprises PMEA or the PMPA chemical compound with emtricitabine or 3TC associating.PMEA and PMPA
Chemical compound has following structure:
PMEA (R wherein
3Be H), PMPA (R
3Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl or CH
2OR
8, R wherein
8Be C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl or C
1-C
6Alkylhalide group).R
6And R
7Be H or C independently
1-C
6Alkyl.R
4And R
5Be H, NH independently
2, NHR or NR
2, wherein R is C
1-C
6Alkyl.R
1And R
2Be H, C independently
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
6-C
20Aralkyl, substituted C
6-C
20Aralkyl, acyloxy methyl ester-CH
2OC (=O) R
9(for example POM) or acyloxy methyl carbonic-CH
2OC (=O) OR
9(for example POC), wherein R
9Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl or substituted C
6-C
20Aryl.R for example
1And R
2Can be new pentane acyloxy methoxyl group, POM ,-CH
2OC (=O) C (CH
3)
3-CH
2O (=O) OC (CH
3)
3Or POC ,-CH
2OC (=O) OCH (CH
3)
2In addition, also for example has the tenofovir of following structure, wherein R
3Be CH
3, R
1, R
2, R
4, R
5, R
6And R
7Be H.Dialkyl phosphonate can be according to following method preparation: people such as Quast (1974) Synthesis 490; People such as Stowell (1990) Tetrahedron Lett.3261; U.S. Patent number 5663159.
The PMPA chemical compound can be mapping enrichment or mapping pure (single stereoisomers), wherein carries R
3Carbon atom can be R or S enantiomer.The PMPA chemical compound can be a racemate, i.e. the mixture of R and S stereoisomer.
Adefovirdipivoxil (9-(2-phosphonium mesitoyl methoxy ethyl) adenine, wherein R
1-R
7=H) be a kind of exemplary PMEA chemical compound (U.S. Patent number 4808716,4724233).As two-Pivalate prodrug, adefovirdipivoxil dipivoxil also is known as two-POM PMEA (R
3-R
7=H, R
1And R
2=-CH
2OC (=O) C (CH
3)
3, pivoxil (pivoxil), POM, new pentane acyloxy methoxyl group), it can effectively resist HIV and hepatitis B B infects (U.S. Patent number 5663159,6451340).According to confirming; Have for a short time of the moderate coordinate repression that HIV is duplicated with the adefovirdipivoxil dipivoxil of other chemical compound coupling with HIV-resistant activity, other chemical compound of this type comprises PMPA, d4T, ddC, nelfinavir (nelfinavir), ritonavir and Saquinavir people (1997) Antiviral Research 36:91-97 such as () Mulato.
The present invention includes the stereoisomer mixture of all enantiomers, diastereomer, racemate and the enrichment of PMEA and PMPA and physiologic function derivant thereof.
Emtricitabine ((-)-cis-FTC, Emtriva
TM) be the single enantiomer of FTC, it is a kind of strong effect NRTI (U.S. Patent number 5047407,5179104,5204466,5210085,5486520,5538975,5587480,5618820,5763606,5814639,5914331,6114343,6180639,6215004 that is approved for treatment HIV; WO 02/070518).This single corresponding isomer emtricitabine has following structure:
The chemical name of emtricitabine comprises: (-)-cis-FTC; β-L-methylol-5-(5-flurocytosine-1-yl)-1, the 3-oxathiolane; (2R, 5S)-5-fluoro-1-[2-(methylol)-1,3-oxathiolane-5-yl] cytosine; With 4-amino-5-fluoro-1-(2-methylol-[1,3]-(2R, 5S)-oxathiolane-5-yl)-1H-pyrimid-2-one.Its CAS registration number comprises: 143491-57-0; 143491-54-7.It should be noted that FTC has two chiral centres on 2 and 5 of oxathiolane ring, so it can comprise that the form of racemic mixture exists with two pairs of optical isomers (being enantiomer) and composition thereof.So FTC not only can be a cis but also can be transisomer or its mixture.The mixture of cis and transisomer is the diastereomer with different physical properties.Every kind of cis and transisomer can comprise that with a kind of or its mixture in two kinds of enantiomers the form of racemate exists.The present invention includes the stereoisomer mixture of all enantiomers, diastereomer, racemate and the enrichment of emtricitabine and physiologic function derivant thereof.For example; The present invention includes for example enantiomer (2R, 5S, cis)-4-amino-5-fluoro-1-(2-methylol-1 of physiologic function derivant; 3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine) and mirror image (2S thereof; 5R, cis)-1: 1 racemic mixture of 4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one or the mixture that this two kinds of enantiomers are formed with any relative amount.The present invention also comprises the mixture of the FTC of cis and trans forms.
The physiologic function derivant of emtricitabine comprises having 1 of following structure, 3-oxathiolane nucleoside:
Above-mentioned 1, in the 3-tetrahydrofuran nucleoside structure, B is a nuclear alkali (nucleobase), comprises that any one can for example purine, 7-deazapurine or pyrimidine pairing form the nitrogen heterocyclic ring group of Watson-Crick hydrogen bond with compensation nuclear alkali or nuclear alkali analog.The instance of B comprises the nuclear alkali of native form: the minor components and the analog of the nuclear alkali of adenine, guanine, cytosine, uracil, thymus pyrimidine and native form; For example 7-denitrogenation adenine, 7-deazaguanine, 7-denitrogenation-guanozola, 7-denitrogenation-8-azaadenine, inosine, nebularine, nitro-pyrrole, nitroindoline, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-flurocytosine, 5-chlorine cytosine, 5-bromine cytosine, 5-iodocytosine, false cytosine, false iso-cytosine, 5-propargyl cytosine, iso-cytosine, isoguanine, 7-deazaguanine, 2-sulfo-pyrimidine, 6-thioguanine, 4-thio-thymine, 4-sulfo-uracil, O
6-methyl guanine, N
6-methyladenine, O
4-methyl thymus pyrimidine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, pyrazolo [3,4-D] pyrimidine (U.S. Patent number 6,143,877 and 6,127,121; WO 01/38584) and the vinylation adenine (Fasman (1989) Practical Handbook of Biochemistry and Molecular Biology, the 385-394 page or leaf, CRC Press, Boca Raton, F1).
Nuclear alkali B can be with the nucleic acid configuration of the native form N-9 through purine for example N-1 for example thymus pyrimidine-1-base and cytosine-1-base and 1 of adenine-9-base and guanine-9-base or pyrimidine; 3-oxathiolane (the Blackburn that links to each other; G. and Gait, M. compiles. " DNA and RNAstructure " in Nucleic Acids in Chemistry and Biology, second edition; (1996) Oxford University Press, the 15-81 page or leaf)..
In addition, above-mentioned 1, in the 3-oxathiolane nucleoside structure, R is H, C
1-C
18Alkyl, substituted C
1-C
18Alkyl, C
2-C
18Alkenyl, substituted C
2-C
18Alkenyl, C
2-C
18Alkynyl group, substituted C
2-C
18Alkynyl group, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
2-C
20Heterocycle, substituted C
2-C
20Heterocycle, phosphonate ester, phosphoric acid phosphonate ester, diphosphonic acid phosphonate ester, phosphate ester, bisphosphate, triguaiacyl phosphate, polyethyleneoxy or prodrug group.
The physiologic function derivant of emtricitabine also comprises 3TC (lamivudine; Epivir
), it is that a kind of AZT (GlaxoSmithKline) by U.S.'s approval and commodity Combivir
by name unites the RTI that is used to treat the HIV-1 infection.Referring to U.S. Patent number 5859021; 5905082; 6177435; 5627186; 6417191.Lamivudine (U.S. Patent number 5587480,5696254,5618820,5756706,5744596,568164,5466806,5151426) has following structure:
For example for some therapeutic use, 3TC can be the physiologic function derivant with the emtricitabine of the physiologic function derivant associating of tenofovir DF or tenofovir DF.
It should be understood that tenofovir DF and emtricitabine and physiologic function derivant thereof can exist with the ketoenol tautomerization form, so any one above-mentioned tautomeric form falls in the scope of the invention all.Generally, in combination of the present invention, use tenofovir DF and the emtricitabine that does not have corresponding enantiomer basically, that is to say to have the corresponding enantiomer that is no more than about 5%w/w.
Prodrug
The present invention includes any prodrug of tenofovir and emtricitabine.The exemplary prodrug of tenofovir is Viread (TDF, Viread
).For phosphoric acid, the diversified prodrug of a lot of structures (Freeman and Ross, Progress inMedicinal Chemistry 34:112-147 (1997) have been described.One type of prodrug commonly used is the acyloxy Arrcostab, and it is the prodrug strategy that is used for carboxylic acid at first, is applied to (1983) J.Pharm.Sci.72:324 on phosphate ester and the phosphonate ester by people such as Farquhar afterwards; And U.S. Patent number 4816570,4968788,5663159 and 5792756.Next, the acyloxy Arrcostab is used to cross-cell membrane and sends phosphonic acids to improve oral administration biaavailability.Similar various acyloxy Arrcostab strategy, alkoxyl carbonyl oxygen base Arrcostab also can be as the prodrug group on the chemical compound in the combination of the present invention to improve bioavailability.The aryl ester of phosphorus-containing groups, particularly phenylester are in the news and can improve oral administration biaavailability (people (1994) J.Med.Chem.37:498 such as DeLambert).Described and contained the phenylester (KhamneiandTorrence, (1996) J.Med.Chem.39:4109-4115) that is positioned at the adjacent carboxylate of phosphate ester.It is reported that benzyl ester generates the parent phosphonic acids.In some cases, the substituent group that is positioned at ortho position or para-position can be accelerated hydrolysis.Benzyl analog with acidylate phenol or alkylated phenol can generate phenolic compound through the enzyme effect, for example esterase, oxidase etc., and cracking then takes place in phenolic compound on benzylic C-O key, generation phosphonic acids and quinone methides intermediate.The case description of this type prodrug is at people such as Mitchell (1992) J.Chem.Soc.Perkin Trans.I 2345; Among the people WO 91/19721 such as Brook.Other benzylic prodrug that contains the carboxylate group (people WO 91/19721 such as Glazier) that links to each other with the benzylic methylene has also been described.The sulfur-bearing prodrug is in the news and can be used for sending in the cell phosphonate ester medicine.This type prodrug ester contains ethylmercapto group, and wherein mercapto combines to form disulphide by the acyl group esterification or with another mercapto.Disulphide is taken off esterification or reduction generates free sulfur-bearing intermediate, and it breaks off subsequently and obtains phosphoric acid and episulfide (people (1993) AntiviralRes. such as Puech, 22:155-174; People such as Benzaria (1996) J.Med.Chem.39:4958).Annular phosphonate also is in the news can be as the prodrug of phosphorus-containing compound.
Prodrug according to the present invention is independently selected from: the list of (1) tenofovir or emtricitabine-, two-, three-phosphate ester, perhaps after patient people takes, can provide (directly or indirectly) said list-, two or any other chemical compound of triguaiacyl phosphate; (2) carboxylate; (3) sulphonic acid ester, for example alkyl or sweet-smelling alkyl sulfonic acid ester (like mesyl); (4) amino-acid ester (for example alanine, L-is valyl or the L-isoleucyl-); (5) phosphonate ester; And (6) phosphonic amide ester.
Ester group (1)-(6) can be replaced by following radicals: straight or branched C
1-C
18Alkyl (like methyl, n-pro-pyl, the tert-butyl group or normal-butyl); C
3-C
12Cycloalkyl; Alkoxyalkyl (like methoxy); Aralkyl (like benzyl); Aryloxy alkyl (like phenoxymethyl); C
5-C
20Aryl is (as choosing wantonly by for example halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl or amino substituted phenyl; Acyloxy methyl ester-CH
2OC (=O) R
9(like POM) or acyloxy methyl carbonic-CH
2OC (=O) OR
9(like POC), wherein R
9Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl or substituted C
6-C
20Aryl.For example, ester group can be :-CH
2OC (=O) C (CH
3)
3,-CH
2OC (=O) OC (CH
3)
3Or-CH
2OC (=O) OCH (CH
3)
2
The exemplary aryl that is present in this type ester comprises phenyl or substituted phenyl.A lot of phosphate ester prodrug groups are described in U.S. Patent number 6312662; People such as Jones (1995) AntiviralResearch 27:1-17; People such as Kucera (1990) AIDS Res.Hum.Retro Viruses6:491-50; People such as Piantadosi (1991) J.Med.Chem.34:1408-14; People such as Hosteller (1992) Antimicrob.Agents Chemother.36:2025-29; People such as Hostetler (1990) J.Biol.Chem.265:611127; And among people (1999) J.Med.Chem.42:4122-28 such as Siddiqui.
Pharmaceutically acceptable prodrug be meant through enzyme effect or common acids or alkali solvolysis in the host metabolism for example hydrolysis or oxidation form the chemical compound of active component.Active component exemplary has unsettled protection base biology in the combination of the present invention on the functional group of this reactive compound.Prodrug comprises can be oxidized, reduction, ammonification, deaminizing, esterification, take off the chemical compound of esterification, alkylation, dealkylation, acidylate, deacylation, phosphorylation, dephosphorylation, or can relate to and form or break off the chemical compound that other functional group of prodrug chemical bond changes or transforms.
The chemical stability of pharmaceutical preparation
The stability of active component in pharmaceutical preparation comprises the production that as far as possible reduces impurity and guarantees enough shelf-life.Active component in the preparation of the present invention is that Viread and emtricitabine have relatively low pKa value, and this shows possibly cause active component generation acid hydrolysis.Pka is that 2.65 emtricitabine (Inc.2003 can be obtained by gilead.Com for Emtriva Product Insert, GileadSciences) forms the 5-floxuridine and examines alkali after 5-flurocytosine nuclear basic hydrolysis deamination.PKa is 3.75 Viread (people " Degradation Kinetics ofOxycarbonyloxymethyl Prodrugs of Phosphonates in Solution " such as Yuan L.; Pharmaceutical Research (2001) Vol.18; No.2; 234-237) also make adenine examine the exocyclic amine hydrolytic deaminzation baseization of alkali easily, make one or two POC ester group hydrolysis (U.S. Patent number 5922695) simultaneously.It is desirable to the treatment combination that Viread and emtricitabine and physiologic function derivant thereof are mixed with the impurity that contains minimum flow and have enough stability.
Combination of the present invention provides the acid degradation to following component to show as chemically stable combination medicine dosage form: (1) first component (for example Viread and physiologic function derivant thereof); (2) second components (for example emtricitabine and physiologic function derivant thereof); (3) the 3rd component of choosing wantonly with antiviral activity.Said the 3rd component comprises anti-hiv agent, comprising: protease inhibitor (PI), NRTI (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor.With co-administered exemplary the 3rd active component of first and second components shown in Table A.First and second components are defined in the previous section title:
Active component in the combinationIn.
Salt
Any chemical compound in the present composition comprises that also its physiology goes up acceptable salt.The physiology of tenofovir DF, emtricitabine and physiologic function derivant thereof goes up acceptable salt and comprises by suitable alkali for example alkali metal (like sodium), alkaline-earth metal (like magnesium), ammonium and NX
4 +(wherein X is C
1-C
4Alkyl), perhaps organic acid fumaric acid, acetic acid, the succinic acid salt of deriving and obtaining for example.Hydrogen atom or amino physiology go up acceptable salt and comprise organic carboxyl acid for example acetic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, hydroxyethylsulfonic acid., newborn diacid and succinic acid; Organic sulfonic acid is methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid and p-methyl benzenesulfonic acid for example; And the mineral acid salt of hydrochloric acid, sulphuric acid, phosphoric acid and sulfamic acid for example.
The physiology of hydroxy compounds upward acceptable salt comprises and suits for example Na of cation
+And NX
4 +(wherein X is independently selected from H or C
1-C
4Alkyl) anion of the said chemical compound of associating.
Use for treatment, it is acceptable that the salt of the active component in the combination of the present invention should be that the physiology goes up, and promptly they should derive and obtain by accepting acid or alkali on the physiology.Certainly, not that the salt of acceptable acid of physiology student or alkali also has its application, for example be used for preparation and purification physiology and go up acceptable chemical compound.All salt (though its whether by can accept on the physiology acid or alkali derive obtain) all fall within the scope of the invention.
The administration of preparation
Although the various active component in the combination can be separately as single therapy agent separate administration, preferably with its form administration as pharmaceutical combination preparations.Can be simultaneously or the combination of continuous administration two components or three components.When continuous administration, this combination can be divided into once, twice or three administrations.
Preferably, two components or three component combinations are with single pharmaceutical dosage form administration.More preferably, two component combinations are with single peroral dosage form administration, and three component combinations are with two kinds of identical peroral dosage form administrations.The example comprises the biplate agent of single tablet or Viread, emtricitabine and the efavirenz of Viread and emtricitabine.
It should be understood that; The administration in the following manner of chemical compound in the combination: perhaps (2) alternately administration of (1) associating each chemical compound administration simultaneously in the combination formulations, be about to chemical compound with independent pharmaceutical dosage forms successively, continuous, parallel or send simultaneously.In rotational therapy, use second and time delay of optional the 3rd active component should be unlikely to make the associating Synergistic treatment beneficial effect that these active component had to incur loss.By means of medication (1) or (2), ideal situation is that the administration of said combination should make every kind of active component obtain peak plasma concentration.Take combination formulations through the dosage regimen of a slice once a day and possibly be applicable to some HIV positive patient.The effective plasma level peak concentration that active component had in the combination should fall in the scope that is approximately 0.001-100 μ M.For particular patient, through obtaining best peak plasma concentration to its individual preparation and dosage regimen.It should be understood that simultaneously or the tenofovir DF of successive administration and emtricitabine or the physiologic function derivant of one of them can be separately or with perhaps any one cooperative programs administration of multiple-unit form.Generally speaking, in rotational therapy (2), the effective dose of each chemical compound is to carry out administration continuously, and in combination formulations therapy (1), and the effective dose of both or more compounds is to carry out administration together.
The combination preparation
When each the independent component in the combination was separated administration, they were to exist with separately pharmaceutical dosage forms usually.Only if qualification is arranged in addition, preparation hereinafter all is meant the preparation that contains this combination or its component composition.It should be understood that with combination of the present invention through the patient with the monolayer medicated bag, or the mode of the patient pack of various preparations (wherein contain remind the patient is correct to use package insert of the present invention) administration constituted the ideal supplementary features of the present invention.The present invention also comprises a kind of double-deck medicated bag, and it contains Viread that the confession of merging form separately takes and emtricitabine or one or both the preparation of physiologic function derivant in them.
Conjoint therapy of the present invention comprises: the combination of (1) tenofovir DF and emtricitabine perhaps (2) contains one or both the combination of physiologic function derivant in them.
The dosage unit preparation that can this combination be mixed with the various active pharmaceutical ingredients that contain constant concentration is regularly for example to use this active component once a day or repeatedly.
Pharmaceutical preparation according to the present invention contains with good grounds combination of the present invention and a kind of or more kinds of pharmaceutically suitable carrier or excipient and other optional therapeutic agent.The pharmaceutical preparation that contains active component can be for being fit to hope the arbitrary form of medication.When being used for oral administration, for example can be prepared into tablet, tablet, lozenge, water or oil suspension, can disperse powder or granule, Emulsion, hard or soft capsule, syrup or elixir (
Remington ' s Pharmaceutical Sciences(Mack Publishing Co., Easton, PA).Hoping to be used for liquid preparations for oral administration can be according to any one preparation of pharmaceutical compositions method preparation known in the art; In order to obtain good to eat preparation; This based composition can contain a kind of or more kinds of adjuvant, comprises antioxidant, sweeting agent, aromatic, coloring agent and antiseptic.Contain with the pharmaceutically acceptable excipient of avirulence that is suitable for preparing tablet mutually the tablet of mixed active component be gratifying.These excipient can be, for example inert diluent such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, cross-linking sodium carboxymethyl cellulose, polyvidone, calcium phosphate or sodium phosphate; Granulation and disintegrating agent such as corn starch or alginic acid; Binding agent such as cellulose, microcrystalline Cellulose, starch, gelatin or Radix Acaciae senegalis; And lubricant such as magnesium stearate, stearic acid or Talcum.Tablet is coating not, also can comprise microencapsulation with disintegrate and the absorption of delay in gastrointestinal tract, thereby lasting release action is provided in a long time according to the known method coating.For example can postpone service time material as separately or with blended glyceryl monostearate of wax or glycerol distearate.
The preparation that is used for oral administration can also be made into active component and the inert solid diluent mixed hard gelatin capsule of starch,pregelatinized, calcium phosphate or Kaolin for example, perhaps processes the Gelseal that wherein active component and water or oleaginous base such as Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil mix.
Water suspension of the present invention contains and the blended active substance of excipient that is suitable for making water suspension.This type excipient comprises suspending agent such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and Radix Acaciae senegalis, disperses or the condensation product (like Tween-81) of the condensation product (like 17 ethylidene oxygen hexadecanols) of condensation product (like Myrj 45), oxirane and the long-chain fatty alcohol of phospholipid (like lecithin), epoxyalkane and the fatty acid of wetting agent such as native form, oxirane and the ester that obtained by fatty acid and the esterification of hexitol anhydride moiety.Water suspension can also contain a kind of or more kinds of antiseptic for example ethyl or n-propyl p-hydroxybenzoate, a kind of or more kinds of coloring agent, a kind of or more kinds of aromatic and a kind of or more kinds of sweeting agent such as sucrose, sucralose or glucide.
Making up oil suspensoid can be through being suspended in active component in vegetable oil such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois or mineral oil such as the liquid paraffin.Oral suspensions can contain thickening agent, for example Cera Flava, hard paraffin and hexadecanol.In order to obtain good to eat oral formulations, can add above-mentioned sweeting agent and aromatic.These compositionss can for example ascorbic acid, BHT etc. preserve through adding antioxidant.
Through disperseing to add entry in powder and the granule, make active component and dispersion or wetting agent, suspending agent and a kind of or more kinds of antiseptic form mixture to the present invention who is suitable for preparing water suspension.Suitable dispersion or wetting agent and suspending agent are given an example in front.Can also there be other excipient, for example sweeting agent, aromatic and coloring agent.
Pharmaceutical composition of the present invention can also be oil or aqueous emulsion or Liposomal formulation form.Oil phase can be for example olive oil or an Oleum Arachidis hypogaeae semen of vegetable oil, and mineral oil is liquid paraffin for example, perhaps their mixture.The natural gum that examples of suitable emulsifiers comprises native form for example Radix Acaciae senegalis and Tragacanth, native form phospholipid for example soybean lecithin, being derived by fatty acid and hexitol anhydride obtains the for example condensation product Tween-81 for example of dehydrated sorbitol mono-fatty acid ester and these part esters and oxirane of ester or part ester.Emulsion can also contain pleasantly sweet and aromatic.Syrup and elixir can also be with for example glycerol, Sorbitol or sucrose preparations of sweeting agent.This type preparation can also contain demulcent, antiseptic, aromatic or coloring agent.
Pharmaceutical composition of the present invention can be the form of sterilization injectable formulation, for example sterilize injectable water or oiliness suspensoid.Said suspensoid can be according to known method, and suitable dispersion of having mentioned above the use or wetting agent and suspending agent are prepared.The sterilization injectable formulation can also be can accept sterilization injectable solutions or suspensoid in diluent or the solvent at the avirulence parenteral, and for example 1, the solution in 3-butane-glycol perhaps is prepared into the form of freeze-dried powder.In acceptable medium, spendable solvent is water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, the sterilization fixed oils also can be used as solvent or suspension media usually.To achieve these goals, any one gentle fixed oils be can use, synthetic glycerine monoesters or diester comprised.In addition, similarly, fatty acid for example oleic acid also can be used for preparing injection.
Pharmaceutical composition of the present invention can be in parenteral injection, for example in intravenous, intraperitoneal, the sheath, in the ventricle, in the breastbone, intracranial, intramuscular or subcutaneous injection, perhaps they also can pass through the infusion methods administration.They preferably use with the sterile water solution agent form that contains other material, and other material for example makes solution and isoosmotic enough salt of blood or glucose.If necessary, can aqueous pharmaceutical suitably be cushioned (preferably its pH is 3-9).The standard pharmaceutical technology that the suitable preparation of parenteral formulation under sterilising conditions can be known is easily by one of skill in the art accomplished.
Pharmaceutical composition of the present invention also can pass through intranasal or inhalation; And can also send by means of suitable propellant from pressurizing vessel or nebulizer with Foradil Aerolizer formoterol fumarate or aerosol spray form easily; Propellant is dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, hydrofluoroalkane for example 1 for example; 1,1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas.In the situation of pressurised aerosol, confirm dosage device through the valve of sending that metered amount is provided.Pressurizing vessel or nebulizer can contain the mixture that for example utilizes ethanol and propellant solution or the suspensoid as the present composition of solvent, and it can also contain for example sorbitan trioleate of lubricant.Can the capsule that be used for inhaler or insufflator and cartridge case (for example by gelatin preparation) be mixed with the for example form of sucrose or starch of the mixture of powders that contains formula (I) chemical compound and suitable powder substrate.Preferred aerosol or the dry powder formulations regulated makes when patient's administration each dosing or " once spraying " contain 20 μ g to 20mg compositionss.The total daily dose of aerosol can be 20 μ g to 20mg, in one day they can with single dose administration, or more generally be with the divided dose administration.
Active component and carrier material merge and obtain one-pack type, and its consumption depends on the host that receives treatment and the concrete model of administration.For example, prepare to supply the delivery formulations in time (time-release) of human oral can close about 1-1000mg active substance chemical compound and suitably and the carrier material of conventional amount used, its consumption can account for total composition about 5 to about 95% (weight: weight).Can prepare the pharmaceutical composition that when taking, easily content is detected.For example, in order to realize volume, prepare to supply the aqueous pharmaceutical of intravenous infusion can contain about 3-500 μ g active component/ml soln agent with about 30mL/ hour speed infusion of suitable.As stated, the discrete unit form that the preparation of the present invention that is fit to oral administration can be prepared to the active component that contains predetermined content separately is capsule, cachet or tablet for example; Powder or granule; Solution in water or on-aqueous liquid or suspensoid; Perhaps oil in water emulsion or Water-In-Oil liquid emulsion.Active component can also with disposablely inject, the form administration of electuary or paste.
Combination of the present invention can be processed the pharmaceutical preparation of unit dosage forms easily.Conventional unit dosage forms preparation contains the active component that content is 1mg to 1g (for example but be not restricted to 10mg to 300mg) separately.Under wide in range ratio, all can obtain the synergy of tenofovir DF and emtricitabine associating, for example be 1: 50 to 50: 1 (tenofovir DF: emtricitabine).In one embodiment, this ratio is about 1: 10 to 10: 1.In another embodiment; The w/w ratio of tenofovir and emtricitabine is approximately 1 in the combination dosage form of co-formulated (for example pill, tablet, Caplet or capsule); That is to say, contain roughly the quite tenofovir DF and the emtricitabine of consumption.In other exemplary joint preparation, tenofovir can be greater or less than FTC.For example, 300mg tenofovir DF and 200mg emtricitabine can be with 1.5: 1 (tenofovir DF: ratio co-formulated emtricitabine).Show that the consumption of antiviral activity is used for combination when in one embodiment, each chemical compound can be with independent use.Exemplary formulation A, B, C, D, E and F (embodiment) have 12: 1 to 1: 1 ratio (tenofovir DF: emtricitabine).The consumption of employed tenofovir DF of exemplary formulation A, B, C, D, E and F and emtricitabine is 25mg to 300mg.Other ratio and the consumption of each chemical compound also falls within the scope of the invention in the said combination.
Unit dosage forms can also further contain tenofovir DF and emtricitabine or any one physiologic function derivant and pharmaceutically suitable carrier wherein.
Those skilled in the art should understand that; Each required absorption of active ingredient of the combination of the present invention that is used for treating depends on various factors; Comprise symptom character, patient age and the situation of receiving treatment, it is finally by the doctor in charge or health care practitioner decision.The factor of need considering comprises administering mode and preparation nature, the weight of animals, age and roughly situation and the disease character and the order of severity of receiving treatment.For example, in the research of the I/II of emtricitabine phase single current system method, the dosage that the patient took is 25mg to 200mg, every day twice, continues for two weeks.In being greater than or equal to each dosage regimen of 200mg, observing virus is had 98% (1.75 log10) or higher inhibition effect.Once a day, dosage is that the emtricitabine of 200mg has on average reduced by 99% (1.92 log10) with viral load.The Viread of 300mg oral tablet form
(tenofovir DF) is used for treatment by the FDA approval and prevention of HIV infects.The Emtriva of 200mg oral tablet form
TM(emtricitabine) is used to treat HIV by the FDA approval.
Can also any two kinds of active component in the unit dosage forms and the 3rd active component be united with while or successive administration.Said three component combinations can while or successive administration.When carrying out administration continuously, said combination can be divided into twice or three administrations.The 3rd active component has HIV-resistant activity, and it comprises protease inhibitor (PI), NRTI (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor.Can unite exemplary the 3rd active component that is used to treat shown in Table A with tenofovir DF, emtricitabine and physiologic function derivant thereof.
Table A
5,6-dihydro-5-azacytidine
5-azepine 2 ' deoxycytidine
5-azacytidine
5-base-carbocyclic ring 2 '-deoxyguanosine (BMS200,475)
9 (arabinofuranosyl base) guanine; 9-(2 ' desoxyribofuranose base) guanine
9-(2 '-deoxidation 2 ' fluorine ribofuranosyl)-2, the 6-diaminopurine
9-(2 '-deoxidation 2 ' fluorine ribofuranosyl) guanine
9-(2 '-the desoxyribofuranose base)-2, the 6-diaminopurine
9-(arabinofuranosyl base)-2, the 6-diaminopurine
Ziagen, Ziagen
Acyclovir, ACV; 9-(2-hydroxy ethoxy methyl) guanine
amdoxivir,DAPD
VX-478 (Amprenavir), Agenerase
;
AraA; 9-β-D-arabinofuranosyl base adenine (vidarabine)
AZT; 3 '-nitrine-2 '; 3 '-Didansine; Zidovudine, (Retrovir
)
BHCG; (.+-.)-(1a, 2b, 3a)-9-[2, two (methylol) cyclobutyl of 3-] guanine
BMS200,475; 5-base-carbocyclic ring 2 '-deoxyguanosine
Buciclovir; (R) 9-(3,4-dihydroxy butyl) guanine
BvaraU; 1-β-D-arabinofuranosyl base-E-5-(2-bromo vinyl) uracil (sorivudine)
Calanolide?A
SHIONOGI (Capravirine)
CDG; Carbocyclic ring 2 '-deoxyguanosine
GS-504, HPMPC; (S)-9-(3-hydroxyl-2-phosphonyl methoxyl propyl group) cytosine
Clevudine, L-FMAU; 2 '-fluoro-5-methyl-β-L-1-
Cytallene; [1-(4 '-hydroxyl-1 base) cytosine]
D4C; 3 '-deoxidation-2 ', 3 '-two dehydrogenation cytidines
DAPD; (-)-β-D-2,6-diaminopurine dioxolanes
DdA; 2 ', 3 '-DIDEOXYADENOSINE
DdAPR; 2,6-diaminopurine-2 ', 3 '-the dideoxy riboside
DdC; 2 ', 3 '-zalcitabine (zalcitabine)
DXG; The dioxolanes guanosine
E-5-(2-bromo vinyl)-2 '-BrdU
F-ara-A; The Arabic glycosyl adenosine (fludarabine) of fluorine
FDOC; (-)-β-D-5-fluoro-1-[2-(methylol)-1,3-dioxolanes] cytosine
FEAU; 2 '-deoxidation-2 '-the fluoro-1-
FIAC; 1-(2-deoxidation-2-fluoro-beta-D-arabinofuranosyl base)-5-iodocytosine
FIAU; 1-(2-deoxidation-2-fluoro-(3-D-arabinofuranosyl base)-5-ioduria glycosides
FLG; 2 ', 3 '-dideoxy-3 '-the fluorine guanosine
FLT; 3 '-deoxidation-3 '-fluorothymidine
Fludarabine; F-ara-A; The Arabic glycosyl adenosine of fluorine
FMAU; 2 '-fluoro-5-methyl-β-L-1-
FMdC
Phosphine formic acid; Phosphine formic acid, PFA
FPMPA; 9-(3-fluoro-2-phosphonyl methoxyl propyl group) adenine
Ganciclovir, GCV; 9-(1,3-dihydroxy-2-third oxygen methyl) guanine
GS-7340; 9-[R-2-[[(S)-[[(S)-1-(the different third oxygen carbonyl) ethyl] amino]-the phenoxy group phosphinyl] methoxyl group] propyl group] adenine
HPMPA; (S)-9-(3-hydroxyl-2-phosphonyl methoxyl propyl group) adenine
HPMPC; (S)-9-(3-hydroxyl-2-phosphonyl methoxyl propyl group) cytosine (GS-504)
Kaletra
(Lopinavir/ritonavir)
Lamivudine, 3TC, Epivir
TM(2R, 5S, cis)-4-amino-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one
L-d4C; L-3 '-deoxidation-2 ', 3 '-two dehydrogenation cytidines
L-ddC; L-2 ', 3 '-zalcitabine
L-Fd4C; L-3 '-deoxidation-2 ', 3 '-two dehydrogenations-5-fluorine cytidine
L-FddC; L-2 ', 3 '-dideoxy-5-fluorine cytidine
Lopinavir
Nevirapine, Viramune
Nucleoside analog A (Oxetanocin A); 9-(the adenine of 2-deoxidation-2-methylol-β-D-erythro form-oxetanosyl)
Nucleoside analog G (Oxetanocin G); 9-(the guanine of 2-deoxidation-2-methylol-β-D-erythro form-oxetanosyl)
Penciclovir
PMEDAP; 9-(2-phosphonyl methoxyl ethyl)-2, the 6-diaminopurine
PMPA, tenofovir; (R)-9-(2-phosphonyl methoxyl propyl group) adenine
PPA; Phosphine acyl acetic acid
Ribavirin; 1-β-D-ribofuranosyl-1,2,4-triazole-3-Methanamide
Sorivudine, BvaraU; 1-β-D-arabinofuranosyl base-E-5-(2-bromo vinyl) uracil
Trifluorothymidine, TFT; Trifluorothymidine
Vidarabine, araA; 9-β-D-arabinofuranosyl base adenine
Zidovudine, AZT, Retrovir
; 3 '-azido-2 ', 3 '-Didansine
Zonavir; The Arabic glycosyl uracil of 5-propinyl-1-
The present invention relates to a kind of three component combinations on the other hand, and it contains tenofovir DF, FTC and has the 9-of following structure [(R)-2-[[(S)-[[(S)-1-(the different third oxygen carbonyl) ethyl] amino] phenoxy group phosphinyl] methoxyl group] propyl group] adenine (also being known as GS-7340) at this paper:
GS-7340 is a kind of prodrug of tenofovir, simultaneously also is the theme of WO02/08241 that applies for the people such as unsettled pending trial U. S. application serial number 09/909,560 and Becker in July 20 calendar year 2001.
For example, three component UDs can contain 1mg to 1000mg Viread, 1mg to 1000mg emtricitabine and 1mg to 1000mg the 3rd active component.As further aspect of the present invention, unit dosage forms can also further contain physiologic function derivant and pharmaceutically suitable carrier of tenofovir DF, emtricitabine, the 3rd active component or these three kinds of active component.
Combination of the present invention can make the patient need not accept the dosage regimen of multiple dose, alleviates needs of patients and remembers and comply with complicated every day of administration time and the burden of dosage regimen.Get in the single dosage form through Viread and emtricitabine are merged, can accomplish ideal every day of dosage regimen with the form of taking single dose or twice or more times divided dose every day.The tenofovir DF of co-formulated and the combination of emtricitabine can be used as single pill and take once every day.
The present invention relates to a kind of patient pack on the other hand, and it contains at least a active component: the physiologic function derivant of any one in Viread, emtricitabine or this combination and contain information-package and the product inset relevant for the explanation of combination method for using of the present invention.
Segregation (segregation) phenomenon of active component in drug powder and granule is a recognized techniques difficult problem, and it is inhomogeneous that it possibly cause active component in final dosage form, to disperse.Some principal element that causes the segregation phenomenon is owing to granular size, shape and density.When preparation contained the single even tablet of various active composition of tool different densities and different-grain diameter, the segregation phenomenon was especially thorny.Fluidizer is the material that is used for improving granule and powder flow behavior traditionally through reducing the friction between the microgranule.Referring to Lieberman, Lachman, & Schwartz, Pharmaceutical Dosage Forms:Tablets, the 1st volume, 177-178 page or leaf (1989) is introduced into as a reference at this.Usually before tablet press, in pharmaceutical composition, add fluidizer to promote particulate matter flowing in tablet pelleter fatal weakness.Fluidizer comprises: silica sol, no asbestos Talcum, lagoriolite, calcium silicates, cellulose powder, microcrystalline Cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, metallic stearate, calcium stearate, magnesium stearate, zinc stearate, stearowet C, starch, starch 1500, Stepanol MG and magnesium oxide.Contain silica sol (embodiment) among the example disc agent formulation A.Fluidizer can be used to improve and improve the component mixing homogeneity (U.S. Patent number 6113920) in the inverase preparation.In order each active component to be obtained and to keep uniformity, can contain fluidizer in the new compositions of the present invention.
The invention provides with various active component be tenofovir DF and emtricitabine or its physiologic function derivant merge enough pharmaceutical preparation uniformly, and the method for using this pharmaceutical preparation.One of the object of the invention is to utilize fluidizer to reduce the segregation phenomenon that takes place in the material course of processing of various active component before tabletting in the pharmaceutical composition.Another purpose of the present invention is to provide a kind of pharmaceutical preparation; It is associated with various active component is tenofovir DF and emtricitabine or its physiologic function derivant and pharmaceutically suitable carrier, the mixture that obtains it is characterized in that having the pharmaceutically acceptable uniformity.
Preparation comprises that those are suitable for the preparation of oral, rectum, intranasal, part (comprising percutaneous, cheek and Sublingual), vagina or non-intestinal (comprising subcutaneous, intramuscular, intravenous and Intradermal) administration.Any means that these preparations can be known according to pharmaceutical field is easily processed unit dosage forms.These methods have been represented another feature of the present invention, comprise various active component and the carrier that is made up of a kind of or more kinds of auxiliary agent are mixed, and keep its chemical stability then.Usually, even and fine and close mixed through these active component and liquid-carrier or finely-divided solid carrier or both are carried out, make formed product then if necessary, so just prepared said preparation.
Can the preparation of the present invention that be suitable for oral administration be processed following discrete unit form: the capsule, Caplet, cachet or the tablet that contain the active component of predetermined content separately; Powder or granule; Solution in water or on-aqueous liquid or suspensoid; Perhaps oil-in-water liquid emulsion or Water-In-Oil liquid emulsion.These active component can also be bolus, electuary or paste form.
Tablet can use a kind of or more kinds of auxiliary agent to suppress or molded obtaining through optional.Compressed tablets can compacting obtains in the suitable machine through being mixed in binding agent (for example polyvidone, gelatin, hydroxypropyl emthylcellulose), lubricant, inert diluent, antiseptic, disintegrating agent (for example primojel, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose), surfactant or dispersant for the various active component (for example powder or granule) of free-flow (free-flowing) form are optional.Molded tablet can be through obtaining with powder compounds molding in suitable machine of inert liquid diluent moistening.These tablets can be chosen wantonly by coating or indentation; And for let wherein active component slowly or continue to disengage, for example can also use cellulose ether derivative of various ratios (like hydroxypropyl emthylcellulose) or methacrylate derivative to carry out preparation to obtain the required curve that disengages.In order to be implemented in the intestinal part rather than to disengage, can choose wantonly enteric coating is provided to tablet at stomach.
Be adapted at that the preparation of topical is included in the lozenge that fragrant substrate (normally sucrose and Radix Acaciae senegalis or Tragacanth) contains active component in the mouth; For example contain the lozenge of active component in gelatin and glycerol or sucrose and the Radix Acaciae senegalis at inert base; And the collutory that in suitable liquid-carrier, contains active component.Can the suitable substrate that the utilization of rectally preparation contains cupu oil for example or salicylate be processed suppository.Topical can also penetrate device through the transdermal electron ion and carry out administration.
The preparation that is fit to vagina administration can be made into vaginal suppository, tampon, Emulsion, gel, paste, foam or spray, and they also contain appropriate carrier known in the art except containing these active component.
Be used to prevent or the preparation of the suitable penis administration of therapeutic use can be made into condom, Emulsion, gel, paste, foam or spray, they also contain appropriate carrier known in the art except containing these active component.
Wherein carrier is the suppository that the pharmaceutical preparation of solid suitable rectally most preferably is made into UD.Suitable carrier comprises cupu oil and this area other material commonly used.Through active combination is mixed with (various) carrier softening or that melt, cooling and molding in mould then can form suppository so easily.
The preparation that is fit to parenterai administration comprises that water and non-water etc. ooze the sterilizing injecting solution agent, and it can contain antioxidant, buffer agent, antibacterial and control preparation and take medicine the isoosmotic solute of blood samples of patients; With water that can contain suspending agent and thickening agent and non-water sterile suspension; And chemical compound specified liposome or other microparticulate systems act on some blood constitutent or a kind of or more kinds of organs.These preparations can be presented on the sealed container for example in ampoule and the bottle that contains UD or multiple dose, can also be stored under the lyophilisation condition simultaneously, before using only need to wherein add the sterilized liquid carrier for example water for injection get final product.Interim injection solution and suspensoid can be obtained by the sterilized powder of describing in detail in the above, granule and preparation tablets.
Exemplary unit dose formulations has such preparation, they contain daily dose or every day divided dose or the above-mentioned active component of center divided dose.It should be understood that; Except the top composition of mentioning especially; Preparation of the present invention can also contain other commonly used composition of this area, and this depends on that institute considers the type of preparation, and for example the preparation of suitable oral administration can contain other composition for example sweeting agent, thickening agent and aromatic.
Each chemical compound in the combination of the present invention can obtain according to conventional method well known by persons skilled in the art.Viread can prepare according to the method that is described in the U.S. Patent number 5977089 for example, and the method for preparing FTC is described among the WO 92/14743, is introduced into as a reference at this.
The compositions purposes
Can with compositions of the present invention according to top described not only safety but also effectively consumption to people or other administration.Said not only safety but effectively consumption depend on that the mammiferous type and size of receiving treatment and treatment hope the result who reaches.Any one that those skilled in the art knew is used for the method for other solid dosage forms of package troche, Caplet or suitable oral administration, as long as this method can not make the various components among the present invention degrade, all is adapted at using in the packing.Combination can be packaged in glass or the plastic bottle.Other solid dosage forms of tablet, Caplet or suitable oral administration can pack and is contained in the various packaging material, the optional simultaneously for example silica gel of desiccant that contains.Packing can be the blister package form of UD.For example can contain a kind of bubble cap tray of tenofovir DF and the another kind of bubble cap tray of emtricitabine pill, tablet, Caplet or capsule in a packing.The patient can respectively take for example pill of a dosage from two bubble cap trays.Perhaps, package also can contain the bubble cap tray of the single pill, tablet, Caplet or the capsule combination that are become with the emtricitabine co-formulated by tenofovir DF.For other combination with and package, combination of the present invention comprises the physiologic function derivant of tenofovir DF and FTC.
Packaging material can also have label and the information that is printed on the relevant pharmaceutical composition above the material.In addition, manufactured goods can contain and relate to product pamphlet, report, points for attention, handbook or inset for information about.The medicine information of this form is known as " package insert " in the pharmaceuticals industry field.Package insert can be attached on the pharmaceutical preparation or be included in the pharmaceutical preparation.Package insert and any one goods label provide the information of relevant wherein pharmaceutical composition.These information and label provide can be by the various forms of information of health care practitioner with patient's utilization, they to this compositions, its dosage form and regulator for example U.S. food and medicine Surveillance Authority desired various other parameters be described.
The mensuration of combination
According to being the standard determination method developed of test anti-HIV-1 compounds (the for example assay method of description in WO02/068058 and the U.S. Patent number 6475491), can record external activity and the susceptiveness of the anti-HIV of combination of the present invention and to the cytotoxicity in MT2 and the peripheral blood vessel mononuclear cell (PBMC) for example of used cell line in the laboratory.Through serial dilution, in having the combination chemical compound of various concentration, measure EC
50Thereby, the mensuration of completion combination.
Formulation examples
Following embodiment has further described and has explained the specific embodiments that falls within the scope of the invention.Correlation technique and preparation usually can referring to
Remington ' s Pharmaceutical Sciences(Mack Publishing Co., Easton, PA).Therefore the embodiment that is given an example only is for exemplary purposes, should it be interpreted as to constitute restriction, and this is that it is fully possible carrying out various modification because only otherwise depart from purport of the present invention and scope.Below embodiment be only used for explaining, and and do not mean that and limit scope of the present invention by any way." active component " expression Viread, emtricitabine or any one physiologic function derivant in them.
Tablet
Through each composition is carried out wet granulation with aqueous solution, add excess of imports granule (extragrannlar) component then, add magnesium stearate and compacting again, thereby prepare following illustrative preparation A, B, C, D, E and F.
Preparation A:
The mg/ tablet
Viread 300
Emtricitabine 200
Microcrystalline Cellulose 200
Lactose monohydrate 175
Primojel 60
Starch,pregelatinized 50
Silica sol 5
Magnesium stearate 10
Total amount: 1000
Preparation B:
The mg/ tablet
Viread 300
Emtricitabine 100
Microcrystalline Cellulose 200
Lactose monohydrate 180
Primojel 60
Starch,pregelatinized 50
Magnesium stearate 10
Total amount: 900
Formulation C:
The mg/ tablet
Viread 200
Emtricitabine 200
Microcrystalline Cellulose 200
Lactose monohydrate 180
Primojel 60
Starch,pregelatinized 50
Magnesium stearate 10
Total amount: 900
Preparation D:
The mg/ tablet
Viread 300
Emtricitabine 25
Microcrystalline Cellulose 200
Lactose monohydrate 180
Primojel 60
Starch,pregelatinized 50
Magnesium stearate 10
Total amount: 825
Preparation E:
The mg/ tablet
Viread 200
Emtricitabine 25
Microcrystalline Cellulose 200
Lactose monohydrate 180
Primojel 60
Starch,pregelatinized 50
Magnesium stearate 10
Total amount: 725
Preparation F:
The mg/ tablet
Viread 100
Emtricitabine 100
Microcrystalline Cellulose 200
Lactose monohydrate 180
Primojel 60
Starch,pregelatinized 50
Magnesium stearate 10
Total amount: 700
Preparation G (contrast delivery formulations):
Through various compositions are carried out wet granulation with aqueous solution, add magnesium stearate then and prepare said preparation G.
The mg/ tablet
Viread 300
Emtricitabine 200
Hydroxypropyl emthylcellulose 112
Lactose B.P. 53
Starch,pregelatinized B.P. 28
Magnesium stearate 7
Total amount: 700
Medicine began to disengage after about 6-8 hour, after 12 hours, disengaged fully.
Capsule
Preparation H:
Through various compositions are mixed, insert then in embedded hard gel (two-part hardgelatin) or the hydroxypropyl methylcellulose capsules, prepare capsule.
The mg/ capsule
Active component 500
Microcrystalline Cellulose 143
Primojel 25
Magnesium stearate 2
Total amount: 670
Preparation I (agent of contrast release capsule):
Through using extruder to push various composition a, b and c; The extrudate circleization is also dry; And then with dried sphere with release-controlled film (d) coating, insert in embedded hard gel or the hydroxypropyl methylcellulose capsules, disengage capsule thereby prepare following contrast.
The mg/ capsule
(a) active component 500
(b) microcrystalline Cellulose 125
(c) lactose B.P. 125
(d) ethyl cellulose 13
Total amount: 763
Preparation J (oral suspensions):
The various compositions of active component and other are mixed, then it is filled as dried powder.Before using, adding purified water fully mixes.
Active component 500mg
Sugar,confectioner's 2000mg
Dimethicone 300mg
Methyl parahydroxybenzoate 30mg
Propyl p-hydroxybenzoate 10mg
Spice, peach 500mg
Purified water is in right amount to 5.00ml
Formulation K (suppository):
Witepsol H15 with 1/5th is 45 ℃ of following fusions in maximum temperature in the steam jacket pot.Active component sieves through 200 tm screen, uses the Silverson that is equipped with cutter head that its stirring is added in this fusion substrate, up to obtaining level and smooth dispersion.Keep mixture to be in 45 ℃, in suspension, add remaining Witepsol H15, stir to guarantee uniform mixing.With the stainless steel sift of whole suspensions through 250 microns, continuous stirring is cooled to 40 ℃ then.Under 38 ℃ to 40 ℃ temperature, 2.02g gained mixture is inserted in the suitable 2ml mould of plastics.Suppository is cooled to room temperature.
Mg/ suppository
Active component 500
Stearic (hard fat), B.P. (Witepsol H15-Dynamit 1770
Nobel)
Total amount: 2270
The combination tablet of fixed dosage
Use wet granulation/fluid-bed drying to prepare the combination tablet of the fixed dosage that contains Viread (TDF) 300mg/ emtricitabine 200mg according to conventional method.Referring to: US 5935946; L.Young (editor) .TabletingSpecification Manual the 5th edition, American Pharmaceutical Association, Washington, DC, (2001); L.Lachman, H.Lieberman (editor) .Pharmaceutical Dosage Forms:Tablets (the 2nd volume), Marcel Dekker Inc., New York, 185-202 (1981); J.T.Fell and J.M.Newton, J.Pharm.Pharmacol.20,657-659 (1968); American Pharmacopeia 24-National Formulary19, " Tablet Friability ", < 1216>chapter, the 2148th page (2000).
Studied granulation water content level (40% to 50%w/w) but and the wet-mixed time for the physico-chemical property of final mixture of powders with and to the influence of mixing homogeneity and briquettability (tablet mouldability).In addition, uniformity of dosage units, mensuration result, stability and the dissolution character of the fixed dosage combination tablet of TDF/ emtricitabine have also been estimated.
Preparation device
Comprise following apparatus: be equipped with pressure cooker and spray nozzle to add high-shear mixer, fluidized bed dryer, mill, roll-type blender, rotary tablet machine and the tablet cleaner unit of granulation water.
Formulation method
Dried milled powder is mixed with ultra granule microcrystalline Cellulose and cross-linking sodium carboxymethyl cellulose, and then mix with magnesium stearate.With remove Powder samples after magnesium stearate is mixed.But estimate bulk density, sieve test and the briquettability of mixture sample.This mixture of powders that is mixed with magnesium stearate is pressed into tablet on preforming device.
Material
Following table 1 has been listed the quantitative composition situation of TDF/ emtricitabine tablet.
Table 1
Composition | % w/w | The unit prescription of tablet core (mg/ tablet) | Content (kg) in every 12kg sample |
Viread a | 30.0 | 300.0 | 3.60 |
Emtricitabine a | 20.0 | 200.0 | 2.40 |
Starch,pregelatinized, NF/EP | 5.0 | 50.0 | 0.60 |
Cross-linking sodium carboxymethyl cellulose, NF/EP | 6.0 | 60.0 | 0.72 |
Lactose monohydrate, NF/EP a | 8.0 | 80.0 | 0.96 |
Microcrystalline Cellulose, NF/EP c | 30.0 | 300.0 | 3.60 |
Magnesium stearate, NF/EP | 1.0 | 10.0 | 0.12 |
Purified water, USP/EP | b | b | b |
Total amount | 100.0 | 1000.0 | 12.00 |
aActual weight is to adjust according to the medicament contg factor (DCF) of Viread and emtricitabine.
bThe water of in dry run, removing.
Characterization apparatus
Utilize heating lamp/balance sysmte to measure moisture through loss on drying.Powder samples is sampled to measure the mixing homogeneity of powder with the sampler that is equipped with compartment.Several diverse locations at blender take out the double sample.A sample to from each position carries out the mixing homogeneity analysis.
Use the sound wave sieve to make number gram sample, the particle diameter of final mixture of powders is measured through sieves.Through calculating sieve before and after the test respectively and segmenting the weight differential between the catcher, obtain remaining in the amount that each sieve is gone up and segmented the final mixture of powders in the catcher thereby measure.Weight through the distribution that will sieve is taken the logarithm, and calculates the geometric mean diameter particle diameter.
Through graduated cylinder is filled with final mixture of powders, measure the hollow graduated cylinder of per unit volume and the weight differential between the solid graduated cylinder then, thereby confirm bulk density.
Use pulverizer, hardness tester, the thickness micrometer that is equipped with printer and weight balance that the fragility of tablet is characterized.
But use the rotary tablet machine that is equipped with plane, inclined-plane puncher to measure the briquettability of final weight as the tablet of 400mg.Mixture of powders uses target upper punch puncher to suppress, and pressure is about 100-250MPa.Measure the external calibration jet power, then tablet thickness and diameter are calibrated.
Tablet hardness uses hardness tester to measure.Tablet thickness uses micrometer to measure, and tablet weight uses the top to load balance measurement.
Wet granulation
In granulator, water is granulated then with powder mixes.Operate with wet-mixed granulating, the constant airspeed of impeller and chopper is remained on reduced levels.After adding water, stop impeller and chopper and rotate, open the granulator mouth and observe the uniformity and the texture of granulating.Close cap is carried out the wet-mixed phase then.Acceptable granule contains the water of 40% w/w and 60% w/w respectively.
Wet milling
In order to improve the uniformity of drying steps, each wet method shot-like particle is used the blender depolymerization that is equipped with sieve and impeller.The wet granular that will pulverize charging at once after wet milling is gone in the fluidisation bed dryer.
Fluid bed drying
It is that about 70 ℃, air-flow are the air drying of about 100cfm that the wet granular that will pulverize uses the intake air design temperature.Target LOD is about 1.0%, and scope is no more than (NMT) 1.5%.Total fluid bed drying time is 53-75 minute.For all exsiccant batch, last LOD is 0.4% to 0.7%.The last delivery temperature of all batches is 47 ℃ to 50 ℃.
Dry method is milled
All dried particles pulverizes through perforated screen.Crusher is equipped with square impeller and gets into operation.Each batch milled, and the back is manual to be transferred in the V blender.
Mix
Each sample uses the V blender to mix.In the situation of three component preparations, be initially the 12kg mixing of materials, mixing the resulting mixture of powders that finally can be used for suppressing in back is that 10.5kg (87.5%) is to 11.1kg (92.5%).Final mixture of powders bulk density is 0.48-0.58g/cc, and the geometric mean diameter particle diameter is 112-221 μ m.Water percent and wet-mixed time effects the particle diameter and the bulk density of last mixture of powders.
Resulting average (n=10) intensity level for tenofovir DF of the mixture of powders of tenofovir DF and emtricitabine is 100.6% to 102.8% of a sample target strength, and relative standard deviation (RSD) is 0.5% to 1.7%.Average (n=10) intensity level with respect to emtricitabine is 101.3% to 104.1% of a sample target strength, and relative standard deviation (RSD) is 0.6% to 1.7%.Last mixture of powders humidity is 0.8% to 1.1% LOD.
Tablet press
Final mixture is used the rotary tablet machine tabletting, and tablet is used film coating then.
In the granulator that is equipped with the 1-L groove, three batches of 300gm preparations (table 2) are granulated.The consumption of component is the basis with the total batch size of 300g in the granule.Batches 1 and 2 difference is that the content of microcrystalline Cellulose is respectively 30% and 20%w/w.Batches 2 with 3 except binding agent is different, and all the other are all identical.Batches 2 contain 5%w/w starch,pregelatinized as binding agent, and batches 3 contain 5%w/w polyvidone as binding agent.
Table 2
Composition | Batch 1%w/w | Batch 2%w/w | Batch 3%w/w |
Viread | 30.0 | 30.0 | 30.0 |
Emtricitabine | 20.0 | 20.0 | 20.0 |
Starch,pregelatinized, NF/EP | 5.0 | 5.0 | N/A |
Polyvidone, USP/NF (C-30) | N/A | N/A | 5.0 |
Cross-linking sodium carboxymethyl cellulose, NF/EP | 6.0 | 6.0 | 6.0 |
Lactose monohydrate, NF/EP | 8.0 | 18.0 | 18.0 |
Microcrystalline Cellulose, NF/EP a | 30.0 | 20.0 | 20.0 |
Magnesium stearate, NF/EP | 1.0 | 1.0 | 1.0 |
Purified water, USP/EP | a | a | a |
Total amount | 100.0 | 100.0 | 100.0 |
aThe water of in dry run, removing.
After adding water, stop impeller and chopper, open the granulation groove and observe the particulate uniformity and texture.In order to obtain the similar granulation uniformity, with batches 1,2 and 3 respectively with 45%, 40% and the water of 30%w/w granulate.Close cap is carried out wet-mixed.Whole batches of wet-mixed of carrying out for 30 seconds obtain acceptable granule.All wet granulars of taking from each sample sieve with depolymerization through sieve is manual.Resulting granules thing in 60 ℃ convection furnace dry about 20 hours makes LOD<1.0%.Again all dried particles of taking from each sample are sieved through sieve is manual.In the V blender of granule being inserted low capacity (300mL), regulating last mixture batch size is 100g.To be that 81g gained mixture mixes with 15g microcrystalline Cellulose, 3g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate from a part of batch 1.To mix with 10g microcrystalline Cellulose, 3g cross-linking sodium carboxymethyl cellulose and 1g magnesium stearate separately from batches 2 and batches 3 86g gained granule.
Carry out purity analysis through reverse hplc (HPLC).Three kinds of sample preparation front and back in table 2 quantize impurity relevant with Viread and emtricitabine among the loose API (active pharmaceutical ingredient) respectively and measure.Said impurity comprises the by-product by ground Suo Puxi (POC) the ester generation hydrolysis of the by-product of the amino generation of the outer shroud hydrolysis of Viread and emtricitabine and Viread.In each batch, the total impurities relevant with Viread and emtricitabine is lower than 1% after being mixed with tablet.
The physico-chemical property of the content through visible outward appearance, water content, sign intensity, purity and catabolite and the tablet of tablet Dissolution Evaluation Viread and emtricitabine.Drug products to being packaged in the sealed container system identical with clinical and commercial sealed container system carries out stability study.In the stability study process, do not find metachromatism or tablet cracking phenomenon.When film-coated Viread and emtricitabine tablet with silica-gel desiccant 40 ℃/75%RH (relative humidity) packing and storing down reach six months after, it still has gratifying stability.When with silica-gel desiccant after packing under the 40 ℃/75%RH and storing six months, the % that finds tenofovir DF or emtricitabine indicates intensity not have obviously reduction (it is defined as >=5% degree of degradation).When under the 40 ℃/75%RH with 3 the gram desiccant packages and store six months after, total catabolite has increased by 1.5% for tenofovir DF, for emtricitabine, increased 0.6-0.7%.
All publications of quoting among this paper all are incorporated herein by reference according to identical degree at this with patent application, just like every piece of independent publication or patent application by specifically be incorporated herein by reference individually the same.
Although in the above some embodiment is described in detail, those of ordinary skills should be understood that and be understood that, only otherwise depart from these instructions.Can in claims scope, carry out various modification.These all modification all are included within the scope of the invention.
Embodiment of the present invention:
A1. pharmaceutical composition, it unites following formula: compound or its physiologic function derivant that contains effective dose:
R wherein
1And R
2Be independently selected from H, C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
6-C
20Aralkyl, substituted C
6-C
20Aralkyl, acyloxy methyl ester-CH
2OC (=O) R
9With acyloxy methyl carbonic-CH
2OC (=O) OR
9, R wherein
9Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl and substituted C
6-C
20Aryl;
R
3Be selected from H, C
1-C
6Alkyl, substituted C
1-C
6Alkyl or CH
2OR
8, R wherein
8Be C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl or C
1-C
6Alkylhalide group;
R
4And R
5Be independently selected from H, NH
2, NHR or NR
2, wherein R is C
1-C
6Alkyl; And
R
6And R
7Be independently selected from H and C
1-C
6Alkyl;
Following formula: compound or its physiologic function derivant with effective dose:
Wherein B is selected from adenine, guanine, cytosine, uracil, thymus pyrimidine, 7-denitrogenation adenine, 7-deazaguanine, 7-denitrogenation-guanozola, 7-denitrogenation-8-azaadenine, inosine, nebularine, nitro-pyrrole, nitroindoline, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-flurocytosine, 5-chlorine cytosine, 5-bromine cytosine, 5-iodocytosine, false cytosine, false iso-cytosine, 5-propargyl cytosine, iso-cytosine, isoguanine, 7-deazaguanine, 2-sulfo-pyrimidine, 6-thioguanine, 4-thio-thymine, 4-sulfo-uracil, O
6-methyl guanine, N
6-methyladenine, O
4-methyl thymus pyrimidine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole and pyrazolo [3,4-D] pyrimidine; And
R is selected from H, C
1-C
18Alkyl, substituted C
1-C
18Alkyl, C
2-C
18Alkenyl, substituted C
2-C
18Alkenyl, C
2-C
18Alkynyl group, substituted C
2-C
18Alkynyl group, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
2-C
20Heterocycle, substituted C
2-C
20Heterocycle, phosphonate ester, phosphoric acid phosphonate ester, diphosphonic acid phosphonate ester, phosphate ester, bisphosphate, triguaiacyl phosphate, polyethyleneoxy;
And pharmaceutically suitable carrier.
B2. the compositions of embodiment A1, wherein in formula 1, R
1And R
2Be selected from H, C independently of one another
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
6-C
20Aralkyl, substituted C
6-C
20Aralkyl, acyloxy methyl ester-CH
2OC (=O) R
9With acyloxy methyl carbonic-CH
2OC (=O) OR
9, R wherein
9Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl and substituted C
6-C
20Aryl; And R
3, R
4, R
5, R
6And R
7Be H or C independently
1-C
6Alkyl.
C3. the compositions of embodiment A1, wherein in formula 2, B is cytosine or 5-halo cytosine.
D4. the combination of embodiment A1, wherein in formula 1, R
1And R
2Be independently selected from H, C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl, substituted C
6-C
20Aryl, C
6-C
20Aralkyl, substituted C
6-C
20Aralkyl, acyloxy methyl ester-CH
2OC (=O) R
9With acyloxy methyl carbonic-CH
2OC (=O) OR
9, R wherein
9Be C
1-C
6Alkyl, substituted C
1-C
6Alkyl, C
6-C
20Aryl and substituted C
6-C
20Aryl; And R
3, R
4, R
5, R
6And R
7Be H or C independently
1-C
6Alkyl; In formula 2, B is cytosine or 5-halo cytosine.
E5. the compositions of embodiment D4, wherein in formula 1, R
1And R
2Be independently selected from H, acyloxy methyl ester-CH
2OC (=O) R
9With acyloxy methyl carbonic-CH
2OC (=O) OR
9, R wherein
9Be C
1-C
6Alkyl; And R
3, R
4, R
5, R
6And R
7Be H or C independently
1-C
6Alkyl; In formula 2, B is that cytosine or 5-halo cytosine and R are H.
F6. the compositions of embodiment E5, wherein in formula 1, R
1And R
2Be independently selected from H and-CH
2OC (=O) OCH (CH
3)
2R
3Be CH
3And R
4, R
5, R
6And R
7Be H; In formula 2, B is that 5-flurocytosine and R are H.
G7. pharmaceutical composition; It contains (the 2R of pharmacy effective dose [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (Viread) or its physiologic function derivant and pharmacy effective dose; 5S; Cis)-4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine) or its physiologic function derivant; And pharmaceutically suitable carrier.
H8. the pharmaceutical preparation of embodiment A1 to G7, it further also contains the third active component that is selected from protease inhibitor, nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor and integrase inhibitor.
I9. the pharmaceutical preparation of embodiment A1 to H8, it is a unit dosage forms.
J10. the symptom that HIV infects in treatment or the prevention infected animals or the method for influence, it comprises pharmaceutical composition from embodiment A1 to I9 to said animal that use.
Claims (34)
1. the treatment effective dose contains [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (Viread) and (2R; 5S; Cis)-4-amino-5-fluoro-1-(2-methylol-1; 3-oxathiolane-5-yl)-(1H)-compositions of pyrimid-2-one (emtricitabine) is used to prepare the purposes of medicine that treatment has the patient of antiviral therapy demand; Described antiviral therapy is made up of anti-HIV treatment, and wherein the total amount of Viread and emtricitabine accounts for the 5wt%-95wt% of total composition in the compositions.
2. according to the purposes of claim 1, wherein said HIV-resistant activity composition is made up of Viread and emtricitabine.
3. according to the purposes of claim 2, wherein said compositions contains about 300mg Viread and about 200mg emtricitabine.
4. according to the purposes of claim 1, wherein Viread and emtricitabine are present in the tablet.
5. according to the purposes of claim 4, wherein Viread and emtricitabine exist with the amount of 300mg and 200mg respectively.
6. according to the purposes of claim 1, wherein prepare with wet granulation.
7. according to the purposes of claim 1, wherein said composition further comprises the 3rd active component that is selected from hiv protease inhibitor, HIV NRTI, HIV non-nucleoside reverse transcriptase inhibitor and hiv integrase inhibitor.
8. according to the purposes of claim 7, wherein said the 3rd active component is selected from Reyataz, Kaletra or Sustiva anti-HIV medicament.
9. according to the purposes of claim 1, wherein said compositions further contains pharmaceutically acceptable fluidizer.
10. according to the purposes of claim 9, wherein said fluidizer is selected from silicon dioxide, microcrystalline Cellulose, metallic stearate, lagoriolite, sodium benzoate, calcium carbonate, calcium silicates, magnesium carbonate, no asbestos Talcum, starch, Stepanol MG, magnesium oxide and combination thereof.
11. according to the purposes of claim 9, wherein said fluidizer is selected from cellulose powder, corn starch, stearowet C, starch 1500 and combination thereof.
12. according to the purposes of claim 10, wherein said metallic stearate is selected from calcium stearate, magnesium stearate, zinc stearate and combination thereof.
13. pharmaceutical preparation; It contains [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (Viread) and (2R; 5S; Cis)-4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine).
14. according to the pharmaceutical preparation of claim 13, it further contains one or more pharmaceutically suitable carrier or excipient.
15. according to the pharmaceutical preparation of claim 14, wherein said pharmaceutically suitable carrier or excipient are selected from pregelatinized Starch, cross-linking sodium carboxymethyl cellulose, polyvidone, lactose monohydrate, microcrystalline Cellulose and magnesium stearate; And combination.
16. according to the pharmaceutical preparation of claim 13, it is a pharmaceutical dosage form.
17. according to the pharmaceutical preparation of claim 16, wherein said pharmaceutical dosage form is a tablet.
18. according to the pharmaceutical preparation of claim 13, wherein Viread and emtricitabine exist with the weight ratio of about 300mg: 200mg.
19. according to the pharmaceutical preparation of claim 18, it contains the Viread of about 300mg and the emtricitabine of about 200mg.
20. according to the pharmaceutical preparation of claim 13, its suitable oral administration.
21. according to the pharmaceutical preparation of claim 20, it is a capsule form.
22. according to the pharmaceutical preparation of claim 13, its suitable mankind that infect once a day.
23. patient pack; What it contained (a) at least a altogether preparation comprises [2-(6-amino-purine-9-yl)-1-methyl-ethoxyl methyl]-phosphonic acids diisopropoxy ketonic oxygen ylmethyl ester fumarate (Viread) and (2R; 5S; Cis)-pharmaceutical preparation of 4-amino-5-fluoro-1-(2-methylol-1,3-oxathiolane-5-yl)-(1H)-pyrimid-2-one (emtricitabine), and (b) information inset; It contains the explanation that is used to treat the patient of antiviral therapy demand relevant for Viread that uses preparation and emtricitabine, and said antiviral therapy is treated by anti-HIV and constituted.
24. according to the patient pack of claim 23, pharmaceutical dosage form wherein is tablet, lozenge or the capsule that contains 300mg Viread and 200mg emtricitabine.
25. according to claim 13 or 23 described pharmaceutical preparatioies, it further comprises the third antiviral agent.
26. according to the preparation of claim 25, wherein said the third antiviral agent is selected from hiv protease inhibitor, HIV NRTI, HIV non-nucleoside reverse transcriptase inhibitor and hiv integrase inhibitor.
27. according to the preparation of claim 26, wherein said the third antiviral agent is the hiv protease inhibitor.
28. according to the preparation of claim 26, wherein said the third antiviral agent is the HIV non-nucleoside reverse transcriptase inhibitor.
29. according to the preparation of claim 26, wherein said the third antiviral agent is selected from Reyataz, Kaletra or Sustiva anti-HIV medicament.
30. oral Pharmaceutical dosage forms, it contains Viread, emtricitabine and Reyataz.
31. oral Pharmaceutical dosage forms, it contains Viread, emtricitabine and Kaletra.
32. oral Pharmaceutical dosage forms, it contains Viread, emtricitabine and Sustiva.
33. comprise the tablet of 300mg Viread, 200mg emtricitabine and carrier and/or excipient, the amount of said carrier and/or excipient is enough to produce after 6 months and be less than 5% the Viread or the acid degradation of emtricitabine arising under 40 ℃/75% relative humidity storage with desiccant one.
34. oral drug preparation, it comprises Sustiva, 300mg Viread, 200mg emtricitabine and pharmaceutically suitable carrier or excipient.
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US60/440,308 | 2003-01-14 | ||
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CN110251476B (en) * | 2019-08-01 | 2022-08-09 | 海思科制药(眉山)有限公司 | Emtricitabine tenofovir pharmaceutical composition |
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