ZA200505852B - Compositions and methods for combination antiviraltherapy - Google Patents
Compositions and methods for combination antiviraltherapy Download PDFInfo
- Publication number
- ZA200505852B ZA200505852B ZA200505852A ZA200505852A ZA200505852B ZA 200505852 B ZA200505852 B ZA 200505852B ZA 200505852 A ZA200505852 A ZA 200505852A ZA 200505852 A ZA200505852 A ZA 200505852A ZA 200505852 B ZA200505852 B ZA 200505852B
- Authority
- ZA
- South Africa
- Prior art keywords
- tenofovir disoproxil
- emtricitabine
- disoproxil fumarate
- hiv
- fumarate
- Prior art date
Links
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- 238000000034 method Methods 0.000 title claims description 18
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Description
f WO 2004/064843 PCT/US2004/000832 4 =o ji!
COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL
THERAPY
This non-provisional application claims the benefit of Provisional Application
Nos. 60/440,246 and 60/440,308, both filed January 14, 2003, which is incorporated herein by reference.
The invention relates generally to combinations of compounds with antiviral activity and more specifically with anti-HIV properties. In particular, it relates to chemically stable combinations of structurally diverse anti-viral agents.
Human immunodeficiency virus (FIV) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes at least three enzymes which are required for viral replication: reverse transcriptase (RT), protease (Prt), and integrase (Int). Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al 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) is essential for viral replication and is an effective target for approved antiviral drugs. The HIV Prt cleaves the viral Gag and Gag-Po) polyproteins to produce ) viral structural proteins (p17, p24, p7 and pb) and the three viral enzymes. Combination therapy with RT inhibitors has proven to be highly effective in suppressing viral replication to unquantifiable levels for a sustained period of time. Also, combination therapy with RT and Prt inhibitors (PI) have shown synergistic effects in suppressing
HIV replication. Unfortunately, a high percentage, typically 30 to 50% of patients currently fail combination therapy due to the development of drug resistance, non- compliance with complicated dosing regimens. pharmacokinetic Interactions, toxicity, and lack of potency. Therefore, there is a need for new HIV-1 inhibitors that are active against mutant HIV strains, have distinct resistance profiles, fewer side effects, less complicated dosing schedules, and are orally active. In particular, there is a need for a less onerous dosage regimen, such as once per day oral dosing, optimally with as few pills as possible.
The use of combinations of compounds can yield an equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy. Lower overall drug doses can reduce the frequency of occurrence of drug-resistant variants of HIV. Many different methods have been used to examine the effects of combinations of compounds acting together in different assay systems (Furman WO 02/0680583). Lower doses predict better patient compliance when pill burden decieases, dosing schedules are simplified and, optionally, if syncrgy between compounds occurs (Loveday, C. “Nucleoside reverse transcriptase inhibitor resistance” (2001) JAIDS Journal of Acquired Immune Deficiency
Syndromes 26:510-S24). AZT (zidovudine™, 3*-azido, 3’-deoxythymidine) demonstrates synergistic antiviral activity in vitro in combination with agents that act at
HIV-1 replicative steps other than reverse transcription, including recombinant soluble
CD4 castanospermine and recombinant interferon-o. However, it must be noted that combinations of compounds can give rise to increased cytotoxicity. For example, AZT and recombinant intcrferon-o. have an increased cytotoxic effect on normal human bone marrow progenitor cells.
Chemical stability of combinations of antiviral agents is an important aspect of co-formulation success and the present invention provides examples of such combinations.
f [LH
There is a need for new combinations of orally-active drugs for the treatment of
A patients infected with certain viruses, e.g. HIV, that provide enhanced therapeutic safety and efficacy, impart lower resistance, and predict higher patient compliance.
SUMMARY OF THE INVENTION bh) The present invention provides combinations of antiviral compounds, in particular compositions and methods for inhibition of HIV. In an exemplary aspect, the mvention includes a composition including tenofovir disoproxil fumarate and emtricitabine which has anti-HIV activity. The composition of tenofovir DF and emtricitabine is both chemically stable and either synergistic and/or reduces the side elfects of one or both of tenofovir DF and emtricitabine. Increased patient compliance is likely in view of the lower pill burden and simplified dosing schedule.
The present invention relates to therapeutic combinations of [2-(6-amino-purin-9- yl)-1-methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate, tenofovir DF, TDF, Viread®) and (2R, 55, cis)- 4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1 H)-pyrimidin-2-one (emtricitabine, Emtriva™, (-)-cis FTC) and their use 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. Another aspect of the invention is a pharmaceutical formulation comprising a physiologically functional derivative of tenofovir disoproxil fumarate or a physiologically functional derivative of emtricitabine.
Therapeutic combinations and pharmaceutical compositions and formulations of the invention include the combination of PMEA or PMPA (tenofovir) compounds with emtricitabine or (2R, SS, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)- pyrimidin-2-one (3TC, lamivudine, Epivir™), and their vse in the treatment of HIV infections.
One aspect of the invention is a method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to, i.e. treating, said animal with a therapeutically effective amount of a combination comprising (2-(6-amino-purin-9-yl)-1-methyl-ethox ymethyl]-phosphonic ha cr acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir DF, TDF) or a ) physiologically functional derivative thereof, and (2R. 5S, cis)-4-amino-S-fluoro-1-(2- hydroxymethyl-1,3-oxathiolan-5-y1)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.
Another aspect of the invention is a unit dosage form of a therapeutic combination comprising tenofovir disoproxil fumarate and emuicitabine, or physiological functional derivatives thereof. The unit dosage form may be formulated for administration by oral or other routes and is unexpectedly chemically stable in view of the properties of the structurally diverse COMpOoNEnts.
Another aspect of the invention is directed to chemically stable combination antiviral compositions comprising tenofovir disoproxil fumarate and emtricitabine. In a further aspect of the invention, the chemically stable combinations of tenofovir disoproxil fumarate and emtricitabine further comprise a third antiviral agent. In this three-component mixture, the unique chemical stability of tenofovir disoproxil fumarate and emtricitabine is taken advantage of in order to enable the combination with the third antiviral agent. Particularly useful third agents include, by way of example and not limitation, those of Table A. Preferably, the third component is an agent approved for antiviral use in humans, more preferably, it is an NNRTI or a protease inhibitor (PI), more preferably yet, it is an NNRTI. In a particularly preferred embodiment, the invention is directed to a combination of the chemically stable mixture of tenofovir disoproxil fumarate and emtricitabine together with efavirenz.
Another aspect of the invention is a patient pack comprising at least onc, typically two, and optionally, three active ingredients and other antiviral agents selected from tenofovir disoproxil fumarate and emtricitabine, and an information insert containing directions on the use of tenofovir disoproxil fumarate and emtricitabine together in combination.
Another aspect of the invention is a process for preparing the combinations hereinbefore described, which comprises bringing into association tenofovir DF and emtricitabine of the combination in a medicament to provide an antiviral effect. In a further aspect of the present invention, there is provided the use of a combination of the present invention in the manufacture of a medicament for the treatment of any of the aforementioned viral infections or conditions.
+ m
= While the invention will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the invention to those claims. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims.
Unless stated otherwise, the following terms and phrases as used hercin are intended to have the following meanings:
When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
The term “chemical stability” means that the two primary antiviral agents in combination are substantially stable to chemical degradation. Preferably, they are sufficiently stable in physical combination to permit commercially useful shelf life of the combination product. Typically, “chemically stable” means that a first component of the mixture does not act to degrade a second component when the two are brought into physical combination to form a pharmaceutical dosage form. More typically, : “chemically stable” means that the acidity of a first component does not catalyzes or otherwise accelerate the acid decomposition of a second component. By way of example and not limitation, in one aspect of the invention, “chemically stable” means that tenofovir disoproxil fumarate is not substantially degraded by the acidity of emtricitabine. “Substantially” in this context means at least about less than 10%, preferably less than 1%, more preferably css than 0.1%, more preferably yet, less than 0.01% acid degradation of tenofovir disoproxil fumarate over a 24-hour period when the products are in a pharmaceutical dosage form.
The terms “synergy” and “synergistic” mean that the effect achieved with the compounds used together is greater than the sum of the effects that results from using the compounds separately, i.e. greater than what would be predicted based on the two active ingredients administered separately. A synergistic effect may be attained when the compounds are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; + or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect
Y ' may be attained when the compounds are administered or delivered sequentially. e.g. in
A separate tablets. pills or capsules, or by different injections In separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered scquentially, i.e. serially, whereas in combination therapy. effective dosages of two or more active ingredients are administered together. A synergistic antiviral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
The term “physiologically functional derivative” means a pharmaceutically active compound with equivalent or near equivalent physiological functionality to tenofovir DF or emtricitabine when administered in combination with another pharmaceutically active compound in a combination of the invention. As used herein, the term “physiologically functional derivative” includes any: physiologically acceptable salt, ether, ester, prodrug, solvate, stereoisomer including enantiomer, diastereomer or stereoisomerically enriched or racemic nuxture, and any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof. “Bioavailability” is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body.
Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
The compounds of the combinations of the invention may be referred to as "active ingredients” or “pharmaceutically active agents.”
The term "prodrug” as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), and/or metabolic chemical reaction(s). “Prodrug moiety” means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-
Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp- 113-191). Prodrug
+ RX] moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug
E delivery, bioavailability and efficacy. A “prodrug” is thus a covalently modified analog of a therapeutically-active compound. “Alkyl” means a saturated or unsaturated, branched, straight-chain, branched, or cyclic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical alkyl groups consist of 1-18 saturated and/or unsaturated carbons, such as normal, secondary, tertiary or cyclic carbon atoms. Examples include, but are not limited to: methyl, Me (-CH3), ethyl, Et (-CH2CH3), acetylenic (-C=CH), ethylene, vinyl (-CH=CH,), 1-propyl, n-Pr, n-propyl (-CH2CH2CHS3), 2-propyl, i-Pr, 1-propyl (-CH(CH3)2), allyl (-CH,CH=CHy,), propargy] (-CHC=CH), cyclopropyl (-C3Hs), 1-butyl, n-Bu, n-buty] (-CH2CH2CH2CH3), 2- methyl-1-propyl, i-Bu, i-butyl (-CH2CH(CH3)2), 2-butyl, s-Bu, s-butyl (-CH(CH3)CH2CH3?), 2-methyl-2-propyl, t-Bu, t-butyl (-C(CH3)3), 1-pentyl, n-pentyl, (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-penty] (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), cyclopentyl (-CsH), 3- methyl-2-butyl (-CH(CH3)CH(CH3)), 3-methyl-1-butyl (-CH2CH2CH(CH3)2). 2- methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CHCH2CHCHoCH3), 5- hexenyl (-CH, CH,CH,CH,CH=CH,) 1-hexyl (-CH(CH3)CH2CH2CH,CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH?3)), cyclohexyl (-CgHyy), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CHoCH3), 4-methyl- 2-penty] (-CH(CH3)CH2CH(CH3)), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2- methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-buty] (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3. "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of onc hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals denved from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-
¥ , vl, 2-phenylethen-]-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-y], \ naphthobenzyl, 2-naphthophenylethan-1-v and the like. The arylalkyl group 6 to 20 carbon atoms e.g., the alkyl morety, including alkanyl, alkenyl or alkyny] groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 10 14 carbon atoms. “Substituted alkyl)”, “substituted aryl”, and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl] respectively, in which one or more hydrogen atoms are each independently replaced with a substituent. Typical substituents include, but are not limited to, -X, -R, -O, -OR, -SR, -S’, -NR32, -NR3, =NR, -CXj, -CN, -OCN, -SCN, -N=C=0, -NCS, -NO, -NO,, =Nj, -N3, NC(=O)R, -C(=O)R, -C(=0)NRR -S(=0),0", -5(=0),01, -S(=0),R, -OS(=0):0R, -S(=0).NR, -S(=O)R, -OP(=0)O,RR -P(=0)O,RR -P(=0)(O"),, -P(=0)(OH)», -C(=0)R, -C(=0)X, -C(S)R, -C(O)OR, -C(0)0', -C(S)OR. -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, ~-C(NR)NRR, where each X is independently a halogen: F, Cl, Br. or I; and each R is independently -H, alkyl, aryl, heterocycle, or prodrug moiety. “Heteroaryl” and "Heterocycle" refer to a ring system in which one or more rin g atoms is a heteroatom, e. g. nitrogen, oxygen, and sulfur. Heterocycles are described m:
Katritzky, Alan R., Rees, C.W., and Scriven, E. Comprehensive Heterocyclic Chemistry (1996) Pergamon Press; Paquette, Leo A; Principles of Modern Heterocyclic Chemistry
W_.A. Benjamin, New York, (1968), particularly Chapters 1, 3, 4, 6,7,and 9; "The
Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons,
New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28. Exemplary heterocycles include but are not limited to substituents, i.e. radicals, derived from pyrrole, indole, furan, benzofuran, thiophene, benzothiophene, 2-pyridyl, 3-pyridy], 4-pyridyl, 2- qumolyl, 3-quinolyl, 4-quinolyl, 2-imidazole, 4-imidazole, 3-pyrazole, 4-pyrazole, pyridazine, pyrimidine, pyrazine, purine, cinnoline, pthalazine, quinazoline, quinoxaline, 3- (1,2,4-N)-triazoly], 5-(1,2,4-N)-triazolyl, S-tetrazolyl, 4-(1-0, 3-N)-oxazole, 5-(1 -0, 3-N)- oxazole, 4-(1-5, 3-N)-thiazole, 5-(1-S, 3-N)-thiazole, 2-benzoxazole, 2-benzothiazole, 4- (1,2,3-N)-benzotriazole, and benzimidazole.
Stereochemical definitions and conventions used herein generally follow S. P.
Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book
Company, New York: and Eliel, E. and Wilen, S., Stereochemistry of Organic
Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds existin optically active forms, i.e., they have the ability to rotate the plane of plane- polarized hight. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are emploved to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound 1s levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two cnantiomeric species, devoid of optical activity.
The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. "Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. "Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
ACTIVE INGREDIENTS OF THE COMBINATIONS
The present invention provides novel combinations of two or more active ingredients being employed together. In some embodiments, a synergistic antiviral effect is achieved. In other embodiments, a chemically stable combination is obtained.
The combinations include at least one active ingredient selected from (1) tenofovir disoproxil fumarate and physiologically functional derivatives, and at least one active ingredient selected from (2) emtricitabine and physiologically functional derivatives.
The term “synergistic antiviral effect” is used herein to denote an antiviral effect which is greater than the predicted purely additive effects of the individual components (a) and (b) ) of the combination.
Tenofovir disoproxil fumarate (also known as Viread®, Tenofovir DF, Tenofovir disoproxil, TDF. Bis-POC-PMPA (US Patent Nos. 5935946, 5922695, 5977089, 6043230, 6069249) is a prodrug of tenofovir, and has the structure:
NH,
C1 JL
AJA
Lo ko
INN,
A and including fumarate salt (HO,CCH,CH,CO5).
The chemical names for Tenofovir disoproxil include: [2-(6-amino-purin-9-yl)-1- methyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonylox ymethy]} ester; 9-[(R)-2- [(bis{[(isopropoxycarbonyljoxyJmethoxylphosphinylimethox ylpropyl adenine: and 2.4,6.8-tetraoxa-5-phosphanonanedioic acid, 5-[{(1R)-2-(6-amino-9H-purin-9 yDh-1- methylethoxy]methyl]-, bis(1-methylethyl) ester, 5-oxide. The CAS Registry numbers include: 201341-05-1; 202138-50-9; 206184-49-8. It should be noted that the ethoxymethyl unit of tenofovir has a chiral center. The R (rectus, right handed
I5 configuration) enantiomer is shown. However, the invention also includes the S isomer.
The invention includes all enantiomers, diastercomers, racemates, and enriched stereoisomer mixtures of tenofovir (PMPA) and physiologically functional derivatives thereof.
PMPA or tenofovir (US Patent Nos. 4808716, 5733788, 6057305) has the structure:
’ ) NH, ) JR. >
CA 0 or
NN,
The chemical names of PMPA, tenofovir include: (R)-9-(2- phosphonylmethox ypropyl)adenine; and phosphonic acid, [[(1R)-2-(6-amino-9H-purin- 9-yh-1 -methylethoxy]methyl]. The CAS Registry number is 147127-20-6.
Tenofovir disoproxil fumarate (DF) is a nucleotide reverse transcriptase inhibitor approved in the United States in 2001 for the treatment of HIV-1 infection in combination with other antiretroviral agents. Tenofovir disoproxil fumarate or Viread® (Gilead Science, Inc.) is the fumarate salt of tenofovir disoproxil. Viread® may be named as: 9-[(R)-2- [[bis[[(isopropox ycarbonyl)ox y]methox yIphosphinyljmethoxy]propylJadenine fumarate (1:1); or 2,4.6,3-tctraoxa-5-phosphanonanedioic acid, 5-[[(1R)-2-(6-amino-9H-purin-9- y)-1-methylethox ylmethyl]-, bis(1-methylethy!) ester, 5-oxide, (2E)-2-butenedioate (1:1). The CAS Registry number is 202138-50-9.
Physiologically functional derivatives of tenofovir disoproxil fumarate include
PMEA (adefovir, 9-((R)-2-(phosphonomethoxy)ethyhadenine) and PMPA compounds.
Exemplary combinations include a PMEA or PMPA compound in combination with emtricitabine or 3TC. PMEA and PMPA compounds have the structures:
SN
N wd 0
N Pe. R* 0 ¢) |_—or ~~ Nor
R3 where PMEA (R? is H) and PMPA (Ris C=C alkyl, C,~Cs substituted alkyl, or
CH20R® where R* is C;-Cg alkyl, C;-Cq hydroxyalkyl or C;-Cg haloalkyl. R® and R’ arc independently H or C;—Cg alkyl. R* and R> are independently H, NH,, NHR or NR, where R is C,--C; alkyl. R! and R? are independently H, C,-Cg alkyl, C;—C; substituted alkyl, C4—Csq aryl, C4—Csg substituted aryl, Cs—Cy arylalkyl, C4—Cyp substituted arylalkyl, acylox ymethyl esters ~CH,0C(=0)R’ (e.g. POM) or acyloxymethyl carbonates ~CH,OC(=0)OR?” (e.g. POC) where R? is C;~Cj alkyl, CC substituted alkyl, C3—Csp aryl or Cs—Cop substituted aryl. For example, Rj and R, may be pivaloyloxymethoxy, POM, —CH,0C(=0)C(CHj);3; —CH,0C(=0)OC(CHs)5; or POC, ~CH,0C(=0)OCH(CHjs),. Also for example, tenofovir has the structure where R? is
CHs, and R', R* R*, R°, R® and R” are H. Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990)
Tetrahedron Lett. 3261; US Patent No. 5663159.
The PMPA compound may be cnantiomerically-enriched or purified (single stercoisomer) where the carbon atom bearing R* may be the R or S enantiomer. The
PMPA compound may be a racemate, i.e. a mixture of R and S stereoisomers.
Adefovir (9-(2-phosphonomethoxycthyl)adenine where Ri-R7 =H) is an exemplary PMEA compound (US Patent Nos. 4808716, 4724233). As the bis-pivalate prodrug, Adefovir dipivoxil, also known as bis-POM PMEA, (R3-R7=H,R, and R, = ~CH20C(=0)C(CHs)s, pivoxil, POM, pivaloyloxymethoxy), is effective against HIV and Hepatitis B infections (US Patent Nos. 5663159, 6451340). Adefovir dipivoxil has demonstrated minor to moderate synergistic inhibition of HIV replication in combination
. | WO 2004064843 PCT/US2004/000832 with other compounds with anti-HIV activity including PMPA, d4T, ddC. nelfinavir, ntonavir, and saquinavir (Mulato et al (1997) Antiviral Research 36:91-97).
The invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of PMEA and PMPA. and physiologically functional derivatives thereof.
Emtricitabine ((-)-cis-FTC, Emtriva™), a single enantiomer of FTC. is a potent nucleoside reverse transcriptase inhibitor approved for the treatment of HIV (US Patent
Nos. 5047407, 5179104, 5204466, 5210085, 5486520, 5538975, 5587480, 5618820, 5763606, 5814639, 5914331, 6114343, 61 80639, 6215004; WO 02/070518). The single enantiomer emtricitabine has the structure:
NH, e LSS
IS
S
The chemical names for emtricitabine include: (-)-cis-I'TC; B-L-hydroxymethyl- 5-(5-fluorocytosin-1-yl)-1,3-oxathiolane: (2R,5S)-5-fluoro-1-[2-(hydrox ymethyl)-1,3- oxathiolan-5-yl)cytosine; and 4-amino-5-fluoro-1 ~(2-hydroxymethyl-[1,3]-(2R,55)- oxathiolan-5-yl)-1H-pyrimidin-2-one. The CAS Registry numbers include: 143491-57- 0; 143491-54-7. 1t should be noted that FTC contains two chiral centers, at the 2 and 5 positions of the oxathiolane ring, and therefore can exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof mcluding racemic mixtures.
Thus, FTC may be either a cis or a trans isomer or mixtures thereof. Mixtures of cis and trans isomers are diastereomers with different physical properties. Each cis and trans isomer can exist as one of two enantiomers or mixtures thereof mcluding racemic mixtures. The invention includes all enantiomers, diastereomers, racemates, and enriched stereoisomer mixtures of emtricitabine and physiologically functional denvatives thereof. For example, the invention includes physiological functional denivatives such as the 1:1 racemic mixture of the enantiomers (2R, SS, cis)-4-amino-5-
. | WO 2004/6484 PCT/US2004/000832 fluoro-1-(2-hydroxymethyi-1 3-oxathiolan-5-y)-(1H)-pyrimidin-2-one (emtricitabine) ] and its mirror image (2S, 3R, cis)-4-amino-3-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan- 5-y1)-(1H)-pyrimidin-2-one, or mixtures of the two enantiomers in any relative amount.
The invention also includes mixtures of cis and trans forms of FTC.
Physiologically functional derivatives of emtricitabine include 1.3 oxathiolane nucleosides having the structure:
TV B
.
In the 1,3 oxathiolane nucleoside structure above, B is a nucleobase including any nitrogen-containing heterocyclic moiety capable of forming Watson-Crick hydrogen bonds in pairing with a complementary nucleobase or nucleobase analog, e.g. a purine, a 7-deazapurine, or a pyrimidine. Examples of B include the naturally occurring nucleobascs: adenine, guanine, cytosine, uracil, thymine, and minor constituents and analogs of the naturally occurring nucleobases, e.g. 7-deazaadenine, 7-dcazaguanine, 7-deaza-8- azaguanine, 7-deaza 8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2- aminopurine, 2-amino-6-chloropurine, 2.6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, S-propynylcytosine, 1socylosine, isoguanine, 7-deazaguanine, 2- thiopyrimidine, 6-thioguanine, 4-thjothymine, 4-thiouracil, O°-methylguanine, N°- methyladenine, 0" methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4- methylindole, pyrazolo[3,4-D]pyrimidines (U.S. Patent Nos. 6,143,877 and 6,127,121;
WO 01/38584), and ethenoadenine (Fasman (1989) in Praciical Handbook of
Biochemistry and Molecular Biology, pp. 385-394, CRC Press, Boca Raton, ED.
Nucleobases B may be attached in the configurations of naturally-occurring nucleic acids to the 1,3 oxathiolanc moiety through a covalent bond between the N-9 of purines, e.g. adenin-9-yl and guanin-9-yl, or N-1 of pyrimidines, e.g. thymin-I-yl and cytosin-1-yl (Blackburn, G. and Gait, M. Eds. “DNA and RNA structure” in Nucleic Acids in
Chemistry and Biology, 2™ Edition, (1996) Oxford University Press, pp. 15-81).
¥ ¢
Also in the 1.3 oxathiolane nucleoside structure above, Ris H, C,~-Cyg alkyl, - C;—C,5 substituted alkyl, C2—Cyg alkenyl, C,—C,g substituted alkenyl. Co—C;g alkynyl,
C5—C,5 substituted alkynyl, Cs—Cyq aryl, C4—Coy substituted aryl, Cz-Cyg heterocycle,
Cy—~Cx substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethylencoxy, or a prodrug moiety.
Physiologically functional derivatives of emtricitabine also include 3TC (lamivudine, Epivir®), a reverse transcriptase inhibitor approved in the United States for the treatment of HIV-1 infection in combination with AZT as Combivir® (GlaxoSmithKline). US Patent Nos. 5859021; 5905082; 6177435; 56271 S6; 6417191.
Lamivudine (US Patent Nos. 5587480, 5696254, 5618820, 5756706, 5744596, 568164, 5466806, 5151426) has the structure:
NH,
Cl
LL
HO o N 0
E SS
= TN
S
For example and for some therapeutic uses, 3TC may be a physiologically functional derivative of emtricitabinc in combination with tenofovir DF or a physiologically functional derivative of tenofovir DF.
It will be appreciated that tenofovir DF and emtricitabine, and their physiologically functional derivatives may exist in keto or enol tautomeric forms and the use of any tautomeric form thereof is within the scope of this invention. Tenofovir DF and emtricitabine will normally be utilized in the combinations of the invention substantially free of the corresponding enantiomer, that is to say no more than about 5% w/w of the corresponding enantiomer will be present.
PRODRUGS
The invention includes all prodrugs of tenofovir and emtrncitabine. An exemplary prodrug of tenofovir is tenofovir disoproxil fumarate (TDF, Viread®). A
. large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997). A comunonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by
Farquhar et al (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester strategy, the alkox ycarbonyloxyalkyl ester, may also cnhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. Aryl esters of phosphorus groups. especially phenyl esters, are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho- or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic
C--O bond to generate the phosphoric acid and the quinone methide intermediate.
Examples of this class of prodrugs are described by Mitchell et al (1992) J. Chen. Soc.
Perkin Trans. 12345; Brook et al WO 91/19721. Stil} other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier et al WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an cthylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds.
Prodrug esters in accordance with the invention are independently selected from the following groups: (1) mono-, di-, and tri-phosphate esters of tenofovir or emtricitabine or any other compound which upon administration to a human subject is
J WO 2004/064845 PCT/LS2004/000832 ) capable of providing (directly or indirectly) said mono-, di, or triphosphate ester; (2) carboxylic acid esters (3) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methancsulphonyl): (4) amino acid esters (for example, alanine, L-valyl or L- isoleucyl); (5) phosphonate; and (6) phosphonamidate esters, b) Ester groups (1)-(6) may be substituted with; straight or branched chain C,-C,g alkyl (for example, methyl, n-propyl, t-butyl, or n-butyl); C3~C;; cycloalkyl; alkoxyalkyl (for example, methoxymethyl); arylalkyl (for example, benzyl); aryloxyalky! (for example, phenoxymethyl); Cs—Cayp aryl (for example, phenyl optionally substituted by, for example, halogen, C;--Cy alkyl, C;~Cy alkoxy, or amuno; acyloxymethyl esters ~CHOC(=O)R” (c.g. POM) or acyloxymethyl carbonates ~CH,OC(=0)OR’ (e.g. POC) where R? is C,-Cj alkyl, C,~Cg substituted alkyl, C4—Cyp aryl or Cg~Cag substituted aryl.
For example, ester groups may be: -CH,OC(=0)C(CHs;)s, —CH,OC(=0)OC(CHj3); or —-CH,OC(=0)OCH(CH>),.
An exemplary aryl moiety present in such esters comprises a phenyl or substituted phenyl group. Many phosphate prodrug moieties are described in US Patent
No. 6312662; Jones et al (1995) Antiviral Research 27:1-1 7; Kucera ct al (1990) AIDS
Res. Hum. Retro Viruses 6:491-501; Piantadosi et al (1991) J. Med. Chem. 34:1408-14;
Hosteller et al (1992) Antimicrob. Agents Chemother. 36:2025-29: Hostetler et al (1990)
J. Biol. Chem. 265:611127; and Siddiqui et al (1999) J. Med. Chem. 42:4122-28.
Pharmaceutically acceptable prodrugs refer to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient. Typical examples of prodrugs of the active ingredients of the combinations of the invention have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
CHEMICAL STABILITY OF A PHARMACEUTICAL FORMULATION
The chemical stability of the active ingredients in a pharmaceutical formulation 18 of concern to minimize the generation of impurities and ensure adequate shelf-life. The active ingredients, tenofovir disoproxil fumarate and emtricitabine. in the pharmaceutical ) formulations of the invention have relatively low pKa values, indicative of the potential to cause acidic hydrolysis of the active ingredients. Emtricitabine, with a pKa of 2.65 (Emtriva™ Product Insert, Gilead Sciences, Inc. 2003, available at gilead.com) is subject to hydrolytic deamination of the 5-fluoro cytosine nucleobase to form the 5-fluoro uridine nucleobase. Tenofovir disoproxil fumarate, with a pKa of 3.75 (Yuan L. et al “Degradation Kinetics of Oxycarbonyloxymethyl Prodrugs of Phosphonates in
Solution”, Pharmaceutical Research (2001) Vol. 18, No. 2, 234-237), is subject also to hydrolytic deamination of the exocyclic amine of the adenine nucleobase, and to hydrolysis of one or both of the POC ester groups (US Patent No. 5922695). 1t is desirable to formulate a therapeutic combination of tenofovir disoproxil fumarate and emtricitabine, and the physiological functional derivatives thereof, with a minimum of impurities and adequate stability.
The combinations of the present invention provide combination pharmaceutical dosage forms which are chemically stable to acid degradation of: (1) a first component (such as tenofovir disoproxil fumarate, and physiological functional derivatives; (2) a + second component (such. as emtricitabine, and physiological functional derivatives; and (3) optionally a third component having antiviral activity. The third component mcludes anti-HIV agents and include: protease inhibitors (P1), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors. Exemplary third active mgredients to be administered in combination with first and second components are shown in Table A. First and second components are as defined in the above section entitled: ACTIVE INGREDIENTS OF
THE COMBINATIONS.
SALTS
Any reference to any of the compounds in the compositions of the invention also includes any physiologically acceptable salt thereof. Examples of physiologically acceptable salts of tenofovir DF, emtricitabine and their physiologically functional derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX, *
) (wherein X is C,—C, alkyl), or an organic acid such as fumaric acid, acetic acid, succinic acid. Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such ag acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as 5 methanesulfonic, cthanesulfonic, benzenesulfonic and p-toluenesulfonic acids: and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na* and NX,* (wherein X is independently selected from H or a Cy-Cy alkyl group).
For therapeutic use, salts of active ingredients of the combinations of the imvention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
ADMINISTRATION OF THE FORMULATIONS
While it is possible for the active ingredients of the combination to be administered alone and separately as monotherapies, it is preferable to administer them as a pharmaceutical co-formulation. A two-part or three-part combination may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in one, two, or three administrations.
Preferably, two-part or three-part combinations are administered in a single pharmaceutical dosage form. More preferably, a two-part combination is administered as a single oral dosage form and a three-part combination is administered as two identical oral dosage forms. Examples include a single tablet of tenofovir disoproxil fumarate and emtricitabine, or two tablets of tenofovir disoproxil fumarate, emtncitabine, and efavirenz.
It will be appreciated that the compounds of the combination may be administered: (1) simultaneously by combination of the compounds in a co-formulation or (2) by alternation, i.e. delivering the compounds serially, sequentially, in parallel or simultaneously in separate pharmaceutical formulations. In alternation therapy, the delay in administering the second, and optionally a third active ingredient, should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. By either method of administration (1) or (2), ideally the combination should be administered to achieve peak plasma concentrations of each of the active ingredients. A one pill once-per-day regimen by administration of a combination co- formulation may be feasible for some HIV-positive patients. Effective peak plasma concentrations of the active ingredients of the combination will be in the range of approximately 0.001 to 100 HM. Optimal peak plasma concentrations may be achieved by a formulation and dosing regimen prescribed for a particular patient. It will also be understood that tenofovir DF and emtricitabine, or the physiologically functional derivatives of either thereof, whether presented simultaneously or sequentially, may be administered individually, in multiples, or in any combination thereof. In general, during alternation therapy (2), an effective dosage of each compound is administered seri ally, where in co-formulation therapy (1), effective dosages of two or more compounds are administered together.
FORMULATION OF THE COMBINATIONS
When the individual components of the combination are administered separately they are generally each presented as a pharmaceutical formulation, The references hereinafter to formulations refer unless otherwise stated to formulations containing either the combination or a component compound thereof. It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, within a package insert diverting the patient to the correct use of the invention is a desirable additional feature of this invention. The invention also includes a double pack comprising in association for separate administration, formulations of tenofovir disoproxil fumarate and emtricitabine, or a physiologically functional derivative of either or both thereof.
The combination therapies of the invention include: (1) a combination of tenofovir DF and emtricitabine or (2) a combination containing a physiologically functional derivative of either or both thereof.
) The combination may be formulated mn a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a penodic, e.g. daily, dose or subdose of the active ingredients.
Pharmaceutical formulations according to the present invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the mtended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared (Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions nay contain one or more agents including antioxidants, sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example pregelatinized starch, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyvicelluose. sodium alginate. polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., Jecithin), a condensation product of an alkylene oxide with a fatty acid (c.g.. polyoxyethylene stearate), a condensation product of ethylene oxide with a Jong chain aliphatic alcohol (e.g, heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g. polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, onc or more flavoring agents and one or more sweetening agents, such as sucrose, sucralose or saccharin.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid,
BHT, etc.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions or liposome formulations. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate. and condensation products of these partial esters with ethylene oxide. such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile mjectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
This suspension may be formulated according to the known art using thosc suitable dispersing or wetting agents and suspending agents which have been mentioned above.
The sterile injectable preparation may also be a stesile injectable solution or suspension
In a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanc- diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewisc be used in the preparation of injectables.
The pharmaceutical compositions of the invention nay be injected parenterally, for example, intravenously, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqucous solutions should be suitably butfered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The pharmaceutical compositions of the invention may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler Or an aerosol spray presentation from a pressurized container or a nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluorocthane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFC 134a), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the h . dosage unit may be determined by providing a valve to deliver a metered amount. The . pressurized container or nebuliser may contain a solution or suspension of the composition, e.g. using a mixture of ethanol and the propellant as the solvent, which may additional contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch. Aerosol or dry powder formulations are preferably arranged so that cach metered dose or "puff" contains from 20 ne to 20 mg of a composition for delivery to the patient. The overall daily dose with an acrosol wil be in the range of from 20 ug to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
The amount of active ingredient that may be combined with the carrier material lo produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 10 about 95% of the total compositions (weight: weight).
The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ug of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 ml/hr can occur. As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredicnt; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
The combinations of the invention may conveniently be presented as a pharmaceutical formulation in a unitary dosage form. A convenient unitary dosage formulation contains the active ingredients in any amount from 1 mg to 1 g each, for example but not limited to, 10 mg to 300 mg. The synergistic effects of tenofovir DF in combination with emtricitabine may be realized over a wide ratio, for example 1:50 to
. 50:1 (tenofovir DF:emtricitabine). In one embodiment, the ratio may range from about 1:10 10 10:1. In another embodiment, the weight/weight ratio of tenofovir to emtricitabine in a co-formulated combination dosage form, such as a pill, tablet, caplet or
Capsule will be about 1, i.e. an approximately equal amount of tenofovir DF and emtricitabine. In other exemplary co-formulations, there may be more or Jess tenofovir than FTC. For example, 300 mg tenofovir DF and 200 mg emtricitabine can be co- formulated in a ratio of 1.51 (tenofovir DF: emtricitabine). In one embodiment, each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone. Exemplary Formulations A,B,C,D,E, and F (Examples) have ratios of 12:1 to 1:1 (tenofovir DF : emtricitabine). Exemplary
Formulations A, B, C, D, E, and F use amounts of tenofovir DF and emtricitabine ranging from 25 mg to 300 mg. Other ratios and amounts of the compounds of said combinations are contemplated within the scope of the invention.
A unitary dosage form may further comprise tenofovir DF and emtricitabine, or physiologically functional derivatives of either thereof, and a pharmaceutically acceptable carrier.
It will be appreciated by those skilled in the art that the amount of active ingredients in the combinations of the invention required for use in treatment will vary according to a variety of factors, including the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or health care practitioner. The factors to be considered include the route of administration and nature of the formulation, the animal's body weight, age and general condition and the nature and severity of the disease to be treated. For example, in a Phase VII monotherapy study of emtricitabine, patients received doses ranging from 25mg to 200 mg twice-a-day for two weeks. At each dose regimen greater or equal to 200 mg, a 98-percent (1.75 log10 ) or greater viral suppression was observed. A once-a- day dose of 200 mg of emtricitabine reduced the viral load by an average of 99 percent (1.92 10g10). Viread® (tenofovir DF) has been approved by the FDA for the treatment and prophylaxis of HIV infection as a 300 mg oral tablet. Emtriva™ (emtricitabine) has been approved by the FDA for the treatment of HIV as a 200 mg oral tablet.
It is also possible to combine any two of the active ingredients in a unitary dosage form for simultaneous or sequential administration with a third active ingredient. The
. three-part combination may be administered simultaneously or sequentially.
When
. adminisiered sequentially. the combination may be administered in two or three administrations.
Third active ingredients have anti-HIV activity and include protease mhibitors (P1), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and integrase inhibitors.
Exemplary third active ingredients to he administered in combination with tenofovir DF, emtricitabine, and their physiological functional denvatives, are shown in Table A.
Claims (41)
1. Use of a therapeutically effective amount of a composition comprising [2- (6-amino-purin-9-yl)-1-methyl-ethoxymethyl}-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R, 58, cis)-4-amino-5-fluoro-1-(2-hydrox ymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2- one (emtricitabine) in the manufacture of a medicament for the treatment of a patient in need of antiviral therapy consisting of anti-HIV therapy.
2. The use according to claim 1 wherein the anti-HIV active ingredients in the composition consist of tenofovir disoproxil fumarate and emtricitabine.
3. The use according to claim 2 wherein the composition comprises about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricnabine.
4. The use according to claim 1 wherein the amount of the total tenofovir disoproxil fumarate and emiricitabine in the compasition in relation to carrier marerial is about 5% to about 95% of the 1018] composition (weight:weight, exclusive of coating).
5. The use according to claim 1 wherein tenofovir disoproxil fumarate and emtricitabine are present in a rablet.
6. The use according to claim 5 wherein tenofovir disoproxil fumarate and ermiricitabine are present 1n an amount of 300 mg and 200 mg respectively. 1 gHEET
7. The use according 10 claim 1 wherein the manufacture is by wel granulation.
8. The use according to claim 4 wherein the weight ratio of the total of tenofovir disoproxil fumarate and emiricitabine in the composition in relation to ingredients other than tenofovir disoproxi! fumarate and emtricitabline is 50:50 (excluding coating).
9. The use according 10 claim 8 wherein the composition comprises 11} weight percent (excluding coarng) tenofovir disoproxil fumarate 30, emiricitabine 20, pregelannized starch S, croscarmellose sodium 6, lactose monohydrate 8, microcrystalline cellulose 30, magnesium stearate 1.
10. The method according to claim I wherein the composition further comprises a third acuve ingredient selected from an HIV protease intubitor (PI), an HIV nucleoside reverse transcriptase inhibitor (NRT), an HIV non- nucleoside reverse transcriptase inhibitor (NNRTI), and an HIV integrase inhibitor.
11. The method according to claim 10 wherein the third active ingredient is selected from the Reyataz, Kaletra, or Sustiva anu-HIV agents. 2 AMENDED SHEET
12. The method according to claim 1 wherein the composition further comprises a pharmaceutically acceptable glidant.
13. The method according tw claim 12 wherein the glidant is selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, metallic siearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and formulations thereof.
14. The method according to claim 13 wherein the metallic stearates are selected from calcium stearate, magnesium stearate, zinc stearate, and formulations thereof.
15. A pharmaceuucal formulation comprising [2-(6-amino-purin-9-yl)-1- methyl-ethox ymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fummarare) and (2R, SS, cis)-4-amino-5-fluoro-1-(2-hydroxymerthyl- N oe . 1,3-oxathiolan-5-y1)-(1H)-pyrimudin-2-one (emiricitabine)
16. The pharmaceutical formulation according to claim 15 further compnsing one or more pharmaceutically acceptable carriers or excipients.
17. The pharmaceutical formulauon according to claim 16 wherein the pharmaceutically acceptable carriers or excipients are selected from pregelatinized starch, croscarmellose sodium, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate, and formulations thereof.
18. The pharmaceutical formulation according to claim 16 wherein the amount of the total tenofovir disoproxil fumarate and emiricitabine in the formulation in 3 = HEET AMENDED S
‘ ¢ . relation to carrier and excipient material (weight:weight, excluding coating) 18 about 5% about 95% (weight ratio 0.08).
19. The pharmaceutical formulation according to claim 18 wherein the weight ratio of tenofovir disoproxil fumarate and entricitabine together: total camer and excipient in the formulation (excluding coating) is 500:1000, 400:900, 325:825, 225:725, 200:700, 500:700, 500:670, 500:763, 500:2840 or 500:2270.
20. The pharmaceutical formulation according to claim 19 wherein the weight rano (excluding coating) is 0.50, 0.44, 0.39, 0.31, 0.29, 0.71, 0.75, 0.65, 0.18 or 0.22.
21. The pharmaceutical formulation according to claim 18 wherein the weight ratio (excluding coating) is from 0.18 10 0.75.
22. The pharmaceuncal formulation according to claim 1S in pharmaceutical dosage form.
23. The pharmaceutical formulation according to claim 22 wherein the pharmaceutical dosage form is a tablet.
24. The pharmaceutical formulation according to claim 15 wherein tenofovir disoproxil fumarate and emtricitabine are present in a ratio of about 300:200 by weight. 4 AMENDED SHEET
IY 5 - L}
25. The pharmaceutical formulation according to claim 24 comprising about 300 mg of tenofovir disoproxil fumarate and about 200 mg of emtricitabine.
26. The pharmaceutical formulation according to claim 15 suitable for oral adnmunistration.
27. The pharmaceutical formulation according ro claim 26 wherein the pharmaceutical dosage form is a capsule.
28. The pharmaceutical formulation according to claim 15 suitable for administration once per day to an infected human.
29. A pauent pack comprising (a) at least one coformulated pharmaceutical formulation comprising [2-(6-amino-purin-9-yl)-1-merhyl-ethoxymethyl]-phosphonic acid diisopropoxycarbonyloxymethyl ester fumarate (tenofovir disoproxil fumarate) and (2R, 58, cis)-4-amuno-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-( 1H)-pyrimidin- 2-one (emtricitabine), and (b) an information insert containing directions for the use of tenofovir disoproxil fumarate and emtricitabine in formulation for the weatment of a patient in need of antiviral weatment consisting of anti-HIV therapy.
30. The panent pack according to claim 29 wherein the pharmaceutical dosage form 1s a 1abler, caplet, or capsule comprising 300 mg of tenofovir disoproxil fumarate and 200 mg of emtricitabine.
31. The pharmaceutical formulation of any of Claims 15 or 29 which further comprises a third antiviral agent. : SHEET AMENDED
[} Jo . .
32. The formulation of Claim 31 wherein the third agent is selected from an HIV protease inhibitor (Pl), an HIV nucleoside reverse transcriptase inhubitor (NRTY), an HIV non- nucleoside reverse transcriptase inhibitor (NNRTI), and an HIV integrase inhibitor.
33. The formulation of Claim 32 wherein the third antiviral agent is a PIL
34. The formulation of Claim 32 wherein the third antiviral agent is an NNRTI.
35. The formulation of Claim 32 wherein the third antiviral agent is selected from the Reyataz, Kaletra, or Sustiva anti-HIV agenis.
36. An oral pharmaceuncal dosage form compnsing tenofovir disoproxil fumarate, emtricitabine and Reyataz.
37. An oral pharmaceutical dosage form comprising tenofovir disoproxil fumarare, emtricitabine and Kaletra.
38. An oral pharmaceutical dosage form comprising tenofovir disoproxil fumarate, emincitabine and Susuva.
39. The pharmaceutical formulation of claim 15S comprising 1n weight percent {excluding coating) tenofovir disoproxi] fumarate 30, emtricitabine 20, pregelatinized q 4 - 0 starch 5, croscarmellose sodium 6, lactose monohydrate 8, microcrystalline cellulose 30, and magnesium stearate 1.
40. A wbler comprising 300 mg of tenofovir disoproxi} fumarate, 200 mg of emiricitabine and carriers and/or excipients sufficient to produce less than 5% acid degradation of tenofovir disoproxil fumarate or emtricitabine afier six months storage with desiccant at 40°C/25% relative humidity.
41. An oral dosage form comprising Sustiva, 300 mg tenofovir disoproxil fumarate, 200 mg of emtriva and pharmaceutically acceptable carriers or excipients. 7 SHEET AMENDED SHEE
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CN103127028A (en) * | 2013-03-14 | 2013-06-05 | 南京恒道医药科技有限公司 | Capsule containing tenofovir disoproxil fumarate |
CN106539807B (en) * | 2015-09-21 | 2020-06-26 | 四川海思科制药有限公司 | Stable pharmaceutical composition and preparation method thereof |
CN110251476B (en) * | 2019-08-01 | 2022-08-09 | 海思科制药(眉山)有限公司 | Emtricitabine tenofovir pharmaceutical composition |
CN112274488B (en) * | 2020-10-22 | 2022-08-26 | 安徽贝克生物制药有限公司 | Emtricitabine and tenofovir compound tablet and preparation method thereof |
-
2004
- 2004-01-13 TW TW93100811A patent/TW200425895A/en unknown
- 2004-01-13 CN CN200480002190.5A patent/CN1738628B/en not_active Ceased
- 2004-01-14 AR ARP040100088 patent/AR043332A1/en unknown
-
2005
- 2005-07-21 ZA ZA200505852A patent/ZA200505852B/en unknown
Also Published As
Publication number | Publication date |
---|---|
AR043332A1 (en) | 2005-07-27 |
CN1738628B (en) | 2012-06-06 |
CN1738628A (en) | 2006-02-22 |
TW200425895A (en) | 2004-12-01 |
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