ZA200604093B - Tocopherol-modified therapeutic drug compounds - Google Patents

Tocopherol-modified therapeutic drug compounds Download PDF

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ZA200604093B
ZA200604093B ZA200604093A ZA200604093A ZA200604093B ZA 200604093 B ZA200604093 B ZA 200604093B ZA 200604093 A ZA200604093 A ZA 200604093A ZA 200604093 A ZA200604093 A ZA 200604093A ZA 200604093 B ZA200604093 B ZA 200604093B
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South Africa
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moiety
compound
therapeutic drug
tocopherol
succinate
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ZA200604093A
Inventor
Zhang Yuehua
Lynn C Gold
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Sonus Pharma Inc
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Description

TY Wo 2005/0425.39 PCT/US2004/036127
TOCOPHEROL-MODIFIED THERAPEUT 11C DRG COMPOUNDS
FIELD OF THE INVENTION
The present invention relates to new therape vile drugs: compositions that include the new therapeutic drugs; and methods for adminissiciing ond using the new therapeutic drugs and cormpositions.
BACKGROUND OF THE FRVENTION
The ability to administer biologically effect ive drugs that are poorly soluble in biocompatible solvents to mammals has been a maior aurdle in the realm of pharmaceutic al and medicinal chemistry. In particislur, difficulties arise when an active drug is either insoluble in waier or unstable in other miccemraiihle solvents.
One way to solubilize medicinal agents is 10 <semically modify them or conjugate them to anothmer molecule to alter the solubility profiB¢ jo murtizular solvent. Conjugates of active drugs, often referred to as prodrugs_ inciude chemical derivatives of biologically-active parent compounds that are conv=eried into the parent compounds in vivo. The rel ease of the active parent drug from the prodrug conjugate may occur as the result of processes such as hydrolysis or enzymatgc cleavage. The rate of release is influenced by~ several factors, including the type of chiemiccl bond joining the active parent drug toe the conjugate moiety.
Incorpeorating a water-soluble moiety (c.g., pcliuthylene glycol, polyglutamate, or polymer) to increase solubility and circulation life «i =» dree nas been investigated by others. The u sz of fatty acids to conjugate to active (Frags Tor purposes of tumor targeting has also been investigated as a means of mmproving tinerazentic index.
Many potent drugs, such as caripieizecin and its analogues (c.g., 10-hydroxycampiothecin and 7-ethyl-1{2-vdroxy camptothecin), taxanes (e.g, paclitaxes], docetaxel), candesartan, amphoterscin 7, azathioprine, cyclosporine, entacapone, danazol, eletriptan, and bosentan. to nanc @ few. are poorly soluble or have poor cell perrmeability. Solubility problems of poter=ual wmerapeutic agents are common and often cause delays ir drug development. Severe] technologies have been developed to facilitate the delivery of poorly soluble and insolubic compounds to patients.
Examples of technologics specifically designed 10 so've solubility problems include complexing a gents, nanoparticles, microemulsions. seiubility enhancing formulations, prodrugs, and novel polvmwr systems.
rr -
Paclitaxel (see structure below), a natural product fourad in the inner bark of the
Pacific Yew tree, is ara example of an important chemotherapeutic agent with wide spectrum of activity aga inst solid tumors, primarily breast, ovarian, colon and non-small cell lung cancer.
No o oH o o
Oy ope 1 z ow = A 5 0
OH OH = S > o
Paclitaxel exerts its antitumor activity by binding to tubulin and stabilizing microtubules and thus blocking cell mitosis. However, paclitaxel, like many other potent biologically active mole cules, has very limited aqueous solubilaty.
Camptothecin (CCPT) (see structure below) is another example of a poorly soluble and difficult to formulat € anti-cancer drug.
IA 0
B C N
ZZ
N \ D y
E © —
OH 0»
CPT is a quinolZine-based alkaloid found in the bark o f the Chinese camptotheca tree and the Asian nottaapodytes tree. CPT includes four plarar rings (ABCD) and one boat conformational ring (E). CPT has been found to have a broad spectrum of antitumor activity, especially in human solid tumors. However, the lactone (ring E) of camptothecin and its derivatives is quite labile in alkaline condition and physiological pH. The opening of this ring to form an acid salt or carboxylate species results in significant loss of anticancer activities. Efforts have been m ade since the early 1960s,
TY WO 2008042339 PCT/US20 04/036127 when CPT was discovered by Wall and Wani, io move upon the anti-cancer activities of camptothecin and its analogues, and to reduce wmvanted toxicities. No successful foxmulation of camptothecin has been d eveloped io dee because of its poor solubility in both water and oruinic solvents. However, wuer-soiuvhle analogues of camptothecin, irinotecan hydrochloride (CAMPTOSAIR} and weporeczn hivdrochloride (HY CAMPTIN), have been developed and are the only camptothecin analogs currently approved by the
Food and Drug Administration.
Recently. a vitamin E (a-tocopherol)-based eniilsion formulation technology for paclitaxel drug delivery has been developed. In ric formulation, paclitaxel is solubilized in a-tocopherol and formulated as an oi J-in-vw ater cmulcion. However, while paclitaxel is soluble in a-tocopherol. the solubility of ciher 2cfive moiciies (including camptothecin and other taxanes) in ¢-tocopherol is limited. Thereiore, there continues to be a need for new methods, which zre both safe and efticacicus, of solubilizing and delivering poorly soluble active drug molecules.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides therapeutic drug compounds that have been modified to increase their Lipophilicity. The compounds of the invention include a one or more therapeutic drug moizies and cine or more lipophilic moieties. The therapeutic drug moiety is covalently coupled io ihe iépophilic moiety either directly or by a linker moiety. Methods for making iz modified therapeutic drugs are also provided.
In another aspect of the invention, coripesiiions that include the cormpounds of the invention are provided. In one embe dimient. ihe composition includes a compound of the invention, optionaily one or more other tne apouiic acents, and a lipophilic medium.
Methods for making ihe compositions are alse 1movided.
In a further aspect, the invention provides emulsion and micelle formulations that mclude a compound of the invention. The emulsion formuiation include an oil phase and an aqueous phase. Thc oil phase includ es a compound of the invention and a lipophilic medium. The emulsicn may be an oil-in-water emuision or a water-in-oil emulsion. The micelle formulation incindes a compound of the invention and an aqueous phase.
Methods for making the emulsion and micelle formuiziions are also provided.
In other aspects, methods for administering the compounds of tlre invention to a subject in need thereof, and methods for treating a condition treatable by administration of a compound of the invention are al so provided.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
FIGURE 1 schematically illustrates reaction of d-a-tocopherol and a therapeutic drug containing a carboxyl group to provide a tocopherol-modified therapeutic drug compound;
FIGURE 2 schematically illustrates tocopherol functionalization with a carbony! chlonde group (-C(=0)CI) and a phosphoric chloride group (-P(=0)OR,Cl), and reaction of the resulting acid chloride and an appropriately functionalized toerapeutic drug compound to provide a tocopherol-modified therapeutic drug compound;
FIGURE 3 schematically illustrates tocopherol functionalization with a dicarboxylic anhydride (succinic anhy~dride), and reaction of the resulting carboxylic acid and an appropriately functionalized therapeutic drug compound to provide a tocopherol-modified therapeutic drug compound;
FIGURE 4 schematically illustrates the preparation of tocopherol succinate camptothecin;
FIGURE 5 schematically illustrates the preparations of tocopherol succinate 10-hydroxycampioihecin and tocopherol succinate 7-ethyi-1U-hydroxycam ptothecin;
FIGURE 6 schematically illustrates the preparation of 10,2 0-di(tocopherol succinate) 7-ethyl-10-hydroxycamptothecin;
FIGURE 7 schematically illustrates the preparation of tocopherol succinate camptothecin containing a poly(ethylene oxide) group;
FIGURE 8 schematically illustrates the preparation of tocopherol succinate paclitaxel;
FIGURE 9 schematically illastrates the preparation of tocopherol succinate docetaxel,
FIGURE 10 schematically illtastrates the preparation of tocopherol terephthlate camptothecin;
TY Wo 008042330 PCT/US2004/036127
FIGURE 11 schematically Hustraes the preparation of tocopherol cyclohexane-1 ,2-dicarboxylate 7-ethyl-1 O-hydrovycamptothecin:
FIGURE 12 is a graph comparing the in vito siability of the lactone form of camptothecin and of two representative tocopherol-modified thera peutic drug compounds of the mvention (SN2300, tocopherol succinate camprothecin; and SN2310, tocopherol succinate 7-ethyl-1 0-hydroxycamptothecin);
FIGURE 13 isa graph comparing Gls, vale reported by NCI for camptothecin, irinotecan hydrochloride (irinotecan), and topoiccan hvdrochloride (topotecan) with Glsg values obtained for two representative tocopheroi-modified therapeutic drug compounds of the invention (SN2300 and SN2310) for ceili lines: H460, HCT-116, HT29, and
OVCAR-3;
FIGURES 14.A and 14B are graphs of concentration-time values after intravenous injection of 13.8 mg/kg of two representative tocopherol-modai fied therapeutic drug compounds of the invention (FIGURE 14A, SN2300: and FIGURE 14B, SN2310); and
FIGURES 15A and 15B are graphs illusiziing tumor growth (mm?) over time in xXenographs treated with saline, irinotecan, and two representative tocopherol-modified therapeutic drug compounds of the invention (SN2300 and SN2 310) in two different tumor models (FIGURE 15A, NCI-H460; and 11 isms I5B, HT-29).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In one aspect, the present invention provisos therapeutic drug compounds that have been modified to increase their hipophilicizy, ha compounds of the invention are modified therapeutic drugs. The compounds of the invention inclu de a therapeutic drug moiety and a lipophilic moiety.
In some embodiments, the compounds ©! ihe invention include more than one therapeutic drug moiety. In some embodiments, 1he compounds of the invention include more than one lipophilic moiety. In other embodimen:s, the compowinds of the invention include more than one therapeutic drug moiety and more than one lipophilic moiety.
In some embod iments, the therapeutic crip moiety is coval ently coupled to the lipophilic moiety throu gh a linker moiety. In other embodiments, the therapeutic drug moiety is directly covalently coupled to the lipophiiic moiety without a linker moiety.
In one embodiment, the lipophilic maoict iz a tocopherol moiety, and the compound is a tocopherol-modified therapeutic drug Compound. The tocopherol-modified therapeutic drug compound (or "ieconherolate d” therapeutic drug compound ) has one or more tocopherol moieties covalently coupled to a therapeutic drug moiety or a tocopherol moiety covalently coupled to one or more therapeutic drug moieties. As noted above, the tocopherol moiety 1s cov alently coupled to the therapeutic drug moiety either directly or through a linker moiety.
In one embodiment, the tocopherol-modified therapeutic drug compounds of the invention can be represented by the general formula (1): (T-L)a(T)mD (1) wherein T is a tocopherol moiety (i.e., a representative lipophilic moiety); L is a linker moiety; n is 0, 1,2, or 3; m is0,1,2,or3:n+mis 1,2, or 3; and D is a therapeutic drug moiety. In this embodiment, the compound includes n T-L moieties (i.e.. toco pherol-linker moieties) and m tocopherol moieties, with the proviso that n +m is 1,2, or 3. Each T-L moiety includes a tocopherol moiety covalently coupled tc a linker moiety. ¥ach of the n T-L moieties is covalently coupled to the therapeutic drug moiety through the T-L moiety's linker moiety. In this embodiment, each of the m tocopherol moieties is directly covalently coupled to the therapeutic drug moiety without a linker moiety.
R_epresentative compounds having formula (1) include those in which n is 0 and m is 1,2, ox 3. These compounds have the general formula:
TD QQ)
In this embodiment, one, two, or three tocopherol moieties are directly covalently coupled to the therapeutic drug moiety.
Representative compounds having formula (1) include those in which m is 0 and nis 1,2, or 3. These compounds have the general formula: (T-L).D 3)
In this embodiment, one, two, or three T-L moieties are covalently coupled to the therapeutic drug moiety through the T-L moiety's linker moiety.
a CWO 2005/042539 PCT/US2004/036127
Representative compounds having formuiz 1) include those in which m 1s 1 or2, and nis 1 or 2. "These compounds have the general formulae; (T-L3{E5D 4) (T-IH{TLD (5) (T-L- (HD (6)
In these embodirments, the compounds «7 tlic invention have tocopherol moieties that are directly covalently coupled to the therepenidc dug moiety without a linker and tocopherol moieties that are covalently coupled io lic therapeutic drug moiety through a linker (i.e., the T-L moi eties).
The compounds of the inveniion described above include one therapeutic drug moiety and one or more lipophihc moieties {(t.g.. tocopherol moieties). In other embodiments, the compounds of the invention include more than one therapeutic drug moicty. In one embodiment, the compounds include two therapeutic drug moieties. In another embodiment, the compounds include three therapeutic drug moieties. For compounds that include more than one :herareutic drug moiety, the therapeutic drug moieties a can be the same or different.
For compounds that include rive hom ome therapeutic drug moiety, the therapeutic drug rmoieties can be incorpor:ies jute the compound in any suitable way. In some embodiments, the therapeutic drug wieistics can be directly covalently coupled (e.g., the compound includes a -D-D- or -72D moi ety). In other embodiments, the therapeutic drug moieties are separalcd in the compound by a linker moiety (e.g., the compound includes a -D-L-D- or -D-I-i3 moiety), a lipophilic moiety (e.g., the compound includes a -D-T-D- or -D-T-D moiety), or a lipophilic-linker moiety (e.g., the compound includes a -D-T-L-D-, -D-T-1.-T3, or -D-I- T-D moiety; or a -D-L-T-L-D- or -D-L-T-L-D moicty).
Representative compounds inciudirg two or thi-ce therapeutic drug moieties have the general formul a: (T-LYDY, (7)
wherein p is 2 or 3. In this embodiment, the two or three therapeutic drug moieties are covalently coupled to the linker moiety. In this instance, the linker includes multiple sites for the attachment of the therapeutic drug compound (ox modified therapeutic drug compound). As is clear from formula (7), the linker moiety is also covalently coupled to the lipophilic moiety (e.g., tocopherol moiety). As noted above, compounds of the invention including more than one therapeutic drug moiety can have formulae other than shown above in formula (7). For example, such a compound can include more than one (e.g., two or three) lipo philic (e.g. tocopherol) moieties.
The compounds of the invention include one or more lipophilic moieties and one or more therapeutic drug moieties that are either directly covalently linked or covalently linked through linker moieties.
As used herein, the term "lipophilic moiety" refers to a chemical moiety having lipophilic or hydrophc bic characteristics and that increases the solubility of a therapeutic drug compound in a lipophilic solvent or environment when covalently coupled to the therapeutic drug compound to provide a compound of the invention. A description of representative lipophilic moieties useful in making the compounds of the invention is provided below.
As used herein, the term "therapeutic drug moiety" refers to a chemical moiety 90 derived from a therapeutic drug compound. A description: of representative therapeutic drug compounds useful in making the compounds of the invention is provided below.
As used herein, the term "linker moiety" refers to ary atom or a group of atoms that covalently link, for example, a lipophilic moieiy iw a therapeutic drug moicty.
A description of representative linkers useful in making thie compounds of the invention is provided below.
Lipophilic Modification of Therapeutic Drug Compounds. A therapeutic drug compound may haves one or more suitable functional groups, or may be modified to include one or more suitable functional groups for cov alent coupling to a lipophilic moiety. Suitable functional groups include, for example, the following groups: hydroxyl group (-OH), amino group (primary amino group, NH, or secondary amino group, _NHR,. where R; is independently selected from H, C.e n-alkyl, Cs.12 branched alkyl, substituted or unsubstituted Cs.¢ cycloalkyl, substituted or unsubstituted aryl, or aralkyl), thiol group (-SH), carboxyl group (-COOH), aldehyde group (-CHO), isocynato group _8-
a Co WO 2005/042539 PCT/US2004/0 36127 (-N=C=0), sulfonic acid group (-SO;H), sulfuric acid croup (-OSO;H), phosphoric acid group (-OPO;3H), phosphonic acid group (-POsH:), allylic halide group, benzylic halide group, substituted benzyiic halide group. and oxiranyl crouy ~-CH(O)CH,).
A therapeutic drug compound may be direci!> coupled to a lipophilic moiety (e.g..a tocopherol moiety) through an ester group -C{=0)0-), carbamate group (-OC(=O)NH-), sulfonate group (-SOs-), sulfate group {-©950;3-), phosphate group (-OPO3R;-, where R; is independently selected from H, Ci. n-alkyl, Cs.12 branched alkyl, substituted or unsubstituted Cj. cycloalkyl, substituted or wisebstituted aryl, or aralkyl), phosphonate group (-PO:R;-, where Ry is independently sclected from H, C,¢ n-alkyl,
Cs,» branched alkyl, substituted or unsubstituted Cie cycloalkyl, substimited or unsubstituted aryl. or aralkyl), or ether group (-0-).
A tocopherol compound, a representative lipophilic compound suitable for making the compounds of the invention, includes a aycroxyl group (-OH). After modification, a tocopherol compound may be covalen:lv coupled to a linker com pound
L5 that includes one or more reactive functional groups. Suitable reactive functional groups include the following groups: hydroxyl group (-QIi). amino group (primary =mino group, -NH, or secondary amino group, -NHR,. where R, ic independently selected from
H, Ci. n-alkyl, Cs.» branched alkyl, substituted or msubstituted Css cyclo alkyl, substituted or unsubstituted aryl, ow aralkyl), thio! group (-SH), carboxyl group (-C(=0)OH), aldehyde group (-CHO),, isocynato group (-N=C=0), sulfonic acid £roup (-SO3H), sulfuric acid group (-OSO3H), phosphoric acid group (-OPOsH), phosphonic acid group (-POsH.), allylic halide group, benzylic hajde Zroup, substituted bermzylic halide group, and oxirany! group (-CH(O)CH,).
Linker Moieties. As noted above, in some emmbocinents, the compounds of the invention include a lipophilic moiety (e.g. tocopherol moiety) covalently coupled to a therapeutic drug moiety by a linker moiety. In addition 1c the embodiments described above, the tocopherol-modified therapeutic drug compounds of the invention cam be represented by the general formula (8):
T-A-R-A'-D =) where T is a tocopherol moiety (i.e., a re presentative hipophiiiz moiety), D is a therape utic drug moiety, and A-R-A' is a linker moiety. It Will be appreciated that for formulae
(1) and (3)-(7) above, each of which includes linker moiety L, the linker moiety L in those compounds can be linker moiety A -R-A'.
In formula 8, groups A and A' are independently selected from O, S, SO, SO»,
NR,, carboxylate group (-C(=0)O-), amide group (-C(=O)NR;-), anhydride group (-C(=0)0C(=0)-), carbamate group (-OC(=0O)NH-), carbonyldioxy group (-OC(=0)O-}, ureylene group (-NR;C(=0)NR>-), phosphate group (-OP(=0)(OR;)O-), phosphamide group (-OP(=0)(NR,)O-), phosphonate group (-OP(OR;)O-), phosphomamide group(-OP(=0)NR;-), sulfate group (-OS0,0-), sulfamide group (-SO,NR;-), stalfonate group (-SO;-), sulfonamide group (-SO;NR;-), and the dicarbonyl group, -C(=O)R3C(=0)-, where Rj; is absent or a divalent alkyl (e.g., -(CH2)p-, n = 1-12), substituted alkyl, branched alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl.
For the above groups, R is a divalent zroup selected from the following groupsz alkyl; substituted alkyl, branched alkyl; cycloalkyl; substituted cycloalkyl: heteroalkyl; substituted heteroalkyl; aryi; substituted aryl; aralkyl; substituted aralkyl; amirzc acid; peptide; polypeptide; protein; mono-, Gi- or polysaccharide; oligomer of ethylene glycol, poly(ethylene glycol); poly(alkylene oxide) polymers, such as poly(ethylene oxxde) and poly(propylene oxide); and poly(ethylene oxide)-poly(propylene oxide) copolymer. For the above groups, R; and Rj are independently selected from Na*, K*, H, Cis n-alkyl,
Ci.;; branched alkyl, substituted or unsubstituted Cs cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl.
As used herein, the term "aryl" refers to monocyclic and polycyclic aromatic compounds having from 6 to 14 carbon or hetero atoms, and includes carbocyclic aryl groups and heterocyclic aryl groups. Representative aryl groups include phenyi, naphthyl, pyridinyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, furanyl, and the like. The term "aralkyl" refers to an alkyl group that is substituted with an aryl group.
The following compounds (compounds 9 to 32) are representative examples of compounds having formula 8.
A linker moiety (L) and therapeutic drug moiety (D) may. be covalently> coupled through an ester group. In one embodiment, the therapeutic drug moiety iricludes a hydroxy! group that is coupled with a carboxyl group of the linker moiety. T he linker moiety may be coupled to a tocopherol moiety through an ether group (compound 9), ester group (compound 10), amine group (compound 11), or amide group (compound 12).
Ly To WO 2005/042539 PCT/US2004/036127 o CoO
O. _D - k
TT Ig SE NI 9 T0
Ri © r oO =
N_ D -
T° NN on ALD 11 12
In another embodiment, the therapeutic dri nwciety (D) includes a carboxyl group that 1s coupled with a hydroxyl group of ths lini: moiety (L). The linker moiety may be coupled 10 a tocopherol moiety through 2: ether groewp (compound 13), ester group (compound 14), amin e group (compound 13), cr amide group (compound 16).
Oo. __ D K +r I JAVS a nyr® o oO 13 14 _N._O_ _D __o. bp
TR hg Sree 0 § EE 16
In the above compounds, divalent group RK 15 zilected #rom alkyl; substituted 15 alkyl; branched alkyl; cycloalkyl; substituted cyeinailnviz heteroalkyl; substituted heteroalkyl; aryl; substituted aryl; aralkyl; substineed arziioyl; amino acid; peptide; polypeptide; protein; mono-, di- or polysaccharide: clicomer of ethylene glycol, poly(ethylene glycol); poly{al kylene oxide) polymers, such as poly(ethylene oxide) and poly(propylene oxide): and poly(ethylene oxide)-poix{manviene <oxide) copolymer. In the above compounds. R; is selecied from HO, n-tidovl, «Cay branched alkyl, -1i-
substituted or unsubstituted Ci cycloalkyl, substituted or unsubstituted aryl, and substituted or munsubstituted aralkyl.
While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing froma the spirit and scope of the invention. A linker moiety (L) and therapeutic drug moiety (D) may be covalently coupled through an amide group. In one embodiment, the therapeutic drug moiety includes an amine group that is coupled a carboxyl groap of the linker moiety. The linker moiety may be coupled to a tocopherol moiety through an ether group (compound 17), ester group (compound 18), amine group (compound 19), or amide group (compound 20).
Q 0 0 i To py
Ry Rq 17 18
Ri 0 o oO
Magy LS NN.
R2 Rq Re 19 : 20
In the above compounds, divalent group R is selected from alkyl; substituted alkyl; bran ched alkyl; cycloalkyl; substituted cycloalkyl; heteroalkyl; substituted heteroalkyl; aryl; substituted aryl; aralkyl; sub stituted aralkyl; amino acid; peptide; polypeptide ; protein; mono-, di- or polysaccharide; oligomer of ethylene glycol, poly(ethyleme glycol); poly(alkylene oxide) polyxmers, such as poly(ethylene oxide) and poly(propyl ene oxide); and poly(ethylene oxide)-poly(propylene oxide) copolymer. In the above compounds, R; and R; are independently selected from H, Cj. n-alkyl, Ci 12 branched aXkyl, substituted or unsubstituted Cz. cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl.
A Ii nker moiety (L) and a therapeutic drug moiety (D) may be covalently coupled through arm ether group (compound 21) or amine group (compound 22). In one embodiment, the therapeutic drug moiety includes a hydroxy group, and in another x WO 2005/042539 PCT/iS2004/036127 embodiment, the therapeutic drug moiety includes an amine 2xroup. The linker moiety may be coupled to a tocopherol moiety through an ether group.
OH ol] Tr <S o Ps : + A ~; 7 A 21 22
In the above compounds, R; is selected from H. Ci.6 n-23kyl, Cs.1o branched alkyl, substituted or unsubstituted Cs. cycloalkyl, substituted or tnsub stituted aryl, or aralkyl.
A tocopherol moiety (T) and a therapeutic drug meiet~v (D) may be covalently coupled through a carbonyldioxy group (-OC(=0)0-) (compovand 23). In this case, the linker moiety is the carbonyldioxy group and the therapeutic drug moiety includes a hydroxyl group. rokos 23
A tocopherol moiety (T) and a therapeutic drug wcicty’ (D) may be covalently coupled through an anhydride group (-C(=0)OC(=0)-). r= one embodiment, the therapeutic drug moiety includes a carboxyl group that is couple=d with a carboxyl group of the linker moiety. The linker moiety may be coupled 1¢ 2 to copherol moiety through an ether group (compound 24), ester group (compound 25}, mize group (compound 26), or amide group (compound 27).
Oo O GC iB) 0
T NPN. Nor Sr ™ oN, 24 25 eo o oo oo
N [1]
Ri 26 27
In the above compounds, divalent group R is selected from alkyl: substituted alkyl; branched alkyl; cycloalkyl: substituted cycloalkyl; heteroalkyl; substituted heteroalkyl; axyl; substituted aryl; aralkyl; substituted aralkyl; amino acid; peptide; polypeptide; Protein; mono-, di- or polysaccharide; oligomer of ethylene glycol, poly(ethylene glycol); poly(alkylene oxide) polymers, such as poly(ethylene oxide) and poly(propylene oxide); and poly(ethylene oxide)-poly(propylene oxide) copolymer. In the above compounds, R; is selected from H, Ci. n-alkyl, Cs.2 branched alkyl, substituted ox unsubstituted Cj cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl.
A tocopherol moiety (T) and therapeutic drug moiety (D) may be covalently coupled throu gh a phosphate, phosphoramide, or thi ophosphate group (compound 28). 0 ~~ Ae —° oo” \ X
X (Ry 28
Inthe above compounds, X is O, NR,, or Sz X; 1s O, NR3, or S; and R, is selected from Na’, KK”, H. Cig n-alkyl, Cs.» branched alkyl, substituted or unsubstituted
Ci gcycloalkyl, substituted or unsubstituted aryl, or aralkyl; and R; and Rj are independently selected from C,¢ n-alkyl, Cs.;2 branched alkyl, substituted or unsubstituted Csi. cycloalkyl, substituted or unsubstituted aryl, or aralkyl.
A tocopherol moiety (T) and a therapeutic drug moiety (D) may be covalently coupled through a sulfate, thiosulfate, or sulfonamide group (compound 29).
AN Vi
PERN
T—-0 X——D 29
In thhe above compounds, X is O, NR;, or S; and R; is selected from H,
Ci.¢n-alkyl, Ca.j2 branched alkyl, substituted or urisubstituted Cs.¢ cycloalkyl, substituted or unsubstituted aryl, or aralkyl.
CT WO0 2005/042539 PCTIUS2004/03612 7
A tocopherol moiety (T) and therapeutic « us oiety (D) may be covalemtly coupled through a ureylene group (-NHC(=O)NH-) (Comound 30). i —— po
R, ks 30
In the above compounds, R; and R, zirc independently selected from
Fl, Cyen-alkyl, Ci,» branched alkyl, substituied «<r unsubstituted Cs cycloalkyl, substituted or unsubstituted aryl, or aralkyl.
A tocopherol moiety (T) and a therapeutic drug imotety (D) may be covalently coupled through a carbamate group (-NR,;C(=0)0- or -GC(=0O)NR,-, compounds 3] ard 32, respectively). 0 0]
A A
31 32
In the above compounds, R; and R. or= independently selected from
H, Cjg¢n-alkyl, Cs, branched alkyl, substituted oz unsubstituted Css cycloalkyl , substituted or unsubstituted aryl, or aralkyl.
Lipophilic Moiety. The compounds of the invention include one Or mores lipophilic moieties. The lipophilic moiety or moieticss increases the solubility of the compound in a lipophilic solvent or environment. In onc embodiment, the lipophilic moiety is a tocopherol moiety.
As used herein, the term "tocopherol moictv” refers to a chemical moiety that is derived from a family of natural or synthetic comuowmxds, also known by their generic names, tocol or vitamin E. In addition to tocophero! coz wnounds, tocotrienol compounds are included in this familv. These compounds incivde 2 chroman head having a phenolic alcohol (C-6) and a phuytyl tail (C-2). These compounds have the following general formula:
POSS PS eS «5 OH
Tocopherols comstitute a series of related benzopyranols (or methyl tocols) In which the C-2 phytyl (sixteen carbon) side chain is saturated. Representative tocopherols include a-tocopherol, C d-form, dl-form, I-form), B-tocopherol (d-form, dl-form, I-form), y-tocopherol (d-form, dl-form, l-form), and &-tocopherol (d-from, dl-form, l-form).
Among tocopherols, oz-tocopherol is the most abundant. Tocotrienols are similar in structure to tocopherols except that the trienols have three double bonds in the C-2 phytyl side chain.
Tocophero} anc tocetrieno! compounds useful in making the com=ounds cf the invention include those= shown below. : : Rs R.
CH; CHg CHa Ho
EE me on
Rq
Tocopherol
Ra =
HaC ~~ x EN oH
R
Tocotrienof cu, beta (B) gamma (1) delta 3
As used herein, the term "tocopherol" refers to any member of the tocopherol family noted above.
Therapeutic Drug Moiety. The compo unds of the invention include one or more therapeutic drug moicties. Virtually any therapeutic drug compound having = suitable functional group, or that can be modified 10 include a suitable functional group, can be covalently coupled to a lipophilic compound io provide a compound of the invention.
Representative functional groups include, for exampie, hydroxyl groups (-OHE), amino groups (p ritnary amino groups, -NH,, and secondary amino groups, -NHR), thiol groups (-SH), carboxyl groups (-COOH), aldehyde groups (-CHO), isocynato groups (-IN=(C=0), sulfonic acid groups (-SOsH), sulfuric acid groups (-OSO3H), phosphoric acicl groups (-OPO3H), phosphonate groups (-PO3;ORR:, and R, and Ry are independently selected from H, C,¢ n-alkyl, Cs.;, branched alkyl, substituted or unsubstituted Cs.6 cy cloalkyl, substituted or unsubstituted aryl, or aralkyl.), allylic halide group, benzylic halide group, substituted benzylic halide group, and oxiranyl group (-CH(O)CHy).
Therapeutic drug compounds useful in making the compounds of the iEvention need not be substantially water insoluble, although tocopherol modification accoerding to the preserat invention is especially well suited for formulating and deliverimg such water-inso luble compounds.
In one embodiment, the therapeutic drug moiety is derived from a therapeutic compound that is substantially insoluble in water. In another embodiment, the therapeutic drug moiety is derived from a therapeuiic compound that is subs®antially insoluble in organic solvents. In another embodiment, the therapeutic drug moiety is derived from a therapeutic compound that is substantially insoluble in water and substantially insoluble in organic solvents. In cne embodiment, the therapeut ic drug compound has a solubility in water at room temperatuic less than about 1000 pg/mml. In one embodiment, the therapeutic drug compound has a solubility in water at room temperature less than about 500 pg/mL. In one embodiment, the therapeutic drug compound has a solubility in water at room tem perature less than about 100 pg/rml. In one embodiment, the therapeutic drug compound has a solubility in water a® room temperature less than about 25 pg/mL.
Rep resentative therapeutic compound drugs useful in making the compounds of the invention include anticancer compounds (e.g... paciiiaxel and its derivatives including docetaxel, camptothecin and its derivatives wetuding 7-ethyl-10-hydroxycamptothecin
WQ 2005/042539 PCT/US2004/036127 (SN38) and 10-hydroxycamptothecin, and doxorubicin and its derivatives), antifungal compounds (e.g., flucanazole), antibacterial compounds (e.g., penicillin G, penicillin V), anti-hypertensive compounds (e.g., hydralazine, candesartara, and carvediol), anti-inflammatory compounds (e.g., isoxicam), antidiabetic compoumds (e.g., metformin), 3 antiviral compounds (e.g., lamivudine), antidepressant compounds (e.g., fluoxetine), : antihistaminic ~~ compounds (e.g., hydroxyzine), anti-arthythmic compounds (e.g., procainamide hydrochloride), anti-hyperlipoproteinemic compounds (e.g., probucol), and compounds for reproductive health (e.g., danazol), and treating
Parkinson's disease (e.g., lazabemide), and immunosuppressive (e.g., azathioprine and cyclosporine) and respiratory (e.g., bosentan) diseases and conditions. ~~ Other therapeutically useful biological materials that can be modified according to the invention, include biologically active proteins, enzymes, and peptides.
In one embodiment, the therapeutic drug moiety is derived from an anticancer compound. Representative anticancer therapeutic compounds inclz:de taxanes. Taxanes 1S include any anti-mitotic taxane, taxane derivative or analog. As used herein, the term "taxane" refers to taxanes, taxines, and taxoids, as well as derivativess or analogs thereof. :
Paclitaxel and its derivatives and analogs are members of the taxane family.
Paclitaxel derivatives include, for example benzoate derivatives of paclitaxel such as 2-debenzoyl-2-aroyl and C-2-acetoxy-C-4-benzoate paclitaxel, 7-deoxytaxol, C-4 aziridine paclitaxel, as well as various paclitaxel conjugates with natural and synthetic polymers, particularly with fatty acids, phospholipids, and glycerides and 1,2-diacyloxypropane-3-amine. Other paclitaxel derivatives include docetaxel; spicatin; taxane-2,13-dione, 5B,9B,10B-trihydroxy-, cyclic 9,10-acetal with acetone, acetate; taxane-2,13-dione, 5B,9B,1 OB-trihydroxy-, cyclic 9,10-acetal with acetone; taxane-2B,58,9B,10B-tetrol, cyclic 9,10-acetal with acetone; taxarae; cephalomannine-7- xyloside; 7-epi-10-de acetylcephalomannine; 10-deacetylcephalomannine; cephalomannine; taxol B; 13-(2',3'-dihydroxy-3'phenylpropionyl)baccatin III; yunnanxol; 7-(4-azidobenzoyl)baccatin III; N-debenzoyltaxol 4A; O-acetylbaccatin IV; 7-(triethylsilyl)baccatin III; ~~ 7,10-di-O-[(2,2,2,-trichloroethoxy)carbonyl]baceatin III: baccatin III 13-O-acetate; baccatin diacetate; baccatin; baccatin VIL; baccatin VI; baccatin
IV; 7-cpi-baccatin Ill; baccatin V; baccatin I; baccatimm III; baccatin A; 10-deactyl-7-epitaxol; epitaxol; 10-deacetyltaxol C; 7-xylosyl-10-deacetyltaxol;
1 0-deacetyltaxol-7-xyloside; 7-epi-iii-deccetvitaxol; 10-deactyltaxol; or 10-deactyltaxol] B.
Other anticancer compounds usciii in making the compounds of the invention include camptothecin and its derivatives including 7-ethyl-10-hydroxycamptothec in (SN38) and 10-hydroxycamptothecin, and dexorub icin and its derivatives.
In certain embodiments, the tiicrapautic drug moiety is derived from paclitaxez], docetaxel, camptothecin, or their derivatives.
For compounds of the invention naving forxmula (2) with m = 1. formula (3) with n= 1, and formula 8, certain compounds are excluded and are not within the scope of thae invention. When the linker moiety is 2-hvdrox ypropylene (-CH2CH(OH)CH,-), thae therapeutic drug moiety 1s not an g-amine seid (e. g., glycine, alanine, proline, cysteine, aminobutyric acid, aspartic acid. glutamic acid). an w-amino acid (e.g., B-alaninc,
Yy-aminobutyric acid, e-aminocaproic acid, 2-zmin oethanesulfonic acid (taurine)), or a peptide containing a cysteine residue bending thaough its N-terminus or thiol group (e.g.,-glutathione). When the linker moiety ig a succinate, the therapeutic drug moiety is not an S-linked amino or amino acid compounra coupled to one of the aliphatic succinate carbons. When the linker moiety is succinate, the therapeutic drug moiety is not ferulic acid or an ester thereof.
In another aspect, methods for rmaiing tha compounds of the invention are provided. There are many ways to coviiently couple a lipophilic compound (e.g., a tocopherol compound) to a therapeutic dvi compound to form a compound of the invention. In one embodiment, a representative tocopherol, d-o-tocopherol, includes a hydroxy! group that may be directly coupicd with a carboxyl group of a therapeutic drug to form a tocopherol-modified therapeuiic drug compound. The preparation of a representative tocopherol-modificd therapeutic commpound of the invention from a carboxylic acid—ontaining therapeutic drug conipourd is illustrated in FIGURE 1.
In another embodiment, a tocopherol may be functionalized at the hydroxyl group with a reagent to attach an active group such as phosphoric chloride (-P(O)OR, CD), phosphonic chloride (-P(O)R|CD), sulfonic chloride (-SOCD, or carbonyl chloride (-COCD. The resulting acid chloride can then be reacted with an appropriately functionalized therapeutic drug compound ie provides a tocopherol-modified therapeutic drug compound.
In FIGURE 2, X 3s O, S. or NH; and R; is independently selected from H,
Ci.¢n-alkyl, Ca.;2 branched alkyl, substituted or unsubstituted Cs.¢ cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted aralkyl.
In another embodiment, a tocopherol may be functionalized at the hydroxyl group with a dicarboxylic acid, ester, or anhydride reagent. Suitable reagents include succinic acid anhydride, 1,2-cycloh exanedicarboxylic anhydride, 2,3-dimethylsuccinic anhydride, 3,3-tetramethylene glutaric anhydride, glutaric anhydride, maleic acid anhydride, phthalic acid anhydride, terephthali ¢ acid, or isophthalic acid to attach a carboxyl group (-COOH).
The resulting carboxyl group may then be directly reacted with an appropriately functionalized therapeutic drug or the carboxyl group may be converted to a more reactive carbonyl chloride group (-COC)), and then the carbonyl chloride group may be coupled with the functional group of the therapeutic drug to form a tocopherol-modified therapeutic drug compound as illustrated in FIGURE 3. In FIGURE 3, X 1s O, S, NH, or
CE=0)0.
In another embodiment, a linker can be coupled to the hydroxyl group of a tocopherol and then a thexapeutic drug can be coupled to an accessible functional group on the linker. The functional group may be, for example, but not limited to, a carboxyl group (-COOH), a poly(ethylene oxide) group (-(CH,CH,0),-H), an aldehyde group (-CHO), an isocyanato group (-N=C=0), a phosphoric acid group (-OPOs;H,), or phosphoric chloride group (-OPO,R;Cl, where R; is a substituted or unsubstituted alkyl or cycloalkyl, a substituted or unsubstituted aryl, or an aralkyl), a phosphonic chloride group (-PO,R;Cl, where R; is a substituted or unsubstituted alkyl or cycloalkyl, a substituted or unsubstituted aryl, or an aralkyl), a sulfuric acid group (-OSOsH), a chlorosulfuric group (-SO;Cl), or an oxiranyl group (-CH(O)CHoz).
The syntheses of representative tocopherol-modified therapeutic drug compounds of the invention are illustrated in FIGURES 4-11 and described in Examples 1-13.
FIGURE 4 illustrates the preparation of a tocopherol succinate camptothecin compound. Tocopherol succinic acid (vitamin E succinic acid) has a free carboxy! group that can couple with a hydroxyl group, amino group, thiol group, or carbonyl chloride group to provide a tocoprherol-modified therapeutic drug having a succinate group as a linker. In FIGURE 4, the carboxyl group of tocopherol acid succinate is coupled with the hydroxyl group of camptothecin. The preparation of tocopherol succinate camptothecin is described in Example 1.
K WO 2005/042539 PCT/US2004/036127
FIGURE 5 illustrates the preparation of tocopherol succinate 10-hydroxycamptothecin and tocopherol succinate 7-ethyl-10-hydroxycamaptothecin (SN38). Tocopherol succinic acid is converted to (hes corresponding acid chloride, and then reacted with 10 -hydroxycamptothecin or /-ethvl -10-hydroxycamptothecir (SN38).
The preparations of tocopherol succinate 10-hvdr oxyvecamptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin arc described in Examples 2 and 3, respectively.
FIGURE 6 illustrates the preparation of 10.2 0-di(tocopherol succinate) SN38, which contains one therapeutic drug (SN38) moiety. two tocopherol moieties, and two linker moieties (succinyl groups). The preparation o f 10, 20-di(tocopherol swuccinate)
SN38 is described in Example 4.
Suitable linker moieties can include an oligomacr or polymer such as a peptide, polypeptide, protein, mono-, di- or polysaccharide:, oligomer of ethylene glycol, poly(ethylene glycol), poly(alkylene oxide) such as poly(ethylene oxicle) and poly(propylene oxide), or poly(ethylene oxide)-poRv(propylene oxide) copolymer.
FIGURE 7 illustrates the preparation of a tocopherol-m «dified camptothecin containing a linker moiety that iracludes a poly(ethylene oxide) group. The preparation. of the tocopherol succinate camptothecin having a linker moi ety that includes a poly(ethylenc oxide) group is described in Example 3.
FIGURE 8 illustrates the preparation of tocopherol succinate paclitaxel. In the : preparation, tocophero 1 succinic acid is converted to the corresponding acid chloride and then reacted with paclitaxel. The preparation of io cophero! succinate paclisaxel is described in Example 6. FIGURE 9 illustrates the preparation of tocopherol staccinate docetaxel. The preparation of tocopherol succinate doce axel is described in Example 7.
FIGURE 10 illustrates the preparation of tocopherol terephthalate camptothecin,
In the preparation, toc opherol is first conjugated with ®erephthalate to form tocopherol terephthalate (Example 9) and is then coupled with camptothecin to form tocopherol terephthalate camptothecin. The preparation of tocophexmol terephthalate camptothecin is described in Example 1 0.
FIGURE 11 illustrates the presparation of tocopherol cyclohexane-1,2-dicarb oxylate SN38. The preparation of tocopherol cyclohexane-1,2-dicarboxylate SN38 is described in Exarmple 11.
The preparatioras of tocopherol succinate doxorubicin and tocopherol succinate hydroxyzine are described in Examples 12 and 13, respectively.
In another aspect, the present invention provides compositions that include the compounds of the invention. The compositions include one or more compounds of the invention, optionally ome or more additional therapeutic agents, and a lipophilic medium.
In one embodiment, a €ocopherol-modified therapeutic d rug compound is dissolved in the lipophilic medium. Because of the lipophilic moiety, the compound has improved lipophilicity compared to the unmodified therapeutic drug compound. The lipophilic medium (or carrier) of” the composition can be any one Of a variety of lipophilic mediums including, for example, oils. In one embodiment, the lipophilic medium includes a tocopherol (e.g., a-tocopherol). Representative oils useful as the lipophilic medium include the following:
Fatty acids and esters thereof, including carboxy lic acids of various chain lengths, mostly straight chain, but which could be branched. examples of which include capric, caprylic, caproic, laurzc, myristic, stearic, oleic, linoleic , behenic, and as well as saturated or unsaturated fatty acids and esters; :
Fatty acids esterified with glycerin to form mono-, di-, or triglycerides, which can be synthetic or deriveed from natural sources, includings, but not limited to, for example, olycerides such as soybean oil, cottonseed oil, rapeseed oil, fish oil, castor oil, Capmul
MCM, Captex 300, Miglyol 812, glyceryl monooleate, triacetin, acetylated monoglyceride, tristearin, glyceryl behenate, and diacetyl tartaric acid esters of . monoglycerides;
Glycerides conjugated to other moieties, stach as polyethylene glycol (for example, Labrasol, Laabrafac, Cremophor EL);
Phospholipids, either natural or synthetic, such as dimyristyl phosphatidylcholine, egg lecithin, and pegylated phospholipids;
Other fatty esters including fatty alcohols (myristyl myristate, isopropyl palmitate), or sugars (sorbitan monooleate, SPAN 80, T'ween 80, sucrose laurate);
Fatty alcohols such as stearyl alcohol, lauryl alcohol, benzyl alcohol, or esters or 300 ethers thereof, such a_s benzyl benzoate;
Fat-soluble vitamins and derivatives, for example, vitamin E (including all of the tocopherols and toco trienols, and tocopherol and tocotrienol derivatives, such as vitamin
E succinate, vitamin E acetate, and vitamin E succinate polyethylene glycol (TPGS)).
TT WO 2005/4233 PCT/US2004/036127
Organic co-solvents can alse po used in the | comppsitiofs, JoBlichil 9 & combination with water, including for exarpic, ethanol, polyethylene glycol, propylene glycol, glycerol, N-methyl pyrrolidone, «ni dimethyl sulfoxide.
The solubilities of two represeriaiive tocoppherol-modificd camptothecin compounds of the invention in several mediums are compared 1o camptothecin in
Example 14.
In a further aspect. the invention provides emulsion, microemulsion, and micelle formulations that include a compound of ihc inventiora. Methods for making the emulsion, microemulsion, and micelle forrzulaiions are also provided.
As used herein, the term "emulsic” refers to a colloidal dispersion of two immiscible liquids, such as an oi} and walcer, in the form of droplets, whose diameter, in general, are between 0.1 and 3.0 microns ans which is typi cally optically opaque, unless the dispersed and continuous phases are reiziztive index matched. Such systems possess a finite stability, generally defined by the 2piiization or relevant reference system, which may be enhanced by the addition of amphini=iiic molecules or viscosity enhancers.
The term "microemulsion" refers to a ticrmodynamically stable isotropically clear dispersion of two immiscible liquids, such as an oil and water, stabilized by an interfacial film of surfactant molecules. The microeiniision has a mean droplet diameter of less than 200 nm, in general between 10-50 ni. in the absences of water, mixtures of oil(s) and non-ionic surfactant(s) form clear and isotropic so Jutions that are known as self-emulsifying drug delivery systems (S205) and can be used to improve lipophilic drug dissolution and oral absorption.
The emulsion and microemulsion ‘aeulations include an oil phase and an aqueous phase. The emulsion or micrcemulsion can be an oil-in-water emulsion or a water-in-oil emulsion. The oil phase incindes one or more <ompounds of the invention and a lipophilic medium, as described above. In one embodiment, the compound is present in the formulation in an amount frem about 0.005 to about 3.0 weight percent based on the total weight of the formulation. In one embodiment, the compound is present in the formulation in an amount rom about 0.01 to about 2.5 weight percent based on the total weight of the formulaic. In one emb odiment, the compound is present in the formulation in an amount from atau: 0.1 to about 1.5 weight percent based on the total weight of the formulation. In cnc embodiment _, the lipophilic medium is present in the formulation in an amoun: irom abort 2 to about 220 weight percent based on the total weight of the formulation. In one embodiment, the lipophilic medium is present in the formulation in an amount from about 4 to about 12 weight percent based on the total weight of the formulation. In one embodiment, the lipophilic medium is present in the formulation in an amount from about 6 to about 10 weight percent based on the total weight of the form ulation.
In one embodiment of the emulsion or microemulsion, the compound is a tocopherol-modifi ed therapeutic drug compound, the lipophilic medium includes a tocopherol, and th e aqueous medium is water.
In additiorh to the compounds of the invention, the emulsion or microemulsion formulations | cara include other components commonly used in emulsions an microemulsions, zand particularly used in pharmaceutical emulsions and microemulsions.
These components include surfactants and co-solvents, among others. Representative surfactants includ e nonionic surfactants such as surface active tocopherol derivatives and surface active po. ymers.
Suitable surface active tocopherol derivatives include tocopherol polyethylene glycol derivatives, such as vitamin E succinate polyethylene glycol (e.g. d-a-tocapherol polyethylene glycol 1000 succinate, TPGS), which is a vitamin E derivative in which a polyethylene glycol is attached by a succinic acid ester at the ring hydroxyl of vitamin E.
As used herein, vitamin E succinate polyethylene glycol" includes vitamin E succinate polyethylene gly col and derivatives of vitamin E polyethylene glycol having various ester and ether links. TPGS is a non-ionic surfactant (HLB = 16-18). TPGS is reported to inhibit P-glycoprotein, a protein that contributes to the development of multi-drug resistance. Embodiments of the formulations of the invention that include TPGS therefore include a P-glycoprotein inhibitor. Surface active tocopherol derivatives (e.g., TPGS) can be present in the formulations of the invention in an amount from about 1 to about 10 weight percent, about 2 to about 6 weight percent, or about 5 weight percent, based on the total weight of the formulation.
Suitable nonionic surfactants include block copolymers of ethylene oxide and propylene oxide known as POLOXAMERS or PLUROINICS. These synthetic block copolymers of having the general structure: H(OCH,CH,),(OC3HgCHy), (OCH,CH,),0¥1. The following variants based on the values of a and b are commercially zxvailable from BASF Performance Chemicals (Parsippany. New Jersey) under the trade name PLURONIC and consist of the group of surfactants designated by
E te WO 2005/042539 PCT/US2004/036127 the CTFA name of POLOXAMER 108. 18S. 217,237,238, 288.338, 407, 101, 105, 122, 123,124, 181, 182, 183, 184, 212, 231, 282,331, 401, 402, 185 _ 215, 234, 235,284, 333, 334, 335, and 403. For the most commonly used POLOXAMLERS 124, 188, 237, 338, and 407 the values of aand b are 12/20, 79/28, 64/37, 141/44 and 101/56, respectively.
In one embodiment, the nonionic surfacian: is present in the feormulation in an amount from about 0.5 to about 5 wei ght percent based on the total wei gt of the formulation.
Co-solvents useful in the formulations include ethanol, polyethylene glycol. propylene glycol, glycerol, N-mnethylpyriolidone, dimethylamide, and dimethylsulfoxide, among others. Polyethylene glycol (PEG) is a hydrophilic, polymerized form of cthylene glycol, consisting of repeating units having the chemical structiare: (-CH,CH,0-). The general formula for polyethylene glycol is H(OCH,CH,), OH. The molecular weight ranges from 200 to 10,000. Such various forms are described by their molecular weights, for example, PEG-200, PEG-300, PEG-400. and the like.
Paclitaxel emulsions and their components are described in U.S. Patent
No.6,458,173 and U.S. Patent No 6.660.286, each expressly incorporated herein by reference in its entirety.
Representative emulsions including tocopherol-modiffied therapeutic drug compounds (e.g., tocopherol succinate docetaxel, tocopherol succinate paclitaxel, tocopherol succinate camptothecin, tocopherol succinate 7-ethyl-10-hydroxycamptothecin., and tocopherol succinate 10-hy droxycamptothecin) are described in Example 15. In vitro cviotoxicities of representative tocopherol-modified therapeutic drug compounds (e.g. tocopherol succinate 7-ethyl-1 O-hydroxycamptothecin and tocopherol succinate camptothecin) are described in Example 36.
In a further aspect, the invention provides micelle formwilations that include a compound of the invention and an aqueous phase. Micelles are o rganized aggregates of one or more surfactants in solution. In one embodiment, the comgpound is present in the formulation in an amount from about 0.005 to about 3.0 weight per-cent based on the total weight of the formulation. In one embodiment, the compound is present in the formulation in an amount from about 0.01 to about 2.5 weight percent based on the total weight of the formulation. In one embodiment, the compound is present in the formulation in an amount from about 0.1 10 about 1.0 weight percent based on the total weight of the formulation. Suitable surfactants include those noted above, and in the amounts noted above. In one embodiment of the micelle formulation, the compound 1s a tocopherol-modified therapeutic drug compound and the surfactant is tocopherol polyethylene glycol succinate (TPGS). Representative micelle formulations including tocopherol-modified therapeutic drug compounds are described in Example 15.
The micelle formulation can also include additional components such as co- solvents inc luding those noted above. In one embodiment, the micelle formulation includes a polyethylene glycol and a lower alkyl alcohol (e.g., ethanol). In one embodiment, the co-solvents are present in zn amount from about 2 to about 20 weight percent based on the total weight of the formulation. The micelle, emulsion, and microemuls3on formulations include an aqueous phase. In one embodiment, the aquieous phase includes deionized water. In another embodiment, the aqueous phase includes saline. In amother embodiment, the aqueous phase is saline buffered with an organic acid (e.g., succirz ate, citrate).
The invention also provides the use of the compounds of the invention in the manufactur< of a medicament. For example, for compounds of the invention that include a therapeutic drug moiety derived from a therapeutic drug compound effective in treating cell prolifesrative disease, the invention provides the use of such compounds in the manufacture of a medicament for the treatment of cell proliferative disease.
In other aspects, methods for administering a compound of the invention to a subject in meed thereof, and methods for treating a condition treatable by administration of a therapeutically effective amount of a compound of the invention are also provided.
These wethods include the administration of the compounds, compositions, emulsion formulations, microemulsion formulations, and micelle formulations described herein.
In one embodiment, the invention provides a method for treating a condition that is treatable by the parent, unmodified therapeutic drug compound (e.g., a cell proliferative disease such as cancer). In the method, a therapeutically effective amount of a compound of the invezntion is administered to a subject in need thereof.
In one embodiment, the invention provides a method for treating a cell proliferative disease by administering a comnpound of the invention having a therapeutic drug moiety derived from a therapeutic drug effective in treating cell proliferative disease. Representative cell proliferative diseases treatable by the compounds of the
CT WO 2005042539 FC T/US2004/036127 ~» 4U 06/04083 invention include hematologic cancers. such as leukemia, lymphoma, and myeloma; and nonhematologic cancers, such a s solic wmor carcinomas (e.g., breast. ovarian, pancreatic, colon. colorectal, non-small cell tung. ond bladder), sarcomas, and ¢liormas.
Therapeutically effective amaimis of the compounds will cen erally range up to the maximally tolerated dosages. but the concentrations are not critica] and may vary widely. The precise amounts exmpio: ed by the attending physician wi Ii vary, of course, depending on the compound, route of wdministration, physical condition of the patient and other factors. The daily do sage may be administered as a singie «insage or may be divided into multiple doses for aciminisiration.
The amount of the compound actually administered will be a therapeutically effective amount, which term is used herein to denote the amount needed to produce a substantial beneficial effect. Tf¥eciive doses may be extrapolaicd =m dose-response curves derived from in vitro or aninal model test systems. The anin—al model is also typically used to determine a desirable dosage range and route of udm Snistration. Such information can then be used to determine useful doses and routes {or zdministration in humans or other mammals. The determination of an effective dose i= well within the capability of those skilled in the art. Thus, the amount actually adm inistered will be dependent upon the individual to which tr2stment is to be applied. and iil preferably be an optimized amount such that the desired effect is achieved without significant side-effects.
Therapeutic efficacy and possible toxicity of the compounds of 1Z+2 invention can be determined by standard pharmaceutical procedures, in cell cultiras or experimental animals (e.g., ED5(q, the dose :h crapeutically effective in 50% of the vopulation; and
LDs5. the dose lethal to 50% of lac population). The dose ratio betes: ‘herapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio ..Dsg to EDs.
Modified therapeutic drug compounds that exhibit large therapevi-ic indices are particularly suitable in the practice of the methods of the invention. Th ¢ data obtained from cell culture assays and anima] studies may be used in formulating 2 =inge of dosage for use in humans or other marmyale. The dosage of such compounds iies preferably within a range of circulating corsceatrations that include the EDs with little or no toxicity. The dosage typically vardes within this range depending upon te dosage form employed. sensitivity of the paiicsnt. 2nd ‘he route of administration. Thus, optimal amoun-ts will vary with the method of administration, and will generally be in accordance with the amounts of conventional medicaments administered in the same or a similar form.
The compounds of the invention can be administered alone. or in combination with ome or more additional therapeutic agents. For example, in the treatment of cancer, the cormpounds can be administered in combination with therapeutic agents including, but not limited to, androgen inhibitors, such as fliatamide and luprolide; antiestrogens, such as tomoxcifen; antimetabolites and cytotoxic agents, such as daunorubicin, fluorouracil, floxur-idine, interferon alpha, methotrexate, plicamycin, mecaptopurine, thioguanine, adriarzaycin, carmustine, lomustine, cytarabine, cyclophosphamide, doxorubicin, estramustine, altretamine, hydroxyurea, ifosfamide, procarbazine, mutamycin, busulfan, mitox_antrone, carboplatin, cisplatin, streptozocin, bleomycin, dactincmycin, and idamy cin; hormones, such as medroxyprogesterone, estramustine, ethinyl estradiol, estracSiol, leuprolide, megestrol, octreotide, diethylstilbestrol, chlorotrianisene, etoposide, podophyliotoxin, and goserelin; nitrogen mustard derivatives, such as melphalan, chlorzmbucil, methlorethamine, and thiotepa, steroids, such as betamethasone; and other antineoplastic agents, such as live Mycobacterium bovis, dicarbazine, asparaginase, leucovorin, mitotane, vincristine, vinblastine, and taxotere. Appropriate amounts in each case —will vary with the particular agent, and will be either readily known to those skilled inthe art or readily determinable by routine experimentation.
Administration of the compounds of the invention is accomplished by any effec tive route, for example, parenteral, topical, or oral routes. Methods of administration inchmde inhalational, buccal, intramedullary, intravenous, intranasal, intrarectal, intra ocular, intraabdominal, intraarterial, intraarticular, intracapsular, intracervical, intra_cranial, intraductal, intradural, intralesional, intramuscular, intralumbar, intramural, intra_ocular, intraoperative, intraparietal, intraperitoneal, intrapleural, intrapulmonary, intrewspinal, intrathoracic, intratracheal, intratympanic, intrauterine, intravascular, and intraventricular administration, and other conventional means. The compounds of the inve=ntion having anti-tumor activity can be injected directly into a tumor, into the vicinity ofa tumor, or into a blood vessel that supplies blood to the tumor.
The emulsion, microemulsion, and micelle formulations of the invention can be nebwlized using suitable aerosol propellants that are known in the art for pulmonary deli very of the compounds.
ER WO 2005/042339 PCT/US2004/036127
The compounds of the invention may be formulated imto a composition that additionally comprises suitable pharmaceutically acceptable carriers, including excipients and other compounds that facilitaic administration of the compournd to = subject. Further details on techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaccuiical Sciences" (Maack Publish ing Co., Easton, PA).
Compositions for oral administration may be formulated sing pharmaceutically acceptable carriers well known in the art, in dosages suitable for oral administration.
Such carriers enable the compositions containing the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, suitable for ingestion by a subject. Compositions for oral use may be formulated, for example, in combination with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable addition) compounds, if desired, to obtain tablets or dragce cores. Suitable excipients in clude carbohydrate or protein fillers. These include, but are not limited to, sugars, incliading lactose, sucrose, mannitol, or sorbitol, starch from corn, wheat, rice, potato, or other plants; cellulose such as methyl cellulose, hydroxy propylmethyl-cellulose, or sodium caxboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins, such as gelatin and collagen. If desired, disinte grating or solubilizing agents may be added, such as the crosslinked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.
Dragee cores are provided with suitable coatings such ass concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrroslidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuifs or pigments may be added tow the ‘zblets or dragee coatings for product identification or 10 characterize the quantity of active compound (i.e., dosage).
Compounds for oral administration may be formulated, for example, as push-fit capsules made of gelatin, as well as soft. sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the conpourds mixed with filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the covalent conjugates Tay be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
For topical or nasal administration, penetrants appropriate to the particular barrier to be permeated are typically used in the formulation. Examples of these are 2-pyrrolidoxae, N-methyl-2-pyrrolidone, ~~ dimethylacetamide, dimethyl-formamide, propylene glycol, methyl or isopropy! alcohol, dimethyl sulfoxide, and azone. Additioxal agents may further be included to make the formulation cosmetically acceptatzle.
Examples Of these are fats, waxes, oils, dyes, fragrances, preservatives, stabilizers, and surface-actave agents. Keratolytic agents such as those known in the art may also be included. Examples are salicylic acid and sulfur. For topical administration, the composition may be in the form of a transdermal ointment or patch for systemic deliv ery of the cormpound and may be prepared in a conventional manner (see, e.g., Baxry,
Dermatolo gical Formulations (Drugs and the Pharmaceutical Sciences--Dekker); Harry's
Cosmetico-logy (Leonard Hili Books).
Fox rectal administration, the compositions may be administered in the forma of suppositories or retention enemas. Such compositions may be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, but are not limited to, cocoa butter and polyethylene glycols.
The amounts of each of these various types of additives will be readily apparent to those skil led in the art, optimal amounts being the same as in other, known formulations designed for the same type of administration.
Compositions containing the compounds of the invention may be manufactured in a mannex similar to that known in the art (e.g. by means of conventional mixing, dissolvin g, granulating, dragee-making, levigating, emulsifying, encapsulating, entrappirag or lyophilizing processes). The compositions may also be modified to provide appropriate release characteristics, sustained release, or targeted release, by conventional means (e.g., coating). As noted above, in one embodiment, the compounds are formulat ed as an emulsion.
Compositions containing the compounds may be provided as a salt and can be formed swith many acids, including but not limited to hydrochloric, sulfuric, acetic, 1 actic, tartaric, malic. and succinic. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
K WO 2005/042539 ’ PCT/US2004/036127
After compositions {ei miniaied to contain a compound anc an acceptable carrier have been prepared, they can =e placed in an appropriate container aad labeled for use.
Thus, in another aspect, the iv =ntion provides kits.
Tocopherol-modificd inciapeutic drug compounds of the Iv" ¢hon are suitable for administration as oil-in-water emulsions and micelle formulatio zc. The compounds provide for high drug loading < ¢nable small volumes for administr zion.
Emulsions containing rocopherol-modified camptothecin compounds of the invention provide for enhanced stability of the compound's I 2cione compared to conventional methods of camnpiciliccin administration. Long plasmz: ji f-life is achieved for the tocopherol-modified can ptothecin compounds resulting in p rionged exposure of a tumor to the compounds. 7: conherol-modified compounds chi eve high permeation through lipoidal membranes of wmor cells. Greater anti-tumor response without an increase in toxicity may ©o ciovided by the tocopherol-mo <iiiied camptothecin compounds of the invention us compared to unmodified campictlerin and currently available camptothecin analogs.
Although the compounds of the invention having formula (2) with m= 1, formula (3) with n = 1, or formula (8 do not include compounds specifically excluded as described above, it will be aprreciated that the compositions, exr=iision formulations, microemulsion formulations, «5 micelle formulations include the compounds of the invention having formulae (1)-(5» without such limitation. Methods for «dministering the compositions, emulsion {tris lations, microemulsion formuiniz ens. and micelle formulations, and methods fur treating a condition treatable oy administering the compositions, emulsion fore icions, microemulsion formule: <nz and micelle formulations are likewise nor limizod with regard to the compounds f the invention.
The following examples =:-¢ provided to illustrate, not limit, 122 invention.
EXAMPLES
EXAMPLE 1
The Preparat ion 27» Representative Tocopherol-Mncii Tia
Camptothecin Cormycsund: Tocopherol Succinate Campic~tizsin
A 500 ml flask was chiare=ed with 10.6 grams of d-a-tocoph =r! succinic acid, 6.97 grams of camptothecin, ©.13 =rums of 2-chloro-1-methylpyridiniv 2m iodide (CMPI]), 5.86 grams of 4-(dimethyizzino)pyridine (DMAP), and 2C ml of dry
N.N-dimethylacetamide. The mise was stirred al room temperainzes for 24 hours, and then heate=d at 50°C for 4 hours. The mixture was cooled to room temperature and then was filter-ed fo remove precipitate and the filtrate was collected. To the filtrate were added 250 ml of chloroform and 150 ml of dejonized-water to extract the product into the chloroform, and the water fraction was removed using a separation funnel. The chloroform fraction was washed with deioru=zed-water (3%150 ml) in a separation funnel, collected , and dried over anhydrous MgSO 4 overnight. The MgSO, was removed by filtration , and the chloroform was removed with a rotary evaporator under reduced pressure to yield a dark-yellow solid. The product was purified by column chromatography on silica gel. (Yield: 9.50 grams, 55.2%). 314 NMR (300 MHz, CDCl): 88.3 18 (s, 1H), 8.163-8.135 (d,] = 8.4 Hz. 1H), 7.927-7. 901(d, J = 7.8 Hz, 1H), 7.842-7.787 (m, 1H), 7.682-7.632 (m, 1H). 7.263-7.242 (d, J = 6.3 Hz, 1H), 5.702-54310 (ABq, -1 = 17.4, Jo = 70 Hz, 2H), 5.190 {s, 2H), 3.014-2_938 (m, 4H), 2.368-0.809 (m, 54H). “lemental anal. Caled. for Cs3HegNoOs: C, 73.92; H, 7.96; N, 3.25.
Found: C, 73.61;
H.7.90z N, 3.17.
EXAMPLE 2
The Preparation of 2 Repres entative Tocopherol-Modified
Camptothecin Compound: Tocophexol Succinate 10-Hydroxycamptothecin
Method 1. A 100 ml flask was charged with 1.06 grams of d-o-tocopherol succinic acid, 0.476 grams of thionyl chloride, and 50 ml of toluene. The mixture was stirred at room temperature overnight. The solvent was removed with a rotary evaporator at 50°C, and the residue was collected. To the residue was added 0.728 grams of 10-hyd_roxycamptothecin and 40 ml of dried tetrahydrofuran with stiring. Then, 0.404 grams of triethylamine in 10 ml of tetrahydrofuran was added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. The mixture was fil tered and white powder was washed with ethyl acetate (3x10 ml). The filtrate was collected. The solvent was removed with a rotary evaporator. The residue was collected. and puarified by column chromatography om silica gel with a mobile phase of acetone and chloroform (1:4, v/v). (Yield: 0.85 grams 48.4%).
MS (Positive ESI): m/z 877 MM)".
Anal. Caled. for Cs3sHesN20o: C, 72.58; H, 7.81; N, 3.19. Found: C, 72.527
H,7.&4;N, 3.21.
Alternatively, tocophercl succinate 10-hydroxycamptothecin can be prepared as described below.
Method 2. A 100 mi flask was charged with 2.65 grams of d-a-tocopherol succinate, 0.89 grams of thionyi chloride, and 20 ml of toluene. The mixture was stirred at room temperature for 24 hours. The toluene and any excess thr cnyl chloride were removed with vacuum distillation at 50°C. The remaining residue wass dissolved in 15 ml of chloromethane to provide Solution A. To a 100 m] flask, 0.9 grams of 10-hydroxycamptothecin, 0.5 ml of triethylamine, and 25 ml of freshly dried
IN.N-dimethylacetamide was added with stirring. Then 15 ml of Soltation A was slowly added into the mixture through a dropping funnel over 5 minutes. Tiae reaction mixture “was stirred at room temperature for 2<4 hours. The mixture was concentrated by vacuum distillation. 150 ml of ethyl acetate was added to the residue. The m Ixture was washed with saturated aqueous NaCl solution, (3x100 ml). The mixiur ¢ was dried over anhydrous MgSO, The MgSO; was removed by filtration and the cth=/ acetate was then removed by vacuum distillation. The crude product was purified by column chromatography on silica gel. (Yield: 1.14 grams, 52.5%).
EXAMPLE 3
The Preparation of a Representative Tocopherol-Modified Canmptothecin
Compound: Tocopherol Succinate 7-Ethyl-10-hydroxycamptothecin
Method 1. A 500 ml flask was charged with 22.5 grams ci d-o-tocopherol succinate, 7.6 grams of thionyl chloride, and 200 ml of toluene. The arixvture was stirred at room temperature for 24 hours. The toluene and the excess thiorayl chloride were removed by vacuum distillaticn. The remaining residue was disso 2d in 100 ml of chloromethane to provide Solution A. Solution A was used immediately, and was not exposed to air. To a 500 m] flask, 7.8 grams of 7-ethyl-10-hydrox yeampoothecin, 7 ml of triethylamine, and 250 ml of freshly» dried N.N-dimethylacetamide was added with stirring. The 100ml of Solution A was slowly added into the mixture thorough a dropping funnel over 30 minutes. The reaction mixture was stirred ar om temperature for 24 hours. The solvent was concentrated by vacuum distillation. 300 m 1 of ethyl acetate was added to the residue. The mixture vvas washed with saturated acuedis NaCl solution, (3 x 200 ml). The mixture was dried over anhydrous MgSOQq. The MS 04 was removed by filtration and the ethyl acetate was then removed by vacuum distilice tion. The crude product was purified by recrvstaliizat ior with acetone. (Yield: 15.18 gra ams, 83.9%).
M™.P. 171°-173°C. '"H NMR (300 MHz, CDCl): & 8.236-8.206 (d, J = 9 Hz, 1H), 7.809-7.801 (d,J=2.4 Hz, 1H). 7.648 (s, 1H), 7.572-7.533 (dq, J; = 2.7 Hz, J» = 9.3 Hz, 1H), 5.781-5.280 (ABq,J,=16.2Hz, J,=134.0 Hz, 2H), 5.253 (s, 2H), 3.863 (s, 1H), 3.136-3.113 (m, 6H), 2.588 (t,2H), 2.091 (s,3H), 2.037 (s, 3H), 1.994 (s, 3H), 1.970-3.852 (m, 2H), 1.821-1.725 (m, 2H), 1.654-0.833 (m, 42H).
MS (Positive ESI): m/z 905 (M)™, 928 (M + Na)".
Anal. Caled. for CssH7aN-Og: C, 72.98; H, 8.02; N, 3.09. Found: C, 72.87;
H, 8.00; N, 2.88.
Alternatively, the tocopherol succinate 7-ethyl-10-hydroxycamptothecin can be prepar ed as described below.
Method 2. A 500 ml flask was charged with 8.48 grams of d—o-tecepherol succinate, 3.81 grams of thionyl chloride, and 250 ml of toluene. The mixture was stirred at room temperature overnight. The toluene, and excess thionyl chloride were removed with & rotary evaporator at 50 °C, arxd the residue was collected. To the residue was added 6.27 grams of 7-ethyl-10-hydroxycamptothecin and 250 ml of sodium-dried tetrahydrofuran with stirring. Then, 3.23 grams of triethylamine in 50 ml of tetrahydrofuran was added dropwise to the mixture. The mixture was stirred at room temperature overnight. The mixture was filtered and the white powder was washed with ethyl acetate (3x50 ml). The filtrate was collected. The solvent was removed with a rotary evaporator. The crude product was purified by recrystallization in acetone. (Yiel d: 8.28 grams, 57.2%).
EXAMPLE 4
The Preparation of a Representative Tocopherol-Modified Camptothecin
Compound: _10.20-Di(tocopherol succinate) 7-Ethyl-10-hydroxycamptothecin
A 100 ml flask was charged with 0.905 grams of tocopherol succinate 7-ettayl-10-hydroxycamptothecin, 0.53 grams of d-a-tocopherol succinic acid, 0.25 5 grams of 2-chloro-1-rmethylpyridinium iodide, 0.244 grams of 4-(dimethylamino)pyridine and 50 ml of dioxane. The mixture was stirred at room temperature for 24 hours. Thin layer chromatography showed that the reaction was com plete. The mixture was filtered to remove the solid phase, and the filtrate was collected. The solvent was removed by vacuum distillation. The crude product was
E WO 2005/()42539 POT/US2004/036127 purified by column chromatezianhy on silica gel with 30% eth? acetate in cyclohexane. (Yield: 0.64 grams, 44.82%). 'H NMR (300 MHz, CDCI): 88.168-8.13 8 (d.J=9.0 tz. 1H), 7.813-7.805 (d.J= 2.4 Hz, 1H), 7.754-7.534 (dd, J, = 21 Hz, J, = 11.4 fiz, iH), 7.197 (s, 1H), 5S 5703-5409 (ABq. J, = 17.4 1x. 1» = 71.0 Hz, 2H), 5.243-3.088 (m. 2H), 3.113-2.857 (m, 10H), 2.606-2.564 (1, J = 4liz, 2H), 2.383-2.184 (m, 2H). 2.09(0-1.723 (m, 22H), 1.588-0.785 (m, 80H).
MS (Positive ESI): m/z 1418 (M+H)*,
Elemental anal. Calcd. for CssH24N20 3: C, 74.34; H. 881: N, 1.98.
Found: C, 74.31; H. 8.96: N. 1.75.
IRV ma Pom: 2925. 2867, 1751, 1665, 161 3, 1657, 1310. 1458, 1413, 1376, 1330, 1218. 1128, 1075, 1060, 1035, 992, 943,923,829, 812. 738. 724. 668.
EXAMPLE 5
The Preparation of a Representative Tocopherol-Modified Camuinihicein Compound:
Tocopherol-Campicthecin Conjugate with &a Hexa( ethviene nlycol) Linker
Preparation of hexalcihviene glycol) tocopherol succinzic. In a 250 ml flask, 2.65 grams of d-a-tocopherol succinic acid and 2.82 grams of hexa{ethylene glycol) was dissolved in 100 ml of tolucnc with stirring. The to Iuene was removed with a rotary evaporator (drying by azeotropic distillation). To thre mixture was added 100 mi of chloroform. 1.08 grams of N,N-dicyclohexylcarbodiimidsz, ind 100 mg of 4-(dimethylamino)pyridine. “he mixture was stirred ovirmigin. Thin layer chromatography with 40% uccione in hexane showed that the reaction was complete.
The mixture was washed “F..c times with delonized-wazer (52100 ml), and the chloroform fraction was coiizeted, and dried over anhyd yous M30: for two hours. After filtration, chloroform was removed by a rotary evaporator. The crude product was purified by column chromatography on silica gel using, successively, the solvents 30% ethyl acetate in hexane, 50% cthyl acetate in hexane, and 30% acetone in hexane. (Yield: 0.53 grams, 13.33%).
Preparation of tocopherol-siiccinyl-hexa(ethylene glycol) succinic acid. A 100 mj flask was charged with 1.42 grams of hexa(ethylene glycol} toconherol succinate prepared above, 0.2 granis of sucoinic acid anhydride, 2 drops of tin (il) ethylhexanoate, and 25 ml of xylene. The mixture was refluxed for 4 hours. Afizr the reaction was complete, the solvent “was removed by a rotary evaporator. The crude product was purified by column chromatography on silica gel. (Yield: 0.864 grams, 54%).
Preparation of tocopherol succinate camptothecin with a hexa(ethylene glycol) linker. A 100 ml flask was charged with 0.822 grams of tocopherol-succinyl-hex=a(ethylene glycol) succinic acid prepared above, 0.3 grams of camptothecin, 0.47 grams of 2-chloro-1-methylpyridinium iodide, 0.45 grams of 4-(dimethylamino)pyridine, and 40 ml of dried N,N-dimethylacetamide. The reaction mixture was stirred at xoom temperature overnight. After the reaction was complete, the solvent was removed by vacuum distillation, and the residue was collected. To the residue was added 100 ml of ethyl acetate. After stirring for 30 minutes, the mixture was filtered to remove precipitate, and the filtrate was collected and concentrated. The crude product was purified by column chromatography on silica gel. (Yield: 0.342 grams, 30.4%). 'H NMR (300 MHz, CDCl3): 5 8.388 (s, 1H), 8.240-8.273 (d, © = 8.2 Hz, 1H), 7.951-7.923 (4, J = 8.4 Hz, 1H), 7.861-7.805 (dt, J; = 1.5 Hz, J» = 84 Hz, 1H), 7.694-7.640 (dt, J; = 12 Hz, J, = 8.1 Hz, 1H), 7269 (s, 1H), 5.708-5.365 (ABq, J,= 17.1 Hz, J» = 85.8 Hz, 2H), 5.283 (s, 2H), 4.273-4.169 (m, 4H), 3.705-3.673 (t, 2H), 3.631-3.550 Cm, 18H), 2.926-2.654 (m, 8H), 2.597-2.552 (t, J = 6.5 Hz, 2H), 2.381-2.2.113 (m, 2H), 2.074 (s, 3H), 2.004 (s, 3H), 1.964 (s, 3H), 1.827-1.683 (m, 2H), 1.655 (s, 3H), 1.544-0.964 (m, 24H), 0.875-0.830 (m, 12H).
MS (Positive ESI): m/z 1225 (M)™. : Elemental armxal. Caled. for CggHiaaN;Oy3: C, 67.62; H, 7.90; N, 2.29.
Found: C, 67.08; H, 8.04; N, 2.07.
IRvma rem? © 2925, 2867, 1735, 1667, 1618, 1563, 1500, 1457, 1405, 1366, 1349, 1232, 1204 1141, 1107, 1060, 994, 945, 859, 813, 787,761, 723, 707.
EXAMPLE 6
The Preparation of a Representative Tocopherol-Modified
Pac}itaxel Compound: Tocopherol! Succinate Paclitaxel
A 250 ml flask was charged with 5.83 grams of tocopherol succinic acid, 2.38 grams of thionyl chloride, and 50 ml of toluene. The mixture was stirred at room temperature overnight. The solvent was removed with a rotary evaporator at 50°C, and the residue was collected. To the residue were added 8.54 grams of paclitaxel and 100 ml of dried tetrahydrofuran with stirring. Then, 1.52 grams of triethylamine in 50 ml of
CT wo 2005/042539 PCT/US200014/036127 tetrahydrofuran was added dropwise to the reaction muixture. The mixture was stirred at room temperature overnight. The mixture was filtere d and the white powder “was washed with ethyl acetate (3x10 ml). The filtrate was collected. The solvent was removed with a rotary evaporator. The residue was collected, and pumrified by recrvstallization in acetone and hexane. (Yield: 11.56 grams, 84.6%).
Anal. Caled. for CyoH;3NO 5: C, 70.31; H, 7.39; N, 1.02. Found: C, 70.02,
H, 7.83; N, 0.93.
EXAMPLE 7
The Preparation of a Representative Tocopherol-Modified
Docetaxel Compound: Tocopherol Staccinate | Docetaxel
A 250 ml flask is charged with 9.86 grams of d-u-tocopherol succinic acid, 5.0 grams of docetaxel, 3.83 grams of dried N,N-dicselohexvlcarbodiimide, 500 mg of 4-(dimethylamino)pyridine, and 150 ml] of chloroforn—1. The mixture is stirred at room temperature overnight. The mixture is filtered to rennove precipitate and the filtrate is collected. The solvent is removed with rotary evapor-ator, and the residue is <ollected.
The crude product is purified by column chromatograplny on silica cel.
EXAMPLE 8
The Preparation of Mono-Tocophe=ro} Phthalate
A 100 mL flask was charged with 8.61 grams «of dl-a-tocepherol, 2.96 frams of phthalic anhydride, 50 mg of tin (II) 2-ethylhezxanoate, and 50ml of dried
N,N-dimethylacetamide. The mixture was stirred at abowut 140 °C for 24 hours, After the mixture was cooled to room temperature, the mixture ~was poured ino 150 ml of cthyl acetate. The mixture was washed three times with saturated aqueous NaCl (3x 100 ml), and dried over anhydrous MgSO, overnight. The crude product was purified by column chromatography on silica gel with 30% ethyl acetate in hexane. (Yield: 3.6 grams, 31.1%). 'H NMR (300 MHz, CDCl3) & ppm: 10.80 «bs, 1H), 8.119-8.063 (rm, 1H), 7.883-7.828 (m, 1H), 7.678-7.616 (m, 2H), 2.627-2.58 2 (i. 2H). 2.123 (s, 3H», 2.112 (s, 3H), 2.081 (s, 3H), 1.868-1.702 (m, 2H), 1.616-1.020 &m, 2411), .874-0.834 (ma, 12H).
Anal. Caled. for C37H 40s: C, 76.78; H, 9.40. Fouand: C.76.57: 4.9.29, [RVmax Sem 3075. 2919, 2858. 1737, 1701, 1578, 1435, 1409, 1373 1276, 1230, 1107, 1071, 913, 738.
EXAMPLE 9
The Preparation of Mono-Tocopherol Terephthalate
A 100 mL flaskz was charged with 4.30 grams of dl-a-tocopherol, 3.32 grams of terephthalic acid, 2.55 grams of 2-chloro-1-methylpyridinium iodide, 0.244 grams of 4-(dimethylamino)pyricline, and 50 ml of dry N,N-dimethylacetamide. The mixture was stirred at 50 °C for 4 bhours. Thin layer chromatography showed that the reaction was complete. After the mixture was cooled to room temperature, the mixture was poured into 150 ml of ethyl acetate. The mixture was washed three times with saturated aqueous
NaCl] (3x100 mL), ancd dried over anhydrous MgSOj4 overmight. The crude product was purified by column chromatography on silica gel with 30% ethyl ether in hexane. (Yield: 1.60 grams, 27 .6%) '"H NMR (300 MHz, CDCl3) & ppm: 11.80 (bs,1H), 8.374-8.259 (q, J; = 8.4Hz,
J,= 26.1Hz, 4H), 2.650-2.607 (t, 2H), 2.130 (s, 3H), 2.066 (s, 3H), 2.024 (s, 3H), 1.895-1.783 (m, 2H), 1 .532-1.083 {m, 24H), 0.878-0.839 (mz, 12H).
Anal. Caled. fo r C37Hs4Os: C, 76.78; H, 9.40. Found: C, 76.64; H, 9.39.
Rv, Fem™: 3062, 2924, 2858, 1737, 1696, 1573, 1460, 1424, 1373, 1276, 1240, 1097, 928, 774, 723.
EXAMPLE 10
The Preparati on of a Representative Tocopherol-Modified Camptothecin
Cormpound: Tocopherol Terephthalate Camptothecin
A 100 mL fla=sk was charged with 1.16 grams of 1mono-tocopherol terephthalate prepared above, 0.70 grams of camptothecin, 0.511 grams of 2-chloro-1-methylpyradinium iodide, and 0.489 grams of 4-(dimethylamino)pyridine.
The mixture was stimred at 50°C overnight. Thin layer chromatography showed the reaction was comple te. After the mixture cooled to room temperature, the reaction mixture was poured ixato 150 ml! of ethyl acetate. The mixture was filtered and the filtrate was collected. The filtrate was washed with saturated aqueous NaCl (3x100 ml), and dried over anhydrous MgSO, overnight. The crude product was purified by column chromatography on silica gel. (Yield: 0.560 grams, 30.8%%) '"H NMR (300 MHz, CDCl3) 8 ppm: 8.387 (s,1H), 8.370-8.242 (q, J, = 8.4 Hz,
Jo= 30.3Hz, 4H), 8. 167-8.139 (d, J = 8.4 Hz, 1H), 7.937-7.910 (d, J = 8.1 Hz, IH), 7.823-7.774 (1, 1H), 7.672-7.625 (t, 1H), 7.260 (s, 1H), 5.823-5.462 (ABq, J, = 17.4 Hz,
EE WO 2005/042539 PCT/US2004/036127
Jo =90.9Hz, 2H), 5.302 (ss, 211). 2.461 (t. 2H). 2.559-2.312 (ma. 21), 2.123 (s, 3H), 2.056 (s. 3H), 2.015 (s, 3H), 1.841.801 (m, 2H), 1.629-1.085 (=. 2711), O0.938-0.789 (m, 12H).
Anal. Calcd. for Cs7HgeN2Og: C, 75.50; H, 7.24; N. *.08. Found: C. 74.91;
H, 7.56; N, 3.02.
IRV pa Hem 3037, 2924, 2858, 1757, 1737. 1675. 1614, 1558, 1450. 1399, 1266, 1235, 1163, 1102, 1 020, 723.
EXAMPLE 11
The Preparation of a Representative Tocopherol-Modifiz¢ Campto thecin Compound:
Tocopherol Cvclohe xane-1.2-dicarboxvlate 7-Ethyl-i0-hvdrox yeamptothecin
Preparation of tocopherol cyclohexane-1,2-dicarboxvlic acid. A mixture of 1.54 grams of 1.2-cyclohexancdicarbolic acid anhydride, 8.6 grams of d-a-tocopherol, 1.34 grams of aluminum trichloride, and 100 ml of cyclohexane in a 250 mil flask was heated under reflux for ahout 30 minutes. After the nuxture cosled to room temperature, it was filtered. The filtrate was washed with a dilute aquecus hydrochloric acid solution and then dried over anhydrous MgSO, The mixture was concentrated, and crude product was purified by column chromatography on silica gel. (Yield: 3.325 grams, 56.9%).
Preparation of tocopherol cyclohexane-1.2-dicarbox ylate T-ethyl-1 0- hydroxycamptothecin. A. mixiure of 1.08 grams of wecinerol cyclohexane-1,2- dicarboxylic acid prepared above, 0.44 grams of thiony! chioride. arad 20 ml of toluene was stirred under nitrogen overnight. The toluene and oueoess thionyl chloride were removed by vacuum distillation, and the residue vos dissolved in 10 ml of dichloromethane to provide Solution A. In a 100 ml nasi, 0.230 grams of SN38 was dissolved in 25 ml of dricc? N.N-dimethylacetamide to provie Solution B. Solution A and 0.186 g of triethylamine were added to Solution 13. The mixture was stirred overnight at room temperature. The crude product wus purified by column chromatography on silica gel. (Yield: 0.59 grams, 68.9%).
EXAMPLE 12
The Preparation of a Representative Tocopherai-Modified
Doxorubicin “"ompound: Tocopherol Succinate Doxorubicin
A 100 ml flask is cherged with equivalent moles (1 mmiiz) of tocopherol succinic acid, doxorubicin, and N,N-dicyclohexylcarbodiimide. znd S0 ml of dry
N,N-dimethylacetamide. Tle mixture is stirred at room temperature until completion of the reaction. The mixture is filtered to remove while precipitate and the filtrate is collected. The solvent is removed with a rotary evaporator, and the residue is collected.
The product is purified by either recrystallization or column chromatography on silica gel.
EXAMPLE 1 3
The Preparation of a Representative Tocopherol-Modified
Hvdroxvzine Compound: Tocopherol Succinate Hvdroxyzine
A 100 ml flask is charged with equivalent moles (1 mmole) of tocopherol succinic acid, and thionyl chloride, and 50 mi of tolueme. The mixture is stirred at room temperature overnight. The solvent is removed with a rotary evaporator at 50°C, and the residue is collected. To the residue are added 1 mmole of hydroxyzine and 40 ml of chloroform with stirring. Then, 1 mmole of triethylamine in 10 ml of chloroform is added dropwise to the reaction mixture at 0-5°C. The mixture is then stirred at room temperature overnight. The mixture is washed with saturated NaHCO; aqueous solution (3x50 tml). The organic phase is collected, and dried with anhydrous MgSOs. The solvent is removed with a rotary evaporator after removal of MgSO,. The residue is collected, and the crude product is purified by either recrystallization or silica column chromatography.
EXAMPLE 14 :
Representative Tocopherol-Modified Therapeutic Drug Compound Solubility
In this example, the solubility of representative tocopherol-modified therapeutic drug compounds of the invention, tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin, was compared to the solubility of camptothecin in a variety of solvents.
The solubility of camptothecin, tocopherol succinate camptothecin, and tocopherol succinate 7-ethyl-10-hydroxycamptothecin was determined in several solvents. Compounds were dissolved in each solvent under constant stirring and tempexature to saturation. The resulting solutions were centrifuged and the supernatant was aralyzed by high performance liquid chromatography (HPLC).
The comparative solubility (mg/g) of camptothecin, tocopherol succinate camptothecin, and tocopherol succinate 7-ethiyl-10-hydroxycamptothecin in various solverits is shown in Table 1.
a WO 2005042539 PCT/US2004/036127
Table 1. Solubility Comparison of Camptotheein and Tocopherol Succinate
Camptothecins.
SAL ]
Canaptothecin VESA | VESA -CPT* | Temperature
Solvent (mele) SN38 ! (mele) 0) cc (mg/g) | ="
PEG-400 | i
NE - 0.017 17.5 Room Temp.
TPGS | - 27.6 >1333 65 4 Vitamin E n - =
USP/NE 1.96 398.2 > 28 83 65
Soybean Oil | 15 5
USP 0.00 3.3 | 45.2 Room Temp. capex 300 | - 4.4 | 96.77 Room Temp.
Tween 80 | 65 — Room 2
Ethanol SA -
FN EE
- 3.8 | 14.4 Room Temp.
Methylene i - dichloride 0? Sl Net
Propylene ]
Glycol, USP 3.2 | 0.4633 Room Temp.
Glycerin 5 n
USP/EP/BP/JP - 2.8 2.541 Room Temp. 1 VESA-SN38: tocopherol succinate 7-ethyl-10-hydroxy-camptothecin 5 2 VESA-CPT: tocopherol succinate camptothecin
The results in Table 1 illustrate that tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin both have substantial solubility in oils, and have particularly high solubility in vitamin E (a-tocophesrol).
EXAMPLE 15
Representative Tocopherol-Modified
Therapeutic Drug Compound-Containing Emulsions
In this example, representative emulsions containing tocopherol-mo dified therapeutic drug compounds of the invention are described.
A. Tocopherol Succinate 7-Ethyl-10-Hydroxycamptothecin Emulsion
Tocopherol succinate 7-ethyl-10-hydroxy camptothecin, prepared as described in
Example 3, was dissolved in vitamin E and then emulsified with the use of a microfluidizer (M110Y Microfluidics) in the presence of d-a-tocopherol polyethylene glycol 1000 succinate (TPGS), Poloxamer 407, amd saline to produce an emulsion having the following: composition (% by weight):
Tocopherol succinate-7-ethyl-10-lxydroxycamptothecin C.69%
Vitamin E 7.31%
TPGS £%
Poloxamer 407 1%
Saline 86%
The emulsion was filtered through a 0.2 gum filter and vialed in sterile glass vials.
Mean partic e size was approximately 50 nM as determined by submicron particle sizer (Nicomp Model 370), with 99% of the particles less than 80 nm. No evidence of precipitation or loss of concentration as measured by HPLC was observed for at least 3 months when stored at 4°C.
B. Tocopherol Succinate 7-Ethyl-10-hydroxycamptothecin Emulsion
Tocopherol succinate 7-ethyl-10-hydrox ycamptothecin, prepared as described in
Example 3. was dissolved in vitamin E and then emulsified with the use of a microfluidizer (M110Y Microfluidics) in the presence of TPGS and saline to produce an emulsion having the following composition (% by weight):
Tocopherol succinate-7-ethyl-10~hydroxycamptothecin 0.69%
Vitamin E 7.31%
TPGS 5%
Saline 87%
This formulation resulted in a more yellow and thicker emulsion than the emulsion prepared as described above that included Poloxamer 407. The emulsion was filtered through a 0.2 pm filter and vialed in sterile glass vials. Mean particle size was approximately 75 nm as determined by submicron particle sizer (Nicomp Model 370), with 99% of the particles less than 1 70 nm. No evidence of precipitation or loss of concentration as measured by HPLC waas observed for at least 3 months when stored at 4 °C.
C. Tocopherol Succinate Camptothecin Emulsion
Tocopherol succinate camptothaecin, prepared as described in Example 1, was dissolved in vitamin E and then emulsified with the use of a microfluidizer (M110Y Microfluidics) in the presence of TPGS, Poloxamer 407, and saline to produce an emulsion having the following composition (% by weight):
Tocopherol succinate carmiptothecin 0.74%
Vitamin E 7.26%
TPGS 5%
Poloxamer 407 1%
Saline 86%
The emulsion was filtered through a 0.2 um filter and vialed in sterile glass vials.
Mean particle size was approximately 49 nm as determined by submicron particle sizer (Nicomp Model 370), with 99% of the particles less than 75 nm. No evidence of precipitation or loss of concentration as measured by HPLC was observed for at least 3 nonths when stored at 4°C.
D. Tocopherol Succinate Camaptothecin Emulsion
Tocopherol succinate camptothecin, prepared ss described in Example 1, was dissolved in vitamin E and then ennlsified with the use of a microfluidizer (M1 10Y Microfluidics) in the presence of TPGS, Poloxamer 407, and saline to Produce an emulsion having the following composEtion (6 by weight):
Tocopherol succinate camptothecin 1.48%
Vitamin E 6.52%
TPGS 5%
Poloxamer 407 1%
Saline 86%
The emulsion was filtered through = 0.2 um {ier and vialed in sterile glass vials.
Mean particle size was approximately 30 xm as determined by submicron particle sizer (Nicomp Model 370), with 99% of the Particles less dan 100 nm. No evidence of
WQ 2005/042539 PCT/US2004/036127 precipitation or loss of concentration as measured by HPLC was observed for at least 3 months when stored at 4°C.
E. Tocopherol Succinate 7-Ethyl-10-hydroxycampiothecin Enz ulsion
Tocopherol succinate 7-ethyX-10-hydroxycamptothecin, prepared as described in
Example 3, was dissolved in vitamin E and then emulsified with the use of a microfluidizer (M110Y Microfluidics) in the presence of TPGS and citric acid buffered saline to produce an emulsion having the following composition (% by weight):
Tocopherol succinate -7-ethyl-10-hydroxycamptothecin 0.69%
Vitamin E 7.31%
TPGS 5%
Citric acid buffered s aline, pH 3.0 87%
The emulsion was filtered ttarough a 0.2 pm fiiter and viaied in sterile glass vials.
Mean particle size was approximately 60 nm as determined by submicron particle sizer (Nicomp Modei 370), with 99% of the particles less then 15C rm. No evidence of precipitation or loss of concentration as measured by HPLC was obsexved for at least 3 months when stored at 4°C and 25°C.
F. Tocopherol Succinate 7-Ethyl-10-hydroxycamptothecin Emulsion
Tocopherol succinate 7-eth y1-10-hydroxycamptothecin, prepareci as described in
Example 3, was dissolved in v-itamin E and then emulsified with the use of a microfluidizer (M110Y Microfluidics) in the presence of TPGS and succinate buffered saline to produce emulsions havings the following composition (% by wex ght):
Formulation 1
Tocopherol succinatte-7-ethyl-10-hydroxycamptothecin 0.69%
Vitamin E 731%
TPGS 5%
Succinate buffered saline, pH 4.0 87%
The emulsion was filtered through a 0.2 pm filter and vialed in sterile glass vials.
Mean particle size was approxim ately 70 nm as determined by submicron particle sizer (Nicomp Model 370). with 99% of the particles less than 170 nm. No evidence of precipitation or loss of concentration as measured by HPLC was observed for at least 3 months when stored at 4°C and 25°C.
E WO 2005/042339 PCT/US2 004/036127
Formulation 2
Tocopherol! suc cinate-7-ethyl-1 O-hydroxycamptothecin 1%
Vitamin E 7%
TPGS 5%
Succinate buffered saline, pH 4.0 87%
The emulsion was filtered through a 0.2 um filter and vialed in sterile glass vials.
Mean particle size was approximately 70 nm as determined by submicron particle sizer (Nicomp Model 370), with 99% of the particles less than 170 nm. No evidence of precipitation or loss of concentration as measured by HPLC was observed for at least 1 month when stored at 4°C, 25 °C, and 40°C.
Formulation 3
Tocopherol succi nate-7-cthyl-1 0-hydroxycamptothecin 1%
Vitamin E 6%
TPGS 4%
Succinate buffered saline, pH 4.0 89%
The emulsion was filtered through a 0.2 pm filter and vialed in sterile glass vials.
Mecan particle size was approxirnately 95 nm as determined by submicron particle sizer (Nicomp Model 370), with 992% of the particles less than 220 nm. No evidence of precipitation or loss of concentration as measured by HPLC was observed for at least 1 month when stored at 4°C, 25°C, and 40°C.
G. Tocopherol Succinate 7-Ethyl-10-hydroxycamptiothecin (VESA-SN38)
Micelle Formulation
Tocopherol succinate 7-ethyl-10-hydroxycamptothecin was dissolved in a mixture containing TPGS, PEG(300), and ethanol at about 50°C — about 60°C with stirring for about 1 hour to form a transparerat solution. To this solution was added either deionized- water (DI-water), Poloxamer 407 and DI-water, Poloxamer 188 and DI-water, or 0.9%
NaCl aqueous solution to form Formulations 1-5 respectively below. The formulations were stirred for a few minutes to form transparent micelle solutions having the following compositions (% by weight):
NWO 2005/042539 PCT/US2004/0361277
Formulation
VESA-SN38 0.2%
TPGS 5%
Ethanol 3%
PEG(300) 5%
DI-water 84.8%
The formulation solution was filtered through a 0.2 pm filter and vialed in sterile glass vials. No evidence of precipitation or loss of concentration as measured by
HPLC was observed for at least 11 weeks when stored at 4°C.
Formulation 2
VESA-SN38 0.2%
TPGS 5%
Poloxamer 407 1.7%
Ethanol 5%
PEG(300) 5%
DI-water 83.1%
The formulation solution was filtered through a 0.2 pm filter and vialed in sterile glass vials. No evidence of precipitation or loss of concentration as measured by
HPLC was observed for at least 11 weeks when stored at 4°C.
Formulation 3
VESA-SN38 0.2%
TPGS 5%
PEG(300) 5%
Ethanol 5%
Poloxamer 188 1.7%
DI-water 83.1%
The formulation solution was filtered through a 0.2 pm filter and vialed in sterile glass vials. No evidence of precipitation or loss of concentration as measured by
HPLC was observed for at least 11 weeks when stored at 4°C, and 25°C.
Formulation 4
VESA-SN38 05% “0 2%
TPGS 2%
PEG(300) 2%
Ethanol 4%
Saline 91.8%
The formulation solution was filtered through a 0.2 pm filter and vialed in sterile glass v-ials. No evidence of precipitation or loss of concentration as measured by
HPLC was observed for at least 1 week wh en stored at 4°C, 25°C, or 40°C.
Formulation 35
VESA-SN38 0.3%
TPGS 5%
PEG(300) 5%
Ethanol 10%
Saline 79.5% "The formulation solution was filtere d through a 0.2 pm filter and vialed in sterile glass vials. No evidence of precipitation or loss of concentration as measured by
HPLC wras observed for at least 3 wecks wh en stered at 4°C.
Hi. Tocopherol Succinate 7-Ethyl-10-hydroxycamptothecin (VESA-SN38)
Micelle Formulation
Tocopherol succinate 7-ethyl-10-hyd roxvcamptothecin was dissolved in a mixture contaiturag TPGS, PEG(300), and ethanol at about 50°C — about 60°C with stirring for about 1 hour to form a transparent solution. To this solution was added succinate buffered saline to form Formulations 1 and 2 below. T he formulations were stirred for a few minutes to form transparent micelle solutions having the following compositions (% by weight):
Formulation 1
VESA-SN38 0.2%
TPGS 2%
Ethanol 4%
PEG(300) 2%
Succinate buffered saline, pH 4.0 91.8%
The formulation solution ~was filtered through a 0.2 um filter and vialed in sterile glass vials.
Formulation 2
VESA-SN38 0.5%
TPGS 5%
Ethanol 10%
PEG(300) 5%
Succinate buffered saline, pH 4.0 79.5%
The formulation solution was filtered through a 0.2 pm filter and vialed in sterile glass vials.
EXAMPLE 16
In vitro Stability of Lactone of Representative Tocopheroi-Modified
Therapeutic Drug Compounds in Presence of Human Albumin in this example, the in wvitro stability in the presence cf krimar albumin of the lactone form of representative tocopherol-modified therapeutic driag compounds of the invention, tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10- hydroxycamptothecin, was comxpared to the in vitro stability of the lactone form of camptothecin.
Because the lactone (ring E) is a critical moiety for camptothecin activity and it is reported not to be stable under physiological conditions (pH = 7.43), the stability of the lactone for tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10- hydroxycamptothecin was determined. The solubilization of tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin in the oil-phase is thought to protect the lactome from hydrolysis and thus provide improved lactone stability in physiological conditions. To evaluate lactone stability, a saline buffered solution (10 mM, pH 7.4) containing 4% human serum albumin wa.s incubated at 37°C in the presence of camptothecin (dissolved in DMSO), tocopherol swccinate camptothecin emulsion (prepared as described in Example 15C, referred to herein as "SN2300 emulsion”) or tocopherol succinate 7-ethyl-10-hydroxyc amptothecin emulsion (prepared as described in Example 15A, referred to herein as "SN2 310 emulsion"). High performance liquid chromatography with fluorescence detection wras used to analyze the decrease in the concentration of the lactone form over time.
- | WO 2005/042339 PCT/US2 004/036127
FIGURE 12 illustrates the percent change in concentration of the lactone form over time for camptothecin, tocopherol succinate camptothecin (SN2300), arad tocopherol succinate 7-ethyl-10-hydroxycam ptothecin (SN2310), in the presence of human serum albumin. The stability of the lactone of tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-1 O-hydroxycamptothecin is greater than that of camptothecin. This dramatic increase in the stability of the lactone may result in increased activity compared to the unmodified camptothecin parent compound.
EXAMPLE 17
In vitro Chtotoxicity of Representative
Tocopherol-Modified Therapeutic Drug Compounds
In this example, the in vitro cytotoxicty of representative tocopher ol-modified therapeutic drug compounds of the invention, tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-h ydroxycamptothecin, was compared to the in vitro cytotoxicity of camptothecin, 10-hy droxycamptothecin, SN38, irinotecan, and 1opotecan.
The in vitro cytotoxicity, as measured by Glso (50% of growth inhibiti on) values, of tocopherol succinate camptothecin and tocopherol succinate “J-ethyl-10- hydroxycamptothecin was investigated and compared to the National Cancer Institute (NCI) Glsp values for camptothecin, 10-hydroxycamptothecin, SN-38, irinotecan, and topotecan in the following cancer cell lines: NC1-H460 (ATCC #HTB-177) (non-small cell lung), HCT-15 (ATCC #CCL-225) (colorectal), HT-116 (ATCC #CCL-247) (colorectal), HT-29 (ATCC #HTB- 38) (colorectal), MCF-7 (ATCC #HTB-22) (breast), and OVCAR-3 (ATCC #HTB-161) (ovarian).
The study was performed using emulsion formulations of tocopherol succinate 7-ethyl-10-hydroxycamptothecin (described in Example 15A) and tocopherol succinate camptothecin (described in Example 15C) diluted in the corresponding cell nxedia. The cells were in contact with varying concentrations of the test article for a period of 48 hours. At the end of 48 hours, staining with ALAMAR BLUE was performed to determine the number of viable cells and calculate the degree of cellular growth inhibition as compared to a control group. The percent of inhibition versus concentration was fit to the Hill equation to determine concentration that produces 50% o f growth inhibition (Gls).
The sensitivity of the tested cell lines to tocopherol succinate campstothecin (SN2300), tocopherol succinate 7-ethyl-10-hydroxycamptothecin ~~ (SN2310), camptothecin, irinotecan, and topotecan is illustrated in Table 2 and Figure 13.
Table 2. Comparative drug concentration that produce 50% cell growth irmhibition (Glso). 10-HO- .
Cell line CPT CPT SN38 Irinotecan | Topotecan | VESA- VESA- (NCO) (NCI) (NCD (NCI) CPT SN38 (NCI)
NCI-H460
Rr . .
HCT-15 :
A
(COLON) 160nM | 356M | 7.9 aM | 31.6 uM 501 nM 20 uM 99 nM
Poor !
OVCAR-3 LL (OVARIAN) 160nM | 62nM | 2.9 nM 31.6 uM activity © 83 nM
HCT-116 ps N . . . (COLON) 27 nM 1 nM 7.9 uM 39.8 nM 449 nM 119 nM
HT29 126 nM | 112 nM InM 12.58 uM 125 nM 434 nM i 91 nM (COLON) - - :
MCF-7 i (BREAST) 13 nM 10 nM 3.98 uM 15.8 nM 325 nM
CPT: Camptothecin; 10-HO-CPT: 10-hydroxycamptothecin; SN38: 7—ethyl-10- hydroxycamtothecin; VESA-CPT: tocopherol succinate camptothecin;
VESA-SN38: tocopherol succinate 7-ethyl-10-hydroxycamothecin.
The results in Table 2 illustrates that formulations of tocopherol—modified therapeutic drug compounds of the inv ention provide effective anti-tumor activity.
FIGURE 13 is a plot of the GI 5 values (concentration that produces 50% growth inhibition) determined for tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin in four of the tested cell lines. The values reported by the NCl in these same cancer cell lines for camptothecin, irinotecan, and topotecan is also included as comparison. A high Glso value corresponds to a low drug conceratration to produce 50% inhibition. From the graph, it is clear that the compounds of the Xnvention,
tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10- hydroxycamptothecin, show a high level of cytetoxic activity similar to camptothecin.
EXAMPLE 18
Pharmacokinetics of Representative Tocopiieral-Modified Therapeutic Drug Compounds 3 In this example, the pharmacokinctics of representative tocopherol-modified therapeutic drug compounds of the invention, tocopherol staccinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin, was c ompared to camptothecin, irinotecan, and topotecan.
The pharmacokinetic profiles of tocopherol succinate camptothecin and 1 0 tocopherol succinate 7-ethyl-10-hydroxyveamptothecin were investigated In
Sprague-Dawley rats following a bolus. intravenous adrministration of emulsion formulations of the drug compounds (SN2300 emulsion and SN2310 emulsion) via the lateral tail vein at a dose of approximately 1< mg of drug com _pound/kg of body weight.
Blood samples were collected for up to 120 hours post dose wia the jugular vein. The concentration of each camptothecin derivative in plasma wvas determined by high performance liquid chromatography (HPLC) with fluorescence detection.
A noncompartmental analysis was carried out using WinNonlin (v4.1).
The pharmacokinetic profiles of tocopherol succinate camptothecin (SN2300) and tocopherol succinate 7-cthyl-10-hydroxycamptothecin (SN2 310) are illustrated in
FIGURES 14A and 14B, respectively. FIGURES 14€A and 14B illustrate concentration-time values after an intravenous 1yection of 13.8 amg of drug compound/kg of body weight for tocopherol succinate campiuthecin (SN2300 emulsion) and tocopherol succinate 7-ethyl-10-hydroxycamptothecin ‘{SN2310 emulsion), respectively. Referring to FIGURES 14A and 14B, a proicnged plasma half-lifes following intravenous administration, particularly for tocophero! succinate camptothecimn, is shown.
The calculated plasma elimination half-life, mean residen ce time, and clearance of tocopherol succinate camptothecin (SN2300), tocopherol succinate 7-ethyl-10- hydroxycamptothecin (SN2310), camptothecin, irinotecan, and #opotecan is provided in
Table 3.
The term "plasma elimination half*life" refers to the time= necessary to reduce the drug concentration in plasma by 50% after cquilibrium is reachecE The term "elimination rate constant” refers to the fraction of drug eliminated per unit o f time. With first-order elimination, the rate of elimination is direciiy proportionaml to the serum drug _31-
concentratio n. There is a linear relationship between rate of elimination and serum drug concentratio-n. Although the amount of drug eliminated in a first-order process changes with concen tration, the fraction of a drug eliminated remains constant.
The term "clearance" refers to a measure of the body's ability to eliminate drug and is a hypothetical volume of distribution of drug which is cleared per unit time (i.e., ml/min) by” any pathway of drug removal. It is important to clarify that the «clearance does not indicate how much drug is being removed, rather, the volume of biological fluid such as blood or plasma that would have to be completely freed of drug 10 account for the elimination The term "volume of distribution refers to a calculated volumes of body fluid that would be required to dissolve the total amount of drug at €he same concentration as that found in the blood. It is a proportionality constant reXating the amount of drug in the body to the measured concentration in biological flui d (blood, plasma, serum).
Table 3. Comparative pharmacokinetic parameters foilowing ir—ravercus administrat ion in rats of tocopherol succinate camptothecin (SN2300) and tocopherol succinate 7-ethyl-10-hydroxycamptothecin (SN2310) compared to camptothecin, irinotecan, and topotecan. (elimination) (hours (I/hr/kg
Camptothecin’ topowes® | vos | oo | 3m
El -Gizawy SA, Hedaya MA. Cancer Chemother. Pharmacol, 43 : 364-370 (1999). ®A tsumi R, Okazaji O Hakusui H. Biol. Pharm. Bull., 18 (8): 1114-1115 (1995).
Table 3 illustrates that the calculated plasma elimination half-life of tocopherol succinate camptothecin (SN2300) and tocopherol] succinate 7-ethyl-10-hydroxycamptothecin (SN2310) is approximately 30-times and 3-tixnes longer than the c.ommercially available analogs, respectively. The higher mean residence time
BE se WO 2005/042539 PCT/US2004/036127
REE RE 1 (MRT) and lower clearance rate suggest a longer tumor exposure time to these new derivatives, which may indicate a potential for increased chena otherapeutic effect.
Througla lipophilic modification of therapeutic drug compounds, the plasma elimination hal f-life of the parent therapeutic drug compound can be increased. The compounds of the invention, by virtue of the lipophilic moiety (e.g., tocopherol moiety), have increased plasma elimination halflife compared to the parent therapeutic drug. As illustrated abowe for tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycamptothecin, the plasma elimination half-life is significantly increased compared to the parent compounds.
EXAMPLE 19
In vivo Anti-Tumor Activity of Representative Tocopherol-Modified
Therapeutic Drug Compounds in Human Tumor Xenographs
In this example, the in vivo anti-tumor activity of representative tocopherol-modi fied therapeutic drug compounds of the invention, tocopherol succinate camptothecin and tocopherol succinate 7-ethyl-10-hydroxycarmptothecin, was compared to the anti-tumor effect of irinotecan.
NCI-H46 0 Human Tumor Xenograft. Athymic mice were subcutaneously implanted with a cell suspension (107 cells/mouse). When tumors reached an appropriate size, animals were randomized into groups of eight and intravenously administered the following compounds at a dose of 15 mg of drug compound /kg of body weight on a schedule of q1dx 5 for two consecutive weeks:
Saline-control group
Irinotecam
SN2300 emulsion
SN2310 emulsion -
HT-29 Haman Tumor Xenograft. Athymic mice were Subcutaneously implanted with 30-40 mg tumor fragments using 12-gauge trocar needles. A sufficient number of mice were implarited with fragments so tumors in narrow wei ght range (100-200 mg) were selected for the trial on staging day (SD). The animals sel ected with tumors in the proper size range were randomized into six groups of 10 animals and intravenously administered the following test compounds:
Saline-control group (qldx3 for 2 weeks)
Irinotecan (15 mg/kg, qldxS5 for 2 week's)
SN23 00 emulsion (15 mg/kg, qldxS for 2 weeks)
SN23 10 emulsion (15 mg/kg, qldx5 for 2 weeks)
SN23 00 emulsion (15 mg/kg, q3dx10)
SN23 10 emulsion (15 mg/kg, q3dx10)
In both xenograph studies, animal body weights and tumors were measured twice weekly following the initiation of dosing. The tumor measurements were performed using a caliper (millimeters); the tumor volume was calculated based on the formula: (Length x width?) /2 = Volume (mm).
The anti-tumor effect of SN2300 and SN2310 emulsions administered to athymic mice implanted with NCI-H460 human tumor ceiis and HT-25 human tumor ceils is craphically represented in FIGURES 15A and 15B, respectively. Although the
SN2300 emnxision showed litle to no anti-tumor effect in this model, the
SN2310 emulsion exhibited substantial anti-tumor effect as compared to both saline control and 111notecan.
The calculated tumor response parameters for the HT-29 xenograft study is provided in Table 4. Fifty-five days after dose initiationn, 30% of mice in the control group were sacrificed because of tumor size (>4000 mm’) and the median tumor size was 3136 mm’. At this same timepoint, 80% of the mice ixa the SN2310 (q3dx10) group presented no measurable tumor. In addition, the SN231Q (qldx5) group had a median tumor size of 126 mm? with 40% having no measurable tumor. At the same time, the irinotecan group showed a median tumor size of 1637 mm. The results indicate that the administration of SN2310 produces significant anti-tumor activity.
Table 4. Calculated Tumor Response Parameters from the HT-29 Xenograft
Study.
Tumor Growth oS lmor Number of animals
Group Schedule gr 5° Inhibition we no ir (Ya T/C) sume | qidns @weeks) | o- | | om 10
SN2300 | qldx5 (2 weeks) ono
C
Tumor Growth Gormor | Number of animals
Group Schedule | Delay (T-C) Inhibition | With no measurable (days) (% T/C) | tumor on Day 55
SN2300 q3dx10 | 6 | 102 | 0/10 q1dxS5 (2 weeks) | > 28 | <4 3 4/10
EE EN TT
* 80% of tumors in this group had still not reached maximum pre-determined size.
T-C = Median Time for Treatment group (T) and Control group (C) to reach a predetermined size. %T/C = (Treated median tumor weight)/ (Control median tumor weight) x 100 (at Day 55).
While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

Claims (47)

The embodimer=ts of the invention in which an exclusive property or privilege is claimed are defined as follows:
1. A compound having the formula (T-L)o(M)nD wherein T is a Ix pophilic moiety; L is a linker moaety: D is a therapeutic drug moiety derived from a therapeutic drug compound having a solubility in water at room temperature less than about 500 pg/ml; n=0,1,2,0r 3 m=20,1,2, or3;and m+n=1,2, or 3; wherein the n T -L moieties are covalently coupled to the therapeutic drug moiety through the linker moZety and the rm lipophilic moieties are covalently coupled to the therapeutic drug moiet-.
2. The compound of Claim 1, wherein the therapeutic drug compound has a solubility in water at rorom temperature less than about 100 pg/mL.
3. The compound of Claim 1, wherein the lipophilic moiety is a tocopherol.
4. The compound of Claim 1, wherein the linker moiety is a succinate.
5. The coxrmpound of Claim 1, wherein the therapeutic drug moiety is a taxane.
6. The coonpound of Claim 1, wherein the therapeutic drug moiety is paclitaxel or a derivati~ve thereof.
7. The compound of Claim 1, wherein the therapeutic drug moiety is docetaxel or a derivative thereof.
8. The co-mpound of Claim 1. wherein the therapeutic drug moiety is camptothecin or a deri~vative thereof.
9. The compound of Claim 1, wherein the therapeutic drug moiety is 10-hydroxycamptothecin or a derivative thereof.
10. The compound of Claim 1, wherein the therapeutic drug moiety is 7-ethyl-10-hydroxycamptothecin or a derivative thereof.
11. "The compound of Claim 1, wherein n = 0.
12. The compound of Claim 1, wherein m = 0.
13. The compound of Claim 1, wherein m = 0 and n = |.
14. The compound of Claim 1. wherein m = 0 ancin = 2.
15. A compound having the formula (T-L)n(T)mD wherein T is a lipophilic moiety; L is a linker moiety; D is a therapeutic drug moiety derived from at least one of paclitaxel, docetaxel, camptothecin, or derivatives thereof: n=0,1,2, or3; m=0,1,2, or 3; and m-+n=1,2 or3; wherein the n T-L. moieties arc covalently coupled to the therapeutic drug moiety through the linker moiety and the m lipophilic moieties are covalently coupled to the therapeutic drug moiety.
16. The compound of Claim 15, wherein the lipophilic moiety is a tocopherol.
17. The compound of Claim 15, wherein the linker moiety is a succinate.
18. The compound of Claim 15, wherein the camptothecin derivative is 10-hydroxycamptothecin.
19. The compound of Claim 15, wherein the camptothecin derivative is 7-ethyl-10-hydroxycamptothecin.
20. Ax compound having the formula T-L-D wherein T is a lipophilic moiety; L is a limker moiety; and D is at least one of paclitaxel, docetaxel, carmptothecin, or derivatives thereof.
21. The compound of Claim 20, wherein the lipophilic moiety is a tocopherol.
22. The compound of Claim 20, wherein the linker moiety is a succinate.
23. The compound of Claim 20, wherein the camptothecin derivative is 10-hydroxycam ptothecin.
24. The compound of Claim 20, wherein the camptothecin derivative is 7-ethyl-10-hydr-oxycamptothecin.
25. "ZTocophero! succinate paclitaxel.
26. "Tocopherol succinate docetaxel.
27. “Tocopherol succinate camptothecin .
28. “Tocopherol succinate 10-hydroxycamptothecin.
29. “Tocopherol succinate 7-ethyl-10-hy droxycamptothecin.
30. _An emulsion, comprising: (a) an oil phase comprising (3) a compound having the formula (T-L)o(T)mD wherein T is a lipophilic moiety; L is a linker moiety; D is a therapeutic drug moiety; n=0,1, 2, 0r3; m=20,1,2,0r3; and m+n=1,2, or 3;
wherein the n T-L moieties are covalently coupled to whe therapeutic drug moiety through the linker moiety and the m lipophilic moieties are covalently coupled to the therapeutic drug moiety; (i1) a lipophilic medium; and (b) an aqueous phase.
31. The emulsion of Claim 30, wherein the therapeutic drug moiety is derived from a therapeutic drug compound having a solubility in water at room temperature less than about 500 pg/mL.
32. The emulsion of Claim 30. wherein the therapeutic drug moiety is at least one of paclitaxel, docetaxel, camptothecin, or derivatives thereof.
33. The emulsion of Claim 30. wherein the lipophilic moiety is a tocopherol.
34. The emulsion of Claim 30, wherein the linker moiety is a succinate.
35. The emulsion of Claim 30, wherein the lipophilic medium comprises tocopherol.
36. A micelle formulation, comprising: (a) a compound having the formula (T-L)n(T)mD wherein T is a lipophilic moiety; L is a linker moiety: D is a therapeutic drug 1moiety; n=0,1,2, or3; m=0, 1,2, or 3; and m+n=1,2 or3; wherein the n T-L moieties are covalently coupled to the therapeutic drug moiety through the linker moiety and the m lipophilic moieties are covalently coupled to the therapeutic drug moiety; and (b) an aqueous phase.
37. The formulation of Claim 36, wherein the therapeutic Grug moiety is derived from a therapeutic drug compound having a solubility in ‘water at room temperature less than about 500 pg/mL.
38. The formulation of Claim 36, wherein the therapeutic dnzg moiety is at least one of paclitaxel, docetaxel, camptothecin, or derivatives thereof.
39. The formulation of Claim 36, wherein the lipophilic moiety is a tocopherol.
40. The formulation of Claim 36, wherein the linker moiety isa succinate.
41. A method for treating a cell proliferative diseas=, comprising administering to a subject in need thereof a therapeutically effective amount of a cempound having the formula (T-L)u(T)uD wherein T is a lipophi lic moiety; L is a linker moiety; D is a therapeutic drag moiety derived from a therapeutic drug compound effect in treating cell proliferative disease; n=0,1,2, or 3; m=0,1,2, or3; and m-+nisl,2 or3; wherein the n T-L moieties are covalently coupled io the therapeu tic drug moiety through the linker moiety and the m lipophilic moieties are covalently coupled to the therapeutic drug moiety.
42. The method of Claim 41, wherein administering the compound comprises administering an emulsion comprising the compound.
43. The method of Claim 41, wherein administering the compound comprises administering a micelle formulation comprising the compound. 44, The method of Claim 41, wherein the therapeutic drug moiety is paclitaxel or a derivative thereof.
1S2004/036127
45. The method of Claim 41, wherein the therapeutic drug moiety is docetaxel or a derivative thereof.
46. The method of Claim 41, wherein the therapeutic drug moiety is camptothecin or a derivative thereof.
47. Use of a compound of any one of Claims 1-29 in the manufacture of a medicament.
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ES2391775T3 (en) * 2004-11-05 2012-11-29 Samyang Biopharmaceuticals Corporation Pharmaceutical formulation to increase the solubility of 10-hydroxycamptothecin compounds in non-aqueous polar solvents
CN102491981B (en) * 2011-11-11 2014-11-19 南京美西宁医药科技有限责任公司 Amphiphilic anti-cancer drug compound modified by water-soluble vitamin E derivative, preparation, preparation method and application for compound
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CN104356380B (en) * 2014-10-23 2016-06-29 浙江工业大学 Epsilon-polylysine-vitamin e succinate amide complex and preparation method thereof and application
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