Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Solid synthetic organic polymer
Reexamination Certificate
1999-11-17
2001-04-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Solid synthetic organic polymer
C514S502000
Reexamination Certificate
active
06218438
ABSTRACT:
FIELD OF THE INVENTION
Copolymer pharmaceutical compositions useful in the therapies of retroviral infections, including, immunodeficiency virus infections (HIV) such as HIV-1 infections.
The compositions have improved therapeutic indexes, reduction of side effects, and reduced treatment costs, and can be used to treat a variety of infectious diseases induced by viruses, bacteria and parasites, including HIV, MLV, HTLV,
E. coli
, micobacteria, RNAse H, and other metal-dependant enzymes which play an important role in reproduction of a pathogen.
BACKGROUND OF THE INVENTION
Infection by the human immunodeficiency virus (HIV) leads to AIDS, an incurable and inevitably fatal disease. A variety of biological agents are currently in use for the treatment of HIV-1 infections (Chaudry M N, and Shepp D H,
Dermatol Clin
. 15:2, 319-29 (1997); Beach J W,
Clin Ther
, 1998 January-February, 20:1, 2-25. HIV is a retrovirus and carries its genetic information as RNA. After infection, this viral genomic RNA must be converted into viral DNA. Multiple steps are involved in this crucial step of HIV replication, each of which is catalysed by the viral enzyme reverse transcriptase (RT) (Arnold, E. et al.,
Drug Des. Discov
., 1996 April, 13:3-4, 29-47). RT has three enzymatic activities, RNA-dependent DNA polymerase activity (RDDP), ribonuclease H activity (RNase H), and DNA-dependent DNA polymerase activity (DDDP). With no mammalian counterpart, RT is an important target for antiviral development. Many such inhibitors have been discovered, including dideoxynucleosides (ddN) such as 3′-azido-3′-deoxythymidine (AZT) and 2′,3′-dideoxy-3′-thiacytidine (3TC) and nonnucleoside inhibitors (NNI) such as nevirapine, quinoxalines, pyridinones and BHAP. Virtually all of these inhibitors are directed against the RDDP and/or DDDP activity of RT.
Once viral DNA synthesis is complete, the viral DNA is integrated into the infected host cell's DNA, in a reaction catalyzed by the viral enzyme integrase (IN). This proviral DNA encodes the genetic information to produce new HIV virions (virus particles), and is inaccessible to antiviral intervention in this state.
Cellular machinery is used to synthesize new HIV RNA and proteins from the genetic information in the proviral DNA. These viral components assemble at the cell plasma membrane, and the nascent virions are shed from the cell. Nascent HIV virions assemble in an “immature” form; viral maturation takes place during and after virion shedding. This maturation involves proteolytic processing of virion proteins, a process, which is carried out by the HIV protease. Immature HIV virions are noninfectious, thus the HIV protease has proven to be another important target for antiviral intervention. Inhibitors of HIV protease include saquinavir, indinavir and ritonavir.
The steps of HIV replication up to the formation of proviral DNA can be considered “pre-integrational” stages, and those involved in the formation of nascent virions after integration of proviral DNA can be considered as “post-integrational.” Current chemotherapy of HIV-infected individuals utilizes combinations of RT inhibitors and HIV protease inhibitors. Clinical efficacy of these combinations is due in part to inhibition at both pre-integrational stages (RT) and post-integrational stages (protease) of HIV replication (McIntosh E M, et al., Acta Biochim Pol, 1996, 43:4, 583-92).
A number of antiviral agents exhibit low solubility and stability in physiological fluids. Often, chemotherapeutic agents are poorly transported across cell membranes. Further, many of these agents are binding with plasma proteins as well as other nonspecific interactions in the blood stream before they can reach the pharmacological target. Additionally, there is another serious problem associated with current anti-HIV chemotherapeutics. Although treatment with currently approved antivirals initially improves the quality of life and longevity of HIV-infected patients, prolonged therapy inevitably leads to drug-resistance (Kuritzkes D R, AIDS, Dec. 10, 1996 Suppl 5: S27-31; Richman D D, Adv Exp Med Biol, 1996, 394: 383-95). Resistance to RT inhibitors correlates with mutations in RT, and resistance to protease inhibitors correlates with mutations in the HIV protease. Clinical appearance of drug-resistant HIV imparts an unfavourable prognosis.
SUMMARY OF THE INVENTION
The present invention relates, among other things, to (1) pharmaceutical compositions and methods for chemotherapeutic agents and (2) pharmaceutical compositions for anti HIV-1 agents, particularly those, whose target cells or tissues are resistant to the biological agent.
The present invention thus relates to compositions for HIV therapy comprising metal and metal-chelating agent (hereinafter-biological agent, or biologically active agent).
In one embodiment, the invention provides a pharmaceutical composition comprising:
(a) a biological agent which is the metal complex of an N-aroyl hydrazone of the general structure (I):
where R
1
, R
2
, and R
3
are H, OH, CH
3
, OCH
3
, C(CH
3
)
3
[-tert-butyl], or phenyl, and X is OCH
3
, or OCH
2
CH
3
. The metal (Me) is any metal that can be chelated by the compound I, for example, Fe(II), Fe(III), Mn(II), Co(II), Mg(II), etc., preferably Fe(III).
In the most preferable form, R
1
is C(CH
3
)
3
, R
2
and R
3
are H, Me is Fe(III), and X is OCH
3
.
The invention may incorporate the use of block copolymers. Some block copolymer architectures are presented below.
The simplest block copolymer architecture contains two segments joined at their termini to give an A—B type diblock. Consequent conjugation of more than two segments by their termini yields A—B—A type triblock, A—B—A—B— type multiblock, or even multisegment A—B—C— architectures. If a main chain in the block copolymer can be defined in which one or several repeating units are linked to different polymer segments, then the copolymer has a graft architecture of, e.g., an A(B)
n
type. More complex architectures include for example (AB)n or A
n
B
m
starblocks which have more than two polymer segments linked to a single center.
In a preferred embodiment, the biological agent is combined with a surfactant that improves solubility of the biological agent and/or its intracellular transport. Preferred surfactants are nonionic or zwitterionic. Preferred nonionic surfactants have block, graft, or starblock copolymer architecture. Preferred block copolymers comprise poly(oxyethylene) and poly(oxypropylene) chain segments. Additionally preferred are compositions wherein the surfactant has a critical micellar concentration (“CMC”) of about 0.5% wt/vol. or less at 37° C. in an isotonic aqueous solution.
In another embodiment, the invention provides a method of targeting a biological agent to a pre-selected tissue. The method comprises administering the composition described above, wherein the targeting moiety is selected to target the tissue, to an animal having the pre-selected tissue.
In yet another embodiment, the invention relates to compositions for the delivery of biologically active agent comprising a poly(oxyethylene)-poly(oxypropylene) block copolymer and a biologically active agent, or derivative thereof, wherein the hydrophobe percentage of the poly(oxyethylene)-poly(oxypropylene) block copolymer is about 50%.
Preferred block copolymers are of the formula:
in which x, y, z, i, and j have values from about 2 to about 800, and wherein for each R
1
, R
2
pair, one is hydrogen and the other is a methyl group.
In another preferred embodiment, the invention relates to compositions for the delivery of a biologically active agent, or derivative thereof, comprising a biologically active agent, or derivative thereof, and a block copolymer of the formula:
wherein for each R
1
, R
2
pair, one is hydrogen and the other is a methyl group.
In another preferred embodiment, the invention relates to compositions for the delivery of a biologically active agent, or derivative thereof comprising a biologically active agent, or deriva
Alakhov Valery
Kabanov Alexander
Klinski Evgueni
Parniak Michael
Fubara Blessing
Mathews, Collins, Shepherd & Gould
Page Thurman K.
Supratek Pharma Inc.
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