Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-02-06
2001-08-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S422000, C514S772100, C514S772300
Reexamination Certificate
active
06277410
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to copolymer pharmaceutical compositions useful in oral administration of a number of biological agents.
BACKGROUND OF THE INVENTION
A variety of biological agents are currently in use for the treatment of diseases and disorders. Many of these agents may be administered topically, rectally, vaginally, by pulmonary route, or parenterally.
However, parenteral administration (such as intramuscular, subcutaneous, intraperitoneal, intra-arterial or intravenous) as well as rectal, vaginal, and pulmonary routes, are often inconvenient, costly, or both. Oral administration thus possesses several advantages over these other routes. It is a convenient, cost-effective mode of administration for the patient.
The present invention relates, among other things, to (1) pharmaceutical compositions and methods for chemotherapeutic agents and (2) pharmaceutical compositions for biological agents, particularly those whose target cells or tissues are resistant to the biological agent.
A number of chemotherapeutic 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 target cancer.
Multi-Drug Resistance
A major roadblock to effective chemotherapeutic treatments is the resistance to biological agents that many neoplasms and microbial infections develop. The sensitivity of neoplastic cells to anti-cancer agents can decrease by a factor as high as 10
3
during the course of a chemotherapeutic regimen. When such resistance develops with respect to one agent, often the target cells are found to also be resistant to a number of other biological agents to which they had not previously been exposed. See Goldstein et al.,
Crit. Rev. Oncol. Hematol
., 12:243-253 (1992);
Goodman and Gilman's The Pharmacological Basis of Therapeutics
, 8th Ed., McGraw-Hill, New York, 1994. One mechanism by which such resistance develops is believed to involve the membrane pump protein gp-170 (a glycoprotein P or P-gp protein). See Goldstein et al.,
Crit. Rev. Oncol. Hematol
., 12:243-253 (1992).
It has now been discovered that these difficulties can be overcome by administering the biological agent in question in a formulation containing micelles of one or more block copolymers with the characteristics described below. Further, it has now been discovered that a certain subset of these block copolymers is particularly effective in delivering drugs and reversing resistance to a biological agent.
The Blood Brain Barrier
The brain is isolated from circulatory blood because the endothelial cell lining of blood vessels in the brain is more selective than it is in other parts of the body with respect to the molecules that are allowed to diffuse into the interstitial space of the brain. The mechanism that isolates the brain is often referred to as a “blood-brain barrier.” As a result of the blood-brain barrier, biological agents that are intended to affect the brain or a disease in the brain often must be administered in high dosage to compensate for the diffusion barrier provided by the blood-brain barrier. Animals to whom the high doses are administered are at greater risk of experiencing toxic or other side effects. It is therefore desirable to enhance the permeability of chemotherapeutic agents across the blood-brain barrier. See,
Goodman's and Gilman's The Pharmacological Basis of Therapeittics
, Eighth Edition, p.11.
In the brain and in other tissues it is often desirable to target a biological agent to a particular tissue at which the agent is anticipated to beneficially act. This desirability is particularly true for chemotherapeutic agents that potentially have highly toxic effects on non-target tissues. For instance, most anti-cancer chemotherapeutic agents function by selectively poisoning replicating cells. This mechanism inevitably targets the rapidly replicating cells, such as those of the bone marrow that generate a number of important blood cells. If the biodistribution of the chemotherapeutic drug is changed so that useful concentrations are maintained in the cancerous tissue or the tissue in which the cancer resides while concentrations distal from the cancer situs are reduced, the scope of toxic side effects will generally be reduced.
Additionally, since cancer, antimicrobial and other biological agents exhibit toxicities, it would be beneficial if dosages were lowered without adversely affecting the therapeutic index.
Tumors of the central nervous system present a particularly difficult therapeutic challenge. Such tumors are often difficult to surgically excise and surgical excision can have unacceptable consequences. These tumors can be difficult to treat with radiation since they are sometimes difficult to precisely locate and are often too close to tissues that are critical to the well-being of the tumor patient. Such tumors cannot be effectively treated by standard chemotherapies since the fraction of the administered chemotherapeutic agent that will reach the tumor is very small. The effective dosage at the tumor cannot be increased by administering higher dosages to the patient, since standard dosages are generally close to the dose that cause unacceptable side effects.
Cytokines
Cytokines are polypeptides secreted by cells. Cytokines play an important role in the interactions between cells in the immune system, and are therefore potentially effective drugs for the treatment of cancer, as well as viral-related and other diseases. The mechanism of action of these protein factors is connected with specific activation of the immune system which, in turn, protects against many pathological processes. Well known are antiviral preparations on the-basis of interferons (Infs) that are already used in clinical practice. For example, clinical tests of interleukin-2 (IL-2) and tumor necrosis factor (TNF) as anticancer drugs have yielded promising results. A great deal of work has been devoted to creation of new drugs on the basis of IL-4 and other lymphokines.
Generally speaking, recombinant cytokines possess low affinity for specific receptors on target cells because of incorrectly formed tertiary structures and the absence of necessary post-translational modifications in bacterial super-producers. Such recombinant preparations display low biological activity, and very high doses are required, producing considerable side effects.
Hormones
Hormones are chemical messenger molecules secreted by endocrine glands which regulate various aspects of metabolism. Insulin, for example, is a protein hormone secreted in the pancreas by the islets of Langerhans. Insulin stimulates catabolism of glucose and blocks glycogenolysis, thereby facilitating diffusion of glucose into most cells. The inability to form insulin results in diabetes mellitus, which is currently treated through insulin injection in conjunction with dietary regulation to control blood sugar levels. Insulin production and thus is of particular interest in molecular biology and enzymology.
It is therefore desirable to administer a biological agent or agents to a patient in a composition which can be administered orally, and which alleviates some or all of the above difficulties.
SUMMARY OF THE INVENTION
The present invention thus relates to compositions for oral administration comprising a biological agent and a block copolymer.
In one embodiment, the invention provides a pharmaceutical composition comprising:
(a) a biological agent;
(b) a polyether block copolymer comprising an A-type linear polymeric segment joined at one end to a B-type linear polymeric segment, wherein the A-type segment is of relatively hydrophilic character, the repeating units of which have molecular weight contributions between about 30 and about 500, wherein the B-type segment is of relatively hydrophobic character, the repeating units of which have molecular weight contributions between a
Alakhov Valery Y.
Batrakova Elena V.
Kabanov Alexander V.
Mathews, Collins Shepherd & Gould P.A.
Raymond Richard L.
Supratek Pharma Inc.
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