Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Carboxylic acid ester
Reexamination Certificate
2000-02-01
2001-10-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Carboxylic acid ester
C514S724000, C514S277000, C514S544000, C514S313000
Reexamination Certificate
active
06303660
ABSTRACT:
The present invention relates to a new approach to deliver anti-cancer agents to solid malignant tumors. Specifically, it relates to a primer composition for local delivery to primary solid malignant tumors or metastases thereof in mammals, including man, prior to administration of anti-cancer agents. Further, it relates to an agent delivery system and a method of delivering an anti-cancer agent to primary solid malignant tumors and metastases thereof.
BACKGROUND
Anti-cancer agents are often administered orally or by injection for transportation by the blood stream to the solid tumors in the liver, lung, breast, colon, rectum, prostate or brain. The anti-cancer agent must be transported by blood to the blood vessels of the tumor, pass the vessel wall, and go through the interstitium to reach the cancer cell. Unfortunately, in many cases, the agents are not as efficient as expected from results of toxicity tests with cultured malignant cancer cells. This is probably due to barriers to agent delivery in solid tumors (R. K. Jain, Sci. Am. 271(1994) 58). Thus, there is a need for improvement in anti-cancer agent delivery to solid tumors.
Solid malignant tumors comprise normal connective tissue cells in addition to malignant cancer cells within the tumor. The malignant cancer cells occupy only a part of the volume of the tumor and they are surrounded by the interstitium, i. e. a collagen rich extracellular matrix which can separate the cancer cells from the unevenly distributed blood vessels, which constitute approximately 1-10% of the tumor.
Rakesh K. Jain (ibid.) recognized inter alia that the abnormally high pressure in the interstitial matrix of a solid tumor can retard the passage of large molecules across vessel walls into the interstitial matrix and thus contribute to a low concentration of agent molecules frequently seen in the interstitial matrix of animal and human tumors growing in mice. He suggested among other things two pressure-related strategies to improve solid tumor therapy, namely injection of an agent mixed with a large amount of fluid directly into the center of a tumor to increase the pressure at the core of the tumor relative to the surrounding tumor tissue so that the agent would spread along the induced pressure gradient, and reduction of the interstitial pressure with the vasodilators pentoxifylline or high, near toxic doses, of the vitamin B3 derivative nicotinamide. Both agents are known to increase the oxygen supply in various tumors which is a benefit for radiation therapy.
DESCRIPTION OF THE INVENTION
The present invention is concerned with means and methods to improve anti-cancer agent delivery to solid malignant tumors in mammals, including man.
Particularly, the invention provides a new approach to anti-cancer agent delivery to primary solid malignant tumors or metastases thereof in that a primer composition is administered locally to lower the interstitial pressure in the solid tumor area, which facilitates the subsequent transport of locally or systemically administered anti-cancer agents to the solid tumors.
Specifically, the present invention is directed to a primer composition for local delivery to primary solid malignant tumors or metastases thereof in mammals, including man, prior to administration of anti-cancer agents, comprising an interstitial pressure-lowering amount of a pharmaceutically acceptable agent which increases the intracellular levels of cyclic adenosine monophosphate (cAMP) in the normal connective tissue cells within the solid malignant tumors, and a vehicle.
Such an agent may be selected from any agents which increase the intracellular levels of CAMP, such as agents that bind to and stimulate receptors at the cell surface of normal connective tissue cells within the tumor, and agents that inhibit CAMP phosphodiesterase.
Specific examples of agents known to bind to and stimulate receptors that increase intracellular levels of cAMP are Bradykinin, Histamine, Vasoactive intestinal polypeptide (VIP), Isoproterenol, Forskolin, and Prostaglandin E
1
, Prostaglandin E
2
, Prostaglandin I
2
and esters of these prostaglandins.
Further, examples of esters of the prostaglandins are Prostaglandin E
1
methyl ester, Prostaglandin E
1
ethyl ester, Prostaglandin E
1
isopropyl ester and
6
a
-Carba-prostaglandin I
2
(Carbacyclin).
Examples of agents known to inhibit cAMP phosphodiesterase are 3-Isobutyl methyl xanthine,Theophylline, Rolipram, Motapizone, Caffeine and Zardarverine.
It should be understood that the pharmaceutically acceptable agent, which increases the intracellular levels of cyclic adenosine monophosphate (cAMP) in normal connective tissue cells within solid malignant tumors, in the primer composition of the present invention, is not limited to the above exemplified agents and that any pharmaceutically acceptable agent which increases the intracellular levels of cyclic adenosine monophosphate (cAMP) in the normal connective tissue cells within solid malignant tumors is comprised by the scope of the invention.
Further, local administration or delivery of the primer composition of the invention is intended to comprise installing or injection to the surroundings of the tumor(s) such as the immediate surrounding tissue or blood vessel supporting the tumor-containing organ, e g via a cannula.
The vehicle of the primer composition according to the invention may be any pharmaceutically acceptable vehicle which is suitable for local delivery of the primer composition of the invention, such as isotonic saline solution, phosphate buffered saline (PBS) solution, ethanol etc.
The interstitial pressure-lowering amount of the agent will be determined empirically for each specific agent which increases the intracellular levels of cAMP, but the amount will normally be in the range of 1 to 10 mg per kg body weight.
The present invention is further directed to an agent delivery system for delivery of anti-cancer agents to primary solid malignant tumors or metastases thereof in mammals, including man. The system comprises
as a first component,
a) a primer composition according to any one of claims
1
-
3
for initial local delivery to a solid tumor area, and
as a second component,
b) a therapeutically effective amount of an anti-cancer agent for subsequent local or systemic administration.
In case a specific anti-cancer agent needs an adjuvant for improved uptake, the delivery system of the invention may comprise such an adjuvant.
The present invention is also directed to a method of delivering an anti-cancer agent to primary solid malignant tumors or metastases thereof in mammals, including man. The method comprises the steps of
a first local administration to the tumor area of a primer composition comprising
an interstitial pressure-lowering amount of a pharmaceutically acceptable agent which increases the intracellular levels of cyclic adenosine monophosphate (cAMP) in the normal connective tissue cells within solid tumors, and a vehicle,
to effect lowering of the interstitial pressure,
followed by
a second local or systemic administration of a therapeutically effective amount of an anti-cancer agent.
The therapeutically effective amount of a specific anti-cancer agent will be determined on the basis of the amount recommended by the manufacturer.
It should be understood that in the present specification and claims the primer composition is administered locally to the tumor area prior to the delivery of an anti-cancer agent so that the interstitial pressure-lowering effect of the primer composition is sufficient to facilitate the transport of the anti-cancer agent to the cancer cells of the solid tumor.
The time interval between the administration of the primer composition and the anti-cancer agent will depend on several patient-related factors and the actual composition and agent. However, from less than a minute to up to a few hours may be used, even though the interval normally will be between 3 minutes and 2 hours, e.g. 5 to 60 minutes, such as 10 to 50 minutes.
The invention is further illustrated by the following experiments, wh
Reed Rolf
Rubin Kristofer
Sjoquist Mats
Bacon & Thomas
Biophausia AB (publ)
Patel Sudhaker B.
Raymond Richard L.
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