Compounds and compositions for delivering active agents

Details Compounds and compositions for delivering active agents Compounds and compositions for delivering active agents

2001-04-19

2003-11-04

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S451000, C514S503000

Reexamination Certificate

active

06642411

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds for delivering active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the delivery of an active agent to a target. The carrier compounds are well suited to form non-covalent mixtures with biologically-active agents for pulmonary, oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, rectal, vaginal, mucosal, transdermal, intradermal, parenteral, intravenous, and intramuscular administration to animals, as well as crossing the blood-brain barrier. Methods for the preparation and administration of such compositions are also disclosed.
BACKGROUND OF THE INVENTION
Conventional means for delivering active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself. Biologically or chemically active agents are particularly vulnerable to such barriers.
For example, in the delivery to animals of biologically active or chemically active pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical barriers include, but are not limited to, pH variations, lipid bi-layers, and degrading enzymes.
These barriers are of particular significance in the design of drug delivery systems. For example, oral delivery of many biologically or chemically active agents would be alternate routes of choice for administration to animals if not for biological, chemical, and physical barriers such as varying pH in the gastro-intestinal membranes. Among the numerous agents which are not typically amenable to oral administration are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly rendered ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption.
Crossing the blood-brain barrier, as well as oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, mucosal, transdermnal or pulmonary delivery to the circulatory system for many biologically active agents could be the route of choice for administration to animals if not for physical barriers such as the skin, lipid bi-layers, and various organ membranes that are relatively impermeable to certain biologically active agents, but one or more of which must be traversed before an agent delivered via these routes can reach the circulatory system. Additionally, delivery such as, for example, sublingual delivery may be impeded by chemical barriers such as the varying pH in the gastrointestinal (GI) tract and the presence of powerful digestive enzymes.
Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation.
Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al. (1976),
FEBS Letters,
Vol. 62, pg. 60; and Hashimoto et al. (1979),
Endocrinology Japan,
Vol. 26, pg. 337.
However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals. For example, U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microsphere carriers as well as methods for their preparation and use. These proteinoid microspheres are useful for the delivery of a number of active agents.
However, there is still a need for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents by various routes.
SUMMARY OF THE INVENTION
The present invention provides compounds having the formula
and salts thereof. These compounds are useful in the delivery of active agents.
Another embodiment of the invention is a composition comprising:
(A) at least one active agent; and
(B) a carrier comprising a compound having the formula
 or a salt thereof.
Also provided are dosage unit forms comprising the composition above and an excipient, a diluent, a disintegrant, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof.
Methods for administering a biologically-active agent to an animal in need of the agent by the pulmonary, oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, rectal, vaginal, mucosal, transdermal, intradermal, parenteral, intravenous, or intramuscular route or crossing the blood-brain barrier with the compositions of the present invention are also provided.


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