Polymeric delivery agents and delivery agents compounds

Details Polymeric delivery agents and delivery agents compounds Polymeric delivery agents and delivery agents compounds

2001-10-09

2003-09-30

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S078160, C424S451000, C424S452000, C424S464000, C424S465000

Reexamination Certificate

active

06627228

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compositions for delivering active agents, and particularly biologically or chemically active agents. The compositions comprise a polymeric delivery agent or delivery agent compound which facilitates the delivery of the active agent to a target. These polymeric delivery agents and delivery agent compounds are well suited to form non-covalent mixtures with active agents for administration to animals. Methods for the preparation and for the 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.
In the delivery to animals of pharmacological and therapeutic agents, barriers are imposed by the body. Physical barriers such as the skin and various organ membranes are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
Oral delivery of many biologically or chemically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers. 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 may be rendered ineffective or may be destroyed in the GI tract by acid hydrolysis, enzymes, or the like, or may simply not be absorbed.
Many delivery agents are fairly hydrophobic, whereas many active agents are hydrophilic. The differential aqueous solubility between the delivery agent and the active agent can be problematic in designing commercially acceptable dosage formulations which exhibit biological activity in vivo. Thus, the ability to alter the solubility of a delivery agent would allow one to tailor the delivery agent to meet the needs of the cargo in order to optimize its bioavailability.
The pH within the gastrointestinal tract typically ranges from about 1 to about 8, while many delivery agents remain soluble over a range of only 2-2.5 pH units. During oral delivery, a significant amount of such a delivery agent could precipitate out in the stomach due to the local acidity. The precipitated delivery agent would then be unavailable for delivery of active agent to a point further along the GI tract. Increasing the span of pH solubility of the delivery agent would allow more effective delivery at lower concentrations of delivery agent.
Delivery agents generally tend to self-aggregate into micellular-like structures. The competition between self association and association with the active agent typically results in at least a portion of the delivery agent being unavailable for effective delivery of the active agent. Thus, a corresponding portion of the active agent that was administered may not be effectively delivered to the target. Inhibiting self aggregation of the delivery agent would increase the availability of delivery agent for delivery of the active agent.
Various delivery agents for oral administration of active agents have been developed in recent years. These delivery agents include proteinoids, modified vegetable proteins, acylated or sulfonated amino acids, acylated or sulfonated amino acid ketones, and acylated or sulfonated amino acid aldehydes. See, U.S. Pat. Nos. 5,401,516; 5,443,841; 5,451,410; 5,541,155; 5,629,020; 5,643,957; 5,693,338; 5,709,861; 5,714,167; 5,766,633; 5,773,647; 5,792,451; 5,820,881; 5,863,944; 5,866,536; and RE35,862. These delivery agents promote systemic absorption of active agents in the gastrointestinal tract. The interaction between the delivery agent and the active agent, as well as the interaction between the delivery agent and the cell membrane, may be important for absorption. See, U.S. Pat. No. 5,714,167.
There is a need for delivery agents whose solubility can be modified for a particular need, thereby changing the concentration of soluble delivery agent which is available for delivery of an active agent.
Therefore, there is a need for alternate and improved delivery agents.
SUMMARY OF THE INVENTION
The present invention provides polymeric delivery agents which are useful in the delivery of active agents. The polymeric delivery agent comprises a polymer conjugated to a modified amino acid or derivative thereof via a linkage group selected from the group consisting of —NHC(O)NH—, —C(O)NH—, —NHC(O)—, —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH
2
NH—, —NHCH
2
—, —CH
2
NHC(O)O—, —OC(O)NHCH
2
—, —CH
2
NHCOCH
2
O—, —OCH
2
C(O)NHCH
2
—, —NHC(O)CH
2
O—, —OCH
2
C(O)NH—, —NH—, —O—, and carbon-carbon bond, with the proviso that the polymeric delivery agent is not a polypeptide or polyamino acid The modified amino acids may be acylated or sulfonated amino acids, ketones or aldehydes of acylated or sulfonated amino acids, salts thereof, or polyamino acids or polypeptides of any of the foregoing.
The polymer may be any polymer including, but not limited to, alternating copolymers, block copolymers and random copolymers, which are safe for use in mammals. Preferred polymers include, but are not limited to, polyethylene; polyacrylates; polymethacrylates; poly(oxyethylene); poly(propylene); polypropylene glycol; polyethylene glycol (PEG) and derivatives thereof, such as PEG-maleic anhydride copolymers; and derivatives and combinations thereof. The molecular weight of the polymer typically ranges from about 100 to abut 200,000 daltons. The molecular weight of the polymer preferably ranges from about 200 to about 10,000 daltons. In one embodiment, the molecular weight of the polymer ranges from about 200 to about 600 daltons and more preferably ranges from about 300 to about 550 daltons.
According to one embodiment, the polymeric delivery agent comprises units having the formula
or salts thereof where R
1
is a modified amino acid which is bonded to the polymer via a linkage group selected from the group consisting of —NHC(O)NH—, —C(O)NH—, —NHC(O)—, —OOC—, —COO—, —NHC(O)O—, —CC(O)NH—, —CH
2
NH—, —NHCH
2
—, —CH
2
NHC(O)O—, —OC(O)NHCH
2
—, —CH
2
NHCOCH
2
O—, —OCH
2
(O)NHCH
2
—, —NHC(O)CH
2
O—, —OCH
2
C(O)NH—, —NH—, —O—, and carbon-carbon bond; R
2
is H or —CH
3
; and R
19
is H or —COCH. Preferably, R
1
is —R
3
—R
4
where R
3
is —NHC(O)NH—, —C(O)NH—, —NHC(O)—, —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH
2
NH—, —NHCH
2
—, —CH
2
NHC(O)O—, —OC(O)NHCH
2
—, —CH
2
NHCOCH
2
O—, —OCH
2
C(O)NHCH
2
—, —NHC(O)CH
2
O—, —OCH
2
C(O)NH—, —NH—, —O—, or carbon-carbon bond; and R
4
has the formula
where
R
5
, R
6
, R
7
, R
8
, and R
9
are independently a bond to R
3
, or H, Cl, Br, F, —OH, —CH
3
, —CH
3
, or —(CH
2
)
m
CH
3
;
R
10
is a bond to R
3
or —COOH, or —C(O)NH—R
11
—R
12
;
R
11
is a substituted or unsubstituted, linear or branched alkylene Slaving a chain length of from about 1 to about 11 or —R
13
—R
14
—;
R
12
is a bond to R
3
or is —COOH, —NH
2
, —OH, —C(O)—R
15
, —COO—R
15
, —NHR
15
, —OR
15
, Cl, or Br;
R
13
is a substituted or unsubstituted phenylene;
R
14
is a substituted or unsubstituted, linear or branched alkylene having a chain length of from about 1 to about 5;
R
15
is a bond to R
3
; and
m is from about 1 to about 4.
Preferably, R
4
is selected from the group consisting of
and salts thereof.
Preferably, R
9
is —OCH
3
or —OH. According to a preferred embodiment, R
10
is —NH—R
11
—R
12
and R
11
is —(CH
2
)
7
—, —(CH
2
)
9
—, —(C
6
H
5
)—, —(CH
2
)—, —(C
6
H
5
)—CH
2
—, or —(CH
2
)
8
—NH—C(O)—CH
2
—.
Another embodiment is a polymeric delivery agent having units of the formula
R
16
—R

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