POLYMER-BASED, SUSTAINED RELEASE DRUG DELIVERY SYSTEM
Disclosed is a sustained release system that includes a polymer and a pharmaceutically active agent dispersed in the polymer. The agent is in granular or particulate form, and has a rate of release from the system that is limited primarily by the rate at which the agent dissolves from the granules into the polymer matrix. Advantageously, the polymer is permeable to the agent and is non-release-rate-limiting with respect to the rate of release of the agent from the polymer.
1 . A sustained-release formulation comprising:
at least one granule comprising a therapeutically effective amount of at least one agent, and
a polymer matrix coating the at least one agent, wherein the at least one agent has a rate of release from the formulation that is limited primarily by the rate at which the at least one agent dissolves into the matrix.
2 . The sustained-release formulation of claim 1 , wherein the at least one agent has a solubility in the polymer matrix of about 10 mg/ml or less.
3 . The sustained-release formulation of claim 1 , wherein the at least one agent has a solubility in the polymer matrix of about 1 mg/ml or less.
4 . The sustained-release formulation of claim 1 , wherein the at least one agent has a solubility in the polymer matrix of about 0.1 mg/ml or less.
5 . The sustained-release formulation of claim 1 , wherein the at least one agent has a solubility in the polymer matrix of about 0.01 mg/ml or less.
6 . The sustained-release formulation of claim 1 , wherein sustained release of the at least one agent occurs for a period of at least 3 hours.
7 . The sustained-release formulation of claim 1 , wherein diffusion of the at least one agent through the polymer matrix is primarily non-release-rate-limiting with respect to the rate of release of the at least one agent from the matrix.
8 . The sustained-release formulation of claim 1 , wherein the polymer matrix is a hydrogel.
9 . The sustained-release formulation of claim 1 , wherein the at least one agent comprises a codrug.
10 . The sustained-release formulation of claim 1 , wherein the polymer matrix is a biocompatible fluid or semisolid, in either case selected so that the at least one agent has low solubility therein.
11 . The sustained-release formulation of claim 10 , wherein the semisolid contains long chain polyethylene glycol (PEG).
12 . The sustained release formulation of claim 1 , wherein the microenvironment of the polymer matrix has a non-physiological pH.
13 . The sustained-release formulation of claim 12 , wherein the microenvironment of the polymer matrix has a neutral pH.
14 . The sustained-release formulation of claim 1 , wherein the at least one agent has low solubility in water.
15 . The sustained-release formulation of claim 1 , wherein the at least one agent has a solubility in water greater than about 10 mg/ml.
16 . The sustained-release formulation of claim 1 , wherein the at least one agent is not ionized within the polymer matrix.
17 . The sustained-release formulation of claim 1 , wherein the polymer matrix is non-bioerodible.
18 . The sustained-release formulation of claim 1 , wherein the polymer matrix is bioerodible.
19 . The sustained-release formulation of claim 1 , wherein the polymer matrix is impermeable to peptides or proteins of about 10 kD or greater.
20 . The sustained-release formulation of claim 1 , further comprising a bio-adhesive or muco-adhesive coating covering at least a portion of said formulation.
21 . The sustained-release formulation of claim 1 , wherein the formulation is affixed to a living body.
22 - 55 . (canceled)
56 . A sustained-release formulation comprising:
a plurality of granules comprising a therapeutically effective amount of a codrug, and
a polymer matrix, wherein the polymer matrix is essentially non-release rate limiting with respect to the rate of release of the codrug from the matrix.
57 . A sustained-release formulation comprising:
a polymer matrix surrounded by physiological tissue, and
a plurality of granules comprising a therapeutically effective amount of a codrug dispersed in said matrix, wherein the granules have a surface area that is at least partially exposed to the surrounding tissue, and wherein the release rate of the codrug from the formulation is proportional to the exposed surface area of the granules.
58 . A sustained-release formulation comprising:
a plurality of granules comprising a therapeutically effective amount of a codrug having a form selected from I, Ia, II, IIa, III, and IIIa, below,
A 1 *(-L-A 2 *) n (I)
A 1 *(-A 2 *) n (Ia)
A 1 *-L-A 2 * (II)
A 1 *-A 2 * (IIa)
A 2 *-L-A 1 *-L-A 2 * (III)
A 2 *-A 1 *-A 2 * (IIIa),
Wherein A 1 * is a residue of a first biologically active compound A 1 ,
A 2 * is a residue of a second biologically active compound A 2 ,
L is a linking group selected from a direct bond and a divalent organic linking group, and
n is an integer having a value of from 1 to 4; and
a polymer matrix, coating the codrug, wherein at least one biologically active compound has a rate of release from the formulation that is limited primarily by the rate at which that biologically active compound dissolves into the matrix.
59 . The sustained-release formulation of claim 56 , wherein the codrug is in prodrug form.
60 . The sustained-release formulation of claim 1 , wherein the at least one granule has a diameter in the range of about 0.01 mm to about 3 mm.
61 . The sustained-release formulation of claim 60 , wherein the at least one granule has a diameter in the range of about 0.1 mm to about 2 mm.
62 . The sustained-release formulation of claim 61 , wherein the at least one granule has a diameter in the range of about 0.3 mm to about 1.5 mm.