Title:  Chemo-mechanical expansion delivery system

United States Patent:  5,935,593

Inventors:  Ron; Eyal S. (Lexington, MA); Roos; Eric (Grafton, MA); Schiller; Matthew E. (Waltham, MA); Orkisz; Michal (Brighton, MA); Staples; Anne (Newtonville, MA)

Appl. No.:  749758

System for delivery of a biologically active substance into an environment. First and second chambers are separated by a moveable partition. The first chamber includes a polymer gel network which undergoes a volume change in response to an environmental condition such as pH. The first compartment includes a screen or membrane for confining the polymer gel network while allowing communication with fluid in an environment. The second compartment contains a biologically active compound or drug which is delivered to the environment through an orifice in the second compartment. Upon the occurrence of the triggering environmental condition, the polymer gel network undergoes a volume change which moves the moveable partition expelling the drug through the orifice. Drug delivery is initiated and continues only when the appropriate environmental condition or trigger is met.

Summary of the Invention

The apparatus according to one aspect of the invention for controlled delivery of a biologically active compound to a biological environment includes first and second compartments separated by a moveable partition. The first compartment includes a screen or membrane forming at least a portion of a side of the first compartment. The first compartment contains a polymer gel network which undergoes a volume change in response to an environmental condition which may vary in the biological environment or which may be external to the environment. The second compartment contains an effective amount of a biologically active compound and includes an orifice communicating with the biological environment. When a preselected condition is encountered, the volume of the polymer gel network changes, causing the moveable partition to move to discharge the biologically active compound into the biological environment through the orifice. In a preferred embodiment, the selected environmental condition is pH. Other environmental triggers are temperature, electric fields, magnetic fields, electromagnetic radiation, light intensity and wavelength, pressure, ionic strength, solvent and osmolarity. It is preferred that the polymer gel network has a known acceptable toxicological profile (KATP). Preferred responsive polymer gel network materials include polysaccharide chains crosslinked with a multifunctional carboxylic acid obtainable from an acyl halide derivative of the acid. The preferred polymer chains are polysaccharides (e.g., starch or cellulose ethers) and the preferred multifunctional carboxylic acid is selected from the group consisting of adipic acid, sebacic acid, succinic acid, citric acid, 1, 2, 3, 4-butanetetracarboxylic acid, and 1, 10-decanedicarboxylic acid. Particularly preferred polymers are cellulose ethers selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. It is preferred that the gel exhibit substantially pressure independent volume changes at hydrostatic pressures in the range of 0.30-1.3 atmospheres.

The responsive polymer gel networks suitable for use in the apparatus of the invention may be responsive to any of a variety of triggers some of which have been set forth above. In particular, the pH-response may be triggered by a change in an environmental condition to which the gel is exposed, such as a change in ion concentration, solvent concentration, electric field, magnetic field, electromagnetic radiation, or mechanical force.

Methods for making crosslinked polymer networks include selecting a polymeric starting material capable of being crosslinked, wherein the polymeric starting material selected for the particular use has a known acceptable toxicological profile for the particular use or for a related use; selecting a crosslinker capable of crosslinking the polymeric starting material, wherein the crosslinker selected for the particular use has a known acceptable toxicological profile for the particular use or for a related use; and contacting the crosslinker and polymeric starting material under conditions sufficient to form the three-dimensional, crosslinked polymer network.

Another method involves selecting a crosslinker capable of crosslinking the polymeric starting material, so that the resulting network, after formation, contains a crosslinkage that has a known acceptable toxicological profile. Preferred methods include the steps of contacting a crosslinker comprising an acyl halide derivative of a multifunctional carboxylic acid with a polysaccharide under conditions sufficient for the three-dimensional, polymer gel network to form so that the gel network includes polysaccharide chains crosslinked with the acid. Particularly preferred methods use a polysaccharide selected from the group consisting of starch and cellulose ethers, which group includes, for example, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and modified food starch.

Preferred methods use a crosslinker that is an acyl halide derivative of a multifunctional carboxylic acid, such as, for example, an acyl halide derivative of adipic acid, sebacic acid, succinic acid, 1,2,3,4-butanetetracarboxylic acid, or 1,10 decanedicarboxylic acid. Other preferred methods use bifunctional crosslinkers such as, for example, divinylsulfone. Still other preferred methods utilize irradiation energy as a crosslinker.

The apparatus and system of the invention is thus a chemo-mechanical system in which the driving force is provided by the non-continuous expansion properties of the hydrogel. The hydrogels of the invention expand at a rate independent of water influx. The hydrogels of the invention may be submerged in water or other liquid and either remain collapsed or swell at their own rate but only upon the appropriate trigger. The delivery system of the invention can also be designed to cycle on and off. By first applying and then removing the trigger, the system would release the drug or stop the release by design and in a controlled fashion. The system of the present invention is also, within limits, independent of the hydrostatic pressure of the fluid in which the device is placed.

Claim 1 of 5 Claims

1. A method for controlled delivery of a biologically active composition to a biological environment comprising:

selecting a drug delivery apparatus comprising:

first and second compartments separated by a moveable partition, the first compartment including a screen or membrane forming at least a portion of a side of the first compartment, the first compartment containing a polymer gel network capable of a volume change in response to an environmental condition which varies in the biological environment,

the second compartment containing an effective amount of the biologically active compound and including an orifice communicating with the biological environment,

disposing the selected apparatus into a varying environment whereupon a change in environment causes a volume change in the polymer network thereby causing the biologically active compound to be delivered to the environment.

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