Title:  Drug release from polymer matrices through mechanical stimulation

United States Patent:  6,748,954

Issued: June 15, 2004

Inventors:  Lee; Kuen Yong (Ann Arbor, MI); Mooney; David J. (Scio., Township, MI)

Assignee:  The Regents of The University of Michigan (Ann Arbor, MI)

Appl. No.:  983320

Filed:  October 24, 2001

Abstract

A method for drug delivery and polymer matrix suited to the method are disclosed. The polymer matrix has reversibly bound thereto a drug or combination of drugs, and is capable of releasing the drug or combination of drugs in response to mechanical stimulation of the polymer matrix. According to the method of this invention, such a polymer matrix is delivered to an in vivo locus, for example the site of a wound, trauma, etc., and mechanical stimulation of said polymer matrix is effected in vivo, thereby releasing the drug or combination of drugs in the area of the in vivo locus.

SUMMARY OF THE DISCLOSURE

The present invention relates to a polymer matrix composition, either naturally derived or synthetic, that is capable of releasing a desired drug or combination of drugs into a surrounding environment, including in vivo, when mechanically stimulated by any of a variety of mechanisms, including, without limitation, external loading and chemical signaling. The drug or combination of drugs are reversibly bound to the polymer matrix, so that release of the drug or combination of drugs from the polymer-matrix can be sustained over a period of time and is linked to the mechanical stimulation (e.g., compression, tensioning, etc.) of the polymer matrix. The invention is also directed to methods of drug delivery using the polymer matrix composition. Further aspects of the invention can be seen from reading the full disclosure, and the invention is not limited to specifically denoted aspects.

According to the method for drug delivery of this invention, a polymer matrix is provided having reversibly bound thereto a drug or combination of drugs, the polymer matrix being capable of releasing said drug or combination of drugs when the polymer matrix is mechanically stimulated; the polymer matrix can be delivered to an in vivo locus, including, by way of example, the site of a wound or trauma or disease or malfunctioning tissue in the body of an animal, including human, and mechanical stimulation, originating either outside of or within the animal body, is applied to the polymer matrix to effect release of the drug or combination of drugs in the area of the in vivo locus. As indicated, such mechanical stimulation can be effected by surrounding tissues, such as tensioning muscles, prompted by various chemical signals or other biological pathways. Alternatively, mechanical stimulation can be produced by external factors, for instance, external loading, electromagnetic signals, etc., that act directly on the polymer matrix, or that mediate mechanical stimulation of the polymer matrix by other means. As per one feature of this invention, feedback controlled external means can be employed to mediate the release of a drug or combination of drugs from the polymer matrices. This can take the form, for instance, of a patient-worn device adapted to produce a mechanical stimulation-inducing signal, such as an electromagnetic signal or chemical stimulant, conveyed to the locus of the polymer matrix to effect drug release directly or be mediating an internal mechanical stimulation.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to the disclosure as a whole, the present invention will be seen to relate to polymer matrix compositions containing a drug and methods for their employment; but not limited thereto. The inventive polymer matrix has reversibly bound thereto a drug or combination of drugs, the polymer matrix being capable of releasing the drug or combination of drugs when mechanically stimulated. By way of example, such mechanical stimulation may take the form of muscle tensioning in vivo in response to chemically mediated signal pathways, or mechanical stimulation induced by natural means (such as walking or running) or by external factors, for instance external loading, electromagnetic signals and low frequency ultrasound. Eternally generated stimuli are preferred since they can be controlled based on the design and development of external devices. Generally speaking, the polymer matrices of this disclosure may be subject to mechanical stimulation by any of a variety of means sufficient to effect the release of drugs, or a combination of drugs, therefrom, including compression and tensioning of in vivo and external origin, both directly applied and mediated by various means, including chemical signals, electromagnetic signals, repeated tensioning, use of shear force, electrical magnetic field and/or low frequency ultrasound can also be used. In one embodiment, the mechanical stimulation is provided by repeated compression of the polymer matrix composition. For example, the frequency of the repeated compression may be from 0.0001 to 100 Hz and the cycle of compression may be repeated 1 to 100 times per day. Preferably, the mechanical stimulation results in deformation of the polymer matrix, the extent of deformation preferably being equal to 1 to 50% of the original size, i.e., the matrix shrinks by 1% to 50% from the stimulation and then at least partially returns to its original size/shape. Elasticity of the matrix to the mechanical stimulation is preferred. As will be appreciated from the remainder of this disclosure, the degree and kind of mechanical stimulation applied to the polymer matrix in the method of this invention, and the mechanism for producing such stimulation, will depend upon considerations including the in vivo environment where the polymer matrix is provided and the drug release rate desired.

Polymers suited for use in the matrices of this invention include any polymers or copolymers capable of forming elastically deformable matrices that can bind a drug or combination of drugs through specific interactions, including, by way of non-limiting example, ionic bonding or secondary forces; such as hydrophobic bonding, hydrogen bonding or biological receptor binding. One type of biological receptor binding that is useful is ligand-receptor interactions. These polymers may be naturally or synthetically derived. In the particular embodiments described herein as exemplary of the present invention, the polymer matrices comprise three-dimensional alginate hydrogels. "Alginate," as that term is used here, refers to any number of derivatives of alginic acid (e.g., calcium, sodium or potassium salts, or propylene glycol alginate). A preferred example of useful polymers includes natural and synthetic alginates. See e.g., the disclosure of PCT/U.S. Ser. No. 97/16890 filed Sep. 19, 1997, for further description of useful alginate materials, which description is incorporated by reference here. Other hydrogel compositions can be employed which, like alginate hydrogels, form elastically deformable matrices, including, without limitation, chitosan, hyaluronate, collagen, gelatin, dextran, pullulan, poly(2-hydroxyethyl methacrylic acid), poly(N-isopropylacrylamide), poly(ethylene oxide), polyphosphazene, polypeptides, elastomers such as polyurethanes, other polysaccharides, and copolymers of these. Of course, those of skill will understand that other polymers, both naturally derived and synthetic, may be used as the matrices of this invention, according to the requirements of elasticity and drug bonding described herein.

In a preferred embodiment, the polymer matrix comprises an ironically cross-linked alginate. This is preferably of 5,000 to 500,000 daltons molecular weight and is cross-linked with Ca²⁺, Mg²⁺, Ba²⁺ and/or Sr²⁺, ions in a concentration, for example, of 0.1 to 0.5 M. The matrix may be present in the composition in an amount of 1 to 5% by weight.

The polymer matrices used can also be modified to enhance or modify their reversible binding to the drug(s). One way of doing this is to conjugate substances to the polymer matrix which provide biological receptor binding cites to reversibly bind certain drugs. Conjugation of heparin and heparin-like substances to the matrix are particularly useful for this purpose, for example, for providing reversible binding sites for growth factor drugs. Modification of the ionic properties of the matrix to enable or enhance reversible ionic binding to drug(s) having corresponding ionic properties for binding is also useful. Ionic binding between modified alginates as the matrix and anti-cancer drug(s) is one preferred embodiment.

The polymer matrix and its method of application is suitable for use with any drug or combination of drugs that reversibly bind the polymer composition of the matrix by specific interactions such as exemplified above. Preferred reversible binding is ironically or through secondary forces. As used herein, the term "drug" refers broadly to any chemical substance that produces a biological response, including, without limitation, conventional pharmaceuticals, growth factors, and w genetic material. Of course, the drugs or combinations of drugs to be employed will Ma depend upon the biological effect or effects it is desired to elicit. As used in this disclosure, the term "growth factor" refers broadly to any intercellular signaling, locally acting polypeptides that serve to control tissue development and/or maintenance, including, without limitation, platelet-derived growth factors, epidermal growth factors, fibroblast growth factors, insulin or insulin-like growth factors, transforming growth factors, nerve growth factors, and vascular endothelial growth factors (VEGF). Growth factors are a preferred drug for use in the invention, particularly (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP). Other drugs useful in the invention include proteins and anti-cancer drugs.

Claim 1 of 33 Claims

What is claimed is:

1. A polymer matrix composition which comprises a hydrogel polymer matrix having reversibly bound thereto at least one drug, wherein said polymer matrix deforms in shape and/or size and releases said at least one drug in response to mechanical stimulation of said polymer matrix.

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