Block and graft copolymers and methods relating thereto

Details Block and graft copolymers and methods relating thereto Block and graft copolymers and methods relating thereto

1995-06-07

2002-11-26

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic nonactive ingredient containing other...

Aftertreated solid synthetic organic polymer

C514S772600, C514S781000, C525S078000, C525S054210

Reexamination Certificate

active

06486213

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to block and graft copolymers, and more specifically, to block and graft copolymers which are effective in drug delivery, including copolymer-drug mixtures for the delivery and controlled release of a drug by topical application.
BACKGROUND OF THE INVENTION
The effective and efficient delivery of a therapeutic drug to a patient is a goal of pharmaceutical science. Targeted drug delivery, such as topical application of a therapeutic drug to a site of action, has many advantages over systemic drug delivery. Typically, adverse side effects associated with systemic delivery may be greatly reduced when a therapeutic drug is delivered locally to the site of action by topical administration. Therapeutic drugs which are systemically administrated are dispersed relatively non-selectively throughout the patient's body and metabolized, thus reducing their therapeutic effectiveness with respect to dosage, as well as increasing the likelihood of adverse reaction. In contrast, an effective dosage of a topically administrated therapeutic drug is often significantly less than that required through systemic administration. The diminution of dosage accompanying topical administration reduces the possibility of adverse reaction to the drug. In addition, drug metabolism of topically administered therapeutics is also minimized, thereby increasing their effectiveness.
While advantageous to systemic delivery, topical administration of a therapeutic drug is far from ideal. Perhaps the greatest single drawback to topical drug administration is the actual delivery of the therapeutic drug to the tissue to be treated. The absorption of the therapeutic drug by the tissue is often a slow process, and therefore requires a relatively long contact time between the tissue and the topical formulation containing the therapeutic drug. For example, topical administration of solutions of therapeutic drugs can be rather problematic. The use of viscous solutions, gels, ointments, lotions, patches, and inserts containing therapeutic drugs is a routine alternative to the administration of therapeutics in solution. These alternative formulations serve to enhance the contact time between the therapeutic drug and the tissue to be treated, thereby increasing the effectiveness of the topical treatment.
Ophthalmic drug delivery presents unique problems. Traditionally, eyedrops are the preferred mode of topical delivery of therapeutic drugs to the eye. Indeed, solutions of therapeutic drugs are routinely administered by this technique. However, it is well known that a major loss of drugs administered to the eye is via the lacrimal drainage system. This drainage is so effective that only a small fraction of the therapeutic drug remains in contact with the eye for any extended period of time. Consequently, topical delivery of therapeutic drugs to the eye via an eyedrop solution is relatively ineffective and requires repetitive treatments. The usual alternatives to the administration of solutions, such as the use of ointments and lotions to prolong tissue contact, are not particularly suitable for drug administration to the eye. Ointments and lotions are physically difficult to administer to the eye, and drug dosage is therefore difficult to control. The use of solid inserts has also been utilized to deliver therapeutic drugs to the eye. While this technique does assure a slow, effective release of the drug, patients often experience difficulty in placing and removing the insert into the cul-de-sac of the eye.
An alternative approach to ophthalmic drug delivery is the use of therapeutic drug formulations which are liquids at room temperature and which are transformed into gels upon warming through contact with tissue. These formulations, deliverable to the eye as liquid drops, may be readily dispensed and their dosage controlled. More significantly, once the liquid formulation is transformed into a gel on the surface of the eye, drainage of the therapeutic drug is retarded and its residence time on the eye is prolonged. The gelling of these formulations is attributable to polymer components which undergo solution-to-gel transitions in response to relatively small changes in environmental conditions (also called “triggers”), such as temperature or pH. Polymers which undergo solution-to-gel transition upon changes in temperature are often referred to as “thermally gelling polymers” or “temperature-sensitive polymers.” Similarly, polymers which undergo solution-to-gel transition as a result of a change in pH are generally referred to as “pH-sensitive polymers.”
Temperature-sensitive polymers which form gels upon warming undergo a solution-to-gel transition at their lower critical solution temperature (“LCST”), also referred to as the “cloud point.” The formation of the gel is believed to result from the gathering of portions of the temperature-sensitive polymers into hydrophobic micro-domains which are maintained in the aqueous gel phase by the hydrophilic portion of the polymer. Such temperature-sensitive polymers, although water soluble at low temperature, generally possess some hydrophobic character. The polymer's hydrophobic character is imparted by part of the monomer or repeat unit from which the polymer is derived. For example, poly(N-isopropylacrylamide) (“NIPAAm”) is well known to change its structure in response to temperature in aqueous solutions (see, e.g., Heskins et al.,
J. Macromol. Sci. Chem
. A2, 1441-45, 1968). At temperatures below the LCST of NIPAAm (i.e., 32° C.), polymer chains of NIPAAm hydrate to form an expanded structure, while at temperatures above the LCST the chains form a compact structure which excludes water. Thus, gel formation is due to the association of the relatively hydrophobic isopropyl groups of the NIPAAm polymer.
Temperature-sensitive polymers have been employed as vehicles for ophthalmic drug delivery. For example, block copolymers of ethylene oxide and propylene oxide have been disclosed in U.S. Pat. No. 4,188,373 for this purpose. However, in this system, the concentration of the polymer must be adjusted to provide the desired solution-to-gel transition temperature. The drawback to this system is that in order to achieve a solution-to-gel temperature suitable for gelling at body temperature, the polymer must be present at a relatively low concentration. Thus, the ability to obtain a gel with the desired properties is limited by the desired physiologically useful temperature range. The necessity for a low polymer concentration, in turn, limits the amount of drug that may be administered by such a polymer system.
Polymers which are sensitive to changes in pH, such as polyacrylic acid (“polyAAc”), have also been utilized to form gels in situ, including use as vehicles in ophthalmic compositions. For example, U.S. Pat. No. 4,888,168 discloses a composition containing the homopolymer polyAAc, and gel formation occurs upon the subsequent addition of an acidic component. Gel formation results in this case by an increase in viscosity associated with the protonation of the carboxylic acid groups at low pH. In water at neutral pH, the carboxy groups of polyAAc are ionized and the polymer is a liquid-in-water solution. Lowering the pH to 4.3-4.5 by the addition of an acid, such as citric acid, results in gel formation due to formation of H-bonded crosslinks between —COOH groups. An undesirable limitation of this system for use as an ophthalmic drug delivery vehicle is that gel formation requires sequential addition of two solutions (i.e., a first polyAAc solution and a second acid solution). In addition, the pH of such an acid solution is undesirable to the eye.
Due to the drawbacks of existing temperature-sensitive and pH-sensitive polymers to provide suitable vehicles for topical drug delivery, researchers have studied random copolymers containing these components for use as a vehicle for topical drug delivery. Such random copolymers, however, have not proved suitable for physiological application. In particular, random copolymers of te

Affiliated with

Also associated with

Rating

Block and graft copolymers and methods relating thereto does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Block and graft copolymers and methods relating thereto, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Block and graft copolymers and methods relating thereto will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2942411