United States Patent:  6,039,977

Assignee:  Alza Corporation (Palo Alto, CA)

Filed:  December 9, 1997

Pharmaceutical hydrogel formulations containing polyvinyl alcohol are provided. The formulations may serve as rug reservoirs in electrotransport drug delivery systems or passive transdermal systems, or they may be used in a variety of other types of dosage forms, e.g., capsules, suppositories, aerosols, and the like. With these formulations, there is virtually no syneresis encountered upon long term storage, an advantage that derives from selecting the quantity of polyvinyl alcohol in the gel to correspond to the polymer's degree of hydrolysis.

SUMMARY OF THE INVENTION

It is a primary object of the invention to provide a pharmaceutical polyvinyl alcohol hydrogel formulation which is stable to syneresis and accordingly can be stored for at least six months at a temperature in the range of 5^oC. to 40^oC., typically 20^oC. to 40^oC., with little or no liquid exuding from the gel.

It is another object of the invention to provide such a formulation in the form of a drug reservoir for electrotransport drug delivery.

It is still a further object of the invention to provide such a formulation in the form of a drug reservoir for passive transdermal drug delivery.

It is a further object of the invention to provide an electrotransport drug delivery device containing such a hydrogel drug reservoir.

It is yet a further object of the invention to provide a method for eliminating syneresis in a pharmaceutical polyvinyl alcohol hydrogel formulation, the method involving selecting a degree of hydrolysis and corresponding percent by weight of polyvinyl alcohol in the gel that is effective in forming a hydrogel which is stable to syneresis.

It is still another object of the invention to provide a method for making a pharmaceutical polyvinyl alcohol hydrogel formulation containing a therapeutically effective amount of drug, the method involving preparing an aqueous solution of a known amount of polyvinyl alcohol and a therapeutic amount of drug, freezing the solution, and thawing the frozen solution for a period of no longer than 5 hours. Another object of the invention provides a method suitable for preparing hydrogel formulations containing heat-labile drugs.

Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.

In one embodiment of the invention then, a pharmaceutical polyvinyl alcohol hydrogel formulation is provided which is stable to syneresis. The formulation involves the selection of a weight percentage of polyvinyl alcohol in the hydrogel to correspond to the degree of hydrolysis of the polyvinyl alcohol polymer.

A second embodiment of the invention provides a method of making the above formulation. The method entails dissolving a predetermined amount of polyvinyl alcohol in an aqueous liquid, combining the polymer solution with a therapeutically effective amount of drug, and gelling the solution by a freeze-thaw process in which thawing is conducted for a time period of 5 hours or less. The resultant hydrogel is mechanically strong and stable to syneresis. The formulation may be used to form a drug reservoir for passive transdermal drug delivery or for electrotransport drug delivery. Alternatively, the formulation may be combined with a pharmaceutically acceptable carrier suitable for other modes of drug administration. An alternative method for incorporating the drug into the hydrogel involves forming the gel in the absence of drug, removing the water, and hydrating the gel with an aqueous drug solution. This method is particularly useful for drugs and/or formulation additives that are heat-sensitive.

Claim 1 of 7 Claims

1. A method for eliminating or reducing syneresis in a pharmaceutical hydrogel formulation comprised of (a) a therapeutically effective amount of a drug in (b) a hydrogel comprised of water and polyvinyl alcohol having an average viscosity molecular weight between approximately 10,000 and 400,000, wherein the polyvinyl alcohol has a predetermined degree of hydrolysis D_h between approximately 95% and 99% and represents Y percent by weight in a range of approximately 10 wt. % to 30 wt % of the hydrogel, the method comprising

a. selecting Y and D_h to correspond to each other such that if D_h is greater than approximately 97.5% then Y is greater than or equal to approximately 5D_h -479 or if D_h is less than approximately 97.5% then Y is greater than or equal to approximately 4.16D_h -385;

b. preparing a solution of polyvinyl alcohol having the parameters selected from step a

c. subjecting said solution to at least a single-cycle freeze-thaw procedure if Dh is greater than approximately 97.5% or subjecting said solution to a multi-cycle freeze-thaw procedure if Dh is less than approximately 97.5%

which provides for a stable hydrogel and reduces or eliminates syneresis upon storage of the formulation for at least six months at a storage temperature in the range of approximately 5^oC. to 40^oC.

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