United States Patent:  6,096,344

Assignee:  Advanced Polymer Systems, Inc. (Redwood City, CA)

Filed:  February 24, 1997

A composition for the sequestration and sustained delivery of an active ingredient in the form of porous particles, the composition comprising the product of the controlled dehydration of particles formed by the reaction of a polymeric anionic material with a polyvalent cation. The composition may be loaded with an active ingredient by soaking the particles in a solution of the active ingredient; and may then be dehydrated. They may then be soaked in a solution of a polymeric cationic material, to form particles providing the controlled release of the active ingredient.

BRIEF SUMMARY OF THE INVENTION

We have now discovered that if we prepare porous particles of a composition (such as calcium alginate microspheres) by dispersing a solution of a polymeric anionic material (such as sodium alginate or other polysaccharides bearing carboxyl functionalities) into a solution of a polycation (such as calcium chloride solution) and then dehydrate the particles by controlled dehydration (e.g. lyophilization), a highly porous bioerodible particle forms into which therapeutic agents can be diffused from an external solution. Once the diffusion process has been completed, the particles may again be dehydrated by controlled dehydration, and then coated with a polycatio. We have further discovered, that the amount of polycation used to coat the particles can control the release of an incorporated active ingredient within unexpectedly wide limits. In this way, crosslinked, polycation coated particles having a drug loading in excess of 50 wt % and that can release drugs in a controlled manner have been achieved.

It is an objective of this invention to provide porous bioerodible compositions for the sequestration and sustained delivery of active ingredients, which compositions are well tolerated by mammals and enable the sequestration and delivery of a greater amount of the active ingredient than prior art compositions. Accordingly, the invention provides macroporous compositions of ionically cross-linked polyanions and polycations into which more than 50 wt % of a water-soluble active agent can be incorporated and from which it can be released in a controlled manner.

Active agents can be introduced subsequently by diffusing the active agent into the porous compositions from an external aqueous solution. Because the active agent is never exposed to harsh experimental conditions or to organic solvents, biological activity is retained.

A preferred embodiment comprises macroporous bioerodible particles prepared from alginate and chitosan, which have been ionically crosslinked and thus have not undergone any changes that would alter their GRAS status. Although a number of experimental procedures can be utilized to prepare the compositions of the invention, a particularly advantageous method uses calcium alginate particles having a preselected size and size distribution which have been created by spraying sodium alginate into a calcium chloride solution and then lyophilizing to create a porous structure, stirring in a drug solution and then incubating in a chitosan solution.

Claim 1 of 36 Claims

1. A time-release delivery vehicle in the form of porous micropheres for the sequestration and sustained delivery of an active ingredient, the vehicle comprising the product of the controlled dehydration of microsperes formed by the reaction of a polymeric anionic material with a polyvalent cation.

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