Title:  End modified thermal responsive hydrogels

United States Patent:  6,316,011

Assignee:  Madash, LLC (Lexington, MA)

Filed:  August 4, 1999

A pharmaceutic composition includes a pharmaceutically acceptable carrier, comprising a reverse thermally viscosifying polymer. The polymer includes a linear block copolymer, wherein at least one block comprises a poloxamer; and at least one block comprises a biocompatible polymer or oligomer, in an aqueous medium. The composition also includes an active agent which imparts a pharmaceutic or cosmetic effect. The composition viscosities in response to an environmental stimulus. The composition is suitable for administration of the pharmaceutical agent across dermal, otic, rectal, vaginal, ophthalmic, esophageal and nasal mucosal membranes.

SUMMARY OF THE INVENTION

The present invention provides compositions which possess improved flow and gelation characteristics. The composition is composed of biocompatible building blocks and includes a component capable of reversible gelation or viscosification. The composition demonstrates excellent bioadhesion and is useful in drug delivery applications.

The composition comprises a linear block copolymer including a polyoxyalkylene, such as poloxamer, end-modified by bioadhesive polymer, which may be poly(acrylic acid), or PAA, in an aqueous-based medium. The polymer is capable of aggregating in response to an increase in temperature.

In one aspect of the invention, the composition is capable of gelation or viscosification at very low solids content. In another aspect, the invention further provides compositions having a minimum solids content which are capable of sustained delivery of an active agent. The composition incorporates poloxamer:poly(acrylic acid) polymer as a carrier.

The present invention overcomes the limitations of the prior art by providing compositions that includes a linear block copolymer capable of bioadhesion and reversible gelation or viscosification upon exposure to the appropriate environmental stimulus.

The present invention further provides a composition for use in pharmaceutic or cosmetic formulations as a surfactant or emulsifier in the solubilization of additives and, in particular, hydrophobic additives, or as a stabilizer to provide stable emulsions at elevated temperatures, or as a suspension agent for otherwise insoluble additives.

New ways of delivering drugs at the right time, in a controlled manner, with minimal side effects, and greater efficacy per dose are continually sought by the drug delivery and pharmaceutical industries. The reversibly gelling polymer of this invention has the physico-chemical characteristics that make it a suitable delivery vehicle for conventional small chemical drugs as well as new macromolecular (e.g., peptides) drugs or therapeutic products. It is particularly well-suited for transmucosal delivery.

These and other aspects of the invention are described.

The reversibly gelling composition comprises a linear copolymer including a polyoxyalkylene component having a hydrophobic region and a hydrophilic region capable of aggregation in response to an environmental stimulus. The polyoxyalkylene is modified at each end by a polymer component to form a linear block copolymer. The polymer component is biocompatible and is selected to increase the molecular weight of the composition. The polymer component does not interfere with the aggregation properties of the polyoxyalkylene.

In a preferred embodiment of the invention, the polymer component possesses bioadhesive or mucoadhesive properties. In a particularly preferred embodiment of the invention, the polymer component includes a poly(vinylcarboxylic acid), such as poly(acrylic acid) and poly(methacrylic acid), and the like. In a preferred embodiment, the polyoxyalkylene comprises a poloxamer.

In another aspect of the invention, a pharmaceutical composition is provided which includes the reversibly gelling block copolymer of the invention and a pharmaceutic agent selected to provide a preselected pharmaceutic effect. A pharmaceutic effect is one which seeks to treat the source or symptom of a disease or physical disorder. Pharmaceutics include those products subject to regulation under the FDA pharmaceutic guidelines, as well as consumer products. In addition, the composition may include agents promote bodily attractiveness or masking the physical manifestations of a disorder or disease, in lieu or in addition to the treatment of a physical disorder. The same agent may have either a cosmetic or pharmaceutical effect, depending upon the amounts used and the manner of administration.

The block copolymer and pharmaceutical compositions of the invention exhibit many advantages. Due to the gelling effect at physiologically appropriate conditions, they possesses the appropriate thickness, emolliency and cosmetic effect with a minimum of solids content. Furthermore, as is described hereinbelow, the linear block copolymer composition may be useful as a suspending agent for otherwise insoluble additives. Additionally, the block copolymer and pharmaceutical compositions of the invention are capable of solubilizing emulsions at elevated temperatures.

In another aspect of the invention, the polyoxyalkylene:poly(acrylic acid) polymer is incorporated into a composition to stabilize and solubilize hydrophobic agents. The composition may be included to increase emulsion stability. Many emulsions, i.e., suspension of small droplets or particles of a first material in a second material, lose viscosity upon heating. The polyoxyalkylene:poly(acrylic acid) block copolymer composition retains its emulsifying properties even with temperature increase.

By "polyoxyalkylene" as that term is used herein, it is meant an oligomer or polymer of an oxyalkylene, or --O(CH₂)_n --, group, where n is in the range of 1 to 10 and where any H may be substituted for a linear or branched alkyl group. In preferred embodiments, n is 2 or 3, and is either unsubstituted or substituted by methyl group. The polyoxyalkylene component of the polymer possesses regions of hydrophobic character, e.g., poly(oxypropylene) blocks, and hydrophilic character, e.g., poly(oxyethylene) blocks in order to facilitate aggregation.

By "gelation" or "viscosification" as those terms are used herein, it is meant a drastic increase in the viscosity of the polymer solution. Gelation is dependent on the initial viscosity of the solution, but typically a viscosity increase at pH 7 and 1 wt % polymer concentration is in the range of preferably 2- to 100-fold, and preferably 5- to 50-fold, and more preferably 10- to 20-fold for a composition which is used in the preparation of the compositions of the invention. Such effects are observed in a simple polymeric solution and the effect may be modified by the presence of other components in the final composition.

By "reversibly gelling" as that term is used herein, it is meant that the process of gelation takes place upon an increase in temperature rather than a decrease in temperature. This is counter-intuitive, since solution viscosity typically decreases with an increase in temperature.

By "end-modified", as that term is used herein, it is meant that the polyoxyalkylene component is modified at its termini by chemical conversion and/or addition to the component. This in contrast to modifications which may occur along the backbone of the polyoxyalkylene.

By "use conditions" as that term is used herein it is meant all conditions to which the composition is likely to be exposed during its use, including during shipment and storage as well as during medical treatment or personal care.

The novel interaction between the constituent polymers components of the reversibly gelling composition permits formation of gels at very low solids content. Gelation and/or viscosification is observed in aqueous solutions having about 0.01 to 20 wt % of the polyoxyalkylene component and about 0.01 to 20 wt % of the end-modifying polymer component. A typical reversibly gelling composition may be comprised of about 0.01 wt % to about 1 to 8 wt %, preferably less than about 4 wt % of total polymer solids (e.g., polyoxyalkylene and biocompatible polymer), and more preferably less than 1 wt % total polymer solids, while still exhibiting reverse thermal viscosification. Of course, the total solids content of the composition, including additives and the pharmaceutic agent, may be much higher.

The relative proportion of polyoxyalkylene polymer and end-modifying polymer may vary in the composition, dependent upon the desired properties of the composition. Exemplary polymer compositions range from about 1:10 to about 10:1 polyoxyalkylene polymer:bioadhesive polymer. In one embodiment, the polyoxyalkylene component is present in a range of about 1 to 20 wt % and the end-modifying polymer is present in a range about of 99 to 80 wt %. In another embodiment, the polyoxyalkylene polymer component is present in a range of about 21 to 40 wt % and the polymer component is present in a range of about 79 to 60 wt %. In another embodiment, the polyoxyalkylene polymer component is present in a range of about 41 to 50 wt % and the polymer component is present in a range of about 59 to 50 wt %. In another embodiment, the polyoxyalkylene polymer component is present in a range of about 51 to 60 wt % and the polymer component is present in a range of about 49 to 40 wt %. In yet another embodiment, the polyoxyalkylene polymer component is present in a range of about 61 to 90 wt % and the polymer component is present in a range of about 39 to 20 wt %. In another embodiment, the polyoxyalkylene polymer component is present in a range of about 81 to 99 wt % and the polymer component is present in a range of about 19 to 1 wt %. A 50:50 mixture of poloxamer and poly(acrylic acid) has been demonstrated to provide the desired thermoviscosifying effect under most circumstances.

The reversibly gelling polymer described above may be included in a composition as a delivery vehicle for an active agent. In addition, the reversibly gelling composition may be included to improve the flow characteristics, thickness and other properties of the composition.

In one aspect of the invention, the reversibly gelling composition is incorporated into a composition to impart thickening properties to the composition at the use and/or application temperature. Such thickening properties include enhanced overall viscosity, as well as a desirable viscosity response with temperature. The composition may be useful as a thickener in pH ranges where other thickeners are not effective.

In another aspect of the invention, the reversibly gelling composition is incorporated into a composition to stabilize and solubilize hydrophobic agents in the composition. The reversibly gelling composition may be included to increase emulsion stability. Many emulsions (a suspension of small droplets or particles of a first material in a second material) lose viscosity upon heating. The reversibly gelling composition retains its emulsifying properties even at elevated temperatures.

In addition, the reversibly gelling composition may be included in the composition to impart emolliency to the composition. The composition may also act as a film-forming agent after it has been applied to the skin or other mucosal membrane. This film-forming agent may be used as a barrier to prevent water loss from the skin which contributes to the moisturization of the skin. The formed-film could also provide protective coating ("band-aid") to protect the tissue against environmental challenge(s) or to provide a mechanical separation between to adjust tissues (adhesion prevention).

In addition, it may be included in the composition to impart emollience to the composition. The composition may also act as a film-forming agent after it has been applied to the skin. This film-forming agent may be used as a barrier to prevent water loss from the skin which contributes to the moisturization of the skin.

Claim 1 of 41 Claims

What is claimed is:

1. A reverse thermally viscosifying composition comprising:

a linear block copolymer comprising:

at least a first polyoxyalkylene block having a hydrophobic region and a hydrophilic region effective to form micclles in solution in response to a change in temperature, and

at least a second block comprising a bioadhesive polymer or oligomer,

wherein the linear block copolymer is dispersed in an aqueous medium and the composition reversibly viscosifiers at a temperature in the range of 22 to 40^oC.

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