Title:  Stable complexes of poorly soluble compounds in ionic polymers

United States Patent:  6,350,786

Assignee:  Hoffmann-La Roche Inc. (Nutley, NJ)

Filed:  September 7, 1999

Stable water-insoluble complexes of poorly soluble compounds molecularly dispersed in water-insoluble ionic polymers are disclosed. Useful insoluble ionic polymers have a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50^o. The compounds are microprecipitated in the ionic polymers in amorphous form. The complexes according to the present invention significantly increase the bioavailability of poorly soluble therapeutically active compounds.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a stable water-insoluble complex composed of a water-insoluble ionic polymer carrier having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50^oC. and a therapeutically active compound in stable amorphous form. This invention also relates to methods of making such complexes and pharmaceutical formulations including such complexes. The advantage of the complexes of the invention include the ability to increase substantially the bioavailability of relatively insoluble therapeutically active compounds and the ability for delivery of such compounds for prolonged periods of time (that is, a sustained release of such compounds into the bloodstream).

As used herein, the following terms shall have the following meanings.

"Compound/polymer complex" or "water-insoluble complex" refer to a physically stable product that forms upon the concurrent precipitation ("microprecipitation") of a therapeutically active compound and a water-insoluble ionic polymer according to the methods described herein.

"Dispersed" means random distribution of a therapeutically active compound throughout an ionic polymer.

"Dissolution Rate" means the speed with which a particular compound dissolves in physiological fluids in vitro.

"Ionic polymer" or "ionic carrier polymer" includes both anionic (negatively charged) and cationic (positively charged) polymers.

"Microprecipitation" means any method by which a compound, in particular a therapeutically active compound, is molecularly dispersed in a polymer.

"Molecularly dispersed" means that the therapeutically active compound(s) is present in the polymer in a final state of subdivision. See, e.g., M. G. Vachon et al., J. Microencapsulation 14(3): 281-301 (1997); M. A. and Vandelli et al., J. Microencapsulation 10(1): 55-65 (1993).

"Patient" refers to a human subject.

"Poorly soluble therapeutically active compound" refers to therapeutically active compounds (e.g. drugs) having an aqueous solubility of less than about 1 mg/mL, often less than about 100 .mu.g/mL.

One aspect of the present invention pertains to pharmaceutical compositions comprising a stable water-insoluble complex composed of a carrier macromolecule that is an ionic polymer and a therapeutically active compound that is stable in its amorphous form. The use of such compound/polymer complex is particularly preferable when the compound is otherwise poorly soluble making it difficult to obtain desirable oral bioavailability of said compound.

According to the present invention, when poorly soluble crystalline therapeutically active compound and a water-insoluble ionic polymer having a molecular weight greater than about 80,000 D and a glass transition temperature equal to or greater than about 50^oC. are microprecipitated, the compound is molecularly dispersed in amorphous form, into the ionic polymer producing a stable, water insoluble complex. Microprecipitation may be accomplished, for example, by any one of the following methods, each of which is further described infra:

a) Spray Drying or Lyophilization Method

b) Solvent-Controlled Precipitation

c) pH-Controlled Precipitation

d) Hot Melt Extrusion Process

e) Supercritical Fluid Technology

Once the therapeutically active compound is so dispersed in the ionic polymer, it retains its amorphous structure even during long term storage, that is, it is "stable". In addition, the ionic polymer protects the compound from detrimental external environmental factors such as moisture and heat, thereby retaining increased solubility and consequent increased bioavailability.

A therapeutically active compound that is contained in a complex amorphous form according to the invention has significantly increase bioavailability in comparison to said compound in its crystalline form and is highly stable over a prolonged period of time. In addition, due to a controlled dissolution rate of the complex in the gastrointestinal fluids, the complex affords sustained release characteristics for the therapeutically active compound dispersed in the compound/polymer complex.

This invention is useful with any therapeutically active compound, but is especially useful for therapeutically active compounds having aqueous solubilities of less than about 1 mg/mL, and especially for compounds having less then 100 .mu.g/mL. Such poorly soluble therapeutically active compounds include, for example, retinoids and protease inhibitors. 

In its crystalline form, Compound I above has extremely poor aqueous solubility (<10 .mu./mL) and bioavailability.

This invention is also useful with the compound tolcapone (marketed by Roche Laboratories Inc. under the brand name Tasmar.RTM.), the compound 13cis-retinoic acid (commercially from available from Roche Laboratories Inc. under the brand name ACCUTANE.RTM.), the compound saquinavir (marketed by Roche Laboratories Inc. as FORTOVASE.TM.).

The ionic polymers suitable for use in accordance with this invention are either cationic or anionic polymers, have a molecular weight of above about 80,000 D, a glass transition temperature equal to or greater than about 50^oC., are relatively insoluble in water and preferably have pH-dependent solubility. Examples of such polymers include polyacrylates (e.g. Eudragit.RTM., Rohm America), chitosan, Carbopol.RTM. (BF Goodrich), polyvinyl acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropylmethyl cellulose phthalate, cellulose acetate terphthalate, hydroxypropyl methyl cellulose acetyl succinate, carboxy methyl cellulose and low substituted hydroxy propyl cellulose. The water-insoluble complexes according to present invention may also be comprised of mixtures of two or more above-described ionic polymers (see, e.g. Examples 9 and 10).

Particularly preferred anionic polymers include Eudragit.RTM. L100-55 (methacrylic acid and ethyl acrylate copolymer) and Eudragit.RTM. L100 or Eudragit.RTM. S100 (methacrylic acid and methyl methacrylate copolymers), all of which are available from Rohm America. Eudragit.RTM. L100-55 is soluble at a pH above 5.5 and practically insoluble at pH below 5.5. The molecular weight of Eudragite L100-55 is approximately 250,000 D and the glass transition temperature is 110^oC. Eudragit.RTM. L100 is soluble at pH above 6 and practically insoluble at pH below 6. The molecular weight of Eudragit.RTM. L100 is approximately 135,000 D and the glass transition temperature is about 150^oC. Eudragit.RTM. S100 is soluble at pH above 7 and practically insoluble at pH below 7. The molecular weight of Eudragit.RTM. S100 is approximately 135,000 D and the glass transition temperature is about 160^oC.

Particularly preferred cationic polymers include Eudragit.RTM. E (Rohm America), which is a copolymer of dimethylaminoethylmethacrylate and neutral methacrylic esters. This polymer is soluble up to pH 4 and is practically insoluble at a pH above 4. The molecular weight of Eudragit.RTM. E is approximately 150,000 D and the glass transition temperature is about 50^oC.

Pharmaceutical compositions of the present invention comprising the water-insoluable complexes of the invention may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, milling, encapsulating, dissolving, compressing, granulating, or lyophilizing processes. In addition to the water-insoluble complexes, these pharmaceutical compositions may also include therapeutically inert, inorganic or organic carriers ("pharmaceutically acceptable carriers"), other than the ionic polymer, and/or excipients. Pharmaceutically acceptable carriers for tablets, coated tablets, dragees and hard gelatin capsules include lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules include vegetable oils, waxes, fats, and semi-solid or liquid polyols.

The pharmaceutical compositions of the invention may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. These compositions may also contain additional therapeutically active compounds or more than one therapeutically active compound/polymer complex.

Claim 1 of 33 Claims

We claim:

1. A pharmaceutical composition comprising a carrier and a water-soluble complex of a therapeutically active, stable amorphous compound selected from the group consisting of 

and a water-insoluble ionic polymer that has a molecular weight greater than about 80,000 D, a glass transition temperature equal to or greater than about 50^oC. and is selected from the group consisting of polyacrylate, chitosan, carboxy vinyl polymers, polyvinly acetate phthalate, cellulose acetate phthalate, polycyanoacrylates, hydroxypropylmethyl cellulose phthalate, cellulose acetate terphthalate, hydroxypropyl methyl cellulose acetate succinate, carboxy methyl cellulose and low substituted hydroxy propyl cellulose, or a mixture of two or more above-described ionic polymers, wherein the therapeutically active compound is molecularly dispersed in the water-insoluble ionic polymer predominantly in amorphous form, as determined by powder X-ray diffraction, and is present in the resulting water-insoluble complex at not less than about 10%, by weight, and the water-insoluble ionic polymer is present in the water-insoluble complex at not less than about 20%, by weight.

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