Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-03-20
2002-12-24
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S501000, C424S499000, C514S383000, C514S384000, C514S471000, C514S254070
Reexamination Certificate
active
06497905
ABSTRACT:
This invention relates to methods and formulations for improving the aqueous solubility of crystalline pharmaceutical compounds having low water solubility by converting them to an amorphous state that is stabilized in a granular pharmaceutical formulation. In particular, it relates to improving the aqueous solubility and bioavailability of azole antifungal medicaments by converting them to the amorphous state, stabilizing this state, and granulating them to form a stabilized granulation thereof. It also relates to pharmaceutical formulations prepared by such methods, to solid dosage forms prepared therefrom, and stabilized aqueous solutions thereof.
BACKGROUND OF THE INVENTION
Many crystalline, pharmaceutical compounds have very slight solubility in aqueous fluids such as those found in the human body. It is well known that changing a crystalline compound into its amorphous state will substantially increase the aqueous solubility of the compound, thereby increasing its bioavailability.
Methods which have been used heretofore to improve aqueous solubility of sparingly soluble active ingredients include inclusion complexation of the active ingredient with amorphous, chemically modified cyclodextrins. Although the active ingredient is not converted from the crystalline state to the amorphous state, the active ingredient/cyclodextrin complex improves solubility of the sparingly soluble ingredients.
In some cases it is possible to melt the crystalline active agent, holding it in the molten state for a finite time and then allow it to cool to an amorphous solid. This method is limited to particular active ingredients which can produce stable amorphous solids and which are not degraded by the heating step.
European patent publication 0852140 A1 discloses a method of converting a sparingly soluble medical substance to a more water-soluble amorphous state, in which a mixture of a sparingly water-soluble medical substance, an amorphous state inducing agent and an amorphous state-stabilizing agent, such as hydroxypropylmethylcellulose, is reported to be heated to a temperature at which the medical substance becomes amorphous.
A methylene chloride solution of an antifungal agent which is dissolution-induced dried by any of several methods, e.g., spray dried, initially at a slow rate and then at a higher rate, produces an amorphous powder of the active ingredient. This powder may then be compacted and dry granulated with excipients to be used in tablets or hard gelatin capsules.
In another procedure to produce amorphous antifungal agents, the agent and hydroxypropylmethylcellulose are dissolved in a methylene chloride/alkanol solution. This solution is then sprayed onto spheres such as sugar spheres in a fluidized bed. A seal coating is then applied to the coated spheres which may then be used to fill hard gelatin capsules.
In another procedure to form an amorphous solid dispersion, a sparingly soluble active agent has been combined with polyvinylpyrrolidone when both components are molten and then allowed to cool. This method reportedly produces a more rapid dissolution of the active agent in water.
A further method for stabilizing itraconazole in its amorphous state is through melt-extruding a mixture of itraconazole and a) water soluble polymer, as set forth in International Application PCT\EP97\02507.
The above methods appear to have varying degrees of success in improving the solubility of a sparingly soluble active agent. However, significant improvement in bioavailability also requires that the resulting solution of the active ingredient be stable. Without this stabilization, crystallization and precipitation of the dissolved active agent may occur, thereby reducing the bioavailability of the active agent that has not yet been absorbed into the patient's bloodstream.
SUMMARY OF THE INVENTION
In accordance with the present invention, improved solubility and bioavailability of a sparingly water-soluble, crystalline pharmaceutically active agent, such as itraconazole, involves melting a normally solid hydrophobic vehicle, such as glyceryl monostearate, dissolving therein a sparingly water-soluble, normally crystalline (that is a compound which is, prior to processing hereunder into its amorphous form, crystalline and sparingly water-soluble at ambient temperature pressure) pharmaceutically active agent at a temperature above the normal melting temperature of the vehicle but below the normal melting or degradation temperature of active agent, then granulating the molten product with a disintegrant and optional additives. In a first embodiment, a stabilizer is added to the molten solution prior to granulation. In a second embodiment the molten solution is granulated with a mixture of a-stabilizer and a disintegrant. In the first embodiment the granulation is preferably conducted in a cooled granulation bed to rapidly cool the stabilized product. In the second embodiment the granulation is conducted at elevated temperature and the resulting granulate is rapidly cooled following a brief granulation period. The resulting granular particles may then be milled to an appropriate particle size, and filled into capsules, or blended with other excipients and processed into solid dosage forms.
The resulting product of this invention thus comprises a granular formulation in which the granular particles comprise a solid solution of an amorphous pharmaceutically active agent which is normally crystalline and sparingly water-soluble at ambient temperature and pressure, dissolved in a molten solution of a pharmaceutically acceptable normally solid hydrophobic vehicle in which the active agent is soluble at elevated temperature; a stabilizing agent to stabilize the active agent in its amorphous state; a disintegrant; and optionally a binder, wherein the dissolved active agent is substantially stabilized in an amorphous state as a solid solution in said granular particles.
Thus a complete, ready-to-use granular formulation is provided in which the amorphous state of the active agent is stabilized for an extended period of time as a solid solution of the amorphous active in the matrix of the hydrophobic vehicle, thereby increasing the solubility and bioavailability of the pharmaceutically active agent when ingested and passing into aqueous media such as that found in the stomach and providing an extended shelf life for the granulation and products made therefrom.
DETAILED DESCRIPTION OF THE INVENTION
The novel formulations of this invention that are useful to solubilize sparingly water-soluble normally crystalline pharmaceutically active agents in aqueous media include a normally solid hydrophobic vehicle, one or more stabilizers, binders, and disintegrants. Basic to the solubilization of a normally crystalline active agent is the necessity of converting it to its amorphous state as a solid solution, and then stabilizing the amorphous state, thus preventing reversion to the crystalline state. The formulations of this invention accomplish this stabilization of the amorphous state of an active agent and maintain it for extended periods of time, providing an extended shelf life for the active agent during which it has improved solubility and bioavailability. A further, unexpected benefit of these formulations is the stabilization of solutions that are prepared from the granular formulations of the solubilized active agent. Such solutions are or may be essentially supersaturated with respect to the intrinsic solubility of the active ingredient, but stabilization in accordance with the present invention substantially prevents recrystallization from occurring.
The novel granular formulations of this invention thus comprise (a) a solid solution of a pharmaceutically active agent which is sparingly water-soluble its normal crystalline state; (b) a normally solid hydrophobic vehicle for said pharmaceutically active agent such that said vehicle is capable of dissolving said pharmaceutically active agent at a temperature above the melting point of said vehicle but below the normal melting point of s
Erkoboni David F.
Stergios Pamela R.
Vladyka, Jr. Ronald S.
Farley Patrick J.
Nguyen Helen
Nickey Donald O.
R.P. Scherer Technologies, Inc.
Webman Edward J.
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