United States Patent:   5,985,326

Assignee:  ICOS Corporation (Bothell, WA)

Filed:   February 6, 1998

Solid dispersions of poorly soluble drugs, such as (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-p yrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione and (+)-N-[1-(adamantanmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-be nzodiazepin-3-yl]-N'-phenylurea, methods of preparing the solid dispersions, and use of the solid dispersions in pharmaceutical compositions are disclosed.

SUMMARY DESCRIPTION OF THE INVENTION

The present invention relates to the field of solid dispersions of poorly water soluble drugs, to processes for their preparation and their use in pharmaceutical compositions. More particularly the present invention relates to solid dispersions in the form of co-precipitates of poorly water soluble drugs and their compositions with a pharmaceutically acceptable carrier or excipient therefor. Specifically, the invention relates to co-precipitates of (a) a potent and selective inhibitor of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) and (b) a potent and selective gastrin and CCK B antagonist, processes for the preparation of such solid dispersions, pharmaceutical compositions containing the same and their use thereof in therapy.

Co-precipitation is a recognised technique for increasing the dissolution of poorly water soluble drugs, such as griseofulvin, ketoprofen, sulphathiazide, spirinolactone, tolbutamide and nifedipine, so as to consequently improve bioavailability thereof. Techniques such as solvent deposition, lyophilization, solvate formation and solid dispersion (of which co-precipitation is an example as described above) have therefore been developed to try to overcome the problem of poor water solubility and resultant low bioavailability.

Solid dispersions in the pharmaceutical field are dispersions of one or more active ingredients, generally poorly water soluble drugs, in an inert carrier or matrix at solid state, which are prepared by either melting the two (fusion), or dissolving them in a solvent, or a combination of approaches, followed by removal of the solvent.

Manufacture of pharmaceutical dispersions by the above referred to melting or fusion technique, involves fusion of the two components where the drug and the carrier are allowed to melt at temperatures at or above the melting point of both the drug and carrier. In the fusion process, the drug and carrier are first blended and both melted in a suitable mixer. The molten mixture is then cooled rapidly to provide a congealed mass which is subsequently milled to produce a powder. The fusion process is technically simple provided that the drug and carrier are miscible in the molten state but this is not always the case and furthermore, the process is limited in that it tends to lead to drug decomposition due to the high temperatures required to melt the two components.

The solvent-based process uses organic solvents to dissolve and intimately disperse the drug and carrier molecules. Identification of a common solvent for both drug and carrier can be problematic, and complete solvent removal from the product can be a lengthy process. In addition, large volumes of solvents are generally required which can give rise to toxicological problems. The drug and carrier are typically dissolved in a solvent such as methylene chloride, acetone, ethanol and mixtures thereof and the solvent is later removed by precipitation techniques, evaporation or the like, while the drug/carrier solid dispersion is collected as a powdered mass.

In the case where there is difficulty with thermal instability and immiscibility between the drug and the carrier, the hybrid fusion-solvent method can be employed. The drug is first dissolved in a small quantity of organic solvent and added to the molten carrier. The solvent is then evaporated to generate a product that is subsequently milled to produce a powder. The pharmacokinetics, dissolution rates and processes for formulation of many different solid pharmaceutical dispersions is discussed at length in an article by Ford J., in Pharm. Acta. Helv. 61, 3; 69-88 (1986).

Co-precipitation techniques employ the use of an organic solvent or solvents to dissolve and intimately disperse the drug and carrier molecules as hereinbefore described. Separation of the drug and carrier from the solvent on precipitation can rely on the solubility properties of either the drug or carrier. For example, Simonelli et al, Journal of Pharmaceutical Sciences, Vol. 58, No. 5, May 1969, describes a co-precipitation process wherein sulfathiazole is dissolved in sodium hydroxide, followed by addition of polyvinylpyrrolidone; hydrochloric acid is then added to effect co-precipitation. This process is based on co-precipitation employing the solubility of the drug at different pH values. Such reliance on the solubility of the drug may be problematic in that it is not generally applicable to poorly water soluble drugs, as many such drugs do not exhibit a pH dependent solubility. Florence et al, Communications, J. Pharm. Pharmac., 1976, 28 601, describes co-precipitation of trifluoperazine embonate and the polymers poly DL-aspartic acid and polymethylmethacrylate. The co-precipitates were prepared by dissolving the drug and polymer in dimethylformamide and adding the solution to a rapidly stirred volume of water. Both polymers and drug are insoluble in water.

In general terms, problems which can be associated with known co-precipitation techniques can include excess solvent usage, identifying carrierldrug combinations which can be effectively precipitated and enhance bioavailability, the use of heat to effect solution which may detrimentally affect the drug, and the like. Co-precipitation techniques are however attractive for the preparation of solid dispersions, in that less solvents and heat are employed when compared to techniques such as co-evaporation and solvent removal may therefore be facilitated.

We have now developed a co-precipitation technique which alleviates the above described disadvantages associated with known techniques, and have also found that co-precipitation offers an advantageous preparation route for solid dispersions of poorly water soluble drugs.

There is therefore provided in a first aspect of the present invention a process of preparing a solid dispersion comprising a poorly water soluble drug or salts or solvates (e.g. hydrates) thereof, and a pharmaceutically acceptable carrier or excipient therefor, which process comprises:

(i) providing an intimate mixture comprising the carrier or excipient and a non-aqueous, water miscible solvent or combination of solvents, and optionally, water;

(ii) co-mixing the intimate mixture obtained in step (a) with a poorly water soluble drug; and

(iii) co-precipitating the poorly water soluble drug and the carrier or excipient.

As used herein, the term "intimate mixture" can denote a solution, suspension, emulsion, colloid, dispersion or the like. Generally, the term "intimate mixture" as used herein denotes a solution.

It has been found surprisingly that small amounts of water in the intimate mixture can aid dissolution of the subsequently added poorly water soluble drug. For example, a 10% ratio of water in a solvent may aid dissolution of the poorly water soluble drug.

In a further aspect, the invention describes a process of preparing a solid dispersion comprising a particular cGMP specific PDE (PDEV) inhibitor. More particularly, co-precipitation overcomes problems associated with other preparatory processes for formulating the subject PDEV inhibitor.

There is therefore provided by the present invention a process of preparing a solid dispersion comprising (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione (hereinafter referred to as Compound A) or salts or solvates (e.g. hydrates) thereof, and a pharmaceutically acceptable carrier or excipient therefor, which process comprises co-precipitating Compound A and the pharmaceutically acceptable carrier or excipient.

In a yet further aspect, the invention describes a process of preparing a solid dispersion comprising a particular gastrin and CCK-B antagonist. More particularly, co-precipitation overcomes problems associated with other preparatory processes for formulating the subject gastrin and CCK-B antagonist.

There is therefore provided by the present invention a process of preparing a solid dispersion comprising (+)-N-[1-(Adamantanmethyl)-2,4dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5benz odiazepin-3-yl]-N'-phenylurea (hereinafter referred to as Compound B) or salts or solvates (e.g. hydrates) thereof, and a pharmaceutically acceptable carrier or excipient therefor, which process comprises co-precipitating Compound B and the pharmaceutically acceptable carrier or excipient. The synthesis and use of Compound B has been previously described in WO93.14074.

Suitably the co-precipitation of Compound A or B comprises the steps of:

(a) providing an intimate mixture of a poorly water soluble drug selected from Compound A or Compound B, the carrier or excipient therefor and a non-aqueous, water miscible solvent or combination of solvents, and optionally, water; and

(b) co-precipitating the compound and the carrier or excipient.

It is generally advantageous in step (a) to first co-mix the carrier or excipient together with the solvent or solvents and optional water, thereby providing an initial intimate mixture, prior to addition of the poorly water soluble drug thereto. Subsequently, the drug can be added to the initial intimate mixture. Optionally, the carrier or excipient and solvent initial intimate mixture can be subjected to heating sufficient to facilitate dissolving of the former in the latter. Such a sequence of steps (also substantially as hereinbefore described according to the first aspect of the present invention) can be beneficial in allowing the employ of heat to effect dissolving, whilst obviating any detrimental affect by the heat on the drug.

A co-precipitation step, substantially as described in step (iii), or substantially as described in step (b), can aptly comprise adding the drug, carrier or excipient and solvent to a co-precipitation medium in which the carrier or excipient is insoluble. The resultant co-precipitate can be separated from the remaining components, suitably by filtering or the like, and the co-precipitate washed to remove residual solvent, and dried. The co-precipitate can then be formulated in a suitable pharmaceutical form employing known formulatory techniques, substantially as hereinafter described.

The carrier or excipient for the drug, and the co-precipitation medium, are respectively chosen so that the carrier or excipient is substantially insoluble in the co-precipitation medium. It is also advantageous that the carrier or excipient has selected dissolution properties in vivo; for example, the carrier or excipient may be such so as to dissolve rapidly (within about 15 to 60 minutes) in vivo, alternatively the carrier or excipient may be such so as to dissolve over a relatively prolonged period of time (typically, 2 to 4 hours) so as to achieve sustained release of drug in vivo.

Suitable carrier or excipients include pharmaceutically acceptable polymeric materials, typical examples being hydroxypropyl methyl cellulose phthalate, polymethylacrylate, hydroxypropyl cellulose and other like carrier or excipient materials. Particularly preferred is hydroxypropyl methyl cellulose phthalate as a carrier or excipient, and there is further provided by the present invention co-precipitates consisting of Compound A and hydroxypropyl methyl cellulose phthalate, and Compound B and hydroxypropyl methyl cellulose phthalate.

Aptly the co-precipitation medium comprises an aqueous medium, which is optimally such that the carrier or excipient is substantially insoluble therein as substantially hereinbefore described.

Conveniently the following combinations of carrier or excipient and co-precipitation medium can be employed in a process according to the present invention:

(a) in the case where the carrier or excipient is hydroxypropyl methyl cellulose phthalate, the co-precipitation medium is suitably a weakly acidic medium (pH in the range of 0.5 to 5.0, typically 0.8 to 2.0), typically 0.5N hydrochloric acid or acetic acid;

(b) in the case where the carrier or excipient is an acid soluble polymethylacrylate, the co-precipitation medium is suitably a neutral or basic medium, (pH in the range 6.0 to 13.0), water or dilute alkali being appropriate representatives of suitable co-precipitation media; and

(c) in the case where the carrier or excipient is hydroxypropylcellulose, an appropriate co-precipitation medium is again water, aptly with a temperature of greater than about 40^oC., such as 70 to 80^oC.

It is of course envisaged that other suitable combinations of carrier or excipient and co-recipitation media may be employed, as will be envisaged by a person skilled in the art. A particularly appropriate combination of carrier or excipient and co-precipitation medium, is hydroxypropyl methyl cellulose phthalate and a dilute acidic medium, substantially as hereinbefore described in point (a) above.

Appropriately, the solvent employed in a process according to the present invention is selected from the group consisting of acetone, methanol, dimethylacetamide, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, and combinations thereof, and optionaly, water, although other suitable solvents could be employed. Generally 9:1 acetone/water, 9:1 tetrahydrofuran/water, or 1:1 acetone/methanol mixtures are employed in a process according to the present invention.

There is still further provided by the present invention a solid dispersion consisting essentially of Compound A or Compound B and a pharmaceutically acceptable carrier or excipient therefor.

Claim 1 of 28 Claims

1. A process of preparing a solid dispersion comprising a poorly water soluble drug or salts or solvates thereof, and a pharmaceutically acceptable carrier or excipient therefor, which process comprises:

(a) providing an intimate mixture comprising: (i) the carrier or excipient and (ii) a neutral, nonaqueous, water miscible solvent or combination of solvents, and optionally, water;

(a) co-mixing the intimate mixture obtained in step (a) with a poorly water soluble drug to form a mixture; and

(c) co-precipitating the poorly water soluble drug and the carrier or excipient by admixing the mixture of step (b) and water having a pH of 0.5 to 13.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.