BACKGROUND OF THE INVENTION

A major difficulty encountered with many organic compounds, particularly those of higher molecular weight and/or those having relatively complicated formulas, such as, pharmaceuticals, is that they are highly insoluble in water. This places significant limitations on the potential uses of these materials. For example, for those organic compounds which are used for industrial purposes, normally, a wide variety of organic solvents can be used. However, such solvents often present problems from the standpoint of cost and/or environmental impact. As a result, normally associa¬ ted with the use of such organic solvents is the problem of their recovery so as to minimize the cost involved with their use, or their neutralization in the sense that the solvents no longer present an environmental or health hazard to humans or animals.

It is thus desirable that such compounds, rather than being utilized in organic solvents, be dissolved in water as the solvent. However, because of the nature of the organic compounds, it is often impossible to achieve a suffi¬ ciently high concentration of the organic material in water to facilitate the particular industrial use or chemical reaction desired.

This is particularly so with organic compounds which are used for agricultural purposes, such as, herbi-

SUEST' _. TUTE SHEET

cides, pesticides, and the like. Thus, such compounds are normally applied to the plants and/or the earth in which the plants are growing and the best means of transporting the material into the plant or the earth is through water trans¬ port. However, because of the insolubility of many of these compounds, it is necessary to formulate them into emulsions or dispersions, usually in the presence of appropriate sur¬ face-activating agents, e.g., surfactants, and the like. The formulation of such emulsions increases the expense and man¬ power in the utilization of these agricultural chemicals. In addition, very often the efficiency of transport into the ecological system is not as high as desired. The ability to dissolve compounds of this nature in water in high concentra¬ tions would represent a significant achievement in this area of use.

With respect to pharmaceutical compounds, water is, of course, the solvent of choice. Indeed, it is normally impossible to use organic solvents as carriers for pharma¬ ceuticals because of the toxicity associated with organic materials or solvents. Moreover, with pharmaceuticals which are used either for oral or injectable dosages, it is desired to have a higher rather than a lower concentration in water, since this decreases the particular amount of the material needed in any given dosage. Often, however, it is extremely difficult to obtain any significant or effective degree of

C Γ^'VT∑"^!"^^ cur:

solubility of such compounds in water so as to enhance their pharmaceutical efficacy.

In the past, it has been known that the use of a quatemized polymer could be used to increase the rate of dissolution of certain organic compounds in water. However, this art does not relate to an increase in solubility, but rather, only to an increase in the rate of dissolution. See L. M. Mortada, "Effect of A Quatemized Polymer and Urea on Dissolution Rate of Phenylbutazone from Solid State Disper¬ sion", Sci. Phar . 48, 241-247 (1980); O.I. Corregan, R.F. Ti ony and M.J. Whelan "The Influence of A Quatemized Po¬ lymer on the Dissolution and Bioavailability of Hydrochloro- thiazide", J.Phar. Pharmac. 28, 703 (1976); and R. Voight and D. Terborg, "Granulometric Determination of the Effect of PVP on Dissolution Rates of Sparingly Soluble Drugs", Pharmazie, 35, 311-312 (1980).

Numerous methods have been utilized for enhancing the solubility of complicated organic chemicals. For ex¬ ample, in U.S. Patent 3,673,163, a method is described for the use of a quatemized polymer having molecular weights in excess of 1,000 by coprecipitating the quatemized polymer with the drug Acronine. However, the increase in solubility obtained was only about 2.5 times the solubility of the com¬ pound. Such an increase in solubility for many of these com¬ pounds is not sufficient to render the use of the compound effective from a commercial or practical point of view.

SUBSTΪTL'TΞ SHΞΞT

Greater increases in solubility of highly insoluble organic compounds have been obtained as disclosed in applica¬ tion Serial Number 106,845, filed October 9, 1987. This has been accomplished by co plexing the organic compound with a solid homopolymer or copolymer of N-viny1-2-pyrrolidone having a molecular weight of greater than 1,000. In this method, a coprecipitation technique is used wherein solid N- vinyl-2-pyrrolidone and the organic compound are first dis¬ solved in a mutual organic solvent and the solution is sub¬ jected to a complexing reaction. Thereafter, the solvent is removed, leaving the water-soluble complex. However, in certain instances, specific organic compounds do not exhibit as high a water-solubility of the complex as might be de¬ sired. Moreover, the method requires several steps, one of which is the removal of the solvent.

This application and U. S. Patent 4,666,992, also generally disclose that the comonomers of N-vinyl-2-pyrroli- done can be quatemized and specifically discloses the use of a copolymer of vinylpyrrolidone and a quatemized dimethyl- a ino-ethyl methacrylate (Gafquat-734) to render D-threo- (1,1'-dihydroxy-1-p-nitrophenylisopropyl)dichloroacetamide soluble.

In addition, U.S. Patent application 161,881, filed February 29, 1988, discloses a method wherein rather than utilizing the co-precipitation technique, an aqueous solution technique is utilized. In this procedure, the organic com-

suBS7.τb Ξ sh'srr

pound is suspended in an aqueous solution of polyvinylpyr- rol- idone. The solution is then heated with stirring for a time to effect dissolution of the organic compound which can be observed visually. Upon cooling, the clear solution of the complexed organic compound can be used as is or, if desired, evaporated to produce a dry powder of the complex. This ap¬ plication discloses only the use of a homopolymer. It does not disclose the use of copoly ers, or quatemized copoly- mers.

The drugs indomethacin and piroxicam are well-known generic drugs which are considered to be highly insoluble in water. Indomethacin is a non-steroidal drug with anti-in¬ flammatory, antipyretic, and analgesic properties. It has been shown to be an effective anti-inflammatory agent appro¬ priate for long-term use in rheumatoid arthritis, ankylosing spondylitis and osteoarthritis, as well as other inflammatory diseases of this type. Piroxicam, similarly is indicated for rheumatoid and osteoarthritis.

SUMMARY OF THE INVENTION

We have discovered a method for substantially in¬ creasing the water solubility of indomethacin and piroxicam in the range of at least 25 times the solubility of indometh¬ acin alone as measured at 25 ^* C at atmospheric pressure. In¬ deed, we have discovered a method for increasing the solubil-

ity of indomethacin or piroxicam in many cases in excess of 100-times its original solubility.

In particular, this is accomplished by forming novel complex products from the reaction between indomethacin and a quatemized compound selected from the group consisting of copolymers of vinylpyrrolidone and dimethylaminoethyl methacrylate quatemized by diethylsulfate; stearylpyrroli- donium chloride; and olealkonium chloride. The complexes with these materials can be prepared utilizing a co-precipi¬ tation type method wherein the compound to be solubilized is dissolved in ethanol and added to a solution of the complex¬ ing material in ethanol. The resulting solution is evaporat¬ ed to provide a water soluble co-precipitate. In addition, we have discovered that indomethacin can also be solubilized utilizing the so-called aqueous solution method wherein the compound to be solubilized is heated in a solution of the quatemized compound in water for a period of time at an elevated temperature to provide a clear solution. This solution may then be used as is, or may be concentrated or completely evaporated to provide a solid complex.

In addition, we have discovered that piroxicam can be solubilized by either the co-precipitation method or the aqueous solution method, utilizing the quatemized copolymers of vinylpyrrolidone and dimethylaminoethyl methacrylate. The present invention provides a facile means for obtaining

^• fr—rr ewrr

water-soluble complexes of each of these materials which hitherto could not be obtained.

This is accomplished by forming a novel complex product from the reaction between the indomethacin or pir¬ oxicam and an aqueous solution of a solid quatemized polymer having a molecular weight greater than 1000 or an aqueous solution of a quatemized compound. The amount of a quater- nized solution and its concentration is adjusted merely to effect dissolution of the indomethacin or piroxicam. Thus, the concentration of the aqueous quatemized compound solu¬ tion is that which is effective to produce dissolution of the indomethacin or piroxicam. The indomethacin or piroxicam is suspended in the aqueous quatemized compound solution and is then heated with stirring at a temperature below the boiling point, e.g., approximately 45-85'C, for a time sufficient to effect dissolution of the indomethacin or piroxicam. This can be observed visually since when the solution is clear, the indomethacin or _^ piroxicam has been dissolved. There¬ after, the clear solution is allowed to cool to room temper¬ ature. This solution of the complexed indomethacin or pirox¬ icam can be used as is, or, if desired, the water can be evaporated or the solution spray-dried to produce a dry pow¬ der of the complex. The thus prepared aqueous solution or powder of the complex exhibits prolonged stability at ambient temperatures.

SUBSTITUTE SHEET

DESCRIPTION OF THE PREFERRED EMBODIMENT More particularly, the method of the present inven¬ tion can be carried out, in the case of indomethacin, by either the co-precipitation method or the aqueous method.

For the co-precipitation method, the complexes of indomethacin and piroxicam are prepared by dissolving the compound and the quatemized compound in an appropriate mutual solvent. Such mutual solvents can include alcohols, such as, Cj-C ₅ alcohols, and preferably, ethanol. Also suitable are carboxylic acids, such as, formic acid, acetic acid, and proprionic acid, ether alcohols, such as, glycol ethers, diethylene glycol, triethylene glycol, hexamethylene glycol, polyethylene glycol and 2,2'-thiodiethanol.

Other solvents may also be used, e.g., lactones, esters, ketones, chlorinated hydrocarbons, lactams, amides, and amines, as well as nitroparaffins. Normally, such materials would be less desirable from a commercial stand¬ point as much as they are generally more expensive than the first-mentioned solvents and, in the case of pharmaceuticals, must be completely removed from the solid material so that they are not present, except as undetectable trace amounts. The essential characteristic of the mutual solvent is that both the quatemized polymer and indomethacin or piroxicam must be highly soluble in the solvent chosen.

In certain instances, a salt of the water-insoluble compound can be formed in aqueous or alcoholic alkaline solu-

run

tion, e.g., NaOH containing water or KOH in ethanol. While such a solution is not a solvent in a theoretical sense, it serves the purpose of the present invention and is thus in¬ cluded within the definition of mutual solvents as used herein.

The process is carried out by first dissolving the quatemized polymer and the indomethacin or piroxicam to be complexed in the mutual solvent. This can be done separately followed by mixing of the two solutions or in the same solu¬ tion. Preferably, each of the solutions contains a concen¬ tration between about 5 to 25 weight % of the quatemized compound and the indomethacin or piroxicam. Most preferably, solutions of from about 8 to about 15% by weight of the com¬ ponents are preferred.

The solutions are then combined in a weight ratio of quatemized polymer to indomethacin or piroxicam of between about 1:1 and about 10:1, preferably, in a ratio of from about 4 to 7:1. The solutions are thoroughly mixed under atmospheric pressure or under a super atmospheric pressure up to about 50 psig at a temperature above 3*C and below the boiling point of the mutual solvent. Preferably, the temperature range would be between about 4*C and 100*c, and most preferably, between about 10*C and about 40*C. Of course, the temperature must be kept below that value which would result in deterioration or degradation of the indometh¬ acin, piroxicam, or the complexing compound. The mixture is

SUBSTITUTE SHEET

agitated under such conditions for a period of time from about 5 minutes to 3 hours and most preferably, between about 10 and 30 minutes in order to complete the complexing reac¬ tion.

After the completion of the reaction, the reaction mixture comprises a liquid phase which contains a complex. The solvent is then removed by conventional means, such as, rotary evaporation, freeze-drying, and the like. Rotary evaporation may be conducted in a vacuum, such as, under pressure of from about 2 to 40 mm Hg, and preferably, not more than 25 mm of Hg. These particular parameters depend upon the particular mutual solvent used as well as the nature of the insoluble organic component, the primary factor being that the conditions used must not deteriorate the organic compound. The remaining solids are recovered and dried in order to remove traces of the solvent.

The dried products may then be readily dissolved in water which produces the formerly insoluble organic compound in a highly dissolved state in aqueous solution.

In those instances where the mutual solvent is an aqueous or alkanolic alkaline solution, after drying, the product which is the salt, is placed in solution and the pH is adjusted to the neutral or acid side to produce the complex of the insoluble compound in solution, rather than in salt form.

SUBSTITUTE SHEET

Indomethacin and piroxicam may also be complexed utilizing the so-called aqueous method. In this case, the method is carried out by suspending the indomethacin or piroxicam in a solution of the quatemized polymer.

The amount of the solution in terms of its volume or weight relative to the weight of the indomethacin or pir¬ oxicam is that required to accomplish complexing. Generally, the concentration of a quatemized polymer in the aqueous solution is in the range from about 20% to 75%, preferably from about 35% to 65%, and most preferably from about 40% to 50%. A quatemized polymer having a weight average molecular weight in the range from about 2,500 to 1,100,000, and pref¬ erably, from about 2,500 to 49,000 is suitable for use in the invention. Most preferably, the molecular weight of the quatemized polymer is from about 2,500 to 27,000.

The suspension may be heated up to a temperature in the range from about 40 ^* C to 100*C, and preferably from about 60*C to 85*C. This is carried out with mechanical stirring, and the rate of heating, while not critical, is generally from about 0.05'C to 2.0 ^• C/minute, and preferably from about 1.0'C to 2.0*C/minute. After reaching the desired tempera¬ ture, it is maintained for a period of time to effect com¬ plete dissolution of the indomethacin or piroxicam which is observed visually. When the solution is clear, the indometh¬ acin or piroxicam has been completely dissolved. Normally, the period of time is from about 0.5 to 3 hours. The solu-

SUBSTITUTE SHEET

tion may be stirred during this heat treatment, i.e., during the period when the solution is maintained at a constant temperature.

Thereafter, the clear indomethacin or piroxicam/ quatemized polymer solution is allowed to cool to ambient temperature. Normally, this is accomplished by letting the solution cool at ambient temperature. More rapid cooling can be effected by refrigeration although the rate of cooling is not critical. Generally, however, it is desired to avoid rapid cooling since it may result in supercooling and preci¬ pitation of the complex. If a solid complex is desired, the solution may be evaporated to dryness or spray dried. Usually, when the solution is spray dried, it is first diluted to a concentration of about 15% by weight.

In an alternate method for the preparation of the complex of the present invention, the aqueous quatemized polymer solution is first heated to a temperature between about 40*C and 100'C^ and preferably from about 60*C to 85*c. The indomethacin or piroxicam is then gradually added to the hot aqueous quatemized polymer solution with constant stirring. The mixture is then maintained at the appropriate temperature with stirring until all of the indomethacin or piroxicam is dissolved and a clear solution is obtained.

Thereafter, the aqueous solution of the indometha¬ cin or piroxicam may be used as is. Alternately, the water may be removed, for example, by evaporation utilizing a

SUBSTITUTE SHEET

rotary evaporator, spray drying, or the like, to produce a dry powder of the complex. This can then be redissolved in water as desired.

In yet another embodiment of the invention, the indomethacin or piroxicam may first be dissolved in an organic solvent which is miscible with water, e.g., ethanol. This solution is then added to an aqueous solution of a qu¬ atemized polymer. The organic solvent is then removed by evaporation.

Examples illustrating the use of co-precipitation (method A) :

Example 1:

Indomethacin (0.2g) was dissolved in 20 ml ethanol and added to a solution of a quatemized copolymer of 80 mol % vinylpyrrolidone and 20 mol % dimethylaminoethyl methacry¬ late (Gafquat-734) 1.0g) in 20 ml ethanol. The resultant solution was rotary evaporated to give a water soluble copre- cipitate. The coprecipitate (1.2 g) could be dissolved in 1.8 g water. The latter quantity is limited by the viscosity of the Gafquat in the water solution.

Example 2:

Piroxicam ( 0.2 g) was dissolved in 20 ml ethanol and added to a solution of Gafquat-734 ( 2.0 g) in 20 ml

SUBSTITUTE SHEET

ethanol. The resultant solution was rotary evaporated to give a water soluble coprecipitate. The coprecipitate (2.2 g) could be dissolved in 1.8 g water. The latter quantity is limited by the viscosity of the Gafquat in the water solu¬ tion.

For method A, the criteria for solubilization was the ability of the coprecipitate to dissolve in water at the 1% and 5% drug levels at room temperature. The dissolution in each case was carried out at room temperature and the evaporation was carried out at about 50'C/O.l mm Hg.

The following examples illustrate the aqueous method (method B) of dissolving these compounds:

Example 3:

Indomethacin (0.2 g) was heated in a solution of Gafquat-734 (1 g) in 1 g water at 85*C for 1.5 hours to give a clear solution containing 9.1% (w/w) of the drug.

Example 4:

Piroxicam (0.2g) was heated in a solution of Gafquat-734 (1.6 g) in 1.6 g water at 85'C for 1.5 hours to give a clear solution containing 5.8% (w/w) of the drug.

_Λ^r - rr _S HEET

For method B, the criteria for solubilization utilizing the aqueous method was the achievement of the following results:

1. The appearance of a clear solution after heating the drug in an aqueous solution of the quate ized system at 85*C for 1.5 hours, and then standing at room temperature for at least 16 hours; and

2. The stability of the solution upon dilution of the concentrate with water at multiples of 4x and lOx of the original volume.

Utilizing the procedures outlined in Examples 1 through 4, the following quaternary systems were tested for their ability to solubilize indomethacin and piroxicam:

SUBSTITUTE SHEET

1. Merquat 100 (Dimethyldiallylammonium Chloride Homopolymer, Polyquaternium-6) (Calgon or Merck, 41.9% solution in water)

2. Merquat 280 (Dimethyldiallylammonium Chloride and Acrylic Acid Copolymer) (Goldschmidt or Merck, 39.5% solution in water)

3. Merquat 550 (Dimethyldiallylammonium Chloride and Acrylamide Copolymer, Polyquatemium-7) (Merck, 10.8% solution in water)

4. Maquat SC18-25% (Stearalkonium Chloride) (Mason, 25% active)

5. UCare Polymer JR-400 (Polymeric quaternary ammonium salt of hydroxyethyl cellulose reacted with a trimethyl ammonium substituted epoxide, Polyquater- nium-10) (Union Carbide)

6. Ammonyx KP (Olealkoniu Chloride) (Onyx, 33.1% solution in water)

7. Mirapol A-15 (Polyquaternium-2) (Miranol, 64.0% solids in water)

8. Onamer-M (Polyquatemium-1) (Onyx, 50% solids in water)

9. Surfadone QS-570 (Stearylpyrrolidonium Chloride) (GAF)

The results obtained with these series of materials are shown in Tables I and II.

SUBSTITUTE SHEET

TABLE I DISSOLUTION OF INDOMETHACIN IN QUAT SYSTEMS

Qua /Drug ouat Svstem Method Ratio (w/w) Q ser ations

Gafquat-734 A 5/1 Dissolution

Merquat 100 (Insoluble in Ethanol, Methanol, Acetone & Chloroform)

Merquat 280 (Insoluble in Ethanol, Methanol, Acetone & Chloroform)

Merquat 550 (Insoluble in Ethanol, Methanol, Acetone & Chloroform)

Maquat SC-25 A 10/1 No Dissolution 5/1 No Dissolution

UCare (Insoluble in Ethanol, Methanol, Acetone & Chloroform)

Ammonyx KP A 10/1 Dissolution 5/1 Dissolution

Onamer-M A 10/1 No Dissolution 5/1 No Dissolution

Surfadone QS -570 A 10/1 Dissolution 5/1 Dissolution

Mirapol A-15 A 10/1 No Dissolution 5/1 No Dissolution

Gafquat-734 B 5/1 Dissolution

Merquat 100 B 10/1 No Dissolution 5/1 No Dissolution

Merquat 280 B 10/1 No Dissolution 5/1 No Dissolution

Merquat 550 B 10/1 No Dissolution 5/1 No Dissolution

Maquat SC-25 B 10/1 No Dissolution 5/1 No Dissolution

UCare B 10/1 No Dissolution

5/1 No Dissolution

Ammonyx KP B 10/1 Dissolution 5/1 Dissolution

Onamer-M B 10/1 No Dissolution 5/1 No Dissolution

Surfadone QS 1-570 B 10/1 Dissolution 5/1 Dissolution

Mirapol A-15 B 10/1 No Dissolution 5/1 No Dissolution

SUBSTITUTE SHEET

TABLE II DISSOLUTION OF PIROXICAM IN QUAT SYSTEMS

Quat/Drug

Q tat Systgff Method Ratio (w/wϊ Observations

Gafquat-734 A 8/1 Dissolution Merquat 100 (Insoluble in Ethanol, Methanol, Acetone 6 Chloroform) Merquat 280 (Insoluble in Ethanol, Methanol, Acetone & Chloroform) Merquat 550 (Insoluble in Ethanol, Methanol, Acetone & Chloroform) Maquat SC-25 A 10/1 No Dissolution 5/1 No Dissolution

UCare (Insoluble in Ethanol, Methanol, Acetone & Chloroform) Ammonyx KP A 10/1 No Dissolution 5/1 No Dissolution

Onamer-M A 10/1 No Dissolution 5/1 No Dissolution

Surfadone QS-570 A 10/1 No Dissolution 5/1 No Dissolution

Mirapol A-15 A 10/1 No Dissolution 5/1 No Dissolution

Gafquat-734 B 10/1 Dissolution

8/1 Dissolution

Merquat 100 B 10/1 No Dissolution

5/1 No Dissolution

Merquat 280 B 10/1 No Dissolution

5/1 No Dissolution

Merquat 550 B 10/1 No Dissolution

5/1 No Dissolution

Maquat SC-25 B 10/1 No Dissolution

5/1 No Dissolution

UCare B 10/1 No Dissolution

5/1 No Dissolution

Ammonyx KP B 10/1 No Dissolution

5/1 No Dissolution

Onamer-M B 10/1 No Dissolution

5/1 No Dissolution Surfadone QS-570 B 10/1 No Dissolution

5/1 No Dissolution

Mirapol A-15 B 10/1 No Dissolution

5/1 No Dissolution

SUBSTITUTE SHEET