WO2000076507A1

WO2000076507A1 - Method for increasing the solubility of morphine and pharmaceutical compositions prepared therefrom

Info

Publication number: WO2000076507A1
Application number: PCT/US2000/014662
Authority: WO
Inventors: Charanjit R. Behl; Ramneik Dua; Malini Gupta; Parvin Rahman; Vincent D. Romeo
Original assignee: Nastech Pharmaceutical Company, Inc.
Priority date: 1999-06-16
Filing date: 2000-05-26
Publication date: 2000-12-21
Also published as: AU6046900A

Abstract

Methods are disclosed for increasing the solubility of morphine through the use of organic acid or its salts as a solubilizing agent. Particularly useful as solubilizing agents are salts of carboxylic acids, such as gluconate, acetate, citrate, lactate, tartrate, aspartate, fumarate, malate, maleate, succinate and combinations thereof. Pharmaceutical compositions containing morphine, and organic acids or its salts as solubilizing agents, are also disclosed.

Description

METHOD FOR INCREASING THE SOLUBILITY OF MORPHINE AND PHARMACEUTICAL COMPOSITIONS PREPARED THEREFROM

BACKGROUND OF THE INVENTION

The present invention relates to methods for increasing the solubility of pharmaceutical agents, and pharmaceutical compositions prepared therefrom. Specifically, the present invention relates to methods for increasing the solubility of morphine, and pharmaceutical compositions containing morphine prepared therefrom.

The compound morphine or (-)7,8-didehydro-4,5α-epoxy-17- methylmorphinan-3,6α-diol, is a phenanthrene derivative that exhibits the following general structure:

Morphine is a centrally acting narcotic analgesic that acts as an agonist primarily at mu, kappa and perhaps delta receptors in the central nervous system. By acting on these receptors, morphine causes analgesia and anesthesia as a result of a receptor-mediated central action on pain perception, together with a receptor- medicated modulatory effect on the central transmission of noxious sensation. Some side effects caused by morphine include drowsiness, respiratory depression and euphoria.

Various morphine compositions are known in the pharmaceutical arts. For example, morphine compositions such as morphine tartrate and morphine lactate are disclosed in U.S. Patent No. 5,880,132 issued to Hill and U.S. Patent No. 5,378,474 issued to Morella et al. for the treatment and prevention of pain or nociception. Some

I polar compositions of morphine including morphine-3-glucuronide and morphine-6- glucuronide are disclosed in U.S. Patent No. 5,629,011 issued to Ilium. While these references discuss different pharmaceutical compositions of morphine, none disclose methods for increasing the solubility of morphine and compositions containing morphine prepared therefrom.

Morphine has been used for a variety of clinical indications. Some examples of such indications include analgesia, for treatment of acute and chronic pain, anesthesia during surgery and to allay anxiety during acute pulmonary edema.

Several delivery routes have been utilized for administering morphine. These routes include oral, rectal, injectable and buccal administration. For example, oral and injectable morphine sulfate are commonly prescribed for cancer pain. Oral and injectable morphine sulfate are available from Abbott Pharmaceuticals Inc., USA., as well as other companies. Other routes of administering morphine, or its salts, have not been utilized because liquid pharmaceutical compositions having an adequate concentration of morphine have not been developed. The failure in developing such compositions is due to low solubility of morphine, and its salts, in pharmaceutically acceptable solvents. For example, in Remington: The Science and Practice of Pharmacy, 19th edition, Volume II, 1995, morphine sulfate is listed as being considered to be very slightly soluble in water, chloroform or ether, and only slightly soluble in alcohol.

Other more desirable delivery routes have been investigated. For example, intranasal delivery of morphine has shown potential for rapid onset and duration of action. Further, intranasal administration offers minimal delays in absorption, is not as invasive as intravenous delivery and achieves therapeutically effective amounts of the drug in plasma. For example, intranasal delivery of morphine is disclosed in U.S.

Patent No. 5,629,011 issued to Ilium and U.S. Patent No. 4,464,378 issued to Hussain for the treatment of chronic and acute pain. The entire disclosures of U.S. Patent Nos. 5,629,011 and 4,464,378 are hereby incorporated by reference. While these references discuss the benefits of intranasal delivery of morphine, there is no consideration of methods of improving the solubility of morphine.

It should be noted that the solubility of morphine sulfate in water and other known solubilities are not high enough to produce formulations of desired concentrations. Thus, there is a need in the art for a method of increasing the solubility of morphine, and its salts, in pharmaceutically acceptable solvents.

Accordingly, it is one of the purposes of the present invention, among others, to provide methods of increasing the solubility of morphine, especially its salts such as morphine sulfate, in pharmaceutically acceptable solvents.

SUMMARY OF THE INVENTION

It has now been discovered that these and other purposes can be achieved by the present invention which provides methods for increasing the solubility of morphine in a pharmaceutically acceptable solvent. The methods include admixing in the solvent, morphine and a solubilizing effective amount of an organic acid or its salt. Morphine used with the methods of the present invention is preferably in the form of a salt, such as morphine sulfate. The amount of morphine admixed in the solvent with the solubilizing effective amount of the organic acid or its salt, is an amount that provides a morphine concentration of at least about 2 mg/mL to about 104 mg/mL. The solvent is preferably a polar solvent such as water. Alternatively, more than one solvent can also be utilized.

The organic acid or its salt is, preferably, a carboxylic acid or its salt. Carboxylic acids that can be utilized with the methods of the present invention include gluconic acid, acetic acid, lactic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, citric acid and combinations thereof. Carboxylic acid salts that can be utilized with the methods of the present invention include gluconate, acetate, citrate, lactate, tartrate, aspartate, fumarate, malate, maleate, succinate and combinations thereof. Preferred carboxylic acid salts include calcium gluconate, sodium acetate, sodium citrate dihydrate, sodium gluconate, sodium lactate, potassium sodium tartrate, ammonium acetate, sodium aspartate, sodium fumarate, sodium malate, sodium succinate, sodium tartrate and combinations thereof. The amount of the organic acid or its salt utilized is preferably an amount that provides the solution with a concentration of at least about 0.1% (1.0% = 1 gram/lOOcc) to about 50.0% of the organic acid or its salt.

The present invention also provides for liquid pharmaceutical compositions for administering morphine to a mammal having improved solubility. The compositions include a pharmaceutically acceptable solvent having morphine and a solubilizing effective amount of an organic acid or its salt. Preferably, morphine is in the form of a salt, such as morphine sulfate. The amount of morphine in the composition is an amount that provides a morphine concentration in the composition of at least about 2 mg/mL to about 104 mg/mL. The solvent is preferably a polar solvent such as water. Alternatively, the solvent can include a mixture of pharmaceutically acceptable solvents.

The organic acid or its salt of the pharmaceutical compositions of the present invention is preferably a carboxylic acid or its salt. Carboxylic acids that can be utilized with the present invention include gluconic acid, acetic acid, lactic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, citric acid and combinations thereof. Carboxylic acid salts that can be utilized with the present invention include gluconate, acetate, citrate, lactate, tartrate, aspartate, fumarate, malate, maleate, succinate and combinations thereof. Preferred carboxylic acid salts include calcium gluconate, sodium acetate, sodium citrate dihydrate, sodium gluconate, sodium lactate, potassium sodium tartrate, ammonium acetate, sodium aspartate, sodium fumarate, sodium malate, sodium succinate, sodium tartrate and combinations thereof. The compositions of the present invention are particularly suitable for the nasal administration of morphine and its salts, to a mammal. Advantageously, as a result of the present invention, morphine and its salts can now be solubilized in pharmaceutically acceptable solvents at concentrations previously unattainable. The ability to solubilize morphine in a solvent facilitates the utilization of drug delivery routes that previously could not effectively be utilized. Thus, the present invention also advantageously provides liquid pharmaceutical compositions having an adequate concentration of morphine.

These and other advantages of the present invention will be appreciated from the detailed description and examples which are set forth herein. The detailed description and examples enhance the understanding of the invention, but are not intended to limit the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention have been chosen for purposes of illustration and description, but are not intended in any way to restrict the scope of the invention. The preferred embodiments of certain aspects of the invention are shown in the accompanying drawings, wherein:

FIG. 1 is a graph showing the solubility of morphine sulfate as a function of calcium gluconate in water at a pH of 5.5;

FIG. 2 is a graph showing the solubility of morphine sulfate as a function of sodium acetate in water at a pH range of 5.6 - 6.0;

FIG. 3 is a graph showing the solubility of morphine sulfate as a function of sodium citrate dihydrate in water at a pH range of 6.0 and 6.6;

FIG. 4 is a graph showing the solubility of morphine sulfate as a function of sodium gluconate in water at a pH of 3.0 and a pH range of 5.6 - 6.0; FIG. 5 is a graph showing the solubility of morphine sulfate as a function of sodium lactate in water at a pH of 3.0 and a pH range of 5.7 - 7.2;

FIG. 6 is a graph showing the solubility of morphine sulfate as a function of potassium sodium tartrate in water at a pH range of 5.5 - 6.8;

FIG. 7 is a graph showing the solubility of morphine sulfate as a function of ammonium acetate in water at a pH range of 5.6 - 6.1 ;

FIG. 8 is a graph showing the solubility of morphine sulfate as a function of sodium aspartate in water at a pH range of 5.5 - 6.2;

FIG. 9 is a graph showing the solubility of morphine sulfate as a function of sodium fumarate in water at a pH range of 5.4 - 6.9;

FIG. 10 is a graph showing the solubility of morphine sulfate as a function of sodium malate in water at a pH range of 5.8 - 7.2;

FIG. 11 is a graph showing the solubility of morphine sulfate as a function of sodium succinate in water at a pH range of 5.8 - 6.3; and

FIG. 12 is a graph showing the solubility of morphine sulfate as a function of sodium tartrate in water at a pH range of 5.2 - 5.6.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for methods for increasing the solubility of morphine in pharmaceutically acceptable solvents. The methods include the step of admixing in the solvent a solubilizing effective amount of an organic acid or its salt, and the morphine. It has been unexpectedly found that through the use of an organic acid or its salt, the solubility of morphine in a pharmaceutically acceptable solvent is dramatically increased. As is well known in the art, moφhine and its salts are very slightly soluble in pharmaceutically acceptable aqueous solvents. This has, in turn, prevented the formulation of liquid pharmaceutical compositions containing an adequate concentration of moφhine.

By reference to moφhine, reference is also made to the various salts of moφhine and, in particular, moφhine sulfate. The amount of moφhine to be utilized in the methods of the present invention is preferably an excess amount. A detailed description of the concentrations of moφhine suitable for the pharmaceutical compositions of the present invention will follow.

As previously described, a solubilizing effective amount of an organic acid or its salt is utilized to increase the solubility of moφhine in the solvent. By reference to a "solubilizing effective amount," reference is made to any amount of an organic acid or its salt utilized to increase the solubility of moφhine over the solubility exhibited by a control composition, at a comparable pH, that does not contain the organic acid or its salt. Preferably, the solubilizing effective amount of the organic acid or its salt is an amount that provides the composition with a solubilizing agent concentration of at least about 0.1% to about 50.0% of the organic acid or its salt. The actual concentration of the organic acid or its salt utilized will vary with the amount of moφhine to be solubilized and with the selection of the organic acid or its salt as the solubilizing agent. It will also depend upon the solubility of the solubilizing agent itself.

It is contemplated that any pharmaceutically acceptable organic acid or its salt can be utilized as the solubilizing agent in the present invention. A preferred class of such solubilizing agents is carboxylic acids or their salts. Carboxylic acid salts that can be utilized in accordance with the present invention include, but are not limited to, acetate, gluconate, ascorbate, citrate, fumarate, lactate, tartrate, malate, maleate, succinate and combinations thereof. Of these carboxylic acid salts, acetate, tartrate and gluconate are preferred. In some circumstances, the desired organic acid salt may not be available in a United States Pharmacopeia (USP) grade. An alternative, therefore, is to utilize the acidic form of the salt in the preparation of the composition and subsequently adjust the pH of the composition to form the salt in situ. For example, in order to provide sodium maleate in situ, one can utilize maleic acid (of USP grade) in the preparation of the composition and subsequently adjust the pH, e.g., with sodium hydroxide.

While not wishing to be bound by theory, it is believed that the organic acid or its salt can interact with moφhine to form an ionic entity in situ, which in turn dramatically increases the solubility of the moφhine. Such ionic interactions are considered weak and reversible, and are not predictable.

Solvents to be utilized in accordance with the present invention include any solvent system, as long as it is pharmaceutically acceptable. The solvent preferably is a polar solvent, since it is believed that the polar nature of the solvent will facilitate the ionic interactions between the organic acid or its salt and the moφhine. Preferably, the polar solvent is water. Combinations of solvents can also be utilized in accordance with the present invention. Combinations of solvents can include combinations of polar solvents, combinations of non-polar solvents, and combinations of polar and non-polar solvents.

As previously described, the organic acid or its salt and moφhine are admixed in the solvent. The mixing of the components can be accomplished by any suitable means. Conventional means of dissolving the pharmaceutical components can be utilized. For example, the components can be stirred, sonicated, shaken or vortexed. The amount of time necessary to facilitate a complete dissolution of moφhine in the solvent will vary with the amount of moφhine utilized, the selected organic acid or its salt and the selected solvent. Typically, a time period of 24 hours is generally adequate. Longer times may be needed to achieve saturation solubilities. These parameters can be easily determined by one skilled in the art. The present invention also provides pharmaceutical compositions for administering moφhine to a mammal. The compositions include a pharmaceutically acceptable solvent having moφhine and a solubilizing effective amount of an organic acid or its salt.

The compositions of the present invention can be delivered to a mammal by a variety of administration routes. These include, but are not limited to, nasal, oral, sublingual, buccal, transdermal, rectal, ocular, intramuscular, intravenous, intraventricular, intrathecal and subcutaneous routes.

One preferred method of administering the pharmaceutical compositions of the present invention to a mammal is by nasal administration. Nasal administration is believed to avoid the so-called "first pass" effect, in which the orally administered moφhine is first circulated through the liver where a significant portion of the moφhine is metabolically inactivated. Thus, the nasal administration of moφhine can allow a lower dosage of moφhine to be utilized to achieve the same therapeutic effect as higher dosages of moφhine via other administration routes.

The concentration of moφhine necessary will vary by the route of drug administration, the frequency of dosing, the amount of moφhine delivered per dose, and the age and weight of the subject. As would be apparent to those skilled in the art, other factors can also affect the concentration of moφhine.

The pharmaceutical compositions of the present invention can preferably contain a buffer to maintain the pH of the composition. Any buffer system can be utilized with the present invention, as long as it is pharmaceutically acceptable. Examples of suitable buffers for the pharmaceutical compositions include, but are not limited to, acetate, citrate and phosphate buffers. Alternatively, the organic acid and its salt can be utilized as the buffer system to maintain the pH of the composition. The pH of the pharmaceutical compositions can vary according to the route of administration. In the nasal application of the pharmaceutical compositions, the pH of the compositions preferably should be maintained from about 3 to about 10, more preferably from about 4 to about 6. Compositions having a pH less than 3, or greater than 10, can increase the risk of irritating the nasal mucosa of the recipient.

The viscosity of the compositions can be maintained at a desired level using a pharmaceutically acceptable thickening agent. One such preferred thickening agent is methyl cellulose because it is readily available and economical to utilize. Other suitable thickening agents include, but are not limited to, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the thickener agent will depend upon the agent selected and the viscosity desired. For example, to administer the moφhine compositions of the present invention as a gel, a viscosity up to 15,000 centistokes per second (cps) can be utilized.

The pharmaceutical compositions of the present invention for nasal administration can also contain a humectant or a soothening/moisturizing agent to inhibit drying of the mucus membrane and to prevent irritation. A variety of pharmaceutically suitable humectants can be employed which include, but are not limited to, sorbitol, mineral oil, vegetable oil and glycerol, membrane conditioners, sweeteners and combinations thereof. The concentration of the humectant or soothening/moisturizing agent(s) in the composition for nasal administration will also vary dependent upon the agent selected.

If desired, pharmaceutical excipients can also be used to localize moφhine or its salts in the nostrils. These excipients can be drawn for bioadhesives and/or mucoadhesives and/or swelling/thickening agents. The pharmaceutical compositions of the present invention can also employ a pharmaceutically acceptable preservative to increase product shelf life. Suitable preservatives that can be utilized include, but are not limited to, benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride, with benzalkonium chloride being particularly preferred. Typically, the preservative is present in a composition in a concentration up to about 2.0% by weight. However, amounts greater than 2.0% can also be utilized if desired. The actual amount of preservative to be utilized can easily be ascertained by the skilled artisan.

The following examples are provided to assist in further understanding the invention. The particular materials and conditions employed are intended to be further illustrative of the invention and are not limiting upon the reasonable scope.

A series of experiments were performed to illustrate features and advantages of the present invention. Initially, a solution of moφhine sulfate was formulated having a suitable pH value. Then, the solubility of moφhine sulfate in water was determined by mixing control compositions of moφhine sulfate in water at various pH values. In particular, the pH values of the control compositions after combining moφhine sulfate in water were between 2.4 and 5.9. The average solubility of moφhine sulfate in water was determined to be about 53.8 mg/mL.

In each of Examples 1-4, various salt solutions at various concentrations were each mixed with moφhine sulfate to determine whether these agents could at some concentration improve the solubility of moφhine sulfate. In particular, in each of Examples 1-4, various concentrations of carboxylic acids or their salts ranging from 0.08%) to 50%) (1.0%= 1 gm/lOOcc), were prepared in water. Moφhine sulfate was then added to these solutions to produce a suspension which was shaken for about 24 hours at about 25 °C. At that time, the suspension was filtered. The concentration of moφhine sulfate and the pH were then determined and recorded. EXAMPLE 1

TABLE 1 compares the solubility of moφhine sulfate in water to the solubility of moφhine sulfate in aqueous salt solutions including either calcium gluconate, sodium acetate, sodium citrate dihydrate, or sodium gluconate.

TABLE 1

NE = No Enhancement

*% Enhancement = (Solubility in Vehicle - Solubility in Purified Water) x 100

(Solubility in Purified Water) From TABLE 1, and FIGS. 1-4, it is readily apparent that calcium gluconate, sodium acetate, sodium citrate dihydrate and sodium gluconate are effective solubilizing agents for moφhine sulfate. For example, as the salt concentration of sodium acetate increased in the moφhine sulfate solution from 0.8% to 8.0%, the solubility of moφhine sulfate improved from 60.5 mg/mL to 98.3 mg/mL, an enhancement of from 12.4% to 82.7% compared to the solubility of moφhine sulfate in water. As the salt concentration of sodium gluconate in the moφhine sulfate solution increased from 1.0% to 10.0%, the solubility of moφhine sulfate improved from 56.3 mg/mL to 82.8 mg/mL, an enhancement of from 4.6% to 53.9% in comparison to the solubility of moφhine sulfate in water. It is readily apparent in this example that the carboxylic acid salts of sodium acetate and sodium gluconate were excellent for solubilizing moφhine sulfate. Thus, through the use of organic acids or their salts, concentrations of moφhine sulfate in pharmaceutically acceptable solvents are achieved that were previously unattainable.

EXAMPLE 2

TABLE 2 compares the solubility of moφhine sulfate in water to the solubility of moφhine sulfate in aqueous salt solutions including either sodium lactate, potassium sodium tartrate or ammonium acetate.

TABLE 2

NE = No Enhancement

*% Enhancement = f Solubility in Vehicle - Solubility in Purified Water x 100

(Solubility in Purified Water) From TABLE 2 and FIGS. 5-7, it is readily apparent that the carboxylic acid salts sodium lactate, potassium sodium tartrate and ammonium acetate are effective as solubilizing agents for moφhine sulfate at concentrations below 15.0%. For example, at salt concentrations of 5.0% and 10.0% of sodium lactate, the solubility of moφhine sulfate was enhanced to 73.6 mg/mL and 85.2 mg/mL, respectively, an enhancement of 36.8 and 58.4% respectively, compared to the solubility of moφhine sulfate in water. At salt concentrations of 10.0% and 15.0% of potassium sodium tartrate, the solubility of moφhine sulfate was enhanced to 93.0 mg/mL and 99.3 mg/mL, respectively, an enhancement of 72.9%) and 84.6%, respectively, compared to the solubility of moφhine sulfate in water which was found to be 53.8 mg/mL. The solubility of moφhine was enhanced from 22.5% to 84.4% compared to the solubility of moφhine sulfate in water, with low concentrations of ammonium acetate between 0.19% and 7.7%, respectively.

It is readily apparent that the carboxylic acid salts of sodium lactate, potassium sodium tartrate and ammonium acetate were excellent for solubilizing moφhine sulfate. In fact, the ammonium acetate salt solution demonstrated extraordinary results by exhibiting moφhine concentrations of 99.2 mg/mL at a salt concentration of 3.8% and of 98.3 mg/mL at a salt concentration of 7.7%. These solubilities are well over a 50% improvement over the control solutions. Thus, through the use of organic acids or their salts, concentrations of moφhine sulfate in pharmaceutically acceptable solvents are achieved that were previously unattainable.

EXAMPLE 3

TABLE 3 compares the solubility of moφhine sulfate in water to the solubility of moφhine sulfate in aqueous salt solutions including either sodium aspartate, sodium fumarate, sodium malate or sodium succinate. TABLE 3

NE = No Enhancement

*% Enhancement = (Solubility in Vehicle - Solubility in Purified Water) x 100

(Solubility in Purified Water) From TABLE 3 and FIGS. 8-11, it is readily apparent that the carboxylic acid salts sodium aspartate, sodium fumarate, sodium malate and sodium succinate are effective as solubilizing agents for moφhine sulfate at concentrations below 5%. For example, at salt concentrations of 0.16% and 1.6% sodium fumarate, the concentration of moφhine sulfate in solution improved to 59.7 mg/mL and

81.3mg/mL, respectively. At salt concentrations of 0.18 and 1.8% sodium malate, the concentration of moφhine sulfate in solution improved to 59.7 mg/mL and 73.0 mg/mL, respectively. It is readily apparent that the carboxylic acid salts of fumarate and succinate exhibited excellent effects on solubilizing moφhine sulfate. In fact, the sodium succinate salt solution demonstrated extraordinary results by exhibiting a moφhine concentration of 80.0 mg/mL at a salt concentration of 2.4% and 85.0 mg/mL at a salt concentration of 4.0%. These solubilities are well over a 50% improvement over the control solution having a solubility of moφhine sulfate in water of 53.8 mg/mL. Thus, through the use of organic acids or their salts, concentrations of moφhine sulfate and pharmaceutically acceptable solvents were achieved that were previously unattainable.

EXAMPLE 4

TABLE 4 compares the solubility of moφhine sulfate in water to the solubility of moφhine sulfate in aqueous salt solutions.

TABLE 4

NE = No Enhancement

*% Enhancement = (Solubility in Vehicle - Solubility in Purified Water) x 100

(Solubility in Purified Water) From TABLE 4 and FIG. 12, it is readily apparent that the carboxylic acid salt sodium tartrate as well as several combinations including carboxylic acid salts are effective as solubilizing agents for moφhine sulfate. For example, as the salt concentration of sodium tartrate increased from 1.94% to 19.4%, the solubility of moφhine sulfate was enhanced from 76.8 mg/mL to 103.8 mg/mL. This is a 42% to

92%o improvement over the solubility of moφhine sulfate in water. The solubility of moφhine sulfate in each of the combinations including carboxylic acid salts improved at least 30.3% in comparison to the solubility of moφhine sulfate in water. Thus, through the use of organic acids or their salts, concentrations of moφhine sulfate and pharmaceutically acceptable solvents are achieved that were previously unattainable.

Examples 1 -4 demonstrate that the solubility of moφhine sulfate is enhanced when it is admixed in aqueous salt solutions including various carboxylic acid salts at various concentrations in comparison to the solubility of moφhine sulfate in water. FIGS. 1-12 show the solubility of moφhine sulfate as a function of the concentration of various carboxylic acid salts. In particular, FIGS. 1 and 4 show that the solubility of moφhine sulfate can be enhanced at concentrations of gluconate below 10% and a pH between 5.4 and 6.0. At a pH of 3.0, gluconate does not enhance the solubility of moφhine sulfate as shown in FIG. 4.

As shown in FIGS. 2 and 7, the solubility of moφhine sulfate is enhanced as the concentration of acetate is increased at a pH range of 5.6 to 6- 1.

In comparison to the solubility of moφhine sulfate in water, the solubility of moφhine sulfate is enhanced at concentrations of tartrate below 20% as shown in FIGS. 6 and 12.

In comparison to the solubility of moφhine sulfate in water, FIGS. 3, 5 and 8- 11 show that the solubility of moφhine sulfate is enhanced at low concentrations of citrate, lactate, aspartate, fumarate, malate and succinate. Thus, while there have been described what are presently believed to be the preferred embodiments of the present invention, those skilled in the art will realize that other and further embodiments can be made without departing from the spirit and scope of the invention, and it is intended to include all such further modifications and changes as come within the true scope of the claims set forth herein.

Claims

WHAT IS CLAIMED IS:

1. A method for increasing the solubility of moφhine in a pharmaceutically acceptable solvent, comprising the step of admixing, in said solvent, moφhine and a solubilizing effective amount of an organic acid or its salt.

2. A method according to Claim 1, wherein said moφhine is moφhine sulfate.

3. A method according to Claim 1 , wherein said solvent is a polar solvent.

4. A method according to Claim 3, wherein said polar solvent is water.

5. A method according to Claim 1 , wherein said organic acid or its salt is a carboxylic acid or its salt.

6. A method according to Claim 5, wherein said carboxylic acid salt is selected from the group consisting of gluconate, acetate, citrate, lactate, tartrate, aspartate, fumarate, malate, maleate, succinate and combinations thereof.

7. A method according to Claim 5, wherein said carboxylic acid is selected from the group consisting of gluconic acid, acetic acid, lactic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, citric acid and combinations thereof.

8. A method according to Claim 1, wherein said solubilizing effective amount of said organic acid or its salt is an amount that provides said solution with a concentration of at least about 0.1 % to about 50.0% of said organic acid or its salt.

9. A method according to Claim 1 , wherein an amount of said moφhine that provides a moφhine concentration of at least about 2 mg/mL to about 104 mg/mL is admixed, in said solvent, with said solubilizing effective amount of said organic acid or its salt.

10. A pharmaceutical composition for administering moφhine to a mammal having improved solubility, comprising a pharmaceutically acceptable solvent having moφhine and a solubilizing effective amount of an organic acid or its salt.

11. A composition according to Claim 10, wherein said moφhine is moφhine sulfate.

12. A composition according to Claim 10, wherein said solvent is a polar solvent.

13. A composition according to Claim 12, wherein said polar solvent is water.

14. A composition according to Claim 10, wherein said solvent comprises a mixture of pharmaceutically acceptable solvents.

15. A composition according to Claim 10, wherein said organic acid or its salt is a carboxylic acid or its salt.

16. A composition according to Claim 15, wherein said carboxylic acid salt is selected from the group consisting of gluconate, acetate, citrate, lactate, tartrate, aspartate, fumarate, malate, maleate, succinate and combinations thereof.

17. A composition according to Claim 15, wherein said carboxylic acid is selected from the group consisting of gluconic acid, acetic acid, lactic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, citric acid and combinations thereof.

18. A composition according to Claim 10, wherein said composition comprises an amount of said moφhine that provides a moφhine concentration in said composition of at least about 2 mg/mL to about 104 mg/mL.