WO2002067992A2

WO2002067992A2 - Drug compositions having enhanced solubility

Info

Publication number: WO2002067992A2
Application number: PCT/US2002/004368
Authority: WO
Inventors: Stephen Hong-Wei Wu
Original assignee: Eastman Chemical Co
Current assignee: Eastman Chemical Co
Priority date: 2001-02-22
Filing date: 2002-02-14
Publication date: 2002-09-06
Anticipated expiration: 2003-08-22

Abstract

A novel composition is provided comprising a monoester tocopheryl polyethylene glycol succinate and an organic adjuvant, that is particularly suitable for enhancing the water solubility of a hydrophobic drug. Also provided are novel hydrophobic drug compositions comprising a hydrophobic drug and a monoester tocopheryl polyethylene glycol succinate, optionally with an organic adjuvant, where the drug compositions are preferably characterized by enhanced water solubility. Also provided is a process for enhancing water solubility of a hydrophobic drug.

Description

DRUG COMPOSITIONS HAVING ENHANCED SOLUBILITY

FIELD OF THE INVENTION This invention relates to drug compositions having enhanced water- solubility. The water solubility of hydrophobic drugs is improved by blending the drug(s) with a mono-ester tocopheryl polyethylene glycol succinate (mono-TPGS), and optionally, an organic adjuvant.

BACKGROUND OF THE INVENTION

Tocopheryl polyethylene glycol succinate (herein TPGS) has been used for various purposes in various pharmaceutical compositions. For example, in U.S. Patent No. 3,102,078, TPGS is described as a solubilizing agent for water-soluble preparations of normally water-insoluble, fat-soluble vitamins.

U.S. Patents No. 5,223,268 and 5,340,589, and European Patent Application Number 514,967 describe sugar beads coated with a drug wherein TPGS is an ingredient of the coating composition.

U.S. Patent No. 5,364,631 describes the use of TPGS as a stabilizer to allow formation of, or maintenance of, the bilayer based liposomes in an acidic environment.

U.S. Patent No. 5,447,729 describes a pharmaceutical preparation wherein a pharmaceutical agent is incorporated into particles comprising a core formed from a hydrophilic material, a hydrophobic material or a hydrophobic emulsion or dispersion, and an alternating sequence of hydrophilic/hydrophobic layers, wherein TPGS is used as a component. U.S. Patent No. 5,583,105 describes an emulsion preconcentrate composition containing cyclosporin, ethanol, a lipophilic and/or amphiphilic solvent, wherein TPGS is disclosed as an emulsifier and adjuvant, and an oxidative inhibitor for fatty oils in the composition. U.S. Patent No. 5,558,876 describes a topical ophthalmic formulation comprising an acidic drug, TPGS, benzalkonium chloride, and caffeine, wherein TPGS is used to solubilize the acidic drug and reduce ocular discomfort. U.S. Patent No. 5,545,407 describes a dermatological composition for treating skin lesions comprising benzoyl peroxide, a topical carrier, and a compound for reducing skin irritation such as TPGS.

U.S. Patent No. 5,891 ,845 describes a pharmaceutical composition comprising a solid solution of active drug components and TPGS that provides controlled release of the drugs into the gastrointestinal tract.

U.S. Patent No. 5,179,122 describes a solid composition comprising vitamin E acetate, TPGS and an inert carrier.

SUMMARY OF THE INVENTION It is an object of the present invention to provide new and improved drug compositions.

It is a further object of this invention to provide new drug compositions having improved and enhanced water solubility characteristics. It is a further object of this invention to provide new compositions that are particularly suitable for enhancing the water solubility of hydrophobic drugs.

It is a further object of this invention to provide a process for enhancing the water solubility of hydrophobic drugs. These and other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description and claims.

In accordance with this invention, it has been found that the above and still further objects are achieved by the following. A composition is provided comprising a monoester tocopheryl polyethylene glycol succinate (mono-TPGS) and an organic adjuvant that is particularly suitable for enhancing the water-solubility of a hydrophobic drug. Further, there are provided compositions comprising a hydrophobic drug and mono-TPGS, and optionally an organic adjuvant, wherein the compositions are preferably characterized by enhanced water solubility of the hydrophobic drug. Further, there is provided a process for enhancing the water solubility characteristic of a hydrophobic drug comprising mixing the hydrophobic drug with mono-TPGS, or with a composition comprising mono-TPGS and an organic adjuvant.

DETAILED DESCRIPTION OF THE INVENTION In accordance with this invention, it has been found that the above and still further objects are achieved by the following. A composition is provided comprising a monoester tocopheryl polyethylene glycol succinate (mono-TPGS) and an organic adjuvant that is particularly suitable for enhancing the water-solubility of a hydrophobic drug. Further, there are provided compositions comprising a hydrophobic drug and mono-TPGS, and optionally an organic adjuvant, wherein the compositions are preferably characterized by enhanced water solubility of the hydrophobic drug. Further, there is provided a process for enhancing the water solubility characteristic of a hydrophobic drug comprising mixing the hydrophobic drug with mono-TPGS, or with a composition comprising mono-TPGS and an organic adjuvant. The compositions comprising mono-TPGS and an organic adjuvant are described in more detail. The mono-TPGS used herein may be produced by any method known in the art. For example, a method that can be employed involves initially producing tocopheryl polyethylene glycol succinate (herein TPGS) by esterifying tocopheryl acid succinate (herein TAS) with polyethylene glycol (herein PEG), in accordance with the process described in U.S. Patent No.2,680,749, incorporated herein by reference. As mentioned in the U.S. Patent No. 2,680,749, esterification of tocopheryl acid esters with polyethylene glycol is a well known procedure. The esterification procedure is said to be desirably effected in a solvent media; promoted by any well known esterification catalyst; desirably effected at elevated temperatures, with water formed during the esterification being removed by azeotropic distillation. The polyethylene glycol (PEG) used in the esterification of the tocopheryl acid succinate (TAS) preferably has a number average molecular weight ranging from 300 to 6000, with a preferred range of from 400 to_.1500.

The resulting polyethylene glycol ester of tocopheryl acid succinate (TPGS) is then contacted by any method known in the art to provide the mono-ester tocopheryl polyethylene glycol succinate (mono-TPGS). For example, as used in the present examples, the TPGS was contacted to yield the mono-TPGS by using a conventional preparation high pressure liquid chromatograph (HPLC) method. The HPLC method used to isolate the mono-TPGS from the TPGS involved the following:

A TPGS sample was dissolved in isopropyl alcohol at 30 weight percent. Into the preparative HPLC system was installed a 2-inch diameter reversed phase column. Utilized herein was Dynamax high performance analytical and preparative column (Varian Inc., California). The column was loaded with a solvent system for the separation. A step gradient program was used throughout the experiment. The solvent system consisted of a combination of acetonitrile (ACN) and isopropyl alcohol (IPA) ranging from 80% ACN/20% IPA to 100% IPA, by weight. The pumps of the HPLC were started and the ultraviolet detector of the HPLC system was turned on. The system was then allowed to run for a few minutes to become stabilized. The injector loop of the HPLC system was loaded with 5 ml of sample solution, and then the sample was injected into the HPLC column. The components of the sample separated on the column, and the mono-TPGS, and other components, were collected upon exiting the colurhn. Solvent was evaporated from the collected sample to obtain the purified mono- TPGS.

The resultant mono-TPGS is miscible with water. The mono-TPGS is then combined with an organic adjuvant to provide a composition that is particularly suitable for enhancing the water solubility of a hydrophobic drug. Any non-volatile or volatile organic adjuvant is suitable for use herein provided that the organic adjuvant is miscible with the mono-TPGS. The amounts of mono-TPGS and organic non-volatile adjuvant present in the composition are such that the weight ratio of mono-TPGS to non-volatile (boiling point above 260°C) organic adjuvant is greater than 80:20, preferably greater than 85:15, up to a maximum of 99:1. Where the organic adjuvant is volatile (boiling point less than 260°C), the weight ratio of mono- TPGS to volatile organic adjuvant is at least 30:70, preferably at least 50:50, up to a maximum of 99:1. The compositions of mono-TPGS and organic adjuvant may be prepared by any method known in the art, such as by admixing or blending the components, or the like. In preparing the compositions of the mono-TPGS and the organic adjuvant, if desired, more than one organic adjuvant may be used. The compositions of mono-TPGS and organic adjuvant must be soluble, dispersible, or miscible with water. As indicated, any organic adjuvant that is miscible with the mono- TPGS is suitable for use in the present invention. Exemplary organic adjuvants suitable for use herein include diester tocopheryl polyethylene glycol succinate, polyethylene glycol, ethanol, propylene glycol, glycofurol, a lipid material such as vegetable oils, medium chain glycerides, vitamin E oils, an emulsifier having an HLB value of 4-12, triacetin, diethyl phthalate, triethyl citrate, sucrose acetate isobutyrate, glycerin, monoglycerides, acetylated monoglycerides, ethoxylated castor oil, fatty acid based emulsifiers suitable for pharmaceutical applications, and the like.

For many purposes, it may be desirable to incorporate other conventional additives with the compositions of the present invention comprising mono-TPGS and at least one organic adjuvant.

In another embodiment of the present invention, compositions are provided comprising any hydrophobic drug and mono-TPGS or a composition comprising mono-TPGS and at least one, or more, organic adjuvant, as described herein. The drug compositions of the present invention comprising mono-TPGS, or a composition comprising mono- TPGS and at least one organic adjuvant, are prepared by any method known in the art. For example, the components of the composition may be admixed or blended, or the like. In preparing the hydrophobic drug- containing compositions of the present invention, and the examples herein, the components were prepared as follows:

Mono-TPGS was liquefied at a temperature above its melting temperature, and the drug was then dissolved in the liquefied mono-TPGS. Heat may be used to ensure that the drug was completely dissolved in the liquefied mono-TPGS. The mixture was cooled to solidify. If desired, other excipients can be mixed with the mixture. Further an organic adjuvant can be added to the mixture of drug and mono-TPGS. The resulting mixture was then admixed with water.

An alternative procedure that may be used involves dissolving mono- TPGS, optionally with an organic adjuvant, in water, and then admixing the drug in the mono-TPGS solution.

In preparing the drug-containing compositions there may be used varied amounts of hydrophobic drug and mono-TPGS, or composition of mono-TPGS and at least one organic adjuvant as follows. The weight ratio of drug to mono-TPGS, or to composition mono-TPGS and organic adjuvant, varies from 1 :100 to 3:1.

In preparing the drug-containing compositions, there is used mono- TPGS, or a composition of mono-TPGS and at least one organic adjuvant, as described herein. The organic adjuvant must be miscible with the mono- TPGS, as stated earlier, and examples of suitable organic adjuvants have been earlier provided. However, as long as the organic adjuvant is miscible with the mono-TPGS, any organic adjuvant is usable in preparing the compositions. Any hydrophobic drug may be used as the drug component of the drug-containing composition of the present invention. A hydrophobic drug is a drug, which in its non-ionized form is more soluble in lipid or fat than in water. In this invention, the water solubility of a hydrophobic drug is usually, but not limited to, less than 0.1 mg/ml. Exemplary hydrophobic drugs suitable for use herein include oil-soluble nutrients such as natural and synthetic tocopheryl and their derivatives including vitamin E acetate, vitamin E succinate, diester tocopheryl polyethylene glycol succinate, beta- carotene, coenzyme Q10, and other oil-soluble nutrients. Also suitable for use herein as the hydrophobic drugs are drugs subjected to p-glycoprotein efflux such as cyclosporin, nifedipine, paclitaxes, digoxin and HIV protease inhibitors such as amprenavir. Other examples of hydrophobic drugs useful herein include griseofulvin, estradiol and its derivatives, fluocinolone acetonide and its derivatives, and triamcinolone acetonide, carbamazapine, hydrocortisone, and ibuprofen. For many purposes, it may be desirable to incorporate other conventional additives with the drug-containing compositions of the present invention.

Preferably, the drug compositions comprising the mono-TPGS, or the composition comprising mono-TPGS and at least one organic adjuvant, will have a solubility in water improved or enhanced as compared to the solubility in water of the hydrophobic drug in the absence of the mono- TPGS component of the composition.

The invention will be more readily understood by reference to the following examples. There are, of course, many other forms of this invention which will become obvious to one skilled in the art, once the invention has been fully disclosed, and it will accordingly be recognized that these examples are given for the purpose of illustration only, and are not to be construed as limiting the scope of this invention in any way.

EXAMPLES

The following test procedures were used in evaluating the analytical properties of the products herein. The solubility in water effects were evaluated by visual observation. Molecular Weight (MWn) - Number average molecular weight was determined by calculation based on the number average MW of polyethylene glycol (PEG) and the MW of tocopherol succinate which are added, and then subtracting from the sum, the MW of water.

Melting Point (MP), °C. was determined by DSC. Differential scanning calorimetry (DSC) was used for determining m. p of PTGS. The instrument used was a Mettler differential scanning calorimeter (Model 821 , Mettler Toledo Inc., Columbus, Ohio). A TPGS sample of about 4.8 mg was placed on the sample holder. The heating and cooling cycles were set between 0°C and 85°C with a 10°C/min heating rate. Cooling was done by liquid nitrogen purge. The melting temperature of TPGS was then determined by the temperature at which abrupt changes of heat absorption curve occurred.

HLB - HLB value was calculated by the following equation: HLB = 20x (M_H/MH + M_L), Where M_H is the formula weight of the hydrophilic portion of the molecule and M is the formula weight of the lipophilic (hydrophobic) portion of the molecule. [M. J. Rosen, "Surfactants and Interfacial Phenomena," 2^nd ed., John Wiley and Sons, New York, 1989, p. 326-329.] CMC - critical micelle concentration was determined by measuring the change of surface tension of aqueous solutions of TPGS. The surface tension values were determined by using a tensiometer (model K-10, Kruss USA, Charlotte, NC). The concentration of TPGS in water ranges from 0.0001 to 0.25 wt %. A distinct change of surface tension values at about 0.02 wt % concentration can be determined.

Example 1

There was provided a typical vitamin E TPGS NF d-alpha-tocopheryl polyethylene glycol succinate, commercially available from Eastman Chemical Company. The vitamin E TPGS NF is described by Eastman as being a water soluble derivative of natural-source vitamin E, and as being prepared by the esterification of the acid group of crystalline d-alpha- tocopheryl acid succinate by polyethylene glycol. The number average molecular weight (MWn) of the polyethylene glycol was 1030. The vitamin E TPGS NF d-alpha-tocopheryl polyethylene glycol succinate was subjected to the preparative HPLC method, described herein, to isolate the mono-TPGS. In more detail, the HPLC instrument used in this example was Sep Tech 800C, modified with 0.03 inch ID (inside diameter) tubing, Valco unions, and Valco injection valve. As described herein, Eastman's commercial Vitamin E TPGS NF sample (100 grams) was dissolved in isopropyl alcohol at 30 weight percent. The preparative HPLC system for separation utilized a 2-inch reversed phase column. The column used was a Dynamax C18 preparative HPLC column (Varian Inc., CA). The column was loaded with a solvent system. A step gradient program consisting of a combination of acetonitrile (ACN) and isopropyl alcohol (IPA) ranging from 80% ACN/20% IPA, to 0% ACN/100% IPA was used throughout the example. The HPLC pumps were started and the ultraviolet detector was turned on. The system was run for a few minutes to become stabilized. The injector loop was loaded with 5 ml of sample solution, and then the sample was injected into the HPLC column. The components of the sample separated on the column, and the purified mono-TPGS was collected upon exiting the column, using a UV detector at 290 nm. The solvent was evaporated from the collected sample to obtain the purified mono-TPGS. The mono-TPGS was characterized by having a MW_n of 1543, a MP of 40°C - 43°C, an HLB value of 13.4, a CMC value of 0.02%, and was miscible with water.

Example 2 In this example, there is described the effect on the water solubility of a hydrophobic drug, resulting from mixing with the drug varying amounts of the mono-TPGS prepared in Example 1. The hydrophobic drug used in Example 2 was diester tocopheryl polyethylene glycol succinate (herein di- TPGS). The Example describes the effect on water solubility of solely drug, with no mono-TPGS component, to solely mono-TPGS, in the absence of drug component. Where there was used a composition, the binary mixtures of hydrophobic drug and the mono-TPGS were prepared by admixing mono-TPGS and di-TPGS in liquid form at the ratios of 85/15, 80/20, and 75/25 by weight, respectively, at a temperature of about 60°C. The mixtures were then allowed to cool to room temperature. The solubility of each mixture was determined by admixing one gram of sample in 10 grams of distilled water for 24 hours. The samples were evaluated visually for the solubility in water property. The compositions, and solubility properties, are reported in Table

From a review of the data in Table I, it is apparent that the hydrophobic drug, the di-TPGS, was not soluble in water. It was not until the weight ratio of mono-TPGS to drug was greater than 80:20, that the mixture formed a clear solution. The above clearly established that mixing mono-TPGS, in a specified amount, with the insoluble drug, resulted in a drug composition having enhanced water solubility.

It is expected that similar results will be achieved when an organic adjuvant is mixed with the mono-TPGS to provide a composition that is mixed with a hydrophobic drug having poor water solubility. The composition comprising the mono-TPGS, the organic adjuvant, and the hydrophobic drug, is expected to have enhanced or improved water solubility.

Example 3

Paclitaxel is a hydrophobic drug that is insoluble in water. The solubility of paclitaxel with, and without, 0.1% of mono-TPGS plus adjuvant in an assay buffer was compared. The assay buffer was Hanks' Balanced Salt Solution which contains 0.14 g/L CaCI₂, 0.40 g/L KCI, 0.10 g/L MgCI₂ ^»6H₂0, 0.10 g/L MgSO -7H₂O, 8.00 g/L NaCI, 0.35 g/L NaHCO₃, and 1.0 g/L D-glucose. To the Hanks solution HEPES buffer (N-2- Hydroxyethylpiperazine-N'-2-Ethane Sulfonic Acid) and D-glucose were added to final concentrations of 10 mM and 15 mM, respectively. The final solution was brought to pH 7.0 ± 0.2.

The solubility of paclitaxel was measured in the assay buffer with and without 0.1% solution containing mono-TPGS (86.3%) and 2 inorganic non-volatile adjuvants, di-TPGS (12.0%) and PEG 1000 (4.4%). Excess paclitaxel powder was introduced to each matrix. The two samples were then agitated for 2 hours and left to stand overnight at room temperature. The samples were then filtered using a 0.45 μM nylon membrane syringe filter and assayed using LC/MS (Liquid Chromatography/Mass

Spectroscopy). The concentration in the filtrate is taken to the equilibrium solubility in each matrix as shown in Table 2.

TABLE 2 Solubility of Paclitaxel at pH 7.0 with and without 0.1 % Solution Containing

Mono-TPGS, di-TPGS and PEG 1000

It is clearly shown that mono-TPGS with the presence of adjuvants di-TPGS and PEG, enhanced the aqueous solubility of paclitaxel by approximately 18 fold.

It should be clearly understood that the forms of the invention herein described are illustrative only and are not intended to limit the scope of the invention. The present invention includes all modifications falling within the scope of the following claims. Moreover, all patents, patent applications, and literature references cited above are incorporated by reference herein for any disclosure pertinent to the practice of this invention.

Claims

1. A composition comprising a monoester tocopheryl polyethylene glycol succinate, and at least one organic adjuvant that is miscible with the monoester tocopheryl polyethylene glycol succinate.

2. The composition according to Claim 1 wherein the polyethylene glycol of the monoester tocopheryl polyethylene glycol succinate has a number average molecular weight ranging from 300 to 6000.

3. The composition according to Claim 2 wherein the polyethylene glycol has a number average molecular weight ranging from 400 to 1500.

4. The composition according to Claim 1 wherein the organic adjuvant is non-volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant greater than 80:20.

5. The composition according to Claim 1 wherein the organic adjuvant is volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant of at least 30:70.

6. A drug composition comprising a hydrophobic drug and a component selected from the group consisting of a monoester tocopheryl polyethylene glycol succinate and a composition comprising a monoester tocopheryl polyethylene glycol succinate and at least one organic adjuvant that is miscible with the monoester tocopheryl polyethylene glycol succinate.

7. The drug composition according to Claim 6 wherein the polyethylene glycol of the monoester tocopheryl polyethylene glycol succinate has a number average molecular weight ranging from 300 to 6000.

8. The drug composition according to Claim 7 wherein the polyethylene glycol has a number average molecular weight ranging from 400 to 1500.

9. The drug composition according to Claim 6 wherein the organic adjuvant of the composition is non-volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant greater than 80:20.

10. The drug composition according to Claim 6 wherein the organic adjuvant of the composition is volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant of at least 30:70.

11. The drug composition according to Claim 6 wherein the component is a monoester tocopheryl polyethylene glycol succinate.

12. The drug composition according to Claini 6 wherein the weight ratio of drug to component ranges from 1:100 to 3:1.

13. A process for improving water solubility of a hydrophobic drug comprising mixing with the hydrophobic drug a component selected from the group consisting of a monoester tocopheryl polyethylene glycol succinate and a composition comprising a monoester tocopheryl polyethylene glycol succinate and at least one organic adjuvant that is miscible with the monoester tocopheryl polyethylene glycol succinate.

14. The process according to Claim 13 wherein the polyethylene glycol of the monoester tocopheryl polyethylene glycol succinate has a number average molecular weight ranging from 300 to 6000.

15. The process according to Claim 13 wherein the organic adjuvant of the composition is non-volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant greater than 80:20.

16. The process according to Claim 13 wherein the organic adjuvant of the composition is volatile and is present in a weight ratio of monoester tocopheryl polyethylene glycol succinate to organic adjuvant of at least 30:70.

17. The process according to Claim 13 wherein the component is a monoester tocopheryl polyethylene glycol succinate.

18. The process according to Claim 13 wherein the weight ratio of drug to component ranges from 1 :100 to 3:1.