Pharmaceutical Eutectic Salt Formation

Abstract

The invention is directed to a pharmaceutical composition that is liquid at 37° C. and 1 atm, comprising a eutectic mixture of at least an active pharmaceutical ingredient (API) salt, a hydrophilic pharmaceutically acceptable eutectic constituent and a polymer solubilizer, and further comprising a precipitation inhibitor (PI). In another aspect, the invention is directed to a method for preparing such a composition.

Claims

1. A pharmaceutical composition that is liquid at 37° C. and 1 atm, said composition comprising providing a eutectic mixture of at least an active pharmaceutical ingredient (API) salt, a hydrophilic pharmaceutically acceptable eutectic constituent and a polymer solubilizer, and further comprising a precipitation inhibitor (PI), wherein said hydrophilic pharmaceutically acceptable eutectic constituent, polymer solubilizer and precipitation inhibitor are each present in the composition in pharmaceutically acceptable amounts.

2. The pharmaceutical composition according to claim 1, wherein the API salt is based on a basic API and an acid, which acid comprises an atomic anion, and wherein said hydrophilic pharmaceutically acceptable eutectic constituent comprises one or more functional groups capable of hydrogen bonding or, wherein the API salt is based on a basic API and an acid, which acid comprises a molecular anion, and wherein said hydrophilic pharmaceutically acceptable eutectic constituent comprises a small moiety capable of forming strong intermolecular bond.

3. The pharmaceutical composition according to claim 1, wherein the API salt is based on an acidic API and a base, which base comprises an atomic cation and wherein said hydrophilic pharmaceutically acceptable eutectic constituent comprises one or more functional groups capable of hydrogen bonding.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable eutectic constituent comprises one or more organic acids, phenolic compounds, terpenoids, organic bases, sugars or sweeteners, glycols, amino acids, quaternary ammonium compounds, or derivatives of these classes or combinations thereof.

5. The pharmaceutical composition according to claim 1, wherein said polymer solubilizer comprises one or more esters and/or lactones of organic acids, one or more dicarboxylic acids and/or esters of dicarboxylic acids, one or more esters, ethers and carbonates of diols and/or triols, one or more glycols or combinations thereof.

6. The pharmaceutical composition according to claim 1, wherein said PI is a polymeric precipitation inhibitor (PPI) that comprises a polymer that is soluble in an aqueous medium at a concentration of greater than 0.1 mg/ml at a pH value in the range of 1 to 8.

7. The pharmaceutical composition according to claim 1, wherein said PI comprises one or more cyclodextrins that are soluble in an aqueous medium at a concentration of greater than 0.1 mg/ml at a pH value in the range of 1 to 8.

8. The pharmaceutical composition that is preferably liquid at claim 1, wherein the precipitation inhibitor is solubilized and homogeneously mixed within the eutectic mixture.

9. (canceled)

10. The pharmaceutical composition according to claim 1, wherein the API is present in a concentration of at least 50 mg/ml based on the total composition.

11. The pharmaceutical composition according to claim 1, wherein the weight ratio of PI to API is between 0.2 to 1 and 40 to 1.

12. The pharmaceutical composition according to claim 1, wherein the molar ratio of the polymer solubilizer to the eutectic constituent is in the range of 20 to 1 and 1 to 10.

13. The pharmaceutical composition according to claim 1 for use in a medical treatment comprising enteral administration.

14. (canceled)

15. A method for preparing a pharmaceutical composition according to claim 1 comprising providing a eutectic mixture of at least an active pharmaceutical ingredient (API) salt, a hydrophilic pharmaceutically acceptable eutectic constituent and a pharmaceutically acceptable amount of a polymer solubilizer, and mixing said eutectic mixture with a pharmaceutically acceptable amount of a precipitation inhibitor (PI) to form said pharmaceutical composition.

16. The pharmaceutical composition according to claim 1 wherein said polymer solubilizer comprises one or more esters and/or lactones of organic acids selected the group consisting of diethyl malate, triethyl citrate, tributyl citrate, ethyl lactate, dimethyl succinate, diethyl succinate, glucuronolactone and D-(+)-glucuronic acid γ-lactone; one or more dicarboxylic acids and/or esters of dicarboxylic acids selected from the group consisting of mono-methyl adipate, dimethyl glutarate and mono-methyl glutarate; one or more esters, ethers and carbonates of diols and/or triols selected from the group consisting of glycerol carbonate, propylene carbonate, ethylene carbonate, 1,2-butylene carbonate, glycerol formal, DL-1,2-isopropylideneglycerol, 1-butoxypropan-2-ol, tri(propylene glycol) methyl ether, dipropylene glycol methyl ether acetate, propylene glycol methyl ether acetate, dipropylene glycol methyl ether, 1-methoxy-2-propanol, diethylene glycol monoethyl ether, 3-methoxy-3-methyl-1-butanol, isosorbide dimethyl ether and dianhydro-d-glucitol; or one or more glycols selected from the group consisting of propylene glycol, dipropylene glycol, butylene glycol, glycerol, tetraglycol, 1,2-hexanediol, 1,2-butanediol, PEG 400 and polyglycerol; or combinations thereof.

17. The pharmaceutical composition according to claim 1 wherein said PI is a polymeric precipitation inhibitor (PPI) that comprises a polymer selected from the group consisting of homopolymers and copolymers of N-vinyl lactams, especially homopolymers and copolymers of N-vinyl pyrrolidone, e.g. polyvinyl pyrrolidone (PVP), copolymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, such as Soluplus®, block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene/polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer®, lauroyl polyoxyglycerides cellulose esters and cellulose ethers; in particular methylcellulose, hydroxyalkylcelluloses, in particular hydroxypropylcellulose, hydroxyalkylalkylcelluloses, in particular hydroxypropylmethylcellulose, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, vinyl acetate polymers such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified “polyvinyl alcohol”), polyvinyl alcohol, oligo- and polysaccharides such as carrageenans, galactomannans and xanthan gum, and mixtures of one or more thereof.

18. The pharmaceutical composition according to claim 1 wherein said PI comprises one or more cyclodextrins selected from the group consisting of alpha cyclodextrin, beta cyclodextrin and gamma cyclodextrin.

19. The pharmaceutical composition according to claim 1 wherein the API is present in a concentration of at least 100 mg/ml, based on the total composition.

20. The pharmaceutical composition according to claim 1 wherein the weight ratio of PI to API is between 0.35 to 1 and 20 to 1.

21. The pharmaceutical composition according to claim 1 wherein the API is present in a concentration of at least 150 mg/ml based on the total composition, and wherein the weight ratio of PI to API is between 0.5 to 1 and 10 to 1.

Description

EXAMPLE 1

[0057] A hydrogen chloride (HCl) salt of itraconazole was prepared and mixed with choline chloride and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. and stirred for 30 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both itraconazole HCL and choline chloride, from 170° C. and 302° C. respectively to less than room temperature (20° C.).

[0058] Dow Chemical®—AFFINISOL® HPMC HME 15LV was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 2

[0059] A hydrogen chloride (HCl) salt of itraconazole was prepared and mixed with xylitol and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 30 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both itraconazole HCL and choline chloride, from 170° C. and 302° C. respectively to less than room temperature (20° C.).

[0060] Dow Chemical®—AFFINISOL® HPMC HME 15LV was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 3

[0061] A hydrogen chloride (HCl) salt of 1-adamantanamine hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with xylitol and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0062] Dow Chemical®—AFFINISOL® HPMC HME 15LV was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 4

[0063] A hydrogen chloride (HCl) salt of 1-Adamantanamine hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with choline chloride and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0064] Dow Chemical®—AFFINISOL® HPMC HME 15LV was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 5

[0065] A hydrogen chloride (HCl) salt of aminoguanidine hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with choline chloride and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0066] Dow Chemical®—AFFINISOL® HPMC HME 15LV was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 6

[0067] A hydrogen chloride (HCl) salt of aminoguanidine hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with xylitol and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0068] Sigma Aldrich® now Merck®-Polyvinylpyrrolidone K90, powder, average M.sub.w 360.000 g/mol. was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 7

[0069] A hydrogen chloride (HCl) salt of propanolol hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with choline chloride and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0070] Sigma Aldrich® now Merck®-Polyvinylpyrrolidone K90, powder, average M.sub.w 360.000 g/mol. was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 8

[0071] A hydrogen chloride (HCl) salt of propanolol hydrochloride was purchased from TCI Chemicals (A0588). The API HCl was mixed with choline chloride and dipropylene glycol at a molar ratio of 0.25:0.5:2. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both API HCL and choline chloride, from 280° C. and 302° C. respectively to less than room temperature (20° C.).

[0072] Sigma Aldrich® now Merck®-Polyvinylpyrrolidone K90, powder, average M.sub.w 360.000 g/mol. was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 9

[0073] A sodium (Na) salt of Cefazolin was purchased from TCI Chemicals (A0588). The API HCl was mixed with xylitol and tripropylene glycol at a molar ratio of 1:0.5:4. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both Cefazolin Na and Xylitol to less than room temperature (20° C.).

[0074] Sigma Aldrich® now Merck®-Polyvinylpyrrolidone K90, powder, average M.sub.w 360.000 g/mol. was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 10

[0075] A disodium (2Na) salt of Fosfomycin was purchased from TCI Chemicals (A0588). The API 2Na was mixed with xylitol and tripropylene glycol at a molar ratio of 1:1:4. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both Fosfomycin 2Na and Xylitol to less than room temperature (20° C.).

[0076] Dow Chemical®—AFFINISOL™ HPMC HME 4M was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 11

[0077] A potassium (K) salt of Lorsartan was purchased from TCI Chemicals (A0588). The API K was mixed with sodium propyl paraben and tripropylene glycol at a molar ratio of 1:0.5:4. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both Lorsartan K and sodium propyl paraben to less than room temperature (20° C.).

[0078] Dow Chemical®—AFFINISOL™ HPMC HME 4M was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 12

[0079] A sodium (Na) salt of Sulfamethazine was purchased from TCI Chemicals (A0588). The API Na was mixed with sodium propyl paraben and tripropylene glycol at a molar ratio of 1:0.7:4. This mixture was heated to 50° C. for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both Sulfamethazine Na and sodium propyl paraben to less than room temperature (20° C.).

[0080] Dow Chemical®—AFFINISOL™ HPMC HME 4M was solubilized in the eutectic mixture at a concentration of 50 mg/ml to enhance the dissolution characteristics of the active ingredient.

EXAMPLE 13

[0081] A hydrogen chloride (HCl) salt of propanolol hydrochloride was produced and mixed with xylitol, sorbitol and triporpylene glycol at a molar ratio of 0.5:0.375:0.375:10. This mixture was heated to 50° C. and stirred for 60 minutes until a colourless and clear solution formed. This mixture was stable at room temperature over the period of 1 month. There was a significant depression in the melting point of both itraconazole HCl, xylitol and sorbitol, from 170° C., 92° C. and 95° C. respectively to less than room temperature (20° C.).

[0082] This itraconazole HCl formulation according to the invention was selected to evaluate the in vivo bioavailability of the API in comparison to a commercial itraconazole formulation, Sporanox® (ex Janssen-Cilag SpA; Italy). The goal of this study was to show the impressive performance of the invented technology when dramatically increasing the concentration of the formulation (13× increase) and increasing the dose (2.2× increase) compared to the best available commercial formulation. The data below shows increased bioavailability even when corrected for the administered higher dose.

[0083] For this purpose, fasted male Sprague-Dawley rats (n=6) with a mass of ˜300 g, were dosed through oral gavage with 1.5 mg of itrazonacole using the 10 mg/ml Sporanox® oral solution. To compare, an additional cohort of fasted male Sprague-Dawley rats (n=6) were dosed with 3.25 mg of itraconazole HCl through a 130.9 mg/ml F4 formulation dosed in size 9 HPMC capsules according to the present invention.

[0084] After dosing, the plasma levels of the API were determined as a function of time. Samples were withdrawn 0, 1, 2, 3, 5, 7, 9, 12, 24 and 48 hours after administering the formulations. API levels were determined by Liquid Chromatography-Mass Spectrometry (LC-MS).

[0085] FIG. 1 depicts the mean plasma levels (ng/mL) of itraconazole achieved with Sporanox® compared to formulation F4. F4 achieves a significantly higher concentration in the blood.

[0086] FIG. 2 also depicts the mean plasma levels (ng/ml) of itraconazole achieved with Sporanox® compared to formulation F4. In this graph, the bioavailability has been normalized to dose. Importantly this graph shows that the bioavailability of itraconazole is increased when increasing the concentration of the formulation 13-fold. This is particularly important as bioavailability typically reduces significantly as the concentration of the formulation increases.