METHOD FOR SOLUBILIZING 5-AMINO-2,3-DIHYDRO-1,4-PHTHALAZINEDIONE

Abstract

The present invention relates to a method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione or salts thereof, to the solubilisate produced by this method and respective uses in pharmaceutical dosage forms. A phosphatidylcholine-based solubilization method is disclosed.

Claims

1. A method for solubilizing 5-amino-2,3-dihydro-1,4-phthalazinedione, comprising the following steps: a) Providing 5-amino-2,3-dihydro-1,4-phthalazinedione in the overall range of 0.1% to 25% per weight at room temperature and a pressure of 0.2 bar to 1 bar; b) Adding in any sequence the solubilization agents of at least one phosphatidylcholine in the overall range of 20% to 80% per weight, at least one medium-chained triglyceride in the overall range of 10% to 70% per weight, at least one lysophosphatidylcholine in the overall range of 1% to 15% per weight, at least one C.sub.2 to C.sub.4 alcohol in the overall range of 1% to 20% per weight, and at least one of glyceryl stearate and/or a saturated or unsaturated C.sub.14 to C.sub.20 fatty acid in the overall range of 0.5% to 10% per weight, respectively, wherein the relative weight percentages of all ingredients add up to 100% and all solubilization agents are independently from one another a food additive and/or a pharmaceutically acceptable excipient; c) Cautiously heating the resulting mixture by continuously increasing the temperature with a continuous temperature increment of 0.5 C./min-3 C./min over a period of 20-60 minutes; d) Stopping the temperature increase in a temperature range of 30 C. to 125 C. as soon as a clear solution is reached; and e) Letting the resulting solubilisate cool down to room temperature.

2. The method according to claim 1, wherein 5-amino-2,3-dihydro-1,4-phthalazinedione is provided in form of a sodium, potassium or lithium salt or a mixture thereof in the overall range of 0.1% to 2% per weight at room temperature and a pressure of 0.2 bar to 1 bar.

3. The method according to claim 1, wherein said at least one saturated or unsaturated C.sub.14 to C.sub.20 fatty acid is oleic acid.

4. The method according to claim 1, wherein said at least one C.sub.2 to C.sub.4 alcohol is ethanol.

5. The method according to claim 1, wherein additionally in step b) at least one antioxidant in the overall range of 0.01 to 10% per weight is added, said at least one antioxidant being a pharmaceutically acceptable excipient.

6. The method according to claim 5, wherein said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol.

7. A solubilisate of 5-amino-2,3-dihydro-1,4-phthalazinedione or of its sodium, potassium or lithium salt or a mixture thereof, produced by a method as defined in claim 1.

8. Prophylactic or therapeutic use of the solubilisate according to claim 7 in medicine.

9. Use of the solubilisate according to claim 7 as an immunomodulator for treating conditions with an overshooting immune reaction or conditions with an immunodeficient background.

10. Prophylactic or therapeutic use of the solubilisate according to claim 8 for enhancing the absorption and/or bioavailability of 5-amino-2,3-dihydro-1,4-phthalazinedione.

11. A pharmaceutical composition containing 5-amino-2,3-dihydro-1,4-phthalazinedione formulated in a solubilisate as defined in claim 6 and at least one pharmaceutically acceptable excipient.

12. A pharmaceutical composition according to claim 11, wherein said pharmaceutical composition is suitable for an oral, parenteral or topical administration.

13. Combination of a solubilisate according to claim 6 and at least one pharmaceutically active agent selected from a group comprising steroidal and non-steroidal anti-inflammatory drugs; immunomodulators; immunostimulatory agents; immunosuppressive agents; antibiotics; anti-infective agents; antiviral agents; antifungal agents; antiprotozoal agents; anthelmintics; analgesics; local anesthetics; anticoagulants; antiplatelet drugs; muscle relaxants; tonic agents; and anabolic agents for use in the prophylaxis and/or treatment of conditions with an overshooting immune reaction or conditions with an immunodeficient background.

14. A pharmaceutical composition according to claim 12, wherein said at least one pharmaceutically acceptable excipient is selected from a group comprising carriers, binding agents, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, permeation enhancers, antioxidants, diluents, pH regulators, fatiquors, solvents, consistency enhancers, hydrotopes, sweeteners, acidifiers, thickening agents, antiadherents, fillers, flavors, sweeteners, opacifiers, flavoring substances and aromatic substances.

15. A pharmaceutical composition according to claim 12 for use in medicine.

Description

EXAMPLES

[0221] In the ensuing examples the relative quantities of the solubilizing agents can be changed inside the margins indicated for each component in the method according to the invention.

[0222] The addition of glyceryl oleate and/or of an antioxidant is optional.

[0223] It is possible to upscale or downscale the indicated amounts according to the desired absolute amount of the agent to be solubilized in the solubilisate. The solubilisate can be portioned according to the desired final amount of the agent that shall be administered to a patient in need thereof.

[0224] In general, the produced solubilisates produced according to the method of the invention had a specific density of 0.92-0.94 kN/m.sup.3.

[0225] In each example the production of a dosage form for the solubilisates according to the invention is described for illustrative purposes. It is understood that the solubilisates according to the invention can be also used in any corresponding dosage form known in the art, e.g. as laid out in Remington: The Science and Practice of Pharmacy, 22.sup.nd edition, Pharmaceutical Press, 2013, which shall be incorporated by reference.

[0226] Standard chemicals were purchased from Sigma-Aldrich, Darmstadt, Germany.

Example 1: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedioneEmbodiment 1

[0227] The following indications refer to the weight percent of the mixture. A solubilisate of ca. 100 ml is generated. 5-amino-2,3-dihydro-1,4-phthalazinedione is provided, and then the solubilizing agents are admixed one by one under stirring for 5 min at room temperature (205 C.) and atmospheric pressure.

TABLE-US-00001 5-amino-2,3-dihydro-1,4- 2.0% phthalazinedione non-hydrogenated soybean PC 46.0% MCT oil 45.6% mixture of 1- 2.2% lysophosphatidylcholine and 2- lysophosphatidylcholine (1:1) ethanol 1.9% oleic acid 0.8% glyceryl stearate 1.2% glyceryl oleate 0.2% alpha-tocopherol 0.1%

[0228] Then the composition is cautiously heated under continued stirring, with an approximate temperature increment of 1 C./min. After ca. 20 min (ca. 40 C.) the composition starts to become a clear solution. This solubilization process lasts for ca. 16 min more. Thus a solubilisate according to the invention is obtained after ca. 36 min at ca. 56 C. Then the heating and the stirring is stopped and the resulting solubilisate is allowed to cool down to room temperature. The solubilisate stays clear and stable over an observation period of minimum 6 months.

Example 2: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedioneEmbodiment 2

[0229] The following indications refer to the weight percent of the mixture. A solubilisate of ca. 100 ml is generated. 5-amino-2,3-dihydro-1,4-phthalazinedione is provided, and then the solubilizing agents are admixed one by one under stirring for 5 min at room temperature (205 C.) and atmospheric pressure.

TABLE-US-00002 5-amino-2,3-dihydro-1,4- 0.15% phthalazinedione 1,2-dioleyl-SN-glycero-3- 60% phosphocholine (DOPC) MCT oil 32.45% 1-lysophosphatidylcholine 2.6% ethanol 2.2% oleic acid 1.1% glyceryl stearate 1.2% glyceryl oleate 0.2% beta-tocopherol 0.1%

[0230] Then the composition is cautiously heated under continued stirring, with an approximate temperature increment of 1.5 C./min. After ca. 23 min (ca. 55 C.) the composition starts to become a clear solution. This solubilization process lasts for ca. 10 min more. Thus a solubilisate according to the invention is obtained after ca. 33 min at ca. 70 C. Then the heating and the stirring is stopped and the resulting solubilisate is allowed to cool down to room temperature. The solubilisate stays clear and stable over an observation period of minimum 6 months.

Example 3: Solubilization of 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt

[0231] The following indications refer to the weight percent of the mixture. A solubilisate of ca. 100 ml is generated. 5-amino-2,3-dihydro-1,4-phthalazinedione sodium salt (in form of the polymorph Form I as described in WO 2011/107295 A1) is provided, and then the solubilizing agents are admixed one by one under stirring for 5 min at room temperature (205 C.) and atmospheric pressure.

TABLE-US-00003 5-amino-2,3-dihydro-1,4- 1.0% phthalazinedione sodium salt non-hydrogenated soybean PC 70.0% MCT oil 21.6% 2-lysophosphatidylcholine 2.6% ethanol 2.2% oleic acid 1.1% glyceryl stearate 1.2% glyceryl oleate 0.2% delta-tocopherol 0.1%

[0232] Then the composition is cautiously heated under continued stirring, with an approximate temperature increment of 1 C./min. After ca. 32 min ca. (52 C.) the composition starts to become a clear solution. This solubilization process lasts for ca. 8 min more. Thus a solubilisate according to the invention is obtained after ca. 40 min at ca. 60 C. Then the heating and the stirring is stopped and the resulting solubilisate is allowed to cool down to room temperature. The solubilisate stays clear and stable over an observation period of minimum 2 months.

Example 4: Preparation of a Liquid Dosage Form for Oral Application

[0233] In 45 ml of a liquid carrier having the following composition (in weight-%)

TABLE-US-00004 water for injection 99.3% citrate buffer 0.5% methyl paraben + propyl paraben 0.1% (ratio 5:1) sodium metabisulfite 0.1%

[0234] 5 ml of the solubilisate of Example 1 are solved. This solution (50 ml) can be filled into a suitable dropper bottle known in the art.

[0235] This formulation does not need an additional emulsifier such as a polysorbate.

Example 5: Preparation of a Liquid Dosage Form for Parenteral Application

[0236] In 245 ml of a liquid carrier having the following composition (in weight-%)

TABLE-US-00005 water for injection 98.9% sodium chloride 0.9% methyl paraben + propyl paraben 0.1% (ratio 10:1) sodium metabisulfite 0.1%

[0237] 5 ml of the solubilisate of Example 1 are solved. This parenteral solution (250 ml) can be filled into a suitable infusion bag known in the art.

[0238] This formulation does not need an additional emulsifier such as a polysorbate.

Example 6: Preparation of a Solid Dosage Form as Soft Gelatin Capsules

Composition of the Soft Gelatin Capsule Shell (in Weight-%):

[0239]

TABLE-US-00006 gelatin 66.3% glycerin 33.0% methyl paraben + propyl paraben 0.1% (ratio 4:1) carmoisine 0.1% titanium dioxide 0.5% aqua dest. 1.3 of gelatin

[0240] A soft gelatin capsule containing a solubilisate of 5-amino-2,3-dihydro-1,4-phthalazinedione is produced according to standard methods, as laid out in: Mahato and Narang, Pharmaceutical Dosage Forms and Drug Delivery, 2.sup.nd ed., chap. 18.3.5. Herein, 1.25 ml of the solubilisate of Example 1 are injected into the die cavity of the provided soft gelatin capsule which is then sealed.

Example 7: Preparation of a Solid Dosage Form as Hard Gelatin Capsules

Composition of the Hard Gelatin Capsule Shell (in Weight-%):

[0241]

TABLE-US-00007 gelatin 85.0% water 14.3% methyl paraben + propyl paraben 0.1% (ratio 4:1) sunset yellow 0.1% titanium dioxide 0.5%

[0242] Hard gelatin capsules (size 000, having a volume of 1.4 ml) are produced by a standard method known in the art. 1.25 ml of the solubilisate as produced in Example 1 are filled into a capsule, respectively. Thereupon the two pieces of the hard gelatin capsules are assembled.

Example 8: Preparation of a Topical Dosage Form as a Cream

The Following Ingredients are Used (in Weight-%):

[0243]

TABLE-US-00008 solubilisate of 5-amino-2,3-dihydro- 3.00% 1,4-phthalazinedione, as of Example 1 cetearyl alcohol (Lanette D) 6.60% glyceryl stearate (Cutina MD) 4.15% ceteareth 20 (Eumulgin B2) 0.40% ceteareth 12 (Eumulgin B1) 1.25% decyl oleate (Cetiol V) 2.50% allantoin 0.15% sodium cetearyl sulfate (Lanette E) 0.65% glycerin 20.70% phenoxyethanol, dehydroacetic acid, 1.00% benzoic acid (Rokonsal ND) aqua 59.60%

[0244] In a first preparation, the solubilisate of 5-amino-2,3-dihydro-1,4-phthalazinedione, cetearyl alcohol, glyceryl stearate, ceteareth 20, ceteareth 12, decyl oleate and sodium cetearyl sulfate are mixed and heated to 70 C. In a second preparation, allantoin, glycerin and aqua are mixed and heated to 70 C. Then the first preparation and the second preparation are slowly mixed and homogenized with a disperser (Ultra-Turrax T-18) for 2-3 min. When cooled down to 35 C., a third preparation consisting of Rokonsal ND is added and homogeneously stirred. The mixture is rehomogenized at ca. 45 C. for 1 min. Then the resulting mixture is allowed to cool down to room temperature under stirring, herein avoiding the inclusion of air. If necessary, the pH can be adjusted with NaOH or citric acid.

[0245] The pH of the cream is 5.40. The stability of the skin cream was minimum 6 months at 40 C. At this temperature no phase separation occurred.

[0246] 50 ml of the resulting cream are packaged into a collapsible suitable aluminum tube known in the art.

Example 9: Preparation of a Topical Dosage Form as a Hydrogel

[0247] A hydrogel is generated by slight modifications of the method disclosed in US 2010/0129448 A1.

[0248] A 3% CMC (carboxy-methyl-cellulose) solution is made by mixing 5 ml of the solubilisate of Example 1 with WFI (water for injection) followed by autoclaving to dissolve fully the CMC into solution, resulting in the formation of a CMC hydrogel. A suspension is made by adding said solubilisate solved in WFI into the CMC hydrogel. Stabilizers (TEA, citric acid) are added to the CMC hydrogel. The resulting combination is mixed under high shear conditions (paddle mixer and sonication) as described in US 2005/0175707 at elevated temperature (40 to 50 C.). Glycerol and additional WFI are also added to the suspension. The amount of excipients added to the hydrogel is controlled to achieve a desired concentration of containing 5-amino-2,3-dihydro-1,4-phthalazinedione.

[0249] The 3% CMC hydrogel suspension is further mixed for 20 minutes, resulting in the formation of a bulk hydrogel suspension. The bulk hydrogel suspension is observed under an optical microscope at 100 magnification. The primary particle size of the suspended particles is less than ca. 10 m, thus permitting topical application of the composition to open wounds or other tissues without abrasion.

Example 10: Preparation of a Solid Dosage Form as a Suppository

Composition of the Suppository Base (in Weight-%):

[0250]

TABLE-US-00009 cocoa butter 97.9% ascorbic acid 0.1% aluminum monostearate 2.0% [0251] 1) For melting, the suppository base is heated to 50-52 C. Then the melted fatty base is slowly cooled down to 36 C. [0252] 2) For each suppository to be cast the respective amount of 0.5 ml of the solubilisate of Example 3 is added to the fatty base. A soft base is formed. [0253] 3) Said soft base is filled into a suppository mold configured for the production of 3 cm long torpedo-shaped rectal suppositories having a weight of ca. 2 g. [0254] 4) The suppositories are let to cool down to room temperature and then are collected.

[0255] The use of the solubilisate according to the invention allows for the production of suppositories without the use of an additional emulsifier and/or a plasticizer. Thus such a suppository according to the invention is free of polysorbate.