Title of Invention	"PHARMACEUTICAL FORMULATIONS CONTAINING VORICONAZOLE"
Abstract	The invention provides a pharmaceutical formulation comprising voriconazole, or a pharmaceutically acceptable derivative thereof, and a cyclodextrin derivative of formula I, wherein R1a-g, R2a-g and R3a'g independently represent OH or O(CH2)4SO3H; provided that at least one of Rla"B represents 0(CH,)4SO3H; or a pharmaceutically acceptable salt thereof.

Full Text

Pharmaceutical formulations containing voriconazole This invention relates to a new pharmaceutical formulation of voriconazole with a sulphobutylether β-cyclodextrin. Voriconazole is disclosed in European Patent Application 0440372 (see Example 7). It has the following structure: and is useful in the treatment of fungal infections. Voriconazole has a low aqueous 10 solubility (0.2mg/ml @ pH 3), and is not stable in water (an inactive enantiomer is formed from recombination of the retro-aldol products of hydrolysis). Thus, development of an aqueous intravenous formulation with a sufficient shelf life is difficult. These problems are magnified by the semi-polar nature of the compound (log D = 1.8) which means that it is not generally solubilised by conventional means such as oils, surfactants or water miscible 15 co-solvents. European Patent Application 0440372 mentions that the compounds disclosed therein may be formulated with cyclodextrin: however, it is now suspected that underivatised or unmetabolised cyclodextrin has toxic effects on the body and so is unsuitable as a 20 pharmaceutical excipient, particularly when administered parenterally. International Patent Application WO 91/11172 discloses sulphoalkylether cyclodextrin derivatives of formula A. (Figure Removed) wherein n is 4, 5 or 6: R1-9 independently represent O" or O-(C2.6 alkylene)-SO", provided that at least one of R1 5 and R2 is O-(C2.6 alkylene)-SO"; and S1-9 independently represent a pharmaceutically acceptable cation (such as H+ or Na+). It has now been found that the solubility of voriconazole in water can be increased by molecular encapsulation with sulphoalkylether cyclodextrin derivatives of the type 10 disclosed in International Patent Application WO 91/11172, particularly when n is 5 (a Pcyclodextrin derivative) and the cyclodextrin ring is substituted by sulphobutyl groups. Thus, according to the present invention, there is provided a pharmaceutical formulation comprising voriconazole, or a pharmaceutically acceptable derivative thereof, and a 5 cyclodextrin derivative of formula I, wherein(Figure Removed) R2a-B independently represent OH or 0(CH2)4SO3H; provided that at least one of Rla"s represents O(CH2)4SO3H; or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of particular interest are salts of the 0(CH2)4SO3H groups, for example alkali metal salts, such as sodium salts. Preferably, the average number of O(CH2)4SO3H groups per molecule of formula I is in the range 6.1-6.9, for example 6.5. This enhances molecular encapsulation resulting in enhanced voriconazole solubility. This effect would not be anticipated because increasing the degree of substitution increases steric hindrance around the cavity of the cyclodextrin 10 and would be expected to reduce complexation efficiency. It is preferred that each O(CH:)4S03H present is in the form of an alkali metal salt (such as the sodium salt). This enhances the affinity of the molecule for voriconazole, which is unexpected because voriconazole is not charged. Preferably, the formulation is for parenteral administration, for example, i.v. administration. The aqueous stability of the voriconazole-cyclodextrin derivative complex is further 20 enhanced by lyophilisation (freeze-drying). The cyclodextrin derivatives used in formulations according to the invention enable the finished lyophilised product to accommodate high levels of moisture (up to 3.0%) without a detrimental effect on stability. Furthermore, the use of such cyclodextrin derivatives controls and minimises the formation of the inactive enantiomer of voriconazole. Generally, in aqueous intravenous and intramuscular formulations according to the invention, the voriconazole will be present at a concentration of from 5 mg/ml to 50 mg ml. for example 10 mg/ml to 30 nig/ml. The cyclodextrin derivative of formula I will be present in a molar ratio of voriconazole:cyclodextrin derivative of from 1:1 to 1:10. for 30 example 1:2 to 1:7. in particular 1:2 to 1:3. The formulations may be lyophilised (freeze dried) for storage prior to use. and made up with water when required. In the following example, the sulphobutylether p-cyclodextrin has an average sulphobutylether substitution of 6.5 per cyclodextrin molecule, and each sulphobutylether unit is present as its sodium salt. 5 Example 1 formulation of voriconazole Ingredient Voriconazole 10 Sulphobutylether p-cyclodextrin Water for injections Specification Pfizer Pfizer Ph. Eur. Total mo/ml 10.000 160.000 to 1.000ml 1.000ml Method: 15 1. With constant stirring, add the sulphobutylether cyclodextrin (SBECD) to 80% of the final volume of water for injections, and continue to stir until all the SBECD has dissolved. 2. Add the voriconazole and dissolve with stirring. 3. Make the solution up to volume with water for injections. 20 4. Filter the resulting solution through a sterile 0.2 mm nylon filter into a sterile container. 5. Fill 20 ml volumes into sterile freeze drying vials and stopper. Lyophilise. Claims: 1. A pharmaceutical formulation comprising voriconazole, or a pharmaceutically acceptable derivative thereof, and a cyclodextrin derivative of formula I, wherein R2a-g independently represent OH or 0(CH2)4SO3H; provided that at least one of R represents O(CH2)4S03H; or a pharmaceutically acceptable salt thereof. 2. A formulation as claimed in claim 1, wherein the average number of O(CH2)4SO3H groups per molecule of formula I is in the range 6.1-6.9. 3. A formulation as claimed in claim 1 or claim 2, wherein each O(CH2)4SO3H present is in the form of an alkali metal salt. 4. A formulation as claimed in any one of the preceding claims, which is adapted for parenteral administration. 5. A formulation as claimed in any one of the preceding claims, wherein the cyclodextrin derivative of formula I is present in a molar ratio of voriconazole:cyclodextrin derivative of from 1:1 to 1:10. 6. A formulation as claimed in any one of the preceding claims, which is a solution in water. 7. A formulation as claimed in any one of claims 1-5, which has been lyophilised. 8. A pharmaceutical formulation substantially as herein described with reference to the foregoing examples.

Documents:

1674-del-1998-abstract.pdf

1674-del-1998-assignment.pdf

1674-del-1998-claims.pdf

1674-del-1998-Correspondence Others-(07-02-2014).pdf

1674-del-1998-Correspondence Others-(14-08-2014).pdf

1674-del-1998-Correspondence Others-(20-08-2014).pdf

1674-del-1998-Correspondence-Others-(16-12-2010).pdf

1674-DEL-1998-Correspondence-Others-(24-06-2010).pdf

1674-DEL-1998-Correspondence-Others-(5-1-2010).pdf

1674-del-1998-correspondence-others.pdf

1674-del-1998-description (complete).pdf

1674-del-1998-form-1.pdf

1674-del-1998-form-19.pdf

1674-del-1998-form-2.pdf

1674-del-1998-Form-3-(14-08-2014).pdf

1674-DEL-1998-Form-3-(24-06-2010).pdf

1674-del-1998-form-4.pdf

1674-del-1998-form-6.pdf

1674-del-1998-gpa.pdf

1674-del-1998-Pre-Grant Opposition-(04-07-2014).pdf

1674-del-1998-Pre-grant-Opposition-(29-06-2012).pdf

1674-del-1998-Written Arguments-(20-08-2014).pdf

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