WO2014108918A2 - An injectable antifungal formulation - Google Patents
An injectable antifungal formulation Download PDFInfo
- Publication number
- WO2014108918A2 WO2014108918A2 PCT/IN2014/000016 IN2014000016W WO2014108918A2 WO 2014108918 A2 WO2014108918 A2 WO 2014108918A2 IN 2014000016 W IN2014000016 W IN 2014000016W WO 2014108918 A2 WO2014108918 A2 WO 2014108918A2
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- WIPO (PCT)
- Prior art keywords
- voriconazole
- cyclodextrin
- formulation
- ready
- hydroxypropyl
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Definitions
- the invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
- the invention also relates to a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
- voriconazole is practically insoluble in water (0.61 mg/ml at a pH 7; 0.2 mg/ml at a pH 3), due to which development of aqueous intravenous formulations, with a sufficient shelf life has proved to be difficult.
- US Patent No. 6,632,803 describes pharmaceutical composition comprising voriconazole and sulfobutyl ether ⁇ -cyclodextrin (SBECD).
- SBECD is significantly costlier than hydroxpropyl ⁇ -cyclodextrin (HPBCD).
- EP 2 018 866 Al describes a process for increasing solubility of voriconazle in aqueous solutions by complexation with beta-cyclodextrin.
- EP 2 018 866 Al fails to disclose long term stability of its formulation in lyophilized form.
- EP 2 409 699 Al discloses pharmaceutical formulation comprising voriconazole, cyclodextrin and glycine, wherein glycine is present in a stabilizing amount.
- WO 2012/171561 discloses pharmaceutical formulation comprising voriconazole, hydroxpropyl ⁇ -cyclodextrin (HPpCD) and lactose, wherein lactose acts as a stabilizing agent.
- Voriconazole is marketed as an intravenous solution, which is available as a lyophilized powder for solution for intravenous infusion and contains 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial. It is a single-dose, unpreserved product. Vials containing 200mg lyophilized voriconazole are intended for reconstitution with water for injection to produce a solution containing lOmg/ml voriconazole and 160mg/ml of sulfobutyl ether beta-cyclodextrin sodium.
- the invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
- Another object of the invention is to provide a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution.
- Yet another object of the invention is to provide a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution, for the treatment of a fungal infections to a person in need thereof.
- Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility or stability of the drug of interest, which in turn can severely limit its therapeutic application.
- Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, chemical modifications, complexation etc. of the drugs with appropriate complexing agents such as cyclodextrins.
- Cyclodextrins are classified upon their properties and pore sizes as - cyclodextrin, ⁇ -cyclodextrin, and ⁇ -cyclodextrin.
- the available cyclodextrin in the invention includes derivatives of cyclodextrin, preferably ⁇ -cyclodextrin or derivatives thereof, having 6.0 - 6.5 A° of diameter for each pore size, and more preferably hydroxypropyl ⁇ -cyclodextrin (HPPCD).
- HPPD hydroxypropyl ⁇ -cyclodextrin
- the degree of molecular substitution of hydroxypropyl ⁇ -cyclodextrin (HPpCD) is preferably 0.2 - 1.0, and more preferably 0.4 - 1.0. If the degree of molecular substitution is too low, the solubility of HPpCD becomes low. In contrast, if it is too high, HP ⁇ CD becomes too viscous too handle.
- a ready to reconstitute injectable voriconazole formulation wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ -cyclodextrin after reconstitution, preferably not more than 140 mg/ml of hydroxypropyl ⁇ - cyclodextrin after reconstitution.
- hydroxypropyl ⁇ -cyclodextrin refers to a compound consisting of a ring of 7 D-glucose units linked by alpha- 1, 4 glycosidic bonds, wherein a certain proportion of the hydroxyl groups are substituted with a 2-hydroxypropyl functional group through an ether bond.
- bioavailability refers to the amount of a biologically active agent within a specific body compartment (such as the blood of the systemic circulation), following administration of the biologically active agent, as a percentage of the amount of the biologically active agent administered.
- present invention provides a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl ⁇ - cyclodextrin after reconstitution comprising the steps of: i) preparing an aqueous solution of voriconazole and hydroxpropyl ⁇ - cyclodextrin at a temperature of atleast 35°C ii) adjusting the pH of the aqueous solution with one or more pH regulating agents iii) optionally adding required amount of one or more pharmaceutically acceptable excipients iv) freeze-drying the solution to provide a lyophilized product for reconstitution.
- the suitable dose for the parenteral administration of voriconazole is between 0.1 to 25 mg/kg, preferably 0.5 to 20 mg/kg, more preferably 1 to 10 mg/kg.
- a ready to reconstitute injectable voriconazole formulation according to the present invention wherein the molar ratio of voriconazole and hydroxypropyl ⁇ -cyclodextrin in the formulation is in the range from about 1 :2 to about 1 :4, more preferably is about 1 :3.
- a ready to reconstitute injectable voriconazole formulation comprises 8 to 16 parts by weight of hydroxpropyl ⁇ -cyclodextrin with respect to voriconazole, more preferably 10 to 14 parts by weight of hydroxpropyl ⁇ -cyclodextrin in respect to voriconazole.
- a ready to reconstitute injectable voriconazole formulation optionally comprises one or more pH regulating agents, wherein the pH of the formulation is from about 3.5 to 7.0, preferably at about pH 4.0 to 6.5.
- one or more pH regulating agents include an acid, a base or a buffer or combinations thereof.
- the acid can be a mineral acid or an organic acid such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid tartaric acid and the likes.
- the base can be oxides, hydroxides, carbonates, bicarbonates and the likes.
- a ready to reconstitute injectable voriconazole formulation according to the present invention can additionally comprise one or more pharmaceutically acceptable excipients such as a sugar alcohol, preferably mannitol, wherein the pH of the formulation is essentially maintained at a range of about 3 to 7, preferably at about pH 4.0 to 6.5.
- Mannitol is a hexahydric alcohol related to mannose and is isomeric with sorbitol. It is a water soluble monomer having no film forming properties.
- a ready to reconstitute injectable voriconazole formulation according to the present invention can be freeze dried to obtain lyophilized powder which can be reconstituted with water for injection prior to administration as an infusion.
- a pharmaceutical kit comprising a ready to reconstitute injectable voriconazole formulation according to the present invention and sterile infusion solutions such as Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection, or Water for Injection.
- the formulations are typically diluted or reconstituted and may be further diluted if necessary, prior to administration.
- the present invention provides a method for treatment of a fungal infection comprising administration of an effective amount of a stable, injectable antifungal formulation comprising voriconazole as per the present invention to the person in need thereof.
- Fungal infections which may be treated by voriconazole have been extensively described in the literature, including EP-A 440 372.
- step (2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
- Example 7 Preparation of ready to reconstitute injectable voriconazole formulation comprising mannitol
- step (2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
- the injectable voriconazole formulation according to present invention has better reconstitution properties such as reconstitution time, appearance of the resulting solution, etc. when the voriconazole, hydroxypropyl ⁇ -cyclodextrin complex according to the present invention is redissolved, in an aqueous medium, which is suitable for injection.
- AUCiast The area under the plasma concentration versus time curve from time zero to the last measurable concentration.
- AUC j nf The area under the plasma concentration versus time curve from time zero to infinity. This is calculated as the sum of the AUCO-t plus the ratio
- a ready to reconstitute injectable voriconazole formulation according to the present invention comprising not more than 150 mg/mL of hydroxypropyl ⁇ - cyclodextrin
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Abstract
The invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution.
Description
FIELD OF INVENTION
The invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution. The invention also relates to a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS Voriconazole, (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl) - l-(lH-l,2,4-triazol-l-yl)-2-butanol, an anti-fungal agent, is disclosed in European patent no. EP 0 440 372 Bl and has following structure.
A problem associated with the use of voriconazole, however, is that voriconazole is practically insoluble in water (0.61 mg/ml at a pH 7; 0.2 mg/ml at a pH 3), due to which development of aqueous intravenous formulations, with a sufficient shelf life has proved to be difficult.
US Patent No. 6,632,803 describes pharmaceutical composition comprising voriconazole and sulfobutyl ether β-cyclodextrin (SBECD). However, SBECD is significantly costlier than hydroxpropyl β-cyclodextrin (HPBCD).
EP 2 018 866 Al describes a process for increasing solubility of voriconazle in aqueous solutions by complexation with beta-cyclodextrin.
However EP 2 018 866 Al fails to disclose long term stability of its formulation in lyophilized form.
EP 2 409 699 Al discloses pharmaceutical formulation comprising voriconazole, cyclodextrin and glycine, wherein glycine is present in a stabilizing amount.
WO 2012/171561 discloses pharmaceutical formulation comprising voriconazole, hydroxpropyl β-cyclodextrin (HPpCD) and lactose, wherein lactose acts as a stabilizing agent.
Voriconazole is marketed as an intravenous solution, which is available as a lyophilized powder for solution for intravenous infusion and contains 200 mg voriconazole and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial. It is a single-dose, unpreserved product. Vials containing 200mg lyophilized voriconazole are intended for reconstitution with water for injection to produce a solution containing lOmg/ml voriconazole and 160mg/ml of sulfobutyl ether beta-cyclodextrin sodium.
However, it has been observed that stability of voriconazole- hydroxypropyl β-cyclodextrin (HPpCD) inclusion complexes is far lower than the inclusion complexes comprising the sulfobutyl ether β-cyclodextrin (SBECD). As such, there remains a need for an injectable antifungal formulation comprising voriconazole.
SUMMARY AND OBJECTIVES OF THE INVENTION
The invention relates to a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution.
Another object of the invention is to provide a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution. Yet another object of the invention is to provide a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution, for the treatment of a fungal infections to a person in need thereof.
DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
Formulation of pharmaceutical dosage forms is frequently hampered by poor aqueous solubility or stability of the drug of interest, which in turn can severely limit its therapeutic application. Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, chemical modifications, complexation etc. of the drugs with appropriate complexing agents such as cyclodextrins.
Cyclodextrins are classified upon their properties and pore sizes as - cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. The available cyclodextrin in the invention includes derivatives of cyclodextrin, preferably β-cyclodextrin or derivatives thereof, having 6.0 - 6.5 A° of diameter for each pore size, and more preferably hydroxypropyl β-cyclodextrin (HPPCD). The degree of molecular substitution of hydroxypropyl β-cyclodextrin (HPpCD) is preferably 0.2 - 1.0, and more preferably 0.4 - 1.0. If the degree of molecular substitution is too low, the solubility of HPpCD becomes low. In contrast, if it is too high, HPβCD becomes too viscous too handle.
Although cyclodextrins have been used to increase the solubility, dissolution rate and/or stability of a great many compounds, it is also known that
there are many drugs for which cyclodextrin complexation either is not possible or produces no apparent advantages.
According to the present invention, there is now provided a ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β-cyclodextrin after reconstitution, preferably not more than 140 mg/ml of hydroxypropyl β- cyclodextrin after reconstitution.
Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
"About," "approximately," and the like, when used in connection with a numerical variable, generally refers to the value of the variable and to all values of the variable that are within ±10% of the indicated value. As used herein, the term "hydroxypropyl β-cyclodextrin" refers to a compound consisting of a ring of 7 D-glucose units linked by alpha- 1, 4 glycosidic bonds, wherein a certain proportion of the hydroxyl groups are substituted with a 2-hydroxypropyl functional group through an ether bond.
As used herein, "bioavailability" refers to the amount of a biologically active agent within a specific body compartment (such as the blood of the systemic circulation), following administration of the biologically active agent, as a percentage of the amount of the biologically active agent administered.
All references herein to voriconazole include references to pharmaceutically acceptable salts, solvates, or derivatives thereof. In a preferred embodiment, present invention provides a process for preparation of a ready to reconstitute injectable voriconazole formulation, wherein
the formulation comprises not more than 150 mg/ml of hydroxypropyl β- cyclodextrin after reconstitution comprising the steps of: i) preparing an aqueous solution of voriconazole and hydroxpropyl β- cyclodextrin at a temperature of atleast 35°C ii) adjusting the pH of the aqueous solution with one or more pH regulating agents iii) optionally adding required amount of one or more pharmaceutically acceptable excipients iv) freeze-drying the solution to provide a lyophilized product for reconstitution.
In another embodiment, the suitable dose for the parenteral administration of voriconazole is between 0.1 to 25 mg/kg, preferably 0.5 to 20 mg/kg, more preferably 1 to 10 mg/kg.
In yet another embodiment, a ready to reconstitute injectable voriconazole formulation according to the present invention, wherein the molar ratio of voriconazole and hydroxypropyl β-cyclodextrin in the formulation is in the range from about 1 :2 to about 1 :4, more preferably is about 1 :3.
In yet another embodiment, a ready to reconstitute injectable voriconazole formulation, according to the present invention comprises 8 to 16 parts by weight of hydroxpropyl β-cyclodextrin with respect to voriconazole, more preferably 10 to 14 parts by weight of hydroxpropyl β-cyclodextrin in respect to voriconazole.
In yet another embodiment, a ready to reconstitute injectable voriconazole formulation, according to the present invention optionally comprises one or more pH regulating agents, wherein the pH of the formulation is from about 3.5 to 7.0, preferably at about pH 4.0 to 6.5.
In a still preferred embodiment, for pH adjustment, one or more pH regulating agents include an acid, a base or a buffer or combinations thereof. The acid can be a mineral acid or an organic acid such as hydrochloric acid, nitric acid, phosphoric acid, acetic acid, citric acid, fumaric acid, malic acid tartaric acid and the likes. The base can be oxides, hydroxides, carbonates, bicarbonates and the likes. The buffering agents can be citrates, acetates, phosphates other organic buffers and the like. The preferred base and acid used in the formulation of present invention for pH adjustment are sodium hydroxide and hydrochloric acid respectively. In yet another embodiment, a ready to reconstitute injectable voriconazole formulation according to the present invention can additionally comprise one or more pharmaceutically acceptable excipients such as a sugar alcohol, preferably mannitol, wherein the pH of the formulation is essentially maintained at a range of about 3 to 7, preferably at about pH 4.0 to 6.5. Mannitol is a hexahydric alcohol related to mannose and is isomeric with sorbitol. It is a water soluble monomer having no film forming properties.
A ready to reconstitute injectable voriconazole formulation according to the present invention can be freeze dried to obtain lyophilized powder which can be reconstituted with water for injection prior to administration as an infusion. In a further embodiment of the invention, there is provided a pharmaceutical kit comprising a ready to reconstitute injectable voriconazole formulation according to the present invention and sterile infusion solutions such as Dextrose Injection, Sodium Chloride Injection, Lactated Ringer's Injection, or Water for Injection. The formulations are typically diluted or reconstituted and may be further diluted if necessary, prior to administration.
In yet another embodiment, the present invention provides a method for treatment of a fungal infection comprising administration of an effective amount of a stable, injectable antifungal formulation comprising voriconazole as per the present invention to the person in need thereof. Fungal infections which may be
treated by voriconazole have been extensively described in the literature, including EP-A 440 372.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention in any way.
Examples
Preparation of ready to reconstitute injectable voriconazole formulation
Table 1
Method:
1) Aqueous solution of voriconazole and hydroxpropyl beta-cyclodextrin was prepared
2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
3) The pH of the resulting solution was adjusted.
4) The solution obtained was filtered through a filter and filled in vials and lyophilized.
Example 7: Preparation of ready to reconstitute injectable voriconazole formulation comprising mannitol
Table 2
Method:
1) Aqueous solution of voriconazole and hydroxpropyl beta-cyclodextrin was prepared
2) The solution obtained from step (1) was kept at a temperature of atleast 35°C to obtain a solution
3) Dispensed quantity of mannitol was added to the above solution
4) The pH of the solution was recorded and volume was made up with water for injection
5) The solution obtained was filtered and filled in vials and lyophilized.
The injectable voriconazole formulation according to present invention has better reconstitution properties such as reconstitution time, appearance of the resulting solution, etc. when the voriconazole, hydroxypropyl β-cyclodextrin complex according to the present invention is redissolved, in an aqueous medium, which is suitable for injection.
The physico-chemical characteristics of the voriconazole, hydroxypropyl β- cyclodextrin complex are given below in table 3. Table 3:
Pharmacokinetic Studies
An open label, balanced, single dose, cross over, randomized, two-period, two- sequence bioavailability study of a ready to reconstitute injectable voriconazole formulation according to the present invention was conducted in six healthy, adult, female beagle dogs by intravenous infusion. Results of this study are depicted in the table 4 below.
Table 4:
*Values are expressed as geometric mean AUCiast: The area under the plasma concentration versus time curve from time zero to the last measurable concentration.
AUCjnf: The area under the plasma concentration versus time curve from time zero to infinity. This is calculated as the sum of the AUCO-t plus the ratio
of the last measurable concentration, to the elimination rate constant.
Test: A ready to reconstitute injectable voriconazole formulation according to the present invention comprising not more than 150 mg/mL of hydroxypropyl β- cyclodextrin
Reference: Formulation comprising more than 150 mg/mL of substituted cyclodextrin
Thus it is evident from the results that ready to reconstitute injectable voriconazole formulation according to the present invention has similar or better bioavailability than the reference product comprising more than 150 mg/mL of substituted cyclodextrin. Thus, the above-listed additives should be taken as merely exemplary, and riot limiting, of the types of additives that can be included in formulations of the invention.
While the invention has been described in detail with respect to specific embodiments thereof, it will be apparent that numerous modifications and variations are possible without departing from the scope of the invention.
Claims
A ready to reconstitute injectable voriconazole formulation, wherein the formulation comprises not more than 150 mg/ml of hydroxypropyl β- cyclodextrin after reconstitution.
A ready to reconstitute injectable voriconazole formulation according to claim 1, wherein the said formulation is lyophilized.
A ready to reconstitute injectable voriconazole formulation according to claim 1, wherein the molar ratio of voriconazole and hydroxypropyl β- cyclodextrin is in the range of about 1 :2 to about 1 :4.
A ready to reconstitute injectable voriconazole formulation according to claim 3, wherein the molar ratio of voriconazole and hydroxypropyl β- cyclodextrin is about 1 :3.
A process for the preparation of a ready to reconstitute injectable voriconazole formulation according to claim 1, comprises the steps of: i) preparing an aqueous solution of voriconazole and hydroxpropyl β- cyclodextrin at a temperature of atleast 35°C ii) adjusting the pH of the aqueous solution with one or more pH regulating agents iii) optionally adding required amount of one or more pharmaceutically acceptable excipients iv) freeze-drying the solution to provide a lyophilized product for reconstitution.
Use of a ready to reconstitute injectable voriconazole formulation according to claim 1, for the treatment of fungal infection, which has
similar or better relative bioavilability than the reference product when measured in animals.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN120CH2013 | 2013-01-08 | ||
| IN120/CHE/2013 | 2013-01-08 |
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| Publication Number | Publication Date |
|---|---|
| WO2014108918A2 true WO2014108918A2 (en) | 2014-07-17 |
| WO2014108918A3 WO2014108918A3 (en) | 2014-12-04 |
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| PCT/IN2014/000016 WO2014108918A2 (en) | 2013-01-08 | 2014-01-07 | An injectable antifungal formulation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019504042A (en) * | 2015-12-21 | 2019-02-14 | 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Oral preparation and production method thereof |
| JP2019506377A (en) * | 2015-12-21 | 2019-03-07 | 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Drug inclusion compound, preparation thereof, and production method therefor |
| TWI738100B (en) * | 2018-10-31 | 2021-09-01 | 法商施維雅藥廠 | Cyclodextrin-based formulation of a bcl-2 inhibitor |
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| EP2018866A1 (en) * | 2007-07-27 | 2009-01-28 | Sandoz AG | Pharmaceutical compositions containing voriconazole |
| EP2409699A1 (en) * | 2010-07-23 | 2012-01-25 | Combino Pharm, S.L. | Stable compositions of voriconazole |
| WO2012171561A1 (en) * | 2011-06-15 | 2012-12-20 | Synthon Bv | Stabilized voriconazole composition |
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| CN1788725A (en) * | 2004-12-15 | 2006-06-21 | 北京博尔达生物技术开发有限公司 | Voriconazole freeze-drying powder injection and its preparation process |
| EP2018866A1 (en) * | 2007-07-27 | 2009-01-28 | Sandoz AG | Pharmaceutical compositions containing voriconazole |
| EP2409699A1 (en) * | 2010-07-23 | 2012-01-25 | Combino Pharm, S.L. | Stable compositions of voriconazole |
| WO2012171561A1 (en) * | 2011-06-15 | 2012-12-20 | Synthon Bv | Stabilized voriconazole composition |
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| JP2019504042A (en) * | 2015-12-21 | 2019-02-14 | 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Oral preparation and production method thereof |
| JP2019506377A (en) * | 2015-12-21 | 2019-03-07 | 広州市香雪製薬股▲ふん▼有限公司Ｇｕａｎｇｚｈｏｕ Ｘｉａｎｇｘｕｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | Drug inclusion compound, preparation thereof, and production method therefor |
| US11007141B2 (en) | 2015-12-21 | 2021-05-18 | Guangzhou Xiangxue Pharmaceutical Co., Ltd. | Oral preparation and preparation method thereof |
| US11071737B2 (en) | 2015-12-21 | 2021-07-27 | Guangzhou Xiangxue Pharmaceutical Co., Ltd. | Drug inclusion complex, preparation thereof, and preparation method thereof |
| TWI738100B (en) * | 2018-10-31 | 2021-09-01 | 法商施維雅藥廠 | Cyclodextrin-based formulation of a bcl-2 inhibitor |
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| WO2014108918A3 (en) | 2014-12-04 |
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