MX2008000669A - Pharmaceutical formulations of endo-n-(9- methyl-9-azabicyclo[3 .3.1]non-3-yl)-1-methyl-1h-indazole-3-carboxamide hydrochloride - Google Patents

Abstract

A pharmaceutical formulation suitable for multi-dose administration comprising endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carboxanide hydrochloride, a preservative selected from the group consisting of alkyl paraben and phenol, and a buffer selected from the group consisting of acetate and phosphate buffers is disclosed.

Description

HYDROCHLORIDE PHARMACEUTICAL FORMULATIONS OF END0-N- (9-METHYL-9-AZABICICLO [3.3.1J ON-3-IL) -1-METHYL-1H-INDAZOL-3-CARBOXAMIDE This invention relates to improved formulations of endohydrochloride -N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide. The formulations of this invention are useful as anti-emetics, particularly in the treatment of emesis induced by cytotoxic agent. BACKGROUND OF THE INVENTION The endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride is used as an anti-emetic , particularly in the treatment of emesis induced by cytotoxic agent, and methods for its synthesis are disclosed in U.S. Patent No. 4,886,808. The endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -1-methyl-lH-indazole-3-carboxamide hydrochloride is commercially available and is also known by the generic name of granisetron hydrochloride. An injectable dosage form of endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride was first marketed as a small vial of single use of 1 mL containing an aqueous solution comprising 1.12 mg of hydrochloride granisetron equivalent to 1 mg of granisetron. The recommended dosage for granisetron hydrochloride is 10 mcg / kg applied intravenously for 5 minutes, beginning within 30 minutes before the initiation of chemotherapy. The single-use vial of 1 mg / mL has proven to be undesirable in a number of ways. The recommended dose is 10 mcg / kg per body weight. Thus, the 1 mL vial is not optimal for patients weighing more than 100 kg, and a portion of a second vial will have to be used and the remaining medication discarded. Similarly, product disposal will occur when administered to low-weight patients who do not require a full dose of 1 mL. Numerous advantages are realized from a suitable multi-dose vial of endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride. The advantages of a multi-dose vial of endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -1-methyl-lH-indazole-3-carboxamide hydrochloride include: producing a dosage based on more efficient weight in order to minimize the waste product, conserve resources, contain costs, make better use of storage space and cost more effective to produce and transport. U.S. Patent No. 6,294,548 discloses a aqueous multidose formulation of endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride and a host of possible preservatives, which includes meta-cresol, benzyl alcohol, methylparaben, propylparaben, and a combination of methylparaben and propylparaben. According to the patent, parabens are effective as preservatives, but unstable in autoclave. The autoclave is preferred by most regulatory agencies to ensure the sterility of pharmaceutical formulations. It has now been found that certain combinations of preservatives and buffer systems produce formulations that are adequately stable during the autoclave. More particularly, it has been found that a pharmaceutical formulation comprising endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride, one or more preservatives selected from the group consisting of alkyl paraben and phenol, and a buffer solution selected from the group consisting of acetate and phosphate buffer solutions can be autoclaved to produce a sterile multidose formulation. DETAILED DESCRIPTION OF THE INVENTION The parabens of the present invention are preferably C 4 alkyl parabens, and salts thereof, which can be used alone or in combination with each other. Particularly preferred is methyl paraben, in an amount of approximately 0.45 to 2.5 mg / mL and propylparaben, in an amount of approximately 0.05 to 0.45 mg / mL. The most preferred paraben preservative system is the combination of methylparaben and propylparaben, wherein methylparaben is present in an amount of about 1.8 mg / mL and propylparaben is present in an amount of about 0.2 mg / mL. Where the preservative is phenol, it may be present in the formulation in an amount of 0.5 to 10 mg / mL, preferably of approximately 5 mg / mL. The buffer solution used in the pharmaceutical formulation of the present invention is an acetate or phosphate buffer solution. An acetate buffer is preferred, which can be prepared from acetic acid and an acetate such as sodium, ammonium or potassium acetate. The amount of buffer used in the formulation will be dictated by the desired pH, with typical pHs ranging from 3.0 to 8.0, preferably from 3.0 to 6.0. The pharmaceutical formulation of the present invention can be sterilized by techniques known in the art, such as aseptic filtration (aseptic filling) or terminal hot sterilization (autoclaving). Terminal hot sterilization, such as by steam or Water heated in cascade, is, as noted previously, preferred for aseptic filling by much more regulatory agencies. The sterilization can be measured by Fn, Equivalent Time of Sterilization Process, which represents the equivalent number of minutes at 121.1 ° C supplied to a container in a sterilization process. According to the present invention, the sterilization is preferably carried out by autoclaving at a temperature of 115 to 125 ° C for a period of 15 to 30 minutes, preferably at 121 ° C +/- 1 ° C for a period of time. from 19-24 minutes. SELECTION STUDY OF THE REGULATORY SOLUTION Table 1 - Formula of the Phosphate Regulatory Solution 'equivalent to 1 mg of Granisetron base Table 2 - Acetate Regulatory Solution Formula "equivalent to 1 mg of Granisetron base Procedure In a suitable composite vessel, add Purified Water equal to approximately 80% batch size at room temperature, then weigh and add Sodium Chloride, USP in the compound container and mix until that everything dissolves Verify complete dissolution by visual inspection Weigh and add the entire amount of regulating agents as provided in Tables 1-2 for each formulation and mix until dissolved, verify complete dissolution by visual inspection. Weigh and add the whole amount of Granisetron HCl to the composite container and mix HC1 Granisetron until it dissolves Measure the pH The Qs the solution to the final weight with purified water Mix the volume for not less than 5 minutes Filter the solution to through a sterilized 0.22 μrn membrane filter.

Fill with the filtered solution the glass vials in full / 4 mL flask and seal the vials with a rubber stopper. Terminally sterilize the filled bottles using a cascade water autoclave for a target F0 of 30. Results The data reveal that all test results are satisfactory. A comparison of the test and the composite results between the autoclaved and autoclaved samples of the buffer solutions of both acetate and phosphate do not indicate any instability in any formulation. CONSERVATIVE SELECTION STUDY Table 3 - Parabeno Formula 'equivalent to 1 mg of Granisetron base Table 4 - Formula of Phenol "equivalent to 1 mg of Granisetron base Procedure Compound a batch of Granisetron Hydrochloride Injection, 1.12 mg / mL, full / 4 mL vial using the acetate buffer system. Add the selected conservator as listed in the above. Qs for the final volume with purified water. Filter the solution using a 0.22 μm membrane filter. Fill the glass bottles with the solution and cover using rubber stoppers (cover the bottles containing phenol with nitrogen). Autoclave the filled fills at 121 ° C for an F0 of 15. Results The stability data reported below reveal that all test results are satisfactory. The evaluation of stability is performed under accelerated stability conditions at 40 ° C ± 2 ° C / 75% ± 5% RH for up to 3 months. The Granisetron test data does not indicate significant stability trends over a 3-month period at 40 ° C. There is no significant increase in the degradation products. The trials of methylparaben and propylparaben and phenol remain stable throughout the study. The antimicrobial preservative effectiveness test is performed at the initial time point and all test results comply with the USP < 51 > for an injectable product.

Table 5 - Stability of the Granisetron / Parabens Formulation Formulation: Each mL contains HC1 Granisetron 1.12 mg / mL, Sodium Chloride, USP 9 mg / mL, Glacial Acetic Acid, USP 0.52 mg / mL, Anhydrous Sodium Acetate, USP 0.82 mg / mL, Methylparaben, NF 1.8 mg / mL, Propylparaben, NF 0.2 mg / mL and Water for injection qs for lmL.

Table 6 Stability of the Granisetron / Phenol Formulation Formulation: Each mL contains HC1 Granisetron 1.12 mg / mL, Sodium Chloride, USP 9 mg / mL, Glacial Acetic Acid, USP 0.52 mg / mL, Anhydrous Sodium Acetate, USP 0.82 mg / mL, Phenol, USP 0.5 mg / mL and Water for Injection qs for 1 mL

Claims (9)

1. CLAIMS 1. A pharmaceutical formulation, characterized in that it comprises endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride, a preservative selected from the group consisting of alkyl paraben and phenol, and a regulatory solution selected from the group consisting of acetate and phosphate buffer solutions.
2. 2. A formulation according to claim 1, characterized in that the preservative comprises one or more C? -4 alkyl paraben, and salts thereof.
3. 3. A formulation according to claim 2, characterized in that the preservative comprises methylparaben and propylparaben.
4. 4. A formulation according to claim 1, characterized in that the preservative comprises phenol.
5. 5. A formulation according to claim 1, characterized in that the buffer is an acetate buffer solution.
6. 6. A formulation according to claim 1, characterized in that the regulatory solution is a phosphate buffer solution.
7. 7. A pharmaceutical formulation, characterized because it comprises endo-N- (9-methyl-9-azabicyclo [3.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride, a combination of methyl- and propylparaben as a preservative, and an acetate buffer solution.
8. 8. A sterile multidose pharmaceutical formulation, characterized in that it comprises endo-N- (9-methyl-9-azabicyclo [3'.3.1] non-3-yl) -l-methyl-lH-indazole-3-carboxamide hydrochloride. , a preservative selected from the group consisting of alkyl paraben and phenol, and a regulatory solution selected from the group consisting of acetate and phosphate buffer solutions.
9. 9. A sterile multi-dose pharmaceutical formulation according to claim 8, characterized in that the sterilization is carried out by aseptic filtration or by autoclaving.