MXPA99011299A - Pharmaceutical compositions containing eletriptan hemisulphate and caffeine - Google Patents

Abstract

The present invention provides an aqueous pharmaceutical composition comprising from 5 to 200 mg/ml of eletriptan hemisulphate and from 0.5 to 2.0%weight/volume of caffeine.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING ELETRIPTAN HEMISULPHATE The present invention relates to pharmaceutical compositions containing eletriptan hemisulfate. More especially, it relates to aqueous pharmaceutical formulations containing eletriptan hemisulfate which are stabilized with caffeine. Eletriptan (UK-116,044), 3 - ([1-methylpyrrolidin-2 (R) -yl] methyl) -5- (2-phenylsufonylethyl) -1 H -indole, is a selective receptor agonist 5- HT? which is in development for the treatment of migraine.

Eletriptan is described in WO-A-92/06973. Eletriptan hemisulfate (molecular weight = 431.6) has a solubility in water (> 100 mg / ml at 4 ° C) greater than eletriptan itself and the alpha and beta polymorphic forms are specifically described in WO-A- 96/06842. However, eletriptan hemisulfate is unstable upon hydrolysis and degrades by hydrolysis and oxidation in aqueous solutions. In fact, a solution of this salt in an aqueous buffer at pH 8 degrades leaving less than 85% (based on the original weight) of eletriptan after leaving it at rest for 12 weeks at 50 ° C. At least five degradation products have been detected by HPLC techniques. This level of stability is very unsuitable for aqueous pharmaceutical formulations of eletriptan, which should have a useful shelf life. Preferably, said formulations will not degrade leaving less than 95% (based on the original weight) of eletriptan at rest in aqueous buffer at pH 8 for 12 weeks at 50 ° C, and, in addition, the total detectable impurities will not exceed 2% in weight after this time. The object of this invention is to provide a stable aqueous pharmaceutical formulation containing eletriptan hemisulfate. A further object of this invention is to provide a stable aqueous pharmaceutical formulation containing eletriptan hemisulfate, which is suitable for intranasal and subcutaneous administration, and which enables the drug to have a good bioavailability and rapid absorption and onset of action when administered from this mode. Higuchi et al .. J. Am. Pharm. Association, XLIV (9), 521 (1955), have reported that caffeine substantially reduces degradation by hydrolysis of benzocaine in aqueous solution. Samie et al., Pharm. Acta. Helv. 58 (1), 28 (1983), have shown that caffeine can improve the photochemical stability of certain phenothiazines. However, this is not a generalized effect for this class of compounds. It was also found that caffeine also exerts a variable effect on the non-photochemical degradation of the phenothiazines examined. Surprisingly, it has now been discovered that caffeine stabilizes aqueous pharmaceutical formulations containing eletriptan hemisulfate and also improves the solubility thereof. In addition, eletriptan hemisulfate has good bioavailability and rapid absorption and onset of action when administered in the form of formulations stabilized in caffeine by the intranasal and subcutaneous routes. It has also surprisingly been found that the stability of such formulations is further increased by the additional presence of an antioxidant (preferably citric acid or ascorbic acid) and / or a solvent (preferably ethanol). The present invention provides an aqueous pharmaceutical composition comprising from 5 to 200 mg / ml of eletriptan hemisulfate and from 0.5 to 2.0% by weight / volume of caffeine. Optionally, an antioxidant may be present. Suitable antioxidants include citric acid and ascorbic acid. Preferably, up to 1.0%, inclusive, in weight / volume of citric acid or ascorbic acid may be present. Optionally, a cosolvent such as ethanol may be present. Preferably, up to 20%, inclusive, by weight / volume of ethanol can be present.

Preferably, the composition is buffered at a pH of 4.0 to 9. 0. Preferably, the composition is buffered at a pH of 7.0 to 9. 0. Preferably, the composition is buffered at a pH of 7.5 to 8. 5. Preferably, the composition is buffered to approximately pH 8. Preferably, the composition is buffered at a pH of 4.0 to 5.0. Preferably, 5 to 150 mg / ml of eletriptan hemisulfate are present. Preferably, 10 to 100 mg / ml of eletriptan hemisulfate are present. Preferably, from 40 to 160 mg / ml of eletriptan hemisulfate are present. Preferably, from 40 to 140 mg / ml of eletriptan hemisulfate are present. Preferably, 60 to 120 mg / ml of eletriptan hemisulfate are present. Preferably, it is present from 1.0 to 2.0% by weight / volume of caffeine.

Preferably, OJ is present at 1.0% by weight / volume of citric acid. Preferably, 0.2 to 1.0% weight / volume of citric acid is present. Preferably, 0.3 to 1.0% weight / volume of citric acid is present. Preferably, 0.2 to 0.4% weight / volume of citric acid is present. Preferably, up to 1.0%, inclusive, in weight / volume of ascorbic acid is present. Preferably, 0.3 to 0.6% by weight / volume of ascorbic acid is present. For intranasal administration, it is preferably present at 1.0 to 20.0% weight / volume of ethanol, more preferably, 2.0 to 10.0% weight / volume of ethanol is present and, most preferably, 2.0 to 6.0% is present. in weight / volume of ethanol. For subcutaneous administration, it is most preferable that up to 10%, inclusive, weight / volume of ethanol is present. The compositions of the present invention may be prepared by conventional procedures, for example, as described in the examples herein. The compositions are buffered to the desired pH. For a pH of the composition of 7.0 to 9.0, a suitable buffer such as tris (hydroxymethyl) methylamine can be used. When tris (hydroxymethyl) methylamine is used, its concentration is preferably maintained at about 0.05M or about 0.02M and a suitable base, for example, aqueous sodium hydroxide solution, is used to achieve the desired pH level. For a pH of the composition of 4.0 to 6.0, a suitable buffer such as citric acid can be used. It will be noted that any polymorphic form or solvate (eg, hydrate) of eletriptan hemisulfate can be used for the purposes of the present invention. Oxidation is one of the main degradation pathways of eletriptan hemisulfate in aqueous solutions. Citric acid and ascorbic acid are well-known antioxidants. However, the results have shown that the additional presence of an antioxidant such as citric acid or ascorbic acid with caffeine further enhances the stability of eletriptan hemisulfate in aqueous solutions, the effect being greater than merely attributable to its antioxidant properties. Essentially, ethanol is present as a cosolvent. However, it has been found that the additional presence of ethanol with caffeine produces an additional unexpected increase in the stability of eletriptan hemisulfate in aqueous solutions. The present compositions are useful for the treatment of a medical condition for which a selective 5-HT-? Receptor agonist is indicated and in particular, for the treatment of migraine, hypertension, emesis, anxiety, an eating disorder , obesity, drug abuse, cluster headache, pain, chronic paroxysmal hemicrania and headache associated with a vascular disorder. The present compositions are particularly suitable for intranasal administration. The nasal route offers a series of advantages such as the ease of administration, obviating the hepatic metabolism of the first step and, in particular, rapid adsorption and onset of action. The normal pH of nasal secretions in healthy adults ranges from 5.5 to 6.5. For an intranasal formulation to have a minimal effect on epithelial integrity, the pH, osmolarity and the type and concentration of the cap should be optimized. A pH of 4.0 to 0.9 is physiologically acceptable and hypertonic and isotonic solutions seem to produce minimal damage to the nasal mucosae. The nasal epithelium is a highly vascularized tissue, covered by a columnar pseudostratified columnar epithelium. Mucociliary nasal clearance due to coordinated movement of the cilia is one of the fundamental barriers to effective intranasal release. The nasal clearance runs at an average speed of approximately 5-6 mm / min and, as a result, the residence time in the nasal cavity is only 20-30 minutes. Therefore, nasal deposition should be considered, as well as the concentration, volume, viscosity and particle size of the formulations, since these can affect the contact time of the formulations in the nasal cavity. In addition, the levels of caffeine, antioxidants (eg, citric acid) and cosolvent (eg, ethanol) used are limited by the level of severity of irritation or damage that may be caused to the nasal mucosa. Preferably, the required concentration of eletriptan hemisulfate for intranasal compositions is approximately 120 mg / ml. A useful storage half life of at least 2 years at room temperature is also desirable. An illustrative intranasal composition is an aqueous composition comprising: 60 mg / ml eletriptan hemisulfate, 1.5% w / v caffeine, 0.3 w / v citric acid and 15% w / v ethanol, the composition being buffered at pH 7.5 to 8.5, preferably about pH 8.0, preferably using tris (hydroxymethyl) methylamine (to a 0.02M solution) and sodium hydroxide. A preferred intranasal composition is an aqueous composition comprising:, 120 mg / ml of eletriptan hemisulfate, 1.5% by weight / volume of caffeine, 0.3% by weight / volume of citric acid and 5% by weight / volume of ethanol, the buffer composition at pH 7.5 to 8.5, preferably at approximately pH 8.0, preferably using tris (hydroxymethyl) metalamine (at a concentration of 0.05M) and sodium hydroxide. The proportions of the excipients in the preferred prior intranasal composition may vary; for example, the caffeine concentration may vary from 1.0 to 2.0% w / v, the concentration of citric acid can vary from OJ to 1.0% w / v and the ethanol concentration from 0 to 20% w / v. Intranasal compositions can be administered using suitable nasal delivery spray devices. Such devices may take the form of aerosol sprayers with metered doses or sprayers with mechanical pumps that do not contain any propellant. The device used directly influences the deposition and resistance time of the composition in the nasal cavity. The size of the droplets generated by the spray device will preferably vary from 60 to 80 microns in order to optimize the residence time of the composition in the nasal cavity. Dosing spray devices (either single-dose or multi-dose) are preferred since they allow an exact and reproducible release of the doses. Airless mechanical pumping devices that have been designed to protect the formulation from oxidation, dust and / or bacterial contamination are preferred. These can also avoid environmental problems associated with propellants based on chlorofluorocarbons (CFCs). Such pumping devices prevent the entry of air into the drug chamber and create a vacuum after each dispensed dose. The vacuum can produce a deformation of the container that would reduce the volume of the package with each actuation. Such devices may also be arranged so as to maintain the drug and the remainder of the solution in separate chambers until the pump is activated, at which time mixing occurs and the composition is administered. The preferred individual dose of eletriptan hemisulfate when administered intranasally ranges from 1 to 50, more preferably from 1 to 20 and, most preferably, from 4 to 16 mg per subject. Therefore, the above spray devices are normally arranged to release from 25 μl to 100 μl of eletriptan hemisulfate in each measured dose or application. The present compositions are also suitable for subcutaneous administration, which has advantages such as a rapid onset of pharmacological action and to avoid hepatic metabolism of the first step. These are administered by devices such as syringes / needles under the skin in a suitable area of the body, for example, in the region of the thigh. The doctor will determine the actual dose that will be the most appropriate for an individual patient and this will vary depending on the age, weight and response of the particular patient. The above doses are exemplary of the average case. Of course, there may be individual cases in which higher or lower dosage ranges are suitable.

It will be appreciated that references to treatment include curative, palliative and prophylactic treatment. The invention is illustrated by the following examples: EXAMPLES The compositions of Table 1 were prepared by the addition of tris (hydroxymethyl) methylamine (sufficient amount to provide a 0.02M concentration in the required composition), caffeine (if necessary) and citric acid (if necessary) to water (sufficient amount so that it represents 80% of the total volume of the required composition). The mixture was stirred to dissolve the solids and the resulting solution was adjusted to the required pH using 1 M aqueous sodium hydroxide solution. The eletriptan hemisulfate was added and stirring continued until the solution was achieved. The pH was again adjusted to the required pH, if necessary, using 1 M aqueous sodium hydroxide solution. Ethanol was then added (if necessary) and the solution was filled to the required final volume with water.

TABLE 1 Footnotes 1.2 precipitation of solutes of these compositions occurred when stored (see table 2).

EXAMPLE 6 An aqueous composition of pH 8 was prepared as follows containing 120 mg / ml eletriptan hemisulfate, 1.5% w / v caffeine, 0.3% w / v citric acid and 5% w / v ethanol. Tris (hydroxymethyl) methylamine (sufficient amount to provide a 0.05M concentration in the required composition), citric acid, ethanol and caffeine to water (sufficient amount to represent 80% of the total volume of the required composition) was added. The mixture was stirred to dissolve the solids and the resulting solution was adjusted to pH 8 using 5M aqueous sodium hydroxide solution. Eletriptan hemisulfate was added and stirring was continued until the dissolution was achieved. If necessary, the pH is re-adjusted to the required pH, using 5M aqueous sodium hydroxide solution. The solution was then filled to the required final volume with water.

PREPARATION 1 Eletriptan hemSulfate A stirred solution of eletriptan (90.0 g, 0.235 mol) in acetone (3195 ml) was cooled to 0-4 ° C and concentrated sulfuric acid (11.77 g, 0.118 mol) was added dropwise over a period of 30 minutes under a nitrogen atmosphere, maintaining the temperature at 0-4 ° C throughout the addition. The resulting suspension was granulated at 0-4 ° C for 2 hours, filtered and the solid was washed with acetone (2 x 90 ml). The product was dried under reduced pressure at 40 ° C overnight (93.7 g). The eletriptan hemisulfate obtained by the above process can be crystallized as follows. Eletriptan hemisulfate (104.3 g) was dissolved in demineralized water (188 ml) with stirring and acetone (1043 ml) was added. The solution was heated to reflux temperature and reflux was maintained during the addition of acetone (1564 ml) over a period of 40 minutes. The solution was cooled to room temperature and seeded. Stirring was continued for 30 minutes and then additional acetone (2085 ml) was added to the suspension for 30 minutes. The mixture was cooled to 0-4 ° C and granulated for 1.5 hours. The solid was removed by filtration, washed with acetone (2 x 130 ml) and dried under reduced pressure at 40 ° C (93.21 g).

STABILITY STUDIES Samples of the compositions described in Table 1 were stored at 50 ° C for 12 weeks. After this time, each sample was analyzed by HPLC using the conditions described below, the results being shown in Table 2.

Chromatographic conditions Column: 15 cm x 0.46 cm d.i. stainless steel, containing a filling of Hypersil BDS C8®, 5 microns or equivalent Mobile phase: aqueous solution of 0.02 M ammonium acetate: methanol (63:35, by volume). The pH of the mixture was adjusted to 6.0 with glacial acetic acid. Operating Temperature: 30 ° C Flow rate: 1.0 ml / min. Detection: Ultraviolet spectrophotometric detector operating at 225 nm. Sample size 10 microliters. A suitable injector wash solution is methanol / water (50:50, by volume). Retention time: Under the conditions described, eletriptan elutes approximately 12, 5-14, 5 minutes after injection. Execution time: 30 minutes for a typical stability assessment.

TABLE 2 Footnotes 1.2 No significant stability measures can be carried out on these compositions since the precipitation of solutes occurs before the expiration of the storage period. In a parallel study, a stable solution was obtained by preparing a composition corresponding exactly to reference A (ref A) in Table 1 by the same procedure specified. After storage for 12 weeks at 50 ° C, the use of the above analytical procedure showed that 80.49% by weight of eletriptan remained and the total detectable impurities were 3.0% by weight. Not all the impurities that were formed were detectable by the analysis procedure used.

Discussion of the results in Table 2 These results clearly show that caffeine stabilizes aqueous formulations containing eletriptan hemisulfate and also improves the solubility thereof. These results also demonstrate that citric acid and ethanol, whether present separately or together, provide improved stability of such formulations. The result of reference C shows that ethanol appears to have a stabilizing effect on aqueous formulations of eletriptan hemisulfate.

Having described the invention as above, the content in the following is declared as property.

Claims (22)

1. NOVELTY OF THE INVENTION CLAIMS 1 .- An aqueous pharmaceutical composition comprising 5 a 200 mg / ml of eletriptan hemisulfate and 0.5 to 2.0% by weight / volume of caffeine.
2. 2. A composition according to claim 1, comprising from 40 to 160 mg / ml of eletriptan hemisulfate.
3. 3. A composition according to claim 1 or 2, comprising 60 to 120 mg / ml of eletriptan hemisulfate.
4. 4. A composition according to any one of the preceding claims, comprising 1.0 to 2.0% weight / volume of caffeine.
5. 5. A composition according to any one of the preceding claims, further comprising an antioxidant.
6. 6. A composition according to claim 5, wherein the antioxidant is citric acid.
7. 7. A composition according to claim 6, wherein up to 1.0%, inclusive, in weight / volume of citric acid is present.
8. 8. A composition according to claim 7, wherein 0.2 to 0.4% weight / volume of citric acid is present.
9. 9. - A composition according to claim 5, wherein the antioxidant is ascorbic acid.
10. 10. A composition according to any one of the preceding claims, further comprising ethanol. 1.
11. A composition according to claim 10, wherein up to 20.0%, inclusive, in weight / volume of ethanol is present.
12. 12. A composition according to claim 11, wherein 2.0 to 10.0% weight / volume of ethanol is present.
13. 13. A composition according to claim 12, wherein 2.0 to 6.0% weight / volume of ethanol is present.
14. 14. A composition according to any of the preceding claims, which is buffered at a pH of 4.0 to 9.0.
15. 15. A composition according to claim 14, which is buffered at a pH of 7.5 to 8.5.
16. 16. A composition according to claim 14, which is buffered at a pH of 4.0 to 5.0.
17. 17. A composition according to claim 1, comprising 120 mg / ml of eletriptan hemisulfate, 1.5% by weight / volume of caffeine, 0.3% by weight / volume of citric acid and 5% by weight / volume of ethanol, the composition being buffered to a pH of 7.5 to 8.5, preferably approximately pH 8.0.
18. 18. - A composition according to claim 17, wherein it is buffered using tris (hydroxymethyl) methylamine and sodium hydroxide.
19. 19. A composition according to any of the preceding claims, for use as a medicine.
20. 20. The use of a composition according to any one of claims 1 to 18, for manufacturing a medicament for the treatment of a disease or condition for which a selective 5-HT-? Receptor agonist is indicated.
21. 21. The use of a composition according to any one of claims 1 to 18, to manufacture a medicament for the treatment of a disease or condition selected from migraine, hypertension, depression, emesis, anxiety, an eating disorder, obesity, drug abuse, cluster headache, pain, chronic paroxysmal hemicrania and headache associated with a vascular disorder.
22. 22. The use according to claim 21, wherein the disease is migraine.