Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-06-29
2004-03-30
Riley, Jezia (Department: 1637)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S001000, C514S023000, C514S025000, C514S946000, C536S001110
Reexamination Certificate
active
06713461
ABSTRACT:
This invention relates to a complex of eletriptan and a sulphobutylether-beta-cyclodextrin, or a pharmaceutically acceptable salt thereof, and to processes for the preparation of, pharmaceutical formulations including, and the uses of, such a complex.
Eletriptan, 3-([1-methylpyrrolidin-2(R)-yl]methyl)-5-(2-phenylsulphonylethyl)-1H-indole, is disclosed in WO-A-92/06973. A preferred hydrobromide salt form of eletriptan is disclosed in WO-A-96/06842. WO-A-99/01135 discloses a pharmaceutical formulation comprising eletriptan hemisulphate and caffeine. WO-A-00/06161 describes the use of eletriptan for the prevention of migraine recurrence.
Eletriptan is a 5HT
1B/1D
receptor agonist and has been shown to be highly effective for the treatment of migraine and the prevention of migraine recurrence. Eletriptan has also been disclosed for the treatment of hypertension, emesis, depression, anxiety, an eating disorder, obesity, drug abuse, cluster headache, pain, chronic paroxysmal hemicrania and a headache associated with a vascular disorder.
In order to administer eletriptan, or a salt thereof, by the intranasal route, it is desirable that a formulation does not produce unacceptable levels of effect, such as irritancy, on the nasal mucosae. It has been found that the formulations described in WO-A-99/01135 comprising eletriptan hemisulphate and caffeine are irritant on the nasal mucosae.
Accordingly, it is an object of the present invention to provide a well-tolerated pharmaceutical formulation of eletriptan, or a salt thereof, that is suitable for administration by the intranasal route.
It is further object of this invention to provide a well-tolerated, stable, aqueous, pharmaceutical formulation containing eletriptan, or a salt thereof, that is suitable for parenteral, preferably, intranasal administration and which enables the drug to have good bioavailability and rapid onset of action.
WO-A-91/11172 and WO-A-94/02518 disclose sulphoalkyl ether cyclodextrin derivatives.
WO-A-98/02186 discloses an inclusion complex of (a) an indole selective serotonin (5-HT
1D
) agonist or a pharmaceutically acceptable salt thereof and (b) an unsubstituted or substituted beta- or gamma-cyclodextrin, together with pharmaceutical compositions thereof.
It has now been found that eletriptan, or a salt thereof, can form a complex with certain sulphobutylether-beta-cyclodextrin derivatives of the type disclosed in WO-A-91/11172. Although this complexation undesirably and unpredictably decreases the aqueous solubility of eletriptan, or a salt thereof, it unexpectedly and advantageously provides a complex which is well-tolerated when administered intranasally, principally since it has a negligible irritant effect on the nasal mucosae in comparison with both the known caffeine formulations of eletriptan disclosed in WO-A-99/01135 and other cyclodextrin complexes of eletriptan.
Accordingly, the present invention provides a complex of eletriptan and a cyclodextrin derivative of the formula (I):
wherein
R
1a-g
, and R
3a-g
each independently represent —OH or —O(CH
2
)
4
SO
3
H; provided that at least one of R
1a-g
represents —O(CH
2
)
4
SO
3
H: or a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable salts of particular interest associated with the eletriptan component are acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Hydrobromide and sulphate, including hemisulphate, salts are preferred. Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
Pharmaceutically acceptable salts of particular interest associated with the cyclodextrin ring component are base salts of the —O(CH
2
)
4
SO
3
H groups, for example, alkali metal salts, such as sodium salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 66, 1-19, 1977.
A pharmaceutically acceptable salt may readily be prepared by mixing together solutions of eletriptan, the cyclodextrin or the complex, and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. When a salt of eletriptan and/or the cyclodextrin are/is separately prepared, these/this may then be used for the preparation of the complex.
A polymorph of eletriptan, or a salt thereof, may also be used for the purpose of the present invention.
Preferably, the average number of —O(CH
2
)
4
SO
3
H groups per molecule of formula (I) is in the range of from 6.1 to 6.9, for example, 6.5 or about 6.5.
It is preferred that each —O(CH
2
)
4
SO
3
H present is in the form of an alkali metal salt (such as the sodium salt).
Preferably, the molar ratio of eletriptan:cyclodextrin derivative of the formula (I) is from 1:1 to 15:1, most preferably from 1:1 to 10:1.
Preferably, eletriptan is present in the form of the hemisulphate salt.
The complex can be administered alone but will generally be administered in admixture with a pharmaceutically acceptable excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
For example, the complex can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed- or controlled-release applications.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the complex may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The complex can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intrasternally, intracranially, intramuscularly or subcutaneously, or it may be administered by infusion techniques. It is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
For oral and parenteral administration to human patients, the daily dosage level of eletriptan will usually be from 0.001 to 0.50 mg/kg (in single or divided doses).
Thus tablets or capsules containing the complex may contain from 5 to 240 mg of eletriptan, or a salt thereof, for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient
Catania Richard L.
Konstas Kristine L.
Kurlandsky David R.
Pfizer Inc.
Riley Jezia
LandOfFree
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