Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2002-04-11
2004-05-25
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S489000, C514S248000, C514S218000, C514S001000, C514S221000
Reexamination Certificate
active
06740306
ABSTRACT:
The present invention relates to imidazotriazinone-containing compositions for nasal administration which, besides the imidazotriazinone, contain a small amount of a local anaesthetic.
Cyclic guanosine-3′,5′-monophosphate phosphodiesterase inhibitors, abbreviated to cGMP PDE inhibitors, have a well known range of effects (cf., for example, EP-A-0 463 756, WO 99/24433). The imidazotriazinones encompassed by the present invention are described in WO 99/24433 as such cGMP PDE inhibitors. Inter alia, the biochemical bases of the process of penile erection were elucidated a few years ago and, on this basis, it was reported that cGMP PDE inhibitors, in particular PDE5 inhibitors, are suitable for treating male erectile dysfunction (cf. Rajfer et al., New England J. Med. 326 (1992), 90; Murray, Drug News & Perspectives 6 (1993), 150). Subsequently, the use of certain cGMP PDE inhibitors for treating male erectile dysfunction was described in WO 94/28902, and one of these (sildenafil citrate, Viagra®) is now proved as medicament which can be administered orally for this indication. One disadvantage of oral administration is, however, that the onset of action is delayed, which is deleterious to the spontaneity desired by the patient especially in this indication. In addition, first pass effects or food effects may impair the efficacy of an orally administered medicament.
In principle, it ought to be possible by nasal administration of an active ingredient to achieve a faster rise in the level of active ingredient in the blood stream and, associated therewith, an accelerated onset of action. There has thus been no lack of proposals in the prior art that cGMP PDE inhibitors be administered nasally, especially for treating male erectile dysfunction (cf. WO 96/32003, WO 97/03985, WO 98/53819, WO 99/24433, EP-A-0 967 214, WO 00/00199). For example, EP-A-0 967 214 describes nasal administration of a sildenafil salt which has better solubility in water, namely sildenafil mesylate, and the faster rise in the level of active ingredient in the blood stream which can be achieved thereby with a smaller amount of active ingredient being necessary compared with the oral route.
However, problems may arise on nasal administration of cGMP PDE inhibitors. Owing to their mechanism of action, these substances are vasodilators. Since PDE5 also occurs in the tissue of the nasal cavity, nasal administration of PDE 5 inhibitors leads to local dilation of the vessels of the nasal mucosa. The result is a condition in the nose which the patient finds unpleasant, such as itching or stinging, or eye-watering, an increase in the nasal airway resistance and/or a nasal blockage, although no local irritation is detectable toxicologically. Although it was described in EP-A-0 967 214 that these effects do not impair rapid absorption of sildenafil mesylate, the unpleasant condition in the nose, which is found to be upsetting particularly during sexual intercourse, the increase in the nasal airway resistance or the nasal blockage remain a not inconsiderable disadvantage.
EP-A-0 992 240, which corresponds to WO 98/53819, proposes to avoid an inadequate absorption of the cGMP PDE inhibitor, caused by the abovementioned disadvantages, by adding vasoconstricting active ingredients such as epinephrine, naphazoline nitrate, tramazoline hydrochloride or tetrazoline, antiallergic substances such as sodium cromoglicate or ketotifen fumarate, suppressors of nasal mucosal secretion such as flutropium bromide or steroids such as, for example, prednisolone, without showing by way of example that this sufficiently prevents the occurrence of the unpleasant feeling for the patient which has been described above.
Nasal administration of local anaesthetics has to date been disclosed for surface anaesthesia before surgical operations in the nasal region. In addition, U.S. Pat. No. 4,602,099 has described the use of local anaesthetics as adjuvants in antirhinoviral medicaments for additional treatments of the symptoms of a rhinovirus infection. The only example of a local anaesthetic used in this patent was benzyl alcohol. It should be noted that benzyl alcohol is also known as preservative or as solubilizer and is described in these functions in EP-A-0 967 214 and WO 00/00199 as one of a plurality of adjuvants which can be used additionally for the formulations mentioned therein. In addition, it has emerged within the scope of the present invention that benzyl alcohol is unable to reduce or prevent the disadvantages described above which occur on nasal administration of cGMP PDE-inhibitors.
WO 99/15171 describes liquid crystal nicotine preparations to which a local anaesthetic is added to avoid disadvantageous effects of nicotine caused by its local irritant effect. In this case, the local anaesthetic acts by blocking peripheral pain receptors. It should be noted that cGMP PDE inhibitors on nasal administration cause such a local irritant effect to only a small extent or not at all.
GB-A-2 315 673 proposed intranasal administration of local anaesthetics such as lidocaine in addition to a 5-HT1D agonist for the treatment of migraines. Besides the effect of interrupting pain transmission which is known for local anaesthetics, this proposal is based on the vasodilating effect of local anaesthetics, which leads to an accelerated absorption of the 5-HT1D agonist and thus to a faster onset of action.
It would therefore have been expected that the disadvantages, described above, based on the vasodilating properties of cGMP PDE inhibitors would be further enhanced through the presence of a local anaesthetic because of its vasodilating effect.
It was the object of the present invention to find an imidazotriazinone-containing composition for nasal administration whose use is not associated with disadvantages such as a nasal condition which is found to be unpleasant, eye-watering, an increase in the nasal airway resistance or nasal blockage.
The above object is achieved by a composition which comprises at least one imidazotriazinone and at least one local anaesthetic, the local anaesthetic not being benzyl alcohol.
It has been found, surprisingly, that only a small amount of a local anaesthetic needs to be added to the imidazotriazinone-containing compositions, to overcome the disadvantages described above. The doses of local anaesthetic necessary for this purpose are generally distinctly less than those necessary for surface anaesthesia. A feeling of local numbness, as occurs after blockade of nerves conducting irritation, by, for example, a local anaesthetic, can therefore be avoided on use of the compositions according to the invention. Furthermore, addition of local anaesthetics to nasal compositions of the cGMP PDE inhibitors according to the invention surprisingly does not lead to build-up of excessive peaks in the plasma levels as would have been expected on the basis of the vasodilating properties of local anaesthetics and the accelerated and increased absorption of the cGMP PDE inhibitor in the nose which was thus to be expected. Thus, on use of the compositions according to the invention, no disadvantages in relation to the duration of action or increased side effects occur.
According to the present invention, the cGMP PDE inhibitor contained in the compositions is a compound of the formula (I)
in which
R
1
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
represents straight-chain alkyl having up to 4 carbon atoms,
R
3
and R
4
are identical or different and represent a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally substituted up to twice, identically or differently, by hydroxyl or methoxy,
or
R
3
and R
4
form, together with the nitrogen atom, a piperidinyl, morpholinyl, thiomorpholinyl ring or a radical of the formula
in which
R
7
denotes hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl having in each case up to 6 carbon atoms, or denotes straight-chain or branched alkyl having up to 6 carbon atoms which is optionally su
Barth Wolfgang
Bauer Richard-Josef
Ohm Andreas
Serno Peter
Siefert Hans-Martin
Haghighatian Mina
Page Thurman K.
Pellegrino Susan M.
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