Compositions for nasal administration

Details Compositions for nasal administration Compositions for nasal administration

2000-06-02

2002-01-29

Azpuru, Carlos A. (Department: 2165)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S502000, C514S772300

Reexamination Certificate

active

06342251

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to compositions for nasal administration of drugs and particularly to compositions for nasal administration of drugs for treating erectile dysfunction, such as apomorphine. The invention also relates to the nasal administration of drugs for treating erectile dysfunction.
Erectile dysfunction is a major medical problem in middle-aged males. A variety of medical treatments has been proposed including local injections as well as hormone therapy. The prostaglandins have been especially useful in this regard.
Other drugs suitable for the treatment of dysfunction include alpha-adrenoreceptor antagonists, e.g. phentolamine, phenoxybenzamine, yohimbine, moxislyte delaquamine; compounds with central D
2
-receptor antagonist activity, e.g. apomorphine; compounds that act primarily by blocking the re-uptake of serotonin into nerve terminals, e.g. tadone and chlorophenylpiperazine; competitive and selective inhibitors of c-GMP type V phosphodiesterases, e.g. sildenafil; L-arginine; and papaverine.
Presently, administration of the above drugs can often involve the local injection of the penis with attendant problems of compliance. A more discreet, non-invasive method for the treatment of erectile dysfunction would be of considerable advantage.
A drug for erectile dysfunction could be given orally in order to be absorbed from the gastrointestinal tract, but it is well known by those skilled in the art that oral absorption can be slow since the drug has to pass through the stomach into the small intestine to the absorptive regions. The appearance of the drug in the intestine can be delayed by food. Thus, oral absorption tends to be erratic and unpredictable. Hence, this route of delivery is not feasible. The buccal cavity, including the sublingual and buccal tissues, is an alternative site for administration. However, generally speaking drug absorption from this site is slow since the tissues of the mouth are not intended for the efficient uptake of substances, unlike the intestines. Moreover, drugs placed in the mouth can be bitter as well as irritant.
The lungs offer another site for the delivery of drugs. The lungs can provide rapid absorption, but administration needs to be conducted with a device in the form of a nebulizer or inhaler and can be limited by the dose. Many drugs are irritant when blown into the lungs and can cause bronchospasm.
It is known that the nasal epithelium has good permeability and a good blood supply and that drugs that are metabolised after oral administration can be well absorbed from the nose since this route avoids the first-pass metabolic effect in the liver. Hence, the nasal administration of drugs for the treatment of erectile dysfunction is potentially attractive and has been attempted. However, side effects and adverse reactions were common.
It is known that the drug apomorphine (6aR)-5, 6, 6a, 7-tetrahydro-6-methyl-4H-dibenzo(d, e, g) quinoline-10, 11-diol hemihydrate can be effective in the treatment of erectile dysfunction (DanJou et al. Brit. J. Clin. Pharmacol. 26, 733, 1988). However, the drug is better known for its use in disease conditions such as Parkinsonism where oral, rectal and nasal routes have been reported. Intranasal apomorphine has been shown to be useful in Parkinson's disease (Sam et al. Eur. J. Drug Metab. Pharmacokinet. 20, 27, 1995; Dewey et al. Clin. Neuropharmacol. 19, 193, 1996), but is associated with transient nasal blockage and a burning sensation. (Kleedorifer et al, Neurology 41, 761, 1991).
The extent of nasal absorption of apomorphine can be enhanced using various agents such as those described by Merkus that include cyclodextrins (WO-91/22445). The bioavailability, defined as the quantity of drug appearing in the systemic circulation as compared to a control in the form of a subcutaneous injection, is stated to be about 40%.
While local reactions and side effects may be acceptable for a patient receiving nasal apomorphine for the treatment of Parkinson's disease, such side effects would be totally inappropriate for an apparently healthy patient taking nasal apomorphine for the treatment of erectile dysfunction.
Attention has been given to the route of administration of apomorphine for use in erectile dysfunction with an emphasis on convenience. Heaton et al. (Neurology, 45, 200-205) compared different routes of administration in a study conducted in patients. They reported that nasal administration of apomorphine gave rapid onset of action but was associated with unacceptable side effects such as yawning, nausea, vomiting, dizziness, blurred vision, diaphoresis, pallor and mild hypertension and, therefore, was not suitable. Their preferred system was a sublingual formulation as further defined in U.S. Pat No. 5,624,677 and WO-95/28930. However, as discussed above, while sublingual formulations can lead to the absorption of drugs, it is known that such absorption can be slow and variable. Moreover, the quantity absorbed may be limited due to the poor permeability of the oral mucosal membranes in man. In addition, a green colouration of the tongue following sublingual apomorphine has been reported together with poor taste and mucosal ulceration.
Thus, the nasal administration of apomorphine has been described in the prior art literature and in patents. The formulations described were generally simple in nature and all would have led to a pulsatile delivery of the drug resulting in a sharp and high initial peak in the plasma level-time profile leading to local reactions and side effects. In particular, none of the nasal formulations described in the prior art comprised an additive intended to modulate the rapid absorption of the drug.
In WO-94/27576 it is disclosed that the nasal delivery of nicotine could be modified to provide a combination of a peak level (to provide the so-called “buzz” effect of nicotine delivered by a cigarette) and a subsequent controlled release phase. Thus, WO-94/27576 deals with the problem of providing input of nicotine into the bloodstream over a prolonged period of time. The reduction of the plasma level-time profile in order to minimize side effects and adverse reactions for drugs used in the treatment of erectile dysfunction such as apomorphine is neither mentioned nor suggested.
Ugowk et al (J. Control. Rel. 48, 1997, 302) has described mucoadhesive nasal forms for apomorphine hydrochloride for the treatment of Parkinson's disease. An attempt was made to incorporate apomorphine into gelatin microspheres, but the encapsulation efficiencies were reported to be sometimes very low. Moreover, the drug was released rapidly. Ugowk et al also described powder formulations of apomorphine together with polycarbophil or carbomer (carboxypolymethylene) where 100 mg of apomorphine was combined with 1 g of polymer and then freeze dried. The compositions of the present invention were not described.
Thus, the prior art teaches that the nasal delivery of most drugs for the treatment of erectile dysfunction tends to be associated with unacceptable side effects.
Controlled release nasal formulations for the treatment of erectile dysfunction have not been described previously.
As a result of investigations into this problem, the applicant has realised that the adverse reactions and side effects associated with the nasal administration of drugs for treating erectile dysfunction such as apomorphine may be the result of an inappropriate plasma level/time profile and, more specifically, a result of an initial high peak plasma level. We have also realised that such side effects may be reduced and even eliminated by combining the drug with certain pharmaceutical excipients that provide a controlled release effect such as polysaccharides and block copolymers containing ethylene oxide (oxyethylene) moieties. More particularly, we have now discovered controlled release nasal formulations for drugs intended for the treatment of erectile dysfunction that will provide an initial rise in plasma level of the drug followed by a more sustained level of drug in

Affiliated with

Also associated with

Rating

Compositions for nasal administration does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Compositions for nasal administration, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions for nasal administration will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2832106