Transdermal patch and topical compositions comprising...

Details Transdermal patch and topical compositions comprising... Transdermal patch and topical compositions comprising...

2001-01-12

2003-07-15

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Web, sheet or filament bases; compositions of bandages; or...

C424S484000, C424S487000, C424S448000

Reexamination Certificate

active

06592893

ABSTRACT:

This application is a 371 of PCT/IE99/00066 filed Jul. 15, 1999.
TECHNICAL FIELD
The present invention refers to the use of substances such as R(−)-propylnorapomorphine hydrochloride thereinafter abbreviated to R(−)-NPA-HCl, or Compound (1)] and S(+)-propylnorapomorphine hydrochloride [S(+)-NPA-HCl, or Compound (2)] and the derivatives thereof, for the treatment of Parkinson's disease, hemicrania, sexual impotence, and psychotic disorders.
More particularly, the invention also concerns a “device” (transdermal patch) for the slow release of said substances through the skin.
PRIOR ART
Apomorphine (11B-13B) has been successfully used as a drug and, especially in the veterinary field, as an emetic. It has recently been found that apomorphine (abbreviated to APO), at suitable dosages, can have beneficial effects on patients with Parkinson's disease, while at lower dosages it is useful in the treatment of hemicrania, sexual impotence and psychotic disorders (4B, 58, 6B, 7B).
In the abovementioned therapeutic indications APO is a powerful dopaminergic agonist drug, administered by the intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), rectal, sublingual or intranasal route. The substance is characterized by a rapid absorption, correlated with a rapid attack (latent period about 15′) and an equally rapid elimination (half-life about 33′) (8B).
The molecule of apomorphine is unstable on exposure to air and to light, oxidizing rapidly. When exposed to air, in fact, preparations based on apomorphine change colour, turning green, thus giving rise to a product which can no longer be used clinically.
For this reason, in order to guarantee the patient the necessary pharmacological cover, with therapeutically effective blood levels that are sufficient and constant over 24 hours, a large number of daily administrations are needed, with limited doses, of the order of 1-5 mg/hour of active principle. Exceeding such a dose by even the slightest amount causes serious side effects, such as vomiting, depression of the central nervous system (CNS) and, in some cases, even death of the patient.
Recently the administration of apomorphine by continuous subcutaneous infusion, by means of small insulin pumps which should guarantee pharmacological cover with the hourly infusion of low doses, without causing side effects, has been proposed and carried out in medical practice. But even this alternative mode of administration is not without disadvantages: already with dosages of 2-5 mg/hour, there is a tendency that subcutaneous granulomas form around the infusion site, which require the suspension of the treatment. This is due to the fact that the drug is practically concentrated at one point: around the point of the needle.
DESCRIPTION OF THE INVENTION
It is an object of the present invention to use a pharmaceutical composition based on R(−)-NPA-HCl (Compound (1)) or S(+)-NPA-HCl (Compound 2) and/or the derivatives thereof, which can be administered to the patient in therapeutically effective doses of active principle, in a continuous manner, without causing the occurrence of serious side effects, such as vomiting and depression of the central nervous system (CNS), due to a high dosage of active principle, or else granulomas around the infusion site (when the dosage is lower), as found with the use of APO.
The activity of Compounds (1) and (2) is 10 times greater than that of APO, and in addition their toxicity is lower in addition, the half-life is greater than that of APO. For this reason, when said compounds are given at suitable doses over 24 hours, effects which are rather more beneficial than those of APO are obtained.
Another object of the present invention is to produce a transdermal patch for the slow release of Compounds (1) and (2), and/or the derivatives thereof, hereinafter also called PATCH-TDSS (TDDS=Transdermal Drug Delivery System). The transdermal patch of the invention will guarantee a therapeutically effective level of Compounds (1) or (2) and/or the derivatives thereof (active principle) over 24 hours, without presenting the disadvantages of the traditional techniques.
This is because, as the patch is of relatively large dimensions (40 cm
2
for example), the active principle can permeate the epidermis through all the 40 cm
2
without any possibility of producing accumulation sites.
Moreover, the greater therapeutic activity allows the dosage to be reduced about 10 times. The greater solubility in water allows the release and index of permeation in vivo to be suitably modified by the addition of suitable permeation activators.


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