Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1996-02-06
1998-07-28
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564229, 564225, 514364, 514631, A61K 3115, C07C25136
Patent
active
057863830
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/DE94/00756 which is now published as WO 95/01168 on Jan. 12, 1995.
The present invention relates to a novel pharmaceutical preparation, containing an active ingredient having at least one active amidine group, and to its use.
In order to treat pneumocystis carinii pneumonia, which affects almost 70% of all AIDS patients without prophylactic measures in the course of their illness, it is known to use aqueous solutions of pentamidine diisethionate with the aid of special atomisers in aerosol form. In this case this known pentamidine diisethionate has a structure as illustrated by the following formula P: ##STR2##
However, the known pentamidine isethionate has the disadvantage that when applied orally it is poorly resorbed, and thus with this type of administration cannot exert any pharmacological effect in the body. For this reason the preparation has been given to the patients intramuscularly or intravenously. The galenic formulations available for this, however, have serious side-effects, which are to be ascribed to the form of administration.
In intravenous administration, intense blood-pressure drop (hypotonia) linked with malaise and vomiting, to the extent of unconsciousness, can occur. Nor does intramuscular administration offer any particular advantages, as frequently extreme pain at the point of injection, leading to tissue necrosis, which require tedious follow-up treatment, are observed.
These side-effects do not occur with the atomisation of pentamidine diisethionate already described. However, only slight to mildly serious cases of pneumocystis carinii pneumonia may be treated by atomisation, as a severe attack renders inhalation of the aerosol impossible, or at least extremely difficult. This form of administration also requires a high degree of cooperation from the patient, as he must learn the correct inhalation technique in order to achieve a uniform distribution of the active ingredient, which is essential for successful therapy.
Some serious disadvantages, however, stand in the way of this form of administration, with its low systemic stress and ensuing lower toxicity. Each administration requires an ambulatory stay in hospital, during which at least one doctor should be present as, in aerosol therapy, frequently (in up to 15% of administrations), bronchial spasm can occur, necessitating medical countermeasures. Also, pulmonary administration requires a special atomiser which can generate a uniform particle size of 0.5 to 30 .mu.m in diameter.
Depending on the type of atomiser and on the type of setting for this apparatus, sufficient concentrations of active ingredient frequently do not reach the required locus of action.
Cases with extrapulmonary involvement cannot be treated in this way. Connected with this, the recurrence rate of pneumocystis carinii pneumonia is increased when proper, regular prophylactic aerosol therapy is not carried out.
As stated above, pharmaceutical preparations containing pentamidine applied orally have practically no pharmacological effect. An essential condition for a therapeutic effect of an active ingredient given orally is its take-up from the gastro-intestinal tract. The most important mechanism for such membrane penetration in this case is passive diffusion. The degree of resorption by way of passive diffusion is dependent on lipophily, and is thus closely connected with the acidity or the basicity of the active ingredient. An intensely basic compound such as pentamidine (pK.sub.4 =11.4) is present in the stomach (pH=1) and in the gut (pH=7.4) in an almost totally ionised form. The molecule is hydrophilic during the entire gastro-intestinal passage. Oral resorption, which is connected with passage through a lipophilic membrane, therefore succeeds only to a very restricted degree. The high basicity of pentamidine is to be ascribed to its functional groups, i.e. the amidines. This is clearly the obstacle which explains why in the past oral administration resulted in entirely insufficient resorption and thus over a long perio
REFERENCES:
patent: 3658832 (1972-04-01), Asato et al.
patent: 3795735 (1974-03-01), Asato et al.
patent: 3819702 (1974-06-01), Lafon et al.
patent: 4921852 (1990-05-01), Murata et al.
patent: 5026724 (1991-06-01), Logan et al.
patent: 5138064 (1992-08-01), Murata et al.
patent: 5322858 (1994-06-01), Canfield et al.
Archiv Der Pharmazie, vol. 325, No. 1, 1992, pp. 61-62.
Arzneimittel Forschung, vol.. 35, No. 7, 1985, pp, 1009-1014.
Arzeimittel Forschung, vol. 42, No. 12, 1992, pp. 1497-1504.
Indian Journal of Chemistry, vol. 22B, No. 9, 1983, pp. 898-900.
Journal of Medicinal Chemistry, vol. 12, No. 3, 1969, pp. 381-383.
Journal of Medicinal Chemistry, vol. 18, No. 4, 1975, pp. 430-432.
The Merck Index, 1989, Merck & Co., Inc. Eleventh Edition, p. 515, paragraph 3256, p. 815, paragraph 5067, p. 1128, paragraph 7071.
Aulakh Charanjit S.
Rotman Alan L.
LandOfFree
Pharmaceutical preparation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical preparation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical preparation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-24004