Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-12-28
1998-04-14
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3144
Patent
active
057391521
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE94/01032 filed Nov. 3, 1994, PUBLISHED AS wo95/13066 mAY 18, 1995.
FIELD OF INVENTION
The present invention relates to emulsions of novel, potent, very short acting, antihypertensive calcium antagonists of the dihydropyridine type with high vascular selecitivity, and to a process for preparing such emulsions. The invention also relates to the use of the emulsion in intravenous administration during surgery and postoperatively in hypertension and for short term treatment of hypertension when oral therapy is not feasible or desirable.
1. Background to the Invention
Steerable blood pressure control is of great importance in many acute clinical situations, e.g. in the majority of patients undergoing cardiac surgery, cerebral surgery, orthopedic surgery or microsurgery. Under such conditions it is often important to rapidly and safely lower blood pressure to a pre-specified level, keeping it there for a pre-determined time, and then rapidly normalizing it again. In these situations it is important to minimize the volumes given to the patient. Therefore it is important to administer a concentrated pharmaceutical preparation.
Short acting dihydropyridines are sparingly soluble in water, but have a moderate to high lipophilicity. There exist today a clear medical need for short acting, steerable antihypertensive drugs for intravenous administration during surgery and postoperatively administered in the form of a reasonably concentrated pharmaceutical preparation with minimal side effects.
2. Prior Art
Emulsions for parenteral nutrition, such as Intralipid.RTM., are well known and have been used for a long time.
There also exist emulsions as drug delivery systems, in the field of dihydropyridines, for treating high blood pressure. In contrast to the present invention these formulations result in long-acting blood pressure effects.
DESCRIPTION OF THE INVENTION
It has now been found that the problems outlined above can be solved by providing an oil-in-water emulsion comprising
When dissolved in conventional solutions the short acting dihydropyridine compounds induce rapid and steerable blood pressure reduction in animals. When dissolved as a lipid emulsion the pharmacological effect remains the same as with conventional solutions.
Emulsions of the invention offer much better solubility and/or less side effects of the vehicle and/or better stability than conventional solutions. Oil-in-water emulsions also prevent the lipophilic dihydropyridine compounds from adherence to the plastic infusion sets etc. that are to be used when administrating the compounds.
The emulsions of the invention are useful as dosage forms for short-acting (i.e. half life in plasma less than 30 minutes) antihypertensive dihydropyridines. The emulsions gives as fast release, together with as fast decay, in pharmacological effect as conventional solutions, but the emulsions offer much better solubility properties, and/or less side effects of the vehicle and/or better stability than conventional solutions.
Below is given a detailed description of the invention.
Pharmaceutical material comprises emulsions or freeze dried material from emulsions or concentrates for reconstitution (self-emulsifying systems).
Emulsion comprises:
Percentages throughout the specification is expressed as weight/weight.
The short acting dihydropyridine compound is selected from the group consisting of a 1,4-dihydropyridine of the general formula I: ##STR1## or pharmaceutically acceptable salts therof, wherein R.sub.1 and R.sub.2 are independently selected from the group consisting of hydrogen, chloro, bromo, nitro, cyano, trifluoromethyl, and R.sub.3 and R.sub.4 are independently selected from straight or branched lower (1-5 carbon atoms) alkyl groups, and including all optical isomers, provided that when R.sub.3 is methyl and R.sub.4 is tert.-butyl, then R.sub.1 /R.sub.2 are not hydrogen/hydrogen, hydrogen/2'-trifluormethyl, 2'-chloro/3'-chloro, and when R.sub.3 is methyl and R.sub.1 /R.sub.2 is hydrogen/3'-nitro, then R.sub.4 are
REFERENCES:
patent: 4711902 (1987-12-01), Serno
Seki, et al., Chemical Abstracts, vol. 115, p. 479, Abstract No. 78948c (1991).
Andersson Kjell Hjalmar
Byrod Eva Kristina
Hansson Anna-Carin
Nordlander Margareta
Westerlund Rolf Christer
Astra Aktiebolag
Spivack Phyllis G.
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