# Patent

## Title
Method for treating cardiac insufficiency with antibiotic A-23187

## Abstract

This is a continuation-in-part application with respect to our copending United States Patent Application 146,298 filed May 24, 1971, now U.S. Pat. No. 3,934,016.

## Background
The present invention relates to an improvement in therapeutic means employed for treatment of localized edemas of humans. More particularly the invention concerns percutaneous use of acetazolamide and the advantages inherent in this manner of introducing the acetazolamide. It is generally recognized that use of a diuretic by mouth for treatment of localized edemas presents metabolic drawbacks such as modification of ionic equilibrium, without contributing any very definitive curative effect on the edema.

In the case of acetazolamide, oral administration causes substantial acidosis (determined by the decrease in the value of the alkaline reserve of the blood) as well as a loss of potassium (detected by the drop of the potassium content of the serum). A good improvement in the treatment would consist in increasing local therapeutic effects of acetazolamide on edemas and decreasing the harmful effects (acidosis and hyperkalemia).

Applicants have found now that by administering acetazolamide percutaneously in the form of an ointment or cream one can reduce localized edemas without repercussion on blood constants.

1. First of all, it was discovered that acetazolamide, contrary to other diuretic molecules, has the property of passing through the epidermal barrier. This property can be shown by the following experiment (from Lipschitz et al., J. Pharm. Exp. Therap. 1943, 79, p. 97). Rats, divided into 3 homogeneous lots, were given an aqueous overload of 5% of their body weight by intraperitoneal injection of physiological salt solution. One control lot received merely an application of the vehicle of the ointment. A series of lots (rats) was treated by application of ointment containing 10% acetazolamide. A series of lots was treated by oral administration of acetazolamide. % increase in diuresis at the Series        end of 4 hr. Probability ______________________________________ Acetazolamide per os in a dose of: 2 mg/kg         22%        0.02 < p < 0.05 5 mg/kg         33%        p < 0.001 10 mg/kg        35%        p < 0.001 20 mg/kg        48%        p < 0.001 Acetazolamide in ointment in a dose of: -10 mg/kg 20%        not significant 20 mg/kg        33%        0.01 < p < 0.02 100 mg/kg       42%        p < 0.001 ______________________________________

The same experiment, carried out by administering other diuretic products such as triamterene, spironolactone, mercaptomerine, theophylline, in ointment form, showed that these substances did not cause diuresis.

2. In the second step, it was sought to determine whether acetazolamide administered as an ointment could inhibit formation of a localized edema caused in an animal and in what dose. A method was used in which an edema of the paw of the rat was caused by injection of kaolin into the plantar aponeurosis. (Method of J. Millebrecht - Arzneimittel Forschung 1954, 4, 607). It was found that acetazolamide significantly opposes formation of edema, first, starting with a dose of 10 mg/kg in ointment form and second, starting with a dose of 50 mg/kg per os.

3. Thereupon the doses causing diuresis or a protective effect with respect to edema, in accordance with the two methods of administration, were compared. The following table is obtained: Dose in mg/kg as from which there Method of  is significantly observed: administration A diuretic effect An anti-edema effect ______________________________________ Per os      2             50 Percutaneous 20             10 ______________________________________

This table makes it possible to note that administration of acetazolamide, percutaneously, makes it possible to obtain antiedema effects in low dose, far before the diuretic effect.

4. It was then verified clinically that administration of acetazolamide in an ointment actually provided a suitable therapeutic effect without causing harmful secondary effects. For this purpose, two classes of patients having localized edemas were selected, namely:

The acetazolamide was administered in the form of a 10% ointment and the results were classified as: disappeared, perfect mobility of the joints. consequence, almost complete disappearance of pain. functional disturbance, attenuation of the pain with persistence of moderate disturbance. disturbance, inadequacy or absence of effect on the pain. Very    Rather  % Very Good Total Good Good Good Zero + Good __________________________________________________________________________ Post-traumatic edemas 78  45  15   9   9  78 Cellulitic edemas 92  25  39  12  16  70 __________________________________________________________________________

The effects on the alkaline reserve and on the blood potassium were determined:

5. It was verified clinically that administration of acetazolamide in an ointment gives therapeutic effects superior to administration by mouth. For this purpose, acetazolamide was administered in succession by one or the other method:

This procedure is necessary in order to eliminate the spontaneous improvement of the edema which favors in particular the first form administered. The results were as follows: Average decrease of edema       Tablets  Ointment Probability ______________________________________ Tablets before ointment 0.68     0.77     10 < p < 50 Ointment Tablets Ointment before tablets 1.81     0.63     1 < p < 2 ______________________________________ Therefore, the administration of ointment proves to be more effective than the administration of tablets, with the probability of 98 to 99%.

The present invention can be carried out by conventional methods, the acetazolamide being incorporated in vehicles compatible with percutaneous administration. Thus it can be presented in the form of a suspension or emulsion, leading to conventional presentations, such as lotions, milks, creams, ointments, etc. The acetazolamide concentration will be between 1 and 50% and will advantageously be established at 10%.

The following examples are given to permit a better understanding of the invention, without, however, limiting its scope: 1.      Anhydrous ointment Formula acetazolamide             10 poly-oxy-ethylene glycol 1500 75 poly-oxy-ethylene glycol 300 15 ______________________________________

In a double-jacketed stainless steel vessel, melt the mixture of poly-oxy-ethylene glycols at 48.degree. C. Slowly add the acetazolamide in very finely pulverized form, with agitation. Cool with agitation to about 20.degree. C and distribute in suitable containers. 2.      Skin Cream Formula acetazolamide             10 poly-oxy-ethylene glycerides 10 polyethylene glycol stearate 300 10 preservatives methyl para-hydroxybenzoate 0.07 propyl para-hydroxybenzoate 0.03 water q.s.p.              100 g ______________________________________

In a stainless steel vessel, melt the mixture of poly-oxy-ethylene glycerides and polyethylene glycol stearate 300 at 38.degree. C. The preservative, which is an anti-fungus and anti-microbic agent, may in particular be a mixture of methyl para-hydroxybenzoate and propyl parahydroxybenzoate. Add the finely pulverized acetazolamide. Stir until completely dispersed. Slowly add an aqueous solution of the preservative, brought to 38.degree. C. Stir until homogeneous. Cool slowly to 20.degree. C with agitation. Distribute into suitable receptacles. 3.      Suspension for Use on the Skin Formula acetazolamide             10 polyethylene glycol stearate 300 10 stearic acid               5 petrolatum oil             3.5 ascorbyl palmitate         3 water q.s.p.              100 g ______________________________________

In a stainless steel vessel, melt at 40.degree. C the mixture of polyethylene glycol stearate 300, stearic acid and oil of petrolatum. Add the finely pulverized acetazolamide. Stir until completely dispersed. Slowly add anaqueous solution of the preservative, brought to 38.degree. C. The preservative may in particular be ascorbyl palmitate. Stir until homogeneous. Cool slowly to 20.degree. C with agitation. Distribute into suitable receptacles.

## Claims

1. A pharmaceutical composition for local external cutaneous treatment of a local subcutaneous edema of a human, the composition comprising a suspension for skin use consisting of the following:

2. A skin cream for local external cutaneous treatment of a local subcutaneous edema of a human, the skin cream comprising:

3. A method for cutaneous local treatment of a local subcutaneous edema of a human which method comprises applying to the skin over the edema a pharmaceutical composition which comprises: the pharmaceutical carrier; said agent being acetazolamide (5-acetamido-1,3,4-thiadiazole -2-sulfonamide), with a range of concentration being between 1% and 50% by weight.

4. A method for cutaneous local treatment of a local subcutaneous edema of a human which method comprises applying to the skin over the edema a pharmaceutical composition which comprises: application, the pharmaceutical carrier; said agent being acetazolamide (5-acetamido-1,3,4,-thiadiazole-2-sulfonamide), with a range of concentration being between 1 and 50% by weight.