Calcium-antagonist compositions intended for inhalation and process for their manufacture

Pharmaceutical compositions for administration by inhalation, wherein calcium-antagonists are employed as the active substances, e.g., metered-sprays of calcium-antagonists, in particular of diltiazem and a process for their manufacture are described.

BACKGROUND OF THE INVENTION 
Long-term therapy for angina pectoris is nowadays usually conducted with 
nitrates such as isosorbide-dinitrate or isosorbide-mononitrate, or with 
calcium antagonists. 
Cutting short an acute angina pectoris attack proves considerably more 
difficult, since the named active substances only allow an immediate onset 
of action with i.v. administration. Furthermore, this can only be carried 
out by the doctor, who is in most cases not at hand when the angina 
pectoris attack occurs. A further disadvantage of parenteral treatment is 
that it can easily lead to postural hypotension in the case of 
calcium-antagonists on account of strong peripheral side-effects upon 
rapid absorption. 
At present the sublingual or inhalation administion of nitroglycerin is the 
only practicable solution open to the patient for treating the attack, 
since this active substance can take an immediate effect on account of its 
physiochemical properties and its special pharmacological profile. 
Since the specialist has hitherto not made therapeutic use of the immediate 
onset of action of calcium antagonists, in the knowledge of the strong 
peripheral effect of this active substance class, practically only 
nitroglycerin remained for treating acute cases, but with nitroglycerin 
one has to reconcile to side-effects such as nausea, dizziness, 
tachycardia, and a sudden drop in blood pressure. 
It has surprisingly been found that calcium-antagonists are immediately 
effective upon inhalational administration and cause an immediate increase 
in the blood flow in the coronary artery without exerting an unfavorable 
influence on the periphery. 
Thus calcium-antagonists are unexpectedly suitable for therapy of angina 
pectoris attacks when administered by inhalation. They have the great 
advantage as compared with the therapy known hitherto that the 
side-effects of nitroglycerin are avoided and the described activity of 
calcium-antagonists, which are concededly drugs of first choice in 
influencing the pathophysiological condition, can also be made use of in 
acute attacks. 
SUMMARY OF THE INVENTION 
Accordingly, the present invention provides a pharmaceutical composition 
for administration by inhalation comprising an inhalation propellant or 
carrier and an effective amount of at least one active substance for 
treating angina pectoris, wherein the active substance is a 
calcium-antagonist. 
Another subject matter of the invention is a process for the preparation of 
a pharmaceutical for the treatment of an angina pectoris attack which 
provides immediate onset of action, characterized in that as the active 
substance a calcium-antagonist in solid or liquid form is incorporated in 
an inhalation propellant or carrier, and that the propellant or carrier 
together with the active substance is filled off under pressure, or by 
cooling below the boiling point of the propellant or carrier, into an 
inhalation receptacle suitable for the inhalation of pharmaceuticals thus 
prepared, which receptacle is then fitted with a gastight seal. 
The invention further provides a method for treating angina pectoris which 
comprises administering to a host suffering therefrom an effective amount 
of a calcium-antagonist by inhalation means. 
DETAILED DESCRIPTION 
Well-known calcium-antagonists are, e.g., nifedipine, verapamil, etafenone, 
prenylamine, perhexiline, and gallopamil. Diltiazem is preferred within 
the framework of this invention as being particularly suitable for the new 
therapy form. 
The active substances, as long as they are soluble in water, such as, for 
example diltiazem.HCl, can be added to an aqueous solution and filled 
under pressure into a spray container with nitrogen. 
A preferred method is to mix the active substance and a suspension 
auxiliary, such as, for example sorbitan triolate at approximately 
5.degree.-20.degree. C. with a fluorocarbon hydride which is liquid at 
this temperature, to transfer this mixture together with the safety 
propellant mixture (fluorocarbon hydride: 12:114) into the spray container 
by means of the cold drawing-off process and to seal the same immediately. 
Another possibility would be to fill the active substance in micronized 
form, i.e., having a particle diameter of between 0.5 and 5 .mu.m, 
together with a corresponding finely-dispersed inhalable carrier such as 
lactose into a hard gelatin capsule and to conduct the therapeutic 
application using a normal mechanical powder-inhaler. 
The dosage of the inhaler should be adjusted in such a way that a one-time 
dose for adults lies between 5 and 50 mg. 
The following Examples are given for the purpose of illustrating the 
invention:

EXAMPLE 1 
1.632 kg diltiazem.HCl (micronized) are mixed with 500 g sorbitan trioleate 
and 37.42 Freon.RTM. 11, at a temperature of approximately 10.degree. C. 
and suspended disagglomerating. The suspension thus obtained is 
subsequently added to 170.45 kg safety propellant mixture 
(Fluorocarbonhydride 12:114) at a temperature of -50.degree. C. and the 
mixture homogenized. It is then filled into aluminum cans in the cold, 
which are then sealed immediately with a metered-dosage valve. 
10,000 cans (effective contents 22 ml) are thus obtained for 300 puff a 250 
.mu.l corresponding to 0.544 mg diltiazem.HCl active substance/puff. 
EXAMPLE 2 
544 g diltiazem.HCl (micronized) are homogeneously mixed with 4.456 kg 
lactose (micronized) and filled into hard gelatin capsules with an active 
substance content of 5.44 mg diltiazem.HCl (corresp. to 5 mg base). 
The capsules can be perforated using a powder inhaler, so that the contents 
of the capsules can be inhaled. 
The following trials were conducted to prove the efficacy of the new 
administration forms. 
The test animals were two mongrel dogs (females, body weight 16 and 18 kg) 
under pentobarbital anesthesia (30 mg/kg i.v. initial). The animals were 
tracheotomized and were supplied with oxygen via a Y-shaped tracheal 
cannula, one branch of which served to carry out substance insufflation, 
using an Engstrom respirator (type ER 300) with ambient air. 
The following parameters of the animals were measured: 
1. ECG leg lead II 
2. Heart rate (R zig-zags triggered from ECG) using a pulse rate meter (in 
beats/min). 
3. Arterial blood pressure in the right femoral artery using a tip catheter 
(in mmHg). 
4. The left ventricular heart pressure using a tip catheter via right 
carotid artery (in mmHg). 
5. The contractility of the heart using an HSE differentiator from the 
isometric part of the left ventricular pressure curve, differentiated as 
dp/dt.sub.max (in mmHg/sec). 
6. The blood flow in the left femoral artery using electromagnetic 
measurement of flow (in ml/min). 
7. The blood flow in the left descending coronary artery. 
All parameters were continuously recorded simultaneously using a direct 
recorder and evaluated and printed out 1, 5, and 10 minutes, respectively 
after application. 
The substance was applied using a compressed air metered-spray resembling a 
pistol. The weight-specific quantity of the original substance was filled 
into the outlet pipe of the metered-spray from the front and completely 
insufflated into the trachea of the animal at a pressure of 0.2 atmosphere 
above atmospheric pressure during the pump-controlled inspiration. The 
insufflation procedure lasts one second in each case and, as has been 
found in previous trials, does not alone have any influence whatsoever on 
the circulation sizes measured. 
The results of the trials are represented in FIG. 1. It can be deduced from 
the curves that neither the heart rate nor the contractility are 
influenced, but that the flow in the coronary artery is dose-dependent and 
increases immediately for a sustained period. 
Further, it can be seen that the arterial blood pressure only decreases 
marginally subsequent to high doses and then only distinctly after 
influencing the coronary flow.