Combined cimetidine-pirensepine formulation for treating peptic ulcers and erosions

An orally administered pharmaceutical composition for treating peptic ulcers and other gastrointestinal conditions associated with hyperacidity, which includes both the H.sub.2 -receptor antagonist cimetidine and the antimuscarinic agent pirenzepine.

BACKGROUND OF THE INVENTION 
The present invention relates to a novel pharmaceutical composition 
suitable for treating peptic ulcers and erosions, and other 
gastrointestinal ailments associated with gastric hyperacidity. More 
particularly, this invention pertains to an orally administered, 
pharmaceutical composition comprised of the histamine H.sub.2 -receptor 
antagonist cimetidine and the antimuscarinic agent pirenzepine, and a 
method of using such a pharmaceutical composition to treat 
gastrointestinal dysfunctions. 
It has been recognized that peptic ulcers and erosions can be treated with 
antimuscarinics, such as atropine, which inhibit the secretion of acid 
into the stomach. However, the effectiveness of such drugs has been 
limited by the significant side effects, e.g. increased heart rate, and 
depressed salivation, which occur at the therapeuttic dosage level. 
More recently, it has been observed that selective histamine H.sub.2 
-receptor antagonist, such as cimetidine, and ranitidine, can be used in 
the treatment of conditions where there is a hypersecretion of gastric 
acid. These antagonists are distinguished from the drugs commonly known as 
"antihistamines", e.g. mepyramine, which selectively block the H.sub.1 
-receptors of histamine to inhibit stimulation of the smooth bronchial and 
other muscles. See, Black et al. (Nature 1972, 236, 385); and Ash and 
Schild (Brit. J. Pharmacol. Chemother, 1966, 27, 427). 
A marked improvement in the healing of peptic ulcers and erosions has been 
noticed based on the use of the H.sub.2 -receptor blockers. More recently, 
the introduction of 24 hour pH-metry has enabled quantitative diagnostic 
and prophylatic information to be reliably gathered in a short time. Such 
techniques have demonstrated that the therapeutic effect of the H.sub.2 
-receptor antagonist is related to an increase in luminal gastric pH, 
particularly between about 11:00 p.m. and 6:00 a.m. 
However, the H.sub.2 -receptor blockers such as cimetidine have also been 
associated with certain undesirable side effects, including diarrhea and 
dizziness. Additionally, it is now known that even the continuous 24 hour 
infusion of high doses of H.sub.2 -receptor blockers will not induce a 
continuous 24 hour anacidity or near-neutral pH values in the stomach. 
Therefore, because it has been demonstrated that blockage of the histamine 
H.sub.2 -receptors alone is not effective to eliminate gastric acidity, it 
has been suggested that the proton secretion associated with peptic ulcers 
is also induced by factors other than H.sub.2 -receptor stimulation. 
Thus, it would be desirable to provide a pharmaceutical composition for 
inhibiting the various mechanisms for proton secretion by which gastric 
hyperacidity results, and which could be administered with reduced 
undesirable side effects. 
At times, particularly in the treatment of the gastric hyperacidity 
associated with Zollinger-Ellison syndrome, conventional doses of 
antimuscarinics and H.sub.2 -receptor antagonists have been given 
separately to the same patient at the same time. Additionally, Londong et 
al. reported in Scand. J. Gastroent. 15 (Suppl. 66): 103 (1980) that the 
combined intravenous injection of the antimuscarinic pirenzepine and the 
H.sub.2 -receptor antagonist cimetidine suppressed stimulated acid 
secretion more than either drug alone. The combined injection was 
reportedly accompanied by such side effects as blurred vision, dry mouth 
and weariness. 
However, there has been no recognition that the antimuscarinic agent 
pirenzepine and the H.sub.2 -receptor antagonist cimetidine should be 
combined in a single oral formulation for effectively treating peptic 
ulcers and other gastrointestinal diseases, at lower effective dosages 
than the dosages at which the separate drug components are conventionally 
administered, with prolonged therapeutic effect and reduced side effects. 
Accordingly, it is an object of the invention to provide an orally 
administered pharmaceutical composition containing the H.sub.2 -receptor 
antagonist cimetidine and the antimuscarinic pirenzepine, which can be 
used to effectively treat peptic ulcers and the other gastrointestinal 
conditions associated with hyperacidity, at lower dosages and with less 
side effects than are associated with the conventional administration of 
the separate drug components. 
Still another object of this invention is the provision of a method for 
treating peptic ulcers and other gastrointestinal conditions associated 
with hyperacidity, by orally administering a pharmaceutical composition 
containing both the H.sub.2 -receptor antagonist cimetidine and the 
antimuscarinic agent pirenzepine. 
These objects and other advantages of the invention will be apparent from 
the detailed description which follows. 
SUMMARY OF THE INVENTION 
The present invention provides an orally administered pharmaceutical 
composition for treating peptic ulcers and other conditions associated 
with gastric hyperacidity, which comprises the antimuscarinic agent 
pirenzepine, and the H.sub.2 -receptor antagonist cimetidine. The 
composition is preferably formulated as an orally administered tablet. 
The invention is also directed to a method for treating a patient suffering 
from a peptic ulcer or other condition associated with gastric 
hyperacidity, including Zollinger-Ellison syndrome, which comprises the 
step of orally administering an effective amount of a pharmaceutical 
composition comprising the antimuscarinic pirenzepine and the H.sub.2 
-receptor antagonist cimetidine. 
DETAILED DESCRIPTION OF THE INVENTION 
While the invention is susceptible to various modifications and alternative 
forms, the preferred embodiments are described herein in detail. It is to 
be understood, however, that it is not intended to limit the invention to 
the specific forms disclosed. On the contrary, it is intended to cover all 
modifications and alternative forms falling within the scope of the 
invention. 
The present invention provides an orally administered pharmaceutical 
composition for treating a patient suffering from a peptic ulcer or other 
ailment associated with gastric hyperacidity, which comprises both the 
antimuscarinic agent pirenzepine and the H.sub.2 -receptor antagonist 
cimetidine. It has been found that the effective dose of the composition 
contains less antimuscarinic agent and H.sub.2 -receptor antagonist than 
the conventionally administered doses of the separate drug components. 
Because lower dosages of the anti-proton secretion drugs are required, the 
composition can be administered with reduced side effects. Additionally, 
patient compliance is encouraged by the lower therapeutic dosage which may 
be administered as a single dose once daily. 
The antimuscarinic agent and H.sub.2 -receptor antagonist used in the 
invention safely decrease proton secretion into the stomach lumen, 
particularly at night, thereby presumably preventing or promoting the 
heating of peptic ulcers and erosions, and other conditions associated 
with gastric hyperacidity. Although the drug components of the composition 
can exist as addition salts, reference will be made throughout this 
specification, for convenience, to the parent compound. 
The antimuscarinic agent pirenzepine which is employed in the invention is 
a tricyclic gastric-acid inhibitor commercially available from Boehringer. 
The preparation of pirenzepine is described in Fr. Patent No. 1,505,795 
(1967), which is incorporated by reference herein. Pirenzepine is 
conventionally administered alone at a recommended daily dosage of 2.0 to 
3.0 mg per kg body weight, or 100-150 mg per adult patient in 2-3 divided 
doses. 
The preparation of the histamine H.sub.2 -receptor antagonist cimetidine 
which is used according to the invention is described in U.S. Pat. No. 
3,950,333 (incorporated by reference herein). Cimetidine is commercially 
available under the brand name Tagamet.RTM. from Smith, Kline and French. 
When administered alone, the recommended daily dosage of cimetidine is 24 
to 32 mg per kg body weight or 1.2-1.6 g/patient in 4 divided doses. 
The weight ratio of pirenzepine to cimetidine in the pharmaceutical 
composition of the invention is preferably from about 1:12 to about 1:5, 
and is most preferably about 1:12. The composition is preferably used in 
adult daily dosage amounts which include about 300 mg cimetidine and about 
25 mg pirenzepine, administered b.i.d., or about 600 mg cimetidine and 
about 50 mg pirenzepine, administered o.d. The recommended daily dosage 
preferably contains about 600 mg of cimetidine and about 50 mg of 
pirenzepine, per about 50-60 kg of body weight. 
The actual therapeutic dosage will of course depend on such factors known 
to those of ordinary skill in the art, including the age and weight of the 
patient, the route of administration, and the type of gastrointestinal 
condition from which the patient suffers. In any event, the composition 
will be administered at dosages and in the manner which the patient's 
attending physician deems calculated to deliver an effective amount of the 
composition based upon the patient's unique condition. 
The composition of the invention is administered orally in a suitable form 
such as a tablet, syrup or elixer, or suspension. The composition is 
preferably orally administered in the form of a tablet. 
Tablets intended for oral use may be prepared according to any method known 
to the art for the manufacture of pharmaceutical composition, and such 
tablet may contain one or more agent selected from the group consisting of 
sweetening agents, flavoring agents, coloring agents, and preserving 
agents, in order to provide a more palatable preparation. Tablets prepared 
according to the invention can also contain other nontoxic 
pharmaceutically acceptable excipients and fillers which are suitable for 
the manufacture of tablets. Such excipients include inert diluents, 
binding agents, lubricating agents, and others known to those skilled in 
the art. The tablets may be uncoated or may be coated by known techniques 
to delay disintegration and absorption in the gastrointestinal tract, 
thereby providing a sustained action over a longer period. 
The pharmaceutical composition is preferably tableted or otherwise 
formulated to include the daily dosage in 1-2 tablets. In other words, the 
composition is preferably formulated so that it need only be administered 
once daily, in order to ensure better patient compliance. 
The pharmaceutical composition of the invention may be used to treat or 
prevent a variety of gastrointestinal dysfunctions. As used herein, the 
phrase "gastrointestinal dysfunction" includes peptic ulcers and other 
conditions associated with gastric hyperacidity. For example, the 
composition may be used to treat peptic ulcer or erosion disease of the 
esophagus, stomach, and duodenum. Alternatively, the composition may be 
used to treat Zollinger-Ellison syndrome, or to treat or prevent the 
hyperacidity, and/or peptic ulcers (including bleeding therefrom) which 
frequently results from neurosurgery, head injury, severe body trauma, and 
burns.

The invention will be further described by reference to the following 
detailed example, which is not intended to be limiting, but rather 
illustrative of some approaches taken. This example may, of course, be 
varied in accordance with the spirit and scope of this illustration. 
EXAMPLE 
Tablets having the following composition were prepared: 
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Cimetidine (Richter, Budapest) 
300 mg 
Pirenzepine.HCl (Ind. Chimiche Italiane) 
25 
Microcrystalline cellulose (Avicel PH 101) 
75 
Starch 40 
Polyvinylpyrrolidone 25 
Hydroxpropylcellulose (KLUCEL HF) 
0.7 
Talcum 15.3 
Magnesium stearate 6.1 
Ultra-amylopectin 15.3 
Microcrystalline cellulose (Avicel PH 102) 
Total per one tablet 511.0 mg 
______________________________________ 
Healthy, informed volunteers, male and female, ate nothing after a noon 
light lunch. At 5:00 p.m., an Ingold pH electrode-probe was inserted 
intranasally, and the intragastric location of the tip was demonstrated by 
the sudden change from a pH of about 6.6 in the oesophagus to a pH of less 
than 1.7 when the tip entered the stomach lumen. The probe cable was taped 
to the subject's face, passed over the ear (left side on all occasions) 
and connected to an Autronic pH-metry apparatus, or a Gastrograpth Mark I 
machine, in a carrying case at hip level (see C. J. Fimmel et al., 
Gastroenterology, 88, 1842, 1985). 
Digital pH measurements were made from 6:00 p.m. to 7:00 a.m. the next 
morning. In Experiment I, at precisely 6:00 p.m. the subjects orally took 
2 tablets of cimetidine-pirenzepine (formulated as described above) with 
about 250 ml water. In Experiment II, the subjects instead took 600 mg of 
cimetidine (SmithKline) alone in tablet form for comparison, in the same 
volume of water as in Experiment I. In Experiment III the subjects took 50 
mg pirenzepine (Boehringer) along with 250 ml water for comparison. 
At precisely 7:00 p.m. the subjects had a standardised evening meal 
consisting of a two-egg omelette and 250 ml milk. No further oral intake 
was allowed until after the electrode probes were removed for 
recalibration at 7:00 a.m. the next morning. There were no noticeable 
side-effects experienced from the drugs whatsoever, and both nights 
involved quiet, undisturbed sleep with no serious discomfort from the 
electrode cables. Each subject served as his/her own control by 
participating in all experiments on consecutive days. The experiments were 
double bond but not randomized. 
Each volunteer was subjected to all three experiments. It was determined 
that the administration of each drug was accompanied by a transient 
increase in pH above the subject's night baseline pH. Mean baseline values 
for each subject were determined by comparing the pH values before and 
after onset of the drug-induced increase in pH. 
The pH values measured over time were used to calculate the data reported 
in the Table which follows, i.e. peak pH values, total durations of pH 
increase until return to baseline, areas-under-the-curve (pH increase vs 
time), and the percentages of total pH values above a given value over a 
period of 12 hours. All figures reported in the table are mean values and 
the "*" symbol is used to indicate statistical significances (P&lt;0.05). 
TABLE 
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Exp. I Exp. II Exp. III 
(cim. & (cim. (pirenz. 
pirenz.) alone) alone) 
______________________________________ 
Baseline pH 0.825 1.0 0.85 
Peak pH response 
6.55* 5.3* 5.0* 
Delta pH response 
5.73* 4.3* 4.15* 
Total duration (h) 
5.6 h.* 4.4 h.* 3.6 h.* 
Area-under-the curve 
123.5* 91.3* 85.7* 
(pH vs. time) 
75% total data (pH) 
&gt;1.45 &gt;1.35 &gt;1.40 
50% total data (pH) 
&gt;2.4* &gt;1.65* &gt;1.58* 
25% total data (pH) 
&gt;5.55* &gt;2.35* &gt;2.28* 
Total pH values &gt;5.5 
25% 4.5% 4.1% 
______________________________________ 
The data provided in the above table should be considered in view of the 
logarithmic basis for pH values. For example, an increase in peak pH value 
of 1.2 units corresponds to a greater than tenfold decrease in proton 
concentration. The data in the above table clearly show that the combined 
cimetidine/pirenzepine treatment was far more effective than either 
cimetidine or pirezepine alone in the following aspects. 
When compared with the administration of cimetidine alone, the combined 
formulation produced a 32.3% higher peak pH response, a 27.3% longer 
duration of action, and a 35.3% greater overall response (as measured by 
area-under-the-curve), and also resulted in 25% of the total measured pH 
data over 12 hours being greater than 5.5. In contrast, only 4.5% of the 
total measured pH data, over the same time period, was greater than 5.5 
when cimetidine was given alone. The comparisons of the combined 
formulation vs. pirenzepine alone showed even greater differences. 
The above data demonstrate that the combined oral formulation provides an 
increased and prolonged therapeutic effect, and can therefore presumably 
be administered at lower effective dosages, in comparison with the 
separate drug components.