ORAL PHARMACEUTICAL COMPOSITION AND ITS USE AS ANTISPASMÓDICO
GENERAL OF THE SMOOTEN MUSCLE AND IN THE TREATMENT OF MODERATE TO SEVERE INTESTINAL CORK
Description of the Invention The present invention relates to a composition containing 20 to 60 mg of Propinox and pharmaceutically acceptable excipients to be administered orally. It also describes the use of said oral formulation as a general antispasmodic of smooth muscle with biliary / digestive, urinary and gynecological applications. Moderate to severe acute intestinal colic has been studied as a type pathology. Propinox (diphenyl- (2-propynyloxy) dimethylaminoethyl acetate hydrochloride) is a product with smooth muscle relaxant activity that has demonstrated its effectiveness both orally and parenterally in controlled clinical studies in pathologies. gastrointestinal and gynecological-obstetric. Usually this compound is used in a dose of 5-10mg orally and 5-10mg / ml parenterally. Propinox has a mechanism of dual action that has been determined by performing "in vitro" pharmacodynamic studies
REF: 136679 in isolated organ with radioligand in human gallbladder. It presents non-selective muscarinic activity less potent than atropine but greater than scopolamine and, on the other, it behaves like a calcium antagonist given its high affinity for the phenylalkylamine and benzodiazepine sites at the level of the L-type calcium channel. Preclinical acute toxicity yielded an LD50 of 663 mg / kg orally and 47 mg / kg intravenously. Subacute toxicity during 12 weeks in rats and rabbits did not show differences with the control animals. This drug lacks mutagenic, teratogenic and histolesive effects after subcutaneous, intramuscular or intravenous administration. Pharmacokinetic studies in dogs and healthy volunteers showed a plasma peak 60 minutes after the oral dose. The analysis of the concentration-time curves supported a two-compartment kinetic model, with an elimination half-life of 4 hours and an apparent volume of distribution of 2 1 / kg. Propinox binds to high-grade plasma proteins (91%) and is eliminated by hepatic biotransformation.
Given that one of the most frequent medical pathologies of consultation in guard services is the colic pain of biliary origin, it was decided to continue investigating this type of pathology in order to find a quick and effective solution to this problem. It is known that the physiological coordination between the contraction of the vesicle and the relaxation of the sphincter of Oddi, favor the rapid evacuation of bile and that the parasympathetic system, predominantly enterohormones such as cholecystokinin, plays a transcendental role in this regulation. The pathophysiology of colic pain has been attributed to an increase in intraluminal pressure in the gallbladder and in the biliary tract due to increased tone and contractile activity of the smooth muscle. Its treatment includes drugs with smooth muscle relaxant activity such as anticholinergics, calcium channel blockers and nitric oxide donors such as nitrates. Dose-response studies were conducted at three dose levels of Propinox (10, 20, 30 mg) administered intravenously in patients with moderate to severe acute biliary colic (De los Santos AR, Martí ML, Di Girolamo G ., Diego Espinosa J., Morano MA, Tobar JC, Del Prete C. Bioscience Ediprint Inc. Vol. XXI, No. 1, 13-18 (1999)). The relaxation of visceral smooth muscle was the therapeutic objective, testing drugs such as antimuscarinics, NSAIDs, opioids, calcium channel blockers and nitric oxide donor drugs with varying degrees of efficacy. The use of natural antimuscarinic agents of tertiary structure such as atropine and scopolamine presented great limitations at therapeutic doses due to the high incidence of side effects dependent on muscarinic blockade, such as dry mucous membranes., cycloplegia, tachycardia and bladder atony. The incorporation of semisynthetic and synthetic derivatives of quaternary structure, limited the passage to CNS and prolonged the duration of action but ganglionic blockade to the muscarinic was added, and orthostatic hypotension and impotence may occur. Propinox has shown "in vitro" pharmacodynamic studies in human gall bladder in dose-response curves and radioligand binding kinetics, a non-selective antagonist activity on muscarinic receptors and L-type calcium channel blocker. This dual activity is synergistic and would explain its visceral smooth muscle depressant action (Baistrocchi RL, Ortí E, De los Santos AR, di Girolamo G, Martí ML, Pico JC, APPTLA 1999; 49: 161-9).
We studied 350 patients with acute biliary colic pain, which were divided into four homogeneous treatment groups, in which the analgesic-antispasmodic activity of three intravenous doses of Propinox (10, 20 and 30 mg) and placebo was evaluated. From the analysis of the results, it appears that 60% of the patients medicated with 30 mg of Propinox did not present pain 120 minutes after the administration of Propinox. All the treatments were well tolerated without registering adverse effects, observing only dry mouth according to the dose of the compound administered. It is concluded that doses of 20 and 30 mg intravenously achieve a greater analgesic and antispasmodic response than that of 10 mg in the treatment of biliary colic pain, lacking the classic side effects of anticholinergic drugs at cardiac, ocular or urination that in general limit or contraindicate the use of drugs with antispasmodic activity. The other pathology studied was colic of intestinal origin. It is known that the physiological control of intestinal mobility is highly complex. Modulation of smooth muscle mobility involves the central nervous system, the autonomic system, neuropeptides and gastrointestinal peptides. The disorders most frequently encountered in medical practice are irritable bowel syndrome, non-ulcerogenic dyspepsia, and diarticulosis, which share common symptoms such as pain and intestinal transit disorders such as constipation and diarrhea. The search for the pathophysiology of such conditions has focused on the abnormal intestinal myoelectric rhythm with increased frequency and duration of peristaltic contractions. It has been found that disorders in visceral mobility and increased intraluminal pressure would be the source of pain. Therefore, it is used in the treatment of this type of smooth muscle relaxing pathologies such as antimuscarinics and calcium channel blocking compounds. Propinox relaxes intestinal smooth muscle by means of antimuscarinic activity and calcium channel blocking activity as seen in in vitro studies (Baistrocchi RL, Orti E, De los Santos AR, di Girolamo G, Marti ML, Pico JC, APPTLA 1999; 49: 161-9 and Baistrocchi RL, Orti E, De los Santos AR, di Girolamo G, Marti ML, Pico JC, Methods Find Exp. Clin. Pharmacol., 21 (10), 659.1999). The efficacy and tolerance of the administered intravenous propinox was studied to establish an optimal dose for the control of acute abdominal pain originated in the painful contraction of the smooth intestinal muscle. Three doses of Propinox were used. (10, 20 and 30 mg) in 400 patients (Di Girolamo G., De los Santos AR, Marti ML, Valdés Quintana £., Godoy MI, Morano MA, Palomino G., Fandiño D., Greggio A. Bioscience Ediprint Inc Vol. XX, No. 1/2, 31-40 (2000)). The analysis of the results showed a pain reduction of 45, 52 and 56% according to the dose. The percentage of asymptomatic patients at 120 minutes was significantly higher in patients who received 20 and 30 mg (68.8% and 73.5% respectively vs 47.7% for 10 mg). The results obtained in this study demonstrated that Propinox is a useful and effective drug for the rapid symptomatic control of abdominal colic pain secondary to disorders of intestinal mobility associated with dyspepsia and irritable bowel syndrome. Higher doses were more effective without significant statistical differences between doses of 20 and 30 mg, with a very low and tolerable incidence of adverse effects. Finally, the results indicated that the dose recommended for conditions similar to those considered in these studies would be 20 mg administered intravenously. Therefore, in previous studies it has been verified that treatment with Propinox in doses of 20-30 mg intravenously in patients with acute intestinal colic or moderate to severe biliary colic produces a faster antispasmodic and analgesic effect, powerful and durable than the doses normally used in therapy. Taking into account these results it was decided in the present invention to orally deliver the same doses to patients with moderate to severe pain to check whether this phenomenon also occurs with the administration of the same doses orally. Accordingly, the object of the present invention is the oral administration of Propinox in doses of 20 to 60 mg as a general antispasmodic of smooth muscle. Moderate to severe acute intestinal colic secondary to functional conditions such as irritable bowel syndrome and dyspepsia was used as a model. We treated 500 patients divided into five groups, with 10, 20 and 30 mg of Propinox orally in a single dose. In addition, two comparative groups were added: one with 30 mg of Propinox intravenously and the other with placebo. It was observed that all treatments performed orally produced a progressive and significant decrease in pain compared to placebo. Unexpectedly, it was observed that at 120 minutes the percentage of patients free of pain with an oral dose of 30 mg was significant (Figure 1), similar to what occurred with intravenous administration. The pain reduction was remarkable both when compared with placebo and with the 10 mg dose. This study allowed us to conclude that the 30 mg dose orally constitutes an undoubted advance in the treatment of abdominal colic pain by providing a rapid onset of action, greater analgesia and a significantly longer effect than the doses normally used in therapy. The surprising thing is that these results are comparable to those already observed with the administration of the same drug in identical doses by intravenous route to a group of 400 patients in the treatment of moderate to severe acute intestinal colic pain and another of 350 patients with colic pain. of biliary origin. In these studies, the dose of 30 mg showed a faster, more intense and lasting effect than the doses normally used in therapy, without a significant modification of the safety profile, which only showed a slight increase in the incidence of dry mouth, a common phenomenon. all anticholinergics. Another aspect of the present invention is the use of this composition as a general antispasmodic of smooth muscle with biliary, digestive, urinary and gynecological applications.
According to what has been described above, we can conclude that the formulation described in a concentration of 20 to 60 mg, administered orally, has turned out to be very. effective as a general antispasmodic of smooth muscle and as a faster, more potent and lasting analgesic. Preferably, it is used in a dose of 20 or 30 mg. Exemplary embodiments Example No. 1 350 patients with moderate to severe acute colic caused by biliary lithiasis documented by ultrasonography and located in the right hypochondrium or epigastrium. The study protocol was reviewed and approved by the Ethics and Clinical Pharmacology Committee of the Hospital de Clínicas José de San Martín, a hospital of the University of Buenos Aires. Those patients who had received analgesic or antispasmodic medication within the previous six hours, insulin-dependent diabetics or decompensated diabetics, carriers of heart failure in functional class III or IV of the New York Heart Association classification, patients with previous history were excluded from the trial. of allergy to propinox, glaucoma, prostate hypertrophy, tachyarrhythmias, ischemic heart disease, neuropsychic disorders that make the weighting and expression of pain and the possible adverse effects of the drug studied difficult. The patients were randomized into four groups: the first group received one ampoule of Propinox 10 mg and 2 ampoules of placebo, the second group two ampoules of Propinox 10 mg and 1 ampoule of placebo, the third group three ampoules of Propinox 10 mg and the fourth group 3 placebo ampoules. The results are expressed in table I and II. Patient follow-up was extended for 120 minutes. The intensity of colic pain at rest was evaluated immediately before the dose using a horizontal analog visual scale of 100 mm and a qualitative scale of 5 levels (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe). The patients were evaluated again with the same methods after 20, 60 and 120 minutes after the dose was administered. On each occasion, the evolution of the accompanying symptoms of this condition was registered, as well as the incidence of adverse effects, such as dry mouth, cycloplegia and tachycardia, induced by the medication. In the final control of the 120 minutes, the patients and the medical essayist made a global evaluation of the efficacy and tolerance of the treatment instituted using a qualitative scale of four levels for efficacy (0 = null, l = regular, 2 = good , and 3 = very good) and of three levels for tolerance (0 = null # l = regular and 2 = good). Table I Parameters Placebo Propinox 10 Propinox 20 Propinox 30 basal mg mg mg
Age (years) 43.06 + 43.67 + 43.29 + 43.74 + 12.15 11.74 13.45 11.65
Weight (kg) 72.56 + 71.88 + 72.07 + 74.80 + 11.38 12.56 13.56 15.89
Height (m) 1.67 + 1.67 + 0.08 1.67 + 0.09 1.67 + 0.10 0.08 Voltage 130.1 + 130 + 14.1 132.3 + 133.12 + arterial 14.1 12.3 13.4 systolic Tension 76.6 + 8.8 77.3 + 10.2 74.5 + 7.9 76.9 + 10.4 arterial Diastolic Frequency 81.3 + 9.4 80.4 + 8.7 82.3 + 7.9 83.7 + 7.5 cardiac Temperature 36.63 + 36.56 + 36.55 + 36.64 + axillary (° C) 0.30 0.21 0.44 0.33
Scale 7.97 + 1.41 7.65 + 1.36 7.92 + 1.38 8.00 + 1.59 visual analogous (nuil) Scale 1 2 - - verbal moderate Scale 59 58 54 46 severe verbal Scale 25 21 36 46 very severe verbal Table II Changes in the intensity of pain at rest valued according to the analog visual scale
* p < 0.05 # p < 0.01
Example 2 400 patients with moderate to severe acute intestinal colic secondary to functional conditions such as irritable bowel syndrome and dyspepsia were studied. In the same way as in the previous example, the protocol was reviewed and approved by the Ethics and Clinical Pharmacology Committee of the Hospital de Clínicas José de San Martín, a hospital of the University of Buenos Aires. The patients were treated and evaluated in the same way as in the previous example. The results are expressed in Tables III and IV.
Table III Placebo Propinox Propinox Propinox 10 mg level 20 mg 30 mg significance between treatments
Number 100 100 100 100 Sex 36 36 45 45 DK male Sex 64 64 55 55 female Age 40.87 + 41.18 + 41.14 + 39.77 + NS 13.87 13.17 12.72 12.81 Weight 71.01 + 71.2 + 69.78 + 71.63 + NS 12.73 13.63 13.1.6 12.42 Height 1.66 + 1.65 + 1.67 + 1.67 + NS 0.08 0.09 0.09 0.08 Voltage 127.66 + 129.05 + 129.18 + 128.25 + NS arterial 16.87 13.15 13.15 12.5 Systolic Voltage 76.87 + 77.71 + 72.6 + 75.9 + NS arterial 12.08 9.02 9.15 8.32 diastolic to Frequency 81.73 + 80.99 + 81.38 + 81.33 + NS to 7.02 6.04 6.92 6.73 heart rate Frequency 17.02 + 17.57 + 16.96 + 16.57 + NS to 2.46 2.49 2.4 2.53 air respirator Temperature 36.71 + 36.71 + 36.73 + 36.66 + NS axillary 0.47 0.36 0.54 0.43 Scale 7.73 + 7.77 + 7.62 + 7.67 + Visual NS 0.85 0.97 1.02 1.13 Analogous Scale 75 78 78 72 Severe Verbal NS Scale 25 22 22 28 Very Severe Verbal 13
Table IV Changes in the intensity of pain at rest assessed according to the visual analog scale
* Difference from baseline = p < 0.0001 ** Difference evaluated after 20 min = p < 0.0001 *** Difference evaluated after 60 min = p < 0.0001
EXAMPLE 3 500 patients were treated with moderate to severe acute intestinal colic, secondary to functional conditions such as irritable bowel syndrome and dyspepsia, divided into five groups, with 10, 20 and 30 mg of Propinox, administered orally in a single dose. Two comparative studies were also added: one with 30 mg of intravenous Propinox and another with placebo. The patients were treated and evaluated in the same way as in the previous examples. At 120 minutes, the percentage of pain-free patients was significant with the oral treatment of Propinox 30 mg as shown in Figure 1; this percentage is surprisingly similar to that obtained when administering Propinox intravenously. The descriptive tables of the treated population and with the results are expressed in Tables V and VI.
Table V Placebo Propinox Propinox Propinox Propinox Level of 10 znn 20 g 30 g 30 mg oral signifiVia Oral via Oral route Intravenous route through nosa treatments
Humerus 100 100 100 100 100 Male sex 32 34 40 40 36 DK
Female 68 66 60 60 64 DK
Age 41.25 + 42.05 + 43.02 + 40.88 + 41.22 + NS 14.57 14.10 12.99 15.84 16.74 Weight 73.01 + 73.22 + 71.42 + 73.60 + 70.25 + NS 14.73 14.58 14.25 14.50 15.36 Height 1.70 + 1.68 + 1.69 + 1.70 + 1.67 + NS 0.15 0.20 0.13 0.28 0.78 Voltage 126.04 + 128.12 + 127.18 + 129.66 + 128.87 + NS arterial 15.05 14.25 14.35 13.5 18.38 Systolic Voltage 78.25 + 76.90 + 75.66 + 78.47 + 77.25 + NS arterial 12.54 8.40 9.30 11.01 10.86 diastolic Frequency 82.53 + 79.08 + 82.41 + 83.02 + 82.81 + Cardiac NS 8.07 6.09 7.06 7.16 7.53 Frequency 18.04 + 16.48 + 17.90 + 17.83 + 16.82 + Respiratory NS 2.86 2.52 2.1 2.70 2.70 Temperature 37.90 + 37.01 + 37.58 + 38.42 + 38.23 + NS axillary 0.57 0.41 0.73 0.68 0.29 Visual scale 8.22 + 8.64 + 8.58 + 8.73 + 8.65 + Analogous NS 1.20 1.27 1.44 1.39 1.52 Verbal scale 77 76 80 75 78 Severe NS Verbal scale 23 25 24 27 26 Very severe NS
Table VI Changes in the intensity of pain at rest assessed according to the visual analog scale
Difference from baseline = p < 0.0001 Difference evaluated after 20 min = p < 0.0001 Difference evaluated after 60 min = p < 0.0001
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.