LT3964B - Material for treating inflamation of gullet and inflamation and ulcer of gastric-bowels - Google Patents

Abstract

This invention describes the use of dimethylpolysyloxane for the treatment of inflammations of the gullet, inflammations and ulcers of the digestive-intestine systems, for example inflammation of the gullet, ulcers of the stomach and duodenum, gastritis. Dimethylpolysyloxane is used together with sylicagel.

Description

The present invention relates to a device for the medical treatment of esophageal and gastrointestinal disorders.

The anti-foaming effect of dimethylpolysiloxane foam has been well studied and used by therapists as a laxative and in preparation for sonography [Β.Χ. BaCHJieHKO h ap. M3BeHHaii 6ojie3Hb, M., MeanmiHa, οτρ. 217-229].

Unexpectedly, dimethylpolysiloxane has been shown to be very effective in treating gastrointestinal inflammatory ulcers.

The anti-foaming effect of dimethylpolysiloxane combines with other physicochemical properties such as film formation and wall adhesion. It has been unexpectedly found that polysiloxane can be administered orally over a long period of time without any adverse effects. In the human esophagus and gastrointestinal tract, polysiloxane forms and maintains a protective layer that promotes the healing process in the aforementioned disorders.

The above preparation according to the present invention is particularly useful in the treatment of disorders of the esophagus, stomach and upper small intestine, such as inflammation of the esophagus, ulcers (gastrointestinal) and gastritis.

According to the present invention, the efficiency of dimethylpolysiloxane is increased when used in combination with silica gel.

This preparation forms a film in the esophagus and in the gastrointestinal tract which has the characteristics of a gel. Such a layer is very similar to physiological mucus, which protects the mucosa of the esophagus and gastrointestinal tract.

These measures protect the esophageal and gastrointestinal mucosa from aggressive gastrointestinal substances such as hydrochloric acid and food-degrading enzymes. The protection afforded by the use of the materials of the present invention inhibits the activity of tissue destructive mechanisms and promotes undisturbed wall regeneration as new cells grow and ulcers are cleansed. The substances of the present invention also promote an increase in gastric pH (block increased acidity).

Studies have been conducted to evaluate the dose-response effect.

1. Distribution of dimethylpolysiloxane and film formation in the stomach.

2. Dimethylpolysiloxane distribution and film formation in the duodenum.

The studies were conducted in 8 healthy male volunteers aged 25 to 40 years (Table 1). The study was conducted as a controlled, randomized phase I crossover study. For cross-examination, 8 volunteers were randomly assigned and received both dosage forms. The tests were conducted every 7 days.

Two doses were given to each subject cross-examined:

I dose: 80 mg dimethylpolysiloxane (2 tablets of 40 mg dimethylpolysiloxane)

Dose II: 160 mg dimethylpolysiloxane (4 tablets of 40 mg dimethylpolysiloxane)

The composition of dimethylpolysiloxane tablets is given in Table 8. No other medications are prescribed before and after the studies. The subjects did not smoke on the day of the study.

Control studies

A comprehensive medical history and internal medical and neurological examinations are collected during the initial phase of the study. In addition, laboratory data are collected.

The following gastroenterological examinations shall be carried out on all subjects during the two study days:

1. Gastroscopy of the esophagus, stomach, and duodenum with recording immediately before chewing a dimethylpolysiloxane tablet.

2. Same study with registration 30 minutes after tablet acceptance.

3. Same examinations with registration 2 hours after tablet intake.

The studies were conducted with each subject twice, with each dose change at seven-day intervals. The second test measures the pH of the gastric contents at each gastroscopy.

Subjects do not fast and eat for six hours prior to gastroscopy and admission.

Each subject is injected subcutaneously with 0.5 mg atropine in 1 ml NaCl in preparation for endoscopy. Novescin Wander 1% solution (OxybuprokainHC1) was used for local anesthesia of the throat and nasopharynx.

Gastroscopy is performed on an Olympus Typ P ₁₀ instrument. Visual observations are recorded and photographs are taken.

Results

1. Change in gastric pH

Table 2 provides an overview of changes in pH values, before and 2 hours after administration.

The dimethylpolysiloxane preparation causes a marked increase in the pH, i.e. a clear shift of pH from strongly acidic to strongly alkaline range regardless of the amount of tablets consumed. Despite the small number of volunteers, this 5% difference is statistically significant.

Subject 7 was excluded from the analysis because a large scar was found on his Narben bulb and the pH value was near the alkaline zone (pH 6.05 and 6.83).

2. Film formation

Table 3 summarizes the results from Tables 4-7. The aim of the study was to monitor and record the effects of dimethylpolysiloxanes on the stomach and duodenum over two hours after ingestion of chewable tablets. The results obtained are not in doubt. Already 2 tablets of dimethylpolysiloxane (80 mg) cause a reaction in all subjects. This reaction is even more pronounced with 4 tablets (160 mg).

Following ingestion of 360 mg on the gastric mucosa, 7 out of 8 subjects develop a relatively large amount of milky secretion, which is a monitoring parameter.

Individual results and summarized results are presented

In Tables 4-7.

The results of visual observations and photodocuments suggest that dimethylpolysiloxane chewable tablets and dimethylpolysiloxane may form an adhesive film on the gastric mucosa and the duodenum at the proximal portion.

Table. History of subjects participating in the study of the therapeutic properties of dimethylpolysiloxane

Average SD Minimum- lus Maximum- lus Central meaning Age 32.15 4.51 25th 40 31.5 years Height 179.75 7.31 170 191 181 cm Weight 78 7.68 63 90 77 kg Systolic blood pressure 116 9, 99 101 130 114.5 mm Hg Diastolic blood pressure 78, 62 8.44 62 90 81 mm Hg Pulse 63.5 10, 94 53 88 60.5 ipm

Table. Changes in gastric pH with dimethylpolysiloxane

Study no. 1 2 3 4 5 6th 7th 8th Before use 1.8 1.9 1.9 1.5 2.1 6, 0 1.6 0 6th 2 8th 1 1 3 9th 30 min after administration 2.0 - - - - - - - 6th 2 or po 2.1 2.0 4.4 7.4 3, 8 2.3 6, 8 2, 6 take the imo 5 4 8th 9th 4 2 3 7th Number of tablets 2 4 4 2 2 2 4 2

The positive effect of pH on the use of the preparation was confirmed by test (p <0.05, two-sided test). No effect of the number of tablets on the increase in pH was observed. Subject 7 appeared to have the bestenotic Narben bulb and was therefore not analyzed.

Table. Positive reaction with dimethylpolysiloxane chewable tablets dimethylpolysiloxane tablets

Test reaction * positive no reaction n

8 * The reaction of five of the eight subjects was milk-secreted dimethylpolysiloxane tablets

Reaction of subjects ¹ * Positive no reaction ** The reaction of one of the eight subjects was a minimal amount of secretion in the milk, the reaction of the others a large amount of secretion.

Table. Results of the first study

Measuring time* Tablets number The result 1 subject 1 4 Signs of antrum gastritis 1 subject 2 4 Stomach juice stomach bottom; in the form of milk, cloudy, with flakes 1 subject 3 4 At the bottom of the stomach minimal quantities; other space up to duodenum - empty 2 subject 1 2 Mild signs of antrum gastritis; duodenum, stomach and esophagus observed macroscopically without lesions 2 subject 2 2 Stomach juice stomach bottom; in the form of milk, cloudy, with flakes 2 subject 3 2 Dairy-based substances at the bottom of the stomach; duodenum and esophagus - empty 3 subject 1 2 Slight esophageal hernia with grade 0-1 reflex; duodenum, stomach and esophagus observed macroscopically without alteration 3 subject 2 2 Stomach juice stomach bottom; in the form of milk, cloudy, with flakes

Table (continued)

Measuring time* Tablets number The result 3 subject 3 2 Small amounts of milk with flakes of sediment; flat stomach covered with film, duodenum empty 4 subject 1 2 Macroscopic observation of duodenum, stomach and esophagus without abnormalities 4 subject 2 4 Gastric juice at the bottom of the stomach; in the form of milk, cloudy, with flakes 4 subject 3 4 Slightly cloudy, milky gastric juice; duodenum, stomach and esophageal observation macroscopically without lesions 5 subject 1 4 Slight oesophageal hernia with grade 0-1 reflex; duodenum, stomach and esophagus under observation macroscopically without lesions 5 subject 2 4 Anthrum bottom covered a dense little substance. Very cloudy, milky liquid. 5 subject 3 4 Dairy flake residues at the bottom of the stomach. Single spots on the bottom. The duodenum hose empty.

Table (continued)

Measuring time* Tablets number The result 6 subject 1 4 Macroscopic observation of duodenum, stomach and esophagus without abnormalities 6 subject 2 4 Single, whitish milky spots on the antrum. Very much cloudy, milky plaque on the bottom of the stomach. 6 subject 3 4 Very cloudy, milky fluid in the bottom of the stomach. Single spots in the antrum. The duodenum is empty. 7 subject 1 2 Narben bulbus without stenosis; stomach and esophagus without lesions 7 subject 2 2 Smooth, milky plaque bottom. Duodenal and the antrum is empty. 7 subject 3 2 Slightly spotty, milky plaque on the bottom of the stomach. Duodenum and the antrum is empty. 8 subject 1 2 Duodenum, stomach and esophagus unchanged 8 subject 2 2 Fluffy, cloudy, milky plaque on the bottom, thin film. Duodenal and the antrum is empty.

Table (continued)

Measuring time* Tablets number The result 8 subject 3 2 Delicate, milky plaque covering the bottom with a thin film, the secretion cloudy. Duodenum and ant- rum empty.

Measuring

Measuring

Measurement time 1 time 2 time 3 just before taking the tablets

0.5 or just after the tablets or just after the tablets

Table

Second test results (after 7 days)

Measuring time* Tablets number The result 1 subject 1 2 Duodenum, stomach and esophagus unchanged, significant antrum gastritis improvement in macro- scopically, pH 1.80 1 subject 2 2 Milk secretion and film were significantly reduced quantity. Other data without changes, pH 2.06 1 subject 3 2 At the bottom of the stomach minimal amounts of secretory milk; duodenal and stomach - no changes, pH 2.15

Table (continued)

Measuring time* Tablets number The result 2 subject 1 4 Again, slight signs of antrum gastritis; duodenum intestine, stomach and esophagus - no change, pH 1.96 2 subject 2 4 Very thick milk juice at the bottom of the stomach. The antrum is empty 2 subject 3 4 Very thick milk juice at the bottom of the stomach. Anthrum and duodenum hose - empty, pH 2,04 3 subject 1 4 Small opening in esophagus hernia with grade 0-1 reflex; duodenum intestine, stomach, and esophagus observed macroscopically without changes, pH 1.92 3 subject 2 4 Very thick milk juice in the antrum and in the stomach. The duodenum hose empty 3 subject 3 4 Large milky plaque and secretion quantities of stomach bottom and antrum, duodenum empty, pH 4.48 4 subject 1 2 Macroscopic observation of duodenum, stomach and esophagus, pH 1.98

Table (continued)

Measuring time* Tablets number The result 4 subject 2 2 Minimum milk form secretion content of the stomach bottom; Anthrax and duodenum - empty 4 subject 3 2 Remnants of cloudy, milky stomach juice at the bottom of the stomach; duodenum hose and antrum - empty, pH 7.49. 5 subject 1 2 Small opening in esophagus hernia with grade 0-1 reflex; pH 1.51 5 subject 2 2 Minimum amount of secretion in the stomach and antrum. The duodenum is empty 5 subject 3 2 A small amount of cloudy secretion in the bottom of the stomach. Duodenum and antrum - empty, pH 3.84 6 subject 1 2 Duodenal, stomach and esophagus without lesions, ph 2.11 6 subject 2 2 Small amount of cloudy secretion in stomach and bottom of stomach. 6 subject 3 2 Minimum amount of secretion duodenum and stomach, pH 2.32.

Table (continued)

Measuring time* Tablets number The result 7 subject 1 4 Narben bulbus without stenosis; stomach and esophagus unchanged, pH 6.03 7 subject 2 4 Small amount of milky, cloudy secretory stomach bottom. Duodenal and the antrum is empty 7 subject 3 4 Minimum amount of non-dairy secretion at the bottom of the stomach. Duodenum and antrum blank, pH 6.83 8 subject 1 4 Duodenum, stomach and esophagus unchanged, pH 1.69 8 subject 2 4 Minimum milky secretion in film form. Chewable tablets in the stomach. The duodenum hose empty 8 subject 3 4 Very high volume cloudy, milky secretion, which covers the bottom of the stomach with a film. Stomach, duodenum and antrum blank, pH 2.67

* Measuring time 1 = just before taking tablets 5 Measuring time 2 = 0.5 hours after taking tablets

Measurement time 3 = 2 hours after taking the tablets

Table. Summary table of study on the healing properties of dimethylpolysiloxane

Subjects number Frequency of observation at the time of appointment during the study 2 tabs 4 tabs 2 tabs 3 tabs 3 + 2 tab. Anthritis gastritis signs 2 Anthritis gastritis improvement determined macroscopically 1 The duodenum hose and second- free 6th 6th 4 4 6th The duodenum hose loose 3 3 1 2 Stomach loose 1 1 1 minimum quantity milky secretion 6th 5 1 2 2 2 Minimum language kis / residue of stained milk of sediment 4 2 2 1 3 Single spots in the second 2 0 2 0 2 Milky, cloudy stomach juice with flakes 4 2 2 2 2

Table (continued)

Subjects number Frequency of observation at the time of appointment during the study 2 tabs 4 tabs 2 tabs 3 tabs 3 + 2 tab. Milky sediment 5 3 2 2 1 2 A lot of liquid milky secretion 3 0 3 1 1 1 Very much milky plaque and secretory remains 1 0 1 1

Table. Investigation of the healing properties of dimethylpolysiloxane

In the study o No. Date Tablets number Inquiry performance time Signs of antrum gastritis 1 15.3 1 Improvement of antrum gastritis as measured by macro- scrupulously 1 22.3 1 Signs of antrum gastritis 2 15.3 1 2 22.3 1 Small esophagus 3 15, 3 1 hernia of diaphragm opening 3 22.3 1 5 15.3 1 5 22.3 1

Table (continued)

The subject No. Date Tablets number Inquiry performance time Narben bulbus without stenosis 7th 15.3 1 7th 22.3 1 Duodenum and 2 15.3 2 3 secondhand loose 3 15.3 2 3 4 22.3 2 2 + 3 5 22.3 2 2 + 3 7th 15.3 2 2 + 3 8th 15.3 2 2 + 3 2 22.3 4 2 + 3 4 15.3 4 3 7th 22.3 4 2 + 3 8th 22.3 4 3 Duodenal 5 15.3 4 3 free 6th 15, 3 4 3 8th 22.3 4 2 Stomach loose 8th 22.3 4 3 Minimum quantity of milk secretory (non-chewed tablets in the stomach) 8th 22.3 4 2 Minimum quantity of milk 1 22.3 2 2 + 3 secretion in the stomach 4 22.3 2 2 + 3 5 22.3 2 3 6th 22.3 2 2

Table (continued)

In the study o No. Date Tablets number Inquiry performance time Minimum quantity of milk 5 22.3 2 2 secretion in the stomach and in the second 6th 22.3 2 2 Minimum amount of stains, 7th 15.3 2 3 milky plaque stomach bottom 1 15.3 4 3 Minimum amount of secretion at the bottom of the stomach 7th 22.3 4 2 Minimum amount of stains, milky plaque in the stomach 7th 15.3 2 3 Minimum amount of secretion in the duodenum and in the antrum 6th 22.3 2 3 Minimum amount of secretion at the bottom of the stomach without milky clouds 7th 22.3 4 3 Single white spots in the second 6th 15.3 4 2 Small amounts of milky plaque with flakes 3 15.3 2 3 Dairy flakes at the bottom of the stomach 5 15.3 4 3 Single spots in the antrum 5 15.3 4 3 6th 15.3 4 3

Table (continued)

In the study o No. Date Tablets number Inquiry performance time Milky, cloudy stomach juice with flakes at the bottom of the stomach 2 3 1 4 15.3 15.3 15.3 15.3 2 2 4 4 2 and 3 2 2 2 and 3 Smooth, milky plaque at the bottom of the stomach 7th 8th 15.3 15.3 2 2 2 2 and 3 The bottom of the stomach is flat and covered with a film 3 15.3 2 3 Anthrax and stomach grained bottom, milky plaque 5 15.3 4 2 The bottom of the stomach is covered with cloudy, milky plaques 6th 15.3 4 2 and 3 Very thick milky secretion at the bottom of the stomach 2 3 22.3 22.3 4 4 2 and 3 2 Very thick milky secretions in the antrum 3 22.3 4 2 A lot of cloudy, milky secretion that wraps the bottom of the stomach 8th 22.3 4 3 Very rich in milky plaque and secretory remains at the bottom of the stomach 3 22.3 4 3 Very rich in milky plaque and secretory remains in the second 3 22.3 4 3

Dimethylpolysiloxane is obtained by hydrolysis and polycondensation of dichlorodimethylsilane with chlorthrimethylsilane. Its various types differ in their viscosity, which is denoted by a number next to the name.

The degree of polymerization (n = 20-400) is chosen such that 2 -1 so that the kinematic viscosity is 20-1000 mm »s (20-1000 cSt).

Dimethylpolysiloxane has the formula:

CH ₃

H ₃ C-Si-O

CH ₃ ch ₃ ch ₃

Si-O- Si-CH ₃ ch ₃ n CH ₃

Silicone foam extinguisher S 184 (Wacker-Chemie) was used to make the chewable tablets used in the studies described above. Similar results were obtained using a polysiloxane having a kinematic viscosity of 100 to 10000 mm ² »s and especially 300 to 3000 mm ² » s ¹ .

Aerosil 2000 was used as fine dispersion silica.

Examples of obtaining chewable tablets are shown in Table 8.

Table. Dimethylpolysiloxane chewable tablet 40 mg

I 1) Dimethylpolysiloxane DAB9 * 40,000 mg 2) Fine dispersion silica DAB9 * 12.555 mg 3) Peppermint Oil DAB9 * 0.300 mg Anise oil DAB9 * 0.033 mg 4) Microcrystalline cellulose DAB9 * 200,000 mg II 5) Mannitol DAB9 * 338.111 mg 6) Saccharin-Na DAB9 * 0.677 mg 7) Carboxymethylcellulose Na DAB9 * 200,000 mg III 9) Magnesium stearate DAB9 * 3.333 mg 10) Maize starch DAB9 * 3.333 mg

* DAB9 - German Pharmacopoeia, Issue 9.

Claims (6)

DEFINITION OF INVENTION Use of dimethylpolysiloxane for the manufacture of a medicament for the treatment of inflammatory processes of the esophagus and for the treatment of inflammatory and ulcerative diseases of the gastrointestinal tract. Use of dimethylpolysiloxane in the manufacture of a medicament for the treatment of oesophageal, gastric and upper small intestine disorders such as oesophagitis, gastric and duodenal ulcer and gastritis. Use according to claim 1 or 2, characterized in that silica gel is added. Use according to claims 1-3, characterized in that the device has a kinematic viscosity of 100 to 10000 mm ² . 5. The method of claim 4, characterized in that the means has a kinematic viscosity of 300 to 3000 mm ² "of ^{the first} Use according to claim 3, characterized in that the device has a kinematic viscosity of about 1000 mm ^2? S ^x .