JPH0154327B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention resides in a novel pharmaceutical formulation for the treatment of tinnitus and vertigo in Meniere's syndrome. It is well known that this type of condition often occurs in older people and requires long-term treatment and therefore requires perfect tolerability of the therapeutic agent. To date, the main drug used to treat this type of disease is 2-methylaminoethylpyridine hydrochloride, also called betahistine hydrochloride. Although this drug has great therapeutic value, caution is required during its use and side effects may occur during administration.
Its use has been limited. Furthermore, this substance has a short duration of action and must be administered frequently. In fact, the daily dose is about 48 mg, but 6
It has been administered in divided doses. Betahistine has a histamine-like effect on the gastric juice-secreting cells of the gastric mucosa, so its use in patients with gastric ulcers or hyperacidity is not recommended. There was therefore a need for new pharmaceutical dosage forms in which the active ingredient is released at a constant rate over a long period of time, which eliminates the risk of intolerance, and which can be used freely. The pharmaceutical formulation of the present invention overcomes the above-mentioned drawbacks and adds a new therapeutic agent to the physician's prescription that is safe and has an effective dose that can be administered over a long period of time. The pharmaceutical formulation according to the invention is a delayed release pharmaceutical formulation for oral administration containing the active ingredient betahistine methanesulfonate (2-methylaminoethylpyridine methanesulfonate), which is formed from starch and stearic acid. Spraying onto the inert core a solution of the active ingredient betahistine methanesulfonate, followed by a solution of a methacrylic acid polymer, or alternatively containing betahistine methanesulfonate and a methacrylic acid polymer. This spraying process is repeated until the desired concentration of betahistine methanesulfonate is obtained on the core to form spherules, the formed spherules are dehydrated, dried and the resulting spherules are It is characterized in that it is formed by filling the small spherules into a pharmaceutically acceptable capsule. As the pH of the digestive juices increases, the formulation according to the present invention
Releases betahistine gradually. Examples of inert substances include, for example, starch, talc, lactose, sucrose, colloidal silica,
Mention may be made of cellulose, magnesium stearate, magnesium phosphate or alumina. Preferred methacrylic acid polymers are those commercially available under the tradename Eudragit. The pharmaceutical dosage form of the invention is provided as a transparent or opaque capsule containing a quantity of spherules in the form of a flavored or unflavored suspension. When the capsule comes into contact with the digestive fluids in the stomach, it opens.
This large number of spherules is released, converting the single dose into a large number of automatically subdivided doses. This subdivision achieves good dispersion and therefore satisfactory absorption and persistence. The capsules of the invention contain 10 to 15 mg of active ingredient;
Preferably 12 mg is included. The daily dose is 2 to 3, preferably 3 capsules. According to the formulation of the invention, it is possible to reduce the therapeutic dose for vertigo caused by Meniere's disease by 50%, and undesirable side effects can be avoided as much as possible. According to the treatment guidelines, the treatment period is 6
It can last from a week to six months. The formulation of the invention was tested for the treatment of vertigo in Meniere's disease and for the treatment of cerebral circulatory failure. Although this treatment was specifically intended for elderly patients (over 70 years of age), younger patients were also treated under the same conditions. Example of manufacturing the pharmaceutical preparation of the present invention Raw material granules of a mixture of starch, sucrose and stearic acid are prepared. The sieved granules are taken to a turbine and processed at a speed and rotation time that results in perfectly spherical granules. Sieve again and dry the granules. Some of the granules are moistened with ethanol and coated with betahistine methanesulfonate solution again using a turbine. Add talc and stearic acid to facilitate coating. The granules are then dried in a draft dryer. Repeat this operation several times. After finishing, coat with a solution of methacrylic acid polymer. The spherules thus obtained are dried in a ventilated dryer for 2 to 4 days. In the next step, the active microspheres are quantified and then the required amount of inactive uncoated microspheres is added to obtain a mixture containing 12 mg betahistine for 240 mg microspheres. The spherules are then filled into capsules, each capsule containing 240 mg of the spherules. Example of manufacturing 100,000 capsules Active microspheres Betahistine methanesulfonate...1200Kg Eudragit, stearic acid, talc, sugar, corn starch, Erosil
…20800Kg Inert small spherules Sucrose, corn starch, stearic acid
...2000Kg 24000Kg Additives in the manufacturing process Distilled water, 95% ethanol, acetone Measurement of the release rate of betahistine methanesulfonate The release rate of betahistine methanesulfonate from the activated microspheres according to the present invention is as follows: It was found that within the limits: 1 hour: less than 40% released 4 hours: less than 80% released 8 hours: 80-89% released In contrast, conventional commercial tablets release their active ingredients in 30 minutes. Almost 100% of it is released. This measurement was carried out using a suitable device under certain conditions that reproduced conditions corresponding to those in the body. That is, the release during the first hour was measured using artificial gastric fluid with a pH of 1.5, and after one hour, the medium was
The 4- and 8-hour release was measured by changing to 6.5-7.5 simulated intestinal fluid. The equipment used was capable of constant stirring and maintaining a constant temperature of 36.5°C to 37.5°C. The spherules from each production batch can be tested as described above and the coating modified accordingly. Determination of bioavailability in humans A delayed release pharmaceutical formulation according to the invention and a conventional commercially available formulation were administered to participants and plasma levels of betahistine were determined. In the case of the present invention, the highest plasma concentration was obtained after 2.5 hours, this plasma level lasted for 8 hours, and even after 12 hours the active ingredient betahistine was found in the plasma. However, with conventional formulations, the maximum plasma concentration was obtained very quickly and lasted for about 2 hours, and by the 3rd hour after administration, the active ingredient betahistine could no longer be found in the plasma. The above results show that the formulation according to the invention has an exceptionally long sustained release and good bioavailability, whereas the conventional formulation releases the active ingredient in a very short time and has an immediate and intense absorption. Therefore, it can be seen that strong side effects appear very early after administration. Clinical Trial A Target Disease - Cerebral Circulation Insufficiency The clinical trial was conducted on 40 patients in a double-blind manner using a placebo as a control drug. The treatment period was 12 weeks, divided into two periods of 6 weeks each, with a 2-week washout period in between. The washout period is to ensure that any residual effects from the treatment are removed. The order of treatments was randomized and the key code generated by the manufacturer was stored in a sealed envelope and not opened until after the study was completed. Medication placement and administration throughout the study period
Standard protocols were followed. Standardization of nursing care, which is considered to be extremely important when developing treatments that are supposed to improve cerebral circulation in the elderly, was particularly strictly adhered to. In the same department, a psychometric test designed to evaluate the Crichton rating scale was conducted, specifically following a thoroughly tested method. Evaluation method: Results were evaluated from clinical and psychological perspectives.
Evaluation was simplified through the use of the Crichton rating scale. Systematic examination of each parameter enabled accurate evaluation of items improved after each treatment. Results were classified as improved, slightly improved, or unchanged, depending on the patient's clinical condition and the number of items improved.
Improvement is an improvement in all item groups, slight improvement is subjective and objective, some improvement is shown by separate parameters, and no change is a persistence of weak quality (medical and psychiatric). This is reflected in the unchanged outcome, worsening compared to the starting point, and unchanged clinical picture. Resistance was evaluated as follows. a Biological resistance Considering the known properties of betahistine, conventional tests were adopted to confirm resistance. The following tests were conducted before and after treatment. Urea Glucose Cholesterol Transaminase SGOT/SGPT Hemoglobin Blood Cell Count b Clinical Tolerance The following tests were performed with particular emphasis on observation of the cardiovascular system. Arterial blood pressure before, during, and after treatment Heart rate before, during, and after treatment Electrocardiogram before and after treatment Observation of the gastrointestinal system, intestinal transit time, nausea, vomiting, and neurological observations were performed by nursing staff, and drug This was followed by a test to measure the effectiveness of the test. Results: Treatment was divided into two periods of 6 weeks each. The results are as follows. Group 1: Placebo-active drug series Placebo Slightly improved 5 (25%) Unchanged 15 (75%) Active drug Improved 16 (80%) Slightly improved 3 (15%) Unchanged 1 (5%) Group 2: Active drug -Placebo series Active drug Improved 12 (60%) Slightly improved 4 (20%) No change 4 (20%) Placebo No change 20 (100%) From these results, the degree of improvement due to active drugs can be summarized as: Improvement 28 (70%) Slight improvement: 7 (17.5%) No change: 5 (12.5%) Analysis of results: In this double-blind, placebo-controlled crossover clinical trial, 40 patients were treated. The advantage of this type of trial is that it only requires a small number of patients. Eleven patients were male (27.5%) and 29 were female (75.5%). The number of patients was the number of subjects commonly used in this type of study. What is noteworthy about the results of this study is that there were no patients who dropped out during the study, and no side effects were observed. It was generally well tolerated, with only a few cases of mild intolerance. The symptoms particularly improved by treatment with the preparation of the present invention are as follows. Placebo-active drug series Anxiety, fear 77% Emotional stability 73.7% Turbulence, confusion 68.5% Reactive depression 64.3% Dizziness 61.5% Appetite 61.5% Headache 54.55% Sleep 53% Tinnitus 50% Active drug-placebo series Anxiety, fear 86.7 % Fatigue 83.4% Emotional stability 73.3% Vitality, confusion 69.2% Reactive depression 62.5% Headache 62.5% Orientation 57% Dizziness 50% The above results indicate that betahistine is clearly effective on cerebral circulation. There is. The results also indicate that the physiological picture of the patient is particularly markedly improved. Certain items, such as dizziness, fatigue, headaches,
The extremely significant improvements observed in sleep, tinnitus, etc. confirm the clinical effectiveness of this drug in treating cerebral circulation failure. Biological tolerability was excellent in all cases;
No changes in blood cell counts, changes in urine or glucose levels, or changes in liver function were observed. B. Subjects - Meniere Syndrome The study was carried out on 25 patients with an average age of 42.5 years. There were 10 male cases and 15 female cases. All patients had Meniere syndrome with disease duration ranging from 6 months to 20 years. The dosage and treatment regimen were determined in conjunction with the effective amount of betahitine, particularly taking into account the specific dosage form of the formulation of the invention. Betahistine was administered at a dose of 3 capsules per day. One capsule contains 12 mg of betahistine methanesulfonate. The treatment period was fixed at least 3 months. In some cases, treatment continued for six or even nine months. The criteria for determining effectiveness are as follows. Meniere's disease in its acute phase is characterized by three symptoms. namely, dizziness, tinnitus and hearing loss. Vertigo is a separate symptom in which patients feel as if objects around them are spinning. The acute phase lasts several hours and may be accompanied by visual sympathetic signs. Evaluation of the clinical effectiveness of drugs was based on this type of inclusion criteria. Before and after each treatment, maze tests, audiograms were performed, and clinical signs, dizziness, nausea,
Otalgia, headache, and tinnitus were evaluated. Analysis of results: Independently of the clinical evaluation, the evaluation of the above-mentioned clinical parameters was classified as very good, good, fairly good, moderately good, and poor. At the same time, particular emphasis was placed on the observation of the gastrointestinal system, as well as the cardiovascular and nervous system tolerance to the formulations of the invention. Conclusions: By the end of the study, no patients had discontinued treatment, no side effects were observed, and this product was extremely well tolerated by all patients. The study was conducted on 25 patients and the following results were obtained. Very good and good 16 patients (64%) Very good and moderately good 6 patients (24%) Poor 3 patients (12%) ,
Similar to A and B above, clinical trials were conducted regarding efficacy and tolerability. The formulation of the invention was administered three times a day and the commercial formulation was administered five times a day. The results obtained are shown in the following table using the above evaluation scale.

[Table] Commercially available preparations 5 5 6 10
2

Claims (1)

[Claims] 1. Spraying a solution of the active ingredient betahistine methanesulfonate (2-methylaminoethylpyridine methanesulfonate) onto an inert core formed from starch and stearic acid, then spraying a solution of the active ingredient betahistine methanesulfonate (2-methylaminoethylpyridine methanesulfonate), Spraying a solution of acrylic acid polymer or a solution containing betahistine methanesulfonate and methacrylic acid polymer and repeating this spraying process onto the core to form a desired concentration of betahistine methanesulfonate. A delayed release pharmaceutical formulation for oral administration formed by repeatedly forming spherules until obtained, dehydrating the resulting spherules, drying, and filling them into pharmaceutically acceptable capsules. . 2. Pharmaceutical preparation according to claim 1, wherein the spherules are filled into capsules in powder form or in the form of a gel for oral administration. 3. A pharmaceutical formulation according to claim 1 or 2, in which the active ingredient is present in an amount of 10 to 15 mg per dose.