RU2537136C1 - Method of obtaining alimemazine tartrate solution for introduction by injection - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention represents method of obtaining alimemazine tartrate solution for introduction by injection, characterised by the fact that sodium sulfate and ascorbic acid are dissolved with constant mixing in water for injections, which has temperature 20-25°C and was preliminarily bubbled with carbon dioxide for 15-25 minutes, after complete dissolution alimemazine tartrate is introduced and mixed for 10-20 minutes, filtered by method of sterilising membrane filtration, obtained solution is packed into dimming glass ampoule with application of gas protection by carbon dioxide with further sterilisation of solution at temperature 100-105°C for 30 minutes.

EFFECT: method improvement.

2 cl, 3 ex

Description

The invention relates to the field of the pharmaceutical industry and medicine and relates to methods for producing new formulations of antipsychotics.

In recent decades, there has been a tendency to increase the prevalence of psychogenic diseases, such as neurosis and other diseases with mild mental disorders, the occurrence, course, compensation and decompensation of which are mainly determined by psychogenic factors.

Among the drugs used to treat such diseases, Alimemazine tartrate has been shown to be effective. The drug was first synthesized in 1958 in the laboratory of the French company Theraplix. This drug quickly became a market leader in its segment, both in Europe and in America. In Canada, alimemazine was produced under the RapesSh brand; in the USA - “Temaril” (trimeprazine tartrate), “Theralen” - in France and Italy, “Repeltin” - in Germany, “Vallergan” - in England, “Teralen” - in the USSR.

Alimemazine is an antipsychotic with moderate activity. With severe psychoses, it is relatively ineffective; It acts primarily as a mild sedative and anti-anxiety agent, has a positive effect on senestopathy, obsession and phobia. It is used mainly for psychosomatic manifestations developing as a result of vascular, traumatic, somatogenic, infectious disorders of the central nervous system and with neurovegetative disorders.

Alimemazine tartrate is produced and prescribed mainly in tablets, for example, under the trade name Teraligen® (Teraligen) (http://www.vidal.ru/poisk_preparatov/teraligen.htm).

A patent is known for the pharmaceutical composition of alimemazine tartrate (RU 2384336 C1). The proposed tablets are intended for oral administration to patients for the correction of psychosomatic manifestations of various etiologies.

However, in the case of a number of emergency conditions, injection of the drug is required.

Known patent US 2928767 (A) - 1960-03-15, disclosing the compositions of the solution for injection containing phenothiazine derivatives. For example, the composition of trimeprazine tartrate is described, including sodium saccharin, sodium sulfite, tartaric acid and water for injection. The solutions are prepared by mixing or dissolving, filtering into ampoules through bacteriological filters and sterilizing the ampoules by autoclaving. This solution can be indicated as the closest analogue (prototype).

The task in the development of the known composition was the protection from the action of light. The opportunity for the preparation of solutions for infusion administration is not revealed.

The problem is solved in a new way to obtain an injection solution of alimemazine tartrate, which can be administered by infusion.

The method is characterized in that in water for injection, having a temperature of 20-25 ° C and pre-sparged with carbon dioxide for 15-25 minutes, sodium sulfite and ascorbic acid are dissolved with constant stirring, after complete dissolution alimemazine tartrate is introduced and mixed 10-20 minutes, filtered by membrane sterilizing filtration, the resulting solution is Packed in ampoules of light-protective glass using gas protection with carbon dioxide, followed by sterilization of the solution at a temperature of 100-105 ° C for 30 minutes.

Preferably, after loading each component, mixing is carried out for 10 minutes.

If necessary, the pH of the solution is adjusted to 4.5-5.5 before packing.

The resulting solution can be stored for at least 2 years.

The possibility of carrying out the invention can be demonstrated by the following examples.

Example 1

Composition for intramuscular administration.

Active substance:

Alimemazine tartrate in terms of dry matter 5.0 mg

Excipients:

Ascorbic acid (LSR-006666/08 or LSR-001713/07) 1.0 mg Sodium sulfite (GOST 195-77, analytical grade) 0.5 mg Water for injection (FS 42-2620-97) up to 1 ml pH from 4.5 to 5.5

Description. Colorless or slightly colored, transparent or slightly opalescent liquid

Freshly prepared water for injection is fed into the reactor. Cool the water to a temperature of 20-25 ° C and sparger with carbon dioxide for 20 minutes. Sulfite and ascorbic acid are charged through a hatch with a working stirrer of sodium. After loading each component are mixing for 10 minutes. After complete dissolution of the auxiliary components, alimemazine tartrate is loaded into the reactor and stirred for 15 minutes. At the end of mixing, a sample of the solution is taken for analysis. Ultraviolet absorption spectra of drug solutions and CO alimemazine tartrate in the region from 250 to 700 nm should have a maximum and a minimum at the same wavelengths.

Upon receipt of positive analysis results, the solution is passed to the filtration. Filter through a sterilizing membrane filter (0.2 μm).

The resulting solution is transferred to the bottling in pre-washed ampoules of 5 ml light-protective glass using gas protection (carbon dioxide) and sealed.

The solution is sterilized in ampoules at a temperature of 100-105 ° C for 30 minutes, the ampoules are checked for leaks. Ampoules with solution are packaged.

The solution is sterile, has an endotoxin limit of about 2.8 UE / mg of alimemazine tartrate, while the known composition has a limit of about 3.5 UE.

Example 2

To infuse the solution, 5 ampoules with an injection solution are diluted with 500 ml of 0.9% sodium chloride solution or 5% glucose solution.

Example 3

The study of pharmacological activity

In accordance with the results of a preliminary study, patients with intense psychomotor agitation, having neurological complaints and anamnestic indications of autonomic dysfunction, were selected.

The test method corresponded to the currently accepted international standards for clinical research: patients were randomly divided into two groups, the first of which (32 people) received alimemazine tartrate injections, and the second (9 people) received a placebo.

The condition of the patients was evaluated by traditional methods, using the Hamilton and Mikhalenko-Nuller depression scales, and the Hamilton anxiety scale. In addition, a psychological study was conducted, including an assessment of the stress indicator in the Luscher test, as well as an assessment according to the “Questionnaire for the identification of vegetative changes”. The examination of patients was carried out twice before the appointment of the study drug and 2 weeks after the start of treatment. The significance of differences was determined using Student's criterion.

The results showed a significant therapeutic effect. 93% of patients were no longer worried about the state of excitability, palpitations, “fading” or “cardiac arrest”, a feeling of lack of air and rapid breathing, tension type headaches, gastrointestinal discomfort and abdominal pain. There was an increase in efficiency. Patients began to fall asleep faster, sleep became deeper and without frequent night awakenings.

The drug was well tolerated and can be introduced into clinical practice.

Claims (2)

1. A method of producing a solution of alimemazine tartrate for injection, characterized in that in water for injection, having a temperature of 20-25 ° C and pre-sparged with carbon dioxide for 15-25 minutes, sodium sulfite and ascorbic acid are dissolved with constant stirring, after of complete dissolution, alimemazine tartrate is introduced and stirred for 10-20 minutes, filtered by the method of sterilizing membrane filtration, the resulting solution is Packed in light-protective glass ampoules using gas protection with dioxide leroda, followed by sterilization of the solution at a temperature of 100-105 ° C for 30 minutes. 2. The method according to claim 1, characterized in that after loading each component are mixed for 10 minutes.