HRP950374A2 - Hypotensive pharmaceutical preparation and a process for the preparation thereof - Google Patents

Description

The field of technology

The invention is from the field of pharmaceutical chemistry.

Technical problem

The invention relates to a pharmaceutical preparation and a process for its preparation. Specifically, the invention relates to a nifedipine spray solution containing 1-5 wt. % nifedipine, 5-24 wt. % poly(ethylene glycol), 5-70 wt. % ethanol, 10-30 wt. % propylene glycol and 0.1-0.5 wt. % of additives and the procedure for obtaining this solution.

State of the art

Blood circulation is known to be effectively regulated by 4-(2-nitrophenyl)-2,6-dimethyl-dimethoxy-carbonyl-1,4-dihydro-pyridine known by the international improper name nifedipine, which is widely used in various types of pharmaceutical preparations for the treatment of morbid conditions related to blood circulation.

The poor solubility of nifedipine is a serious problem both for absorption from solid pharmaceutical preparations and for maintaining nifedipine in a dissolved state in the case of liquid pharmaceutical preparations. These difficulties are often solved by adding large amounts of surfactants to pharmaceutical preparations.

Recently, solid pharmaceutical preparations of nifedipine have become available which are either relatively long-acting or relatively fast-acting after administration. However, the treatment of anginal attacks or hypertonic emergencies requires a simple procedure of introduction into the body and then immediate action. In principle, these requirements have recently been met by the use of liquid pharmaceutical preparations, more precisely spray solutions.

DE-P 33 07 422 describes a solution that can be introduced into the body orally in the form of drops or by intravenous infusion. A known solution contains 0.5-10 wt. % of dihydropyridine derivatives, eg nifedipine, 20-60 wt. % agent for increasing solubility, preferably glyceryl-poly(ethylene glycol) and 80-40 wt. % diluent which includes water, ethanol, propylene glycol and/or poly(ethylene glycol). The disadvantage of the known preparation is the high content of surface-active agent, which can lead to irritation of the oral mucosa in the case of oral ingestion.

DE-P 35 44 692 discloses a spray solution in which a dihydropyridine derivative such as nifedipine is dissolved in poly(ethylene glycol) and ethanol, optionally in the presence of water and glycerol; the solution contains 3-15 wt. % polyvinylpyrrolidone. According to the description, the active substance of the pharmaceutical preparation has a fast effect, but it also has a drawback related to the fact that polyvinylpyrrolidone easily forms a solid film, which is why the sprayer is often clogged due to the drying of polyvinylpyrrolidone. Even when the sprayer is not completely blocked, the amount of sprayed nifedipine dose is not known because the sprayed dose is less than the required amount, so the solid polyvinylpyrrolidone secreted in the sprayer is washed away with a solvent. In this way, if a known pharmaceutical preparation is used infrequently, the dispersed dose will always be lower than the intended amount.

EP 190 292 discloses a pharmaceutical preparation that can be converted into an aerosol. The preparation consists of nifedipine dissolved in a solvent containing poly(ethylene glycol) and/or glycerol poly(ethylene glycol)-oxystearate, and the solution is atomized using a propellant or a pump in the carrier gas stream. According to the examples of the description, the solvent composed of ethanol may also contain water and glycerol. A preparation suitable for sublingual administration is also known from certain examples.

According to our research, the hypotensive action of a known pharmaceutical preparation is not sufficient for the effective treatment of anginal attacks or hypertonic emergencies.

Description of the solution to the technical problem with examples

The aim of the invention is to obtain a solution that can be sprayed using a pump, which is suitable for sublinal administration and which, even in a small dose, lowers blood pressure in a short time.

It was found that the above goal can be achieved with a nifedipine solution containing, apart from the usual components, 2-4 wt. % ethyl oleate.

It is surprising that the hypotensive effect of nifedipine becomes significantly stronger in the presence of 2-4 wt. % of ethyl oleate, that is, synergism is shown between nifedipine and 2-4 wt. % ethyl oleate (the percentage of ethyl oleate is given in relation to the mass of the entire preparation). This synergism was demonstrated by the following test:

LATI and Charles River male rats that were spontaneously hypertonic were used in the research. For each dose, 8 animals weighing 250-300 grams were used.

The animals were anesthetized by intraperitoneal administration of 90 mg/kg chloralose and 600 mg/kg urethane, then they were tracheotomized and a catheter was inserted into the left femoral artery of each rat. Blood pressure was determined and continuously recorded using a Statham P 23Gb tonometer. 30 minutes after the surgical intervention, a 10-minute control period was left, the sample to be examined was transferred to the oral mucosa of the animals, and the blood pressure was recorded for the next 60 minutes.

The following samples were tested:

- Solution of example 1. The dose transferred to the oral mucosa contained 3 mg of nifedipine and 3 wt. % of ethyl oleate (the last number refers to the mass of the solution that was introduced into the body).

- A solution similar to that of example 1, however, it contains 2.5 wt. % ethyl oleate. The dose transferred to the oral fold contained 3 mg of nifedipine and 2.5 wt. % of ethyl oleate (the last number refers to the mass of the solution that was introduced into the body).

- A solution similar to that of example 1, however, it contains 3.5 wt. % ethyl oleate. The dose transferred to the oral fold contained 3 mg of nifedipine and 3.5 wt. % of ethyl oleate (the last number refers to the mass of the solution that was introduced into the body).

- A solution similar to that of example 1, however, it did not contain ethyl oleate. The dose delivered to the oral mucosa contained 3 mg of nifedipine.

- A solution similar to that of example 1, however, without nifedipine. The dose transferred to the oral mucosa contained 3 wt. % of ethyl oleate (the last number refers to the mass of the solution that was introduced into the body).

In case of deviation from the composition of example 1, the amount of solvent was increased or decreased according to the change in the amount of ethyl oleate, i.e. the absence of nifedipine. In each case, an amount of solution containing 3 mg of nifedipine was introduced into the body of the animals. (the same amount - 0.103 g - of the solution without nifedipine was also introduced into the body of the animals).

The reduction in blood pressure caused by the tested solutions is shown in the following table. Blood pressure was measured 10, 20, 30, 40, 50 and 60 minutes after the introduction into the body of the tested solution, and compared with the blood pressure value that was measured before the introduction of the solution to obtain the pressure reductions given in the table.

Table

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It can be seen from the above data that the hypotensive effect of the preparation of the invention is significantly higher than the sum of the hypotensive effect of the ingredients determined separately. Therefore, there is synergism between nifedipine and ethyl oleate.

The spray nifedipine solution of the invention is obtained by forming a solution of 1-5 wt. % nifedipine, 5-24 wt. % poly(ethylene glycol), 50-70 wt. % ethanol, 10-30 wt. % propylene glycol and 0.1-0.5 wt. % additives in a known way and by mixing with 2-4 wt. % of ethyl oleate during the preparation of nifedipine solution.

Generally, nifedipine is dissolved in a mixture of organic solvents or a part thereof and the remaining ingredients are added to the resulting nifedipine solution. Ethyl oleate is mixed with a mixture of organic solvents containing nifedipine, before or after the addition of the other ingredients.

One or more additives can be a means of improving taste, for coloring, etc.

The obtained solution is preferably filtered and introduced into aerosol containers. A suitable pump is placed in each container, which is closed and equipped with a sprinkler. Since nifedipine is quite sensitive to light, the nifedipine solution should be protected from light during these operations.

The pharmaceutical preparation is well absorbed sublingually and has a significant effect in a very short period of time, so it is suitable for the effective treatment of anginal attacks and hypertonic emergencies. Spraying is done mechanically, using a pump, so the environment is not polluted by the propellant.

The invention is further illustrated by the following examples.

Example 1

2.9 parts by mass of nifedipine are added to a mixture of 10 parts by mass of poly(ethylene glycol) (molecular weight: 400) and 18.2 parts by mass of propylene glycol. The obtained mixture is heated to 75°C with stirring, then 3 mass parts of ethyl oleate and 65.8 mass parts of ethyl alcohol are added and the mixing is continued at 75°C. The homogeneous solution is cooled to 35-40°C and 0.1 mass part of the flavor enhancer is added, the mixture is stirred for another 5 minutes and filtered through a glass filter with pore size G4, under nitrogen. The filtrate is placed in aerosol containers with a capacity of 20 g, a mechanical atomizer (eg a pump) is placed in each container, which is closed and equipped with an atomizer.

Example 2

5 parts by mass of nifedipine are dissolved in a mixture of 10 parts by mass of poly(ethylene glycol) (molecular weight: 400) and 64.5 parts by mass of ethyl alcohol at 55-60°C with stirring. 16.9 parts by mass of propylene glycol and 3.5 parts by mass of ethyl oleate are added to the obtained solution with stirring, the mixture is cooled to 35°C and 0.1 parts by mass to improve the taste are added with stirring. Next, the procedure for example 1 is followed.

Example 3

1 mass part of nifedipine is dissolved in 64.5 mass parts of ethyl alcohol at 55-60°C with stirring, and then, with constant stirring, 12 mass parts of poly(ethylene glycol) and 19 mass parts of propylene glycol are added at the same temperature. With stirring, add 2.5 parts by mass of ethyl oleate to the obtained solution, cool the mixture to 35oC and add 0.1 parts by mass of a flavor enhancer. The procedure from example 1 is then followed.

Claims (2)

1. Spray solution containing 1-5 mass % nifedipine, 5-24 mass. % polyethylene glycol 50-70 wt. % ethanol, 10-30 wt. % propylene glycol and 0.1-0.5 wt. % of additives, indicated by the fact that it also contains 2-4 wt. % ethyl oleate to enhance the hypotensive effect of nifedipine. 2. Procedure for preparing a spray nifedipine solution from a homogeneous solution of 1-5 wt. % nifedipine, 5-24 wt. % poly(ethylene glycol), 50-70 wt. % ethanol, 10-30 wt. % priopylene glycol and 0.1-0.5 wt. % of additives, indicated by the fact that during the preparation nifedipine solution is mixed with 2-4 wt. % ethyl oleate.