DE19903894A1 - Synergistic muscle relaxant combination of vecuronium and rocuronium, is effective at low doses and gives rapid onset of action and short recovery time - Google Patents

Abstract

A synergistic medicament combination comprises (apart from inert carriers, stabilizers, diluents and/or solvents) the amino-steroidal, non-depolarizing muscle relaxants vecuronium (VC) and rocuronium (RC).

Description

The invention relates to a combination product of two non-depolarizing Muscle relaxants, Vecuronium and Rocuronium, for common and simultaneous use in patients undergoing surgery have to undergo a quick start, but only briefly need continuous, complete muscle relaxation.

If surgery is performed under general anesthesia, that is Administration of muscle relaxants (MR) mostly an integral part of the Anesthesia. The muscle relaxation serves on the one hand to secure the Airways by inserting the breathing tube into the trachea (Intubation) safely and gently. On the other hand, the ensures absolute immobilization of the patient during the operation, so that the surgeon is offered optimal operating conditions.

Medications are available to the anesthesiologist to perform muscle relaxation with different modes of action, namely depolarizing and non- depolarizing MR, available. The ones currently used in the clinic Substances are listed below and in a nutshell characterized.

• - The depolarizing relaxants succinylcholine and suxamethonium [ED ₉₅ 0.1 mg / kgKG] have a very quick response time of 45-60 seconds and an ultra-short duration of action of 8-15 minutes. However, because of their extremely high potential for side effects, they are only used in special indications, e.g. B. used in an emergency. In the United States, the use of depolarizing MR in pediatric anesthesia in elective surgery is not permitted due to the high risk of side effects.
• - Mivacurium [ED ₉₅ = 0.075 mg / kgKG] is the only short-acting, non-depolarizing MR with a recovery period of 18-25 min. however, with clinically recommended doses of 2.5 times ED _95, the exposure time of this substance is approximately 2-3 minutes. In addition, histamine release as well as an acceleration of the heart rate (tachycardia) and a drop in blood pressure (hypotension) are to be expected with intravenous administration.
• - Rocuronium [ED ₉₅ = 0.3 mg / kgKG] has the fastest stroke time of 60-90 sec. Of the medium-length, non-depolarizing MR, but the time taken for the muscles to fully recover (<90%) up to 40 min. Clinically significant side effects are rarely observed.
• - Vecuronium [ED ₉₅ = 0.04 mg / kgKG] has a recovery time of 45-55 min at a stroke time of 2-3 min. Clinically significant side effects are extremely rare.
• - Atracurium [ED ₉₅ = 0.25 mg / kgKG] also has a stroke time of 2-3 minutes and a recovery time of 45-50 minutes. Histamine release is almost always to be expected after administration of Atracurium, and cardiovascular side effects such as tachycardia and hypotension are more common.
• - Cisatracurium [ED ₉₅ = 0.05 mg / kgKG] has a striking time of 3-4 min and a recovery time of 55-60 min. Clinically significant side effects rarely occur.
• - Of the long-acting MR, only pancuronium and Pipecuronium a role in the clinic. Both have a very long attack time and work for more than 1 hour until the muscles fully recover.

To achieve intubation readiness at the beginning of anesthesia, at least twice ED ₉₅ is usually required. The indicated attack times and durations therefore relate to this so-called intubation dose.

In terms of patient safety, in addition to the obvious Minimizing the side effects primarily as fast as possible Velocity of action and a short duration of action with faster and safer Muscle strength recovery worth striving for. There is a fast attack time required to get one as soon as possible in the already anesthetized patient Insert ventilation tube (tube) into the trachea. This will  early protection against pulmonary aspiration from e.g. B. stomach contents or blood and also created a safe ventilation option.

With a short duration of action, an MR becomes more controllable, the required dose can be adjusted more precisely to the operative events and the recovery of the Muscle strength becomes complete early after the end of the surgery his. A risk to the patient results from one Relaxant overhang, which is often the case for short-term operations (e.g. in the Pediatric Anesthesia) can occur.

In order to be outstandingly suitable for clinical use and to minimize the risk for the patient, the anesthetists therefore place the following pharmacodynamic requirements on an ideal muscle relaxant:

• 1. Fast stroke time ≦ 60 sec. (I.e. the time from the start of the injection up to muscle relaxation of ≧ 95%) after administration of the intubation dose.
• 2. short duration of action and rapid recovery of muscle strength ≦ 15 min.
• 3. no cardio-vascular side effects
• 4. no histamine liberation
• 5. Antagonizability of the effect.

As can be seen from the list, is currently clinical among those worldwide used muscle relaxants none that meet the above requirements completely corresponds. In particular, there is no non-depolarizing MR, which causes a very quick onset of action with a short duration of action.

Although by using the so-called 'priming' method in which a small dose of the muscle relaxant every 2-4 minutes before the actual intubation dose is applied, the stroke time of the medium-long acting substances Vecuronium, Atracurium and Rocuronium can be accelerated, however, the duration of action of the Substances not shortened.

Only the depolarizing MR have both a fast response time and also have an ultra-short duration of action, but due to their numerous,  potentially life-threatening side effects for routine use unsuitable and their use is therefore only justified in extreme emergencies.

The invention is therefore based on the object of a muscle relaxant To provide, which meets the above requirements for an ideal MR better fulfilled than the previously available drugs and that has fewer or at least no more side effects than these.

It was found that the combination of vecuronium and rocuronium also with simultaneous intravenous administration to a synergistic Increased effectiveness leads. This potentiation is obviously based on one Change in the pharmacokinetic behavior of the substances with common Application, the cause of which is a change in protein binding behavior is justified.

The result of the observed synergism is a significantly accelerated onset of complete muscle relaxation, which can also be achieved if less than the simple ED _{95 of} each of the two substances is administered. By reducing the intubation dose by means of a combination of the two MRs, the duration of muscle relaxation is shortened in a dose-dependent manner at the same time, without the rapid onset of action being impaired.

Ultimately, the pharmaceutical combination described according to the invention ceases new muscle relaxant with its own active profile, which is characterized by the sole application of one of the two combiners cannot be achieved.

• - Example 1: When using a 1:10 solution containing 0.2 mg / ml vecuronium and 2 mg / ml rocuronium, a dose of 0.1 ml / kg KG is administered. This corresponds to a dose of 0.02 mg / kgKG Vecuronium and 0.2 mg / kgKG Rocuronium, i.e. less than the simple ED _{95 of} each substance. After intravenous administration of the solution in the above-mentioned dose to an adult patient, the response time was 60-90 seconds and the recovery time was 15-20 minutes.
• - Example 2: When using a solution in a ratio of 1: 8, the 0.2 mg / ml Vecuronium and 2.5 mg / ml Rocuronium contains a dose of 0.1  ml / kgKG administered. This corresponds to an application of 0.02 mg / kgKG Vecuronium and 0.25 mg / kg KG Rocuronium. After intravenous administration of the Solution in the above dose in a child under 10 Years, a stroke time of 50-60 sec. And a recovery period resulted from 12-15 min.

Because of the close chemical relationship between Vecuronium and Rocuronium, in both cases it is MR from the group of Aminosteroids, a mixture of the two substances is possible without any problems. At Pharmaco-industrial production of the combination of substances in a suitable manner Mixing ratio and filling in appropriate ampoules can Anesthesiologists have an almost ideal muscle relaxant ready to use be put.

Claims (8)

1. Synergistic drug combination, which in addition to one or several, the pharmacological effects of muscle relaxation are not influencing carrier or stabilizing substances and / or diluents or Solvents as pharmacologically active components the aminoseroid, contains non-depolarizing muscle relaxants Vecuronium and Rocuronium. 2. Pharmaceutical combination according to claim 1, characterized in that in the combination on a part by weight of Vecuronium each 1-100, preferably however 5-25, parts by weight of rocuronium come. 3. Means according to one or more of the preceding claims, characterized characterized that the use unit Vecuronium and Rocuronium in Ratio 1: 1 to 1: 100, but preferably in a ratio of 1: 5 to 1:25. 4. Means according to one or more of the preceding claims, characterized characterized in that the ready-to-inject solution is 0.001-10 mg / ml vecuronium and contains 0.01-100 mg / ml rocuronium. 5. Means according to one or more of the preceding claims, characterized characterized in that in the solution for injection Vecuronium and Rocuronium in a ratio of 1: 1 to 1: 100, but preferably in a ratio of 1: 5 to 1:25, are included. 6. Means according to one or more of the preceding claims, characterized characterized that vecuronium and rocuronium in a common Dose unit available. 7. Means according to one or more of the preceding claims, characterized characterized that vecuronium and rocuronium in separate dose units available. 8. Use of the combination preparation according to claims 1-8 for generalized muscle relaxation of patients as part of a General anesthesia and / or intensive care.