WO1999027914A1 - A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane for intramuscular administration - Google Patents

A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane for intramuscular administration Download PDF

Info

Publication number
WO1999027914A1
WO1999027914A1 PCT/EP1998/007519 EP9807519W WO9927914A1 WO 1999027914 A1 WO1999027914 A1 WO 1999027914A1 EP 9807519 W EP9807519 W EP 9807519W WO 9927914 A1 WO9927914 A1 WO 9927914A1
Authority
WO
WIPO (PCT)
Prior art keywords
intramuscular
pharmaceutical formulation
intramuscular administration
bispiperidinylandrostane
monoquaternary
Prior art date
Application number
PCT/EP1998/007519
Other languages
French (fr)
Inventor
Jane Cyran
Original Assignee
Akzo Nobel N.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Akzo Nobel N.V. filed Critical Akzo Nobel N.V.
Priority to AU18744/99A priority Critical patent/AU1874499A/en
Publication of WO1999027914A1 publication Critical patent/WO1999027914A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • a pharmaceutical formulation of monoquatemary 2,16- bispiperidinylandrostane for intramuscular administration A pharmaceutical formulation of monoquatemary 2,16- bispiperidinylandrostane for intramuscular administration
  • the invention relates to an intramuscular formulation comprising a neuromuscular blocking agent.
  • the invention also relates to a method of manufacturing a preparation for intramuscular administration, and to a method of providing muscle relaxation comprising the intramuscular administration of a neuromuscular blocking agent.
  • Neuromuscular blockers which have curare-like effects, have acquired an essential position in medical practise.
  • such drugs are important in order to block unwanted muscle movements and to reduce muscle tension.
  • emergency situations require a rapid onset of action of such a drug when administered to patients.
  • the known drugs are given intravenously in order to reach rapidly the sites of action in the muscles.
  • Intravenous administration has the disadvantage that this route of administration requires meticulous and careful manipulation, which is often difficult in emergency situations.
  • the active ingredient for an intramuscular formulation should not only be safe, but it should be extremely rapidly absorbed from the intramuscular depot. This depends on the properties of the active ingredient and of other constituents of the formulation. A combination which causes any painful, allergenic or other local damaging action on the muscle is unsuitable for intramuscular formulation.
  • Rocuronium is sufficiently rapidly absorbed from the intramuscular depot to be useful for intramuscular pharmaceutical formulations.
  • the intramuscular administration of rocuronium induces initially vigorous movement in 50 % of the patients. This reaction has been ascribed to local pain, because also with intravenous administration of rocuronium half of the patients experienced pain. This pain is severe in 12 % of the patients. Furthermore, the duration of action of 60-90 min is long which limits its clinical utility.
  • the present invention gives a solution to the problem of finding a safe and rapidly acting pharmaceutical formulation for intramuscular administration of a neuromuscular blocker with a short duration of action.
  • a pharmaceutical formulation for intramuscular administration of a neuromuscular blocker comprising the compound having the formula
  • the compound according to formula I, or a pharmaceutically acceptable salt or solvate thereof is surprisingly appropriate for an intramuscular pharmaceutical formulation because it is rapidly cleared from the intramuscular depot and consequently has a short onset of action and a short duration of action. Furthermore, it is safe and has a diminished propensity for local irritation.
  • the invention provides for a pharmaceutical formulation of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof, to be administered into one or more muscles.
  • pharmaceutical formulation refers to fluid or solid ready for use for intramuscular injections or requiring only a few simple manipulations before being ready for use.
  • the formulation can be used for the preparation of a product aimed at the intramuscular administration of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof.
  • Such a product is characterised in that the manipulations required before the formulation can be injected is at most opening the sterile packaging, mixing or diluting with diluent and filling a syringe up to the desired dosage.
  • the product may have technical provisions in order to facilitate these manipulation steps or to allow omission of one or more of these steps, and the product can comprise instructions for use for generalised neuromuscular blockade via intramuscular administration of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of this invention is that it provides for a method of providing neuromuscular blockade in an animal or human that requires neuromuscular blockade, via intramuscular administration of a formulation comprising a compound as defined above.
  • the invention provides also for the use of a compound according to claim I for the preparation of a product for administration of said compound in order to provide for neuromuscular blockade in vertebrates which administration is carried out intramuscularly.
  • the formulation may be presented in unit-dose or multi-dose containers for example in prefilled and ready to use injection syringes, sealed ampoules or vials filled with the injectable formulation injection fluid, or ampoules or vials containing the solid formulation to which shortly before use the diluent can be added.
  • the formulation may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use
  • the formulation when ready for injection should be isotonic and compatible with the natural constitution of the muscle.
  • Further additives in the fluid or instant powder of the formulation can be diluents, solubilizers, salts and/or natural sugars for making the injection fluid isotonic, buffers, preservatives, stabilisers, such as antioxidants, inert gases, chelating agents, and a local anaesthetic.
  • water and water miscible fluids can be used, for example ethyl alcohol, polyethylene glycol, carboxymethylcellulose, polysorbate and glycerol.
  • Salt constituents of the formulation are for example NaCI, MgCI 2 , CaCI 2 , KCI, and organic salts such as sodium lactate and the like.
  • Components for osmotic adjustment can be creatinine, glucose, mannitol and other carbohydrates.
  • Suitable buffers are for example salts of citric acid, acetic acid and phosphoric acid. Preferred is a phosphate buffer.
  • Suitable antimicrobial agents are for example phenylmercuric nitrate, benzylalcohol, thimerosal, benzethonium chloride and benzalkonium chloride, phenol, cresol and chlorobutanol. Preferred is benzylalcohol.
  • Chelating agents can be for example sodium salt of ethylenediaminetetraacetic acid or cyclodextrin derivatives like hydrdxypropyl-beta-cyclodextrin.
  • a local anaesthetic can be lidocaine or xylocaine.
  • the active ingredient in a suitable embodiment of the invention should be present in an amount of 0.5-1000 mg per injection volume, preferably between 1 and 500 mg enabling the administration of the required dosage for an animal or human.
  • the dosage will be between 0.5 and 15 mg/kg of the active ingredient, the exact dose and number of injections of the formulation will vary with the age, size, health condition and fat constitution of the individual subject or animal to whom the neuromuscular blocker is to be administered. Variations of the formulation may also depend on the choice of the muscle or muscles to be injected with the formulation.
  • a total dosage per event for humans should preferably be within the range of 3-10 mg/kg for adults and between 2- 8 mg/kg for children.
  • Example 1 Comparison of rapacuronium bromide, succinylcholine and rocuronium with intramuscular administration.
  • Female cats are anaesthetised by intraperitoneal administration of a mixture of ⁇ -chloralose (80 mg/kg) and sodium pentobarbitone (5 mg/kg). Anaesthesia is maintained by additional doses of ⁇ -chloralose as required.
  • the cats are tracheotomized and throughout the experiment artificially ventilated with room air at a rate of 25-28 breaths per minute and a stroke volume of 15 ml/kg. Rectal temperature is maintained between 37 and 38.5°C.
  • a catheter is placed in the left external jugular vein for the administration of the neuromuscular blocking compounds and additional doses of anaesthetic.
  • the tibialis anterior muscle in the left hindlimb is dissected free from the surrounding muscles and the cut tendon is tied by a linen thread to a force displacement transducer (for example a Grass FT03). Twitches of the tibialis anterior muscle are induced at 10 sec intervals by stimulating the sciatic nerve with a 25 msec duration rectangular electrical pulse. The stimulus voltage is to be adjusted to approximately twice that required to induce maximal twitches of the muscle. Tibialis anterior muscle twitches are amplified and recorded on an ink-writing recorder (for example Grass 7D).
  • an ink-writing recorder for example Grass 7D
  • Succinylcholine is dissolved in a concentration of 2 or 3 mg/ml of water containing 0.9 % NaCI.
  • the other neuromuscular blocking compounds are dissolved in a concentration of 10 mg/ml of phosphate/citrate buffer as described in example 3 and injected intravenously via the jugular vein or intramuscularly using the quadriceps muscle in the right leg.
  • the intramuscular injection volume was 0.27-0.44 ml based on sensitivities and weights of the individual cats. Temperature of the skin surface of the quadriceps muscle is maintained between 36 and 38°C.
  • Onset time The time from injection to maximum reduction in twitch tension, or complete block of twitch tension.
  • Recovery time The time taken for twitch tension to return from 25 to 75% of the control.
  • Duration 90 The time elapsing between drug injection and 90% recovery of the twitch response.
  • Dose response data show that the intramuscular dose that produces 100% block within 5 minutes is about 6 x the intravenous dose which produces 50% block of the twitch response.
  • the intramuscular test dose is 6 x the intravenous 50% effect dose for rapacuronium bromide and 5 x the intravenous 50% effect dose for succinylcholine and rocuronium.
  • rapacuronium bromide was administered as an intramuscular injection with the formulation as described in example 3.
  • the time course and intensity of neuromuscular blockade of the adductor pollices muscle (T1 ) was measured by mechanography.
  • Blockade of the respiratory muscles was indirectly estimated by measurements of spontaneous ventilation (Vent. Depr.).
  • the intramuscular dose for the first infant was 3 mg/kg and for the first young child was 5 mg/kg.
  • the dose of the next subject in each group was based on the results with the foregoing subject.
  • the results in this example show that the preferred doses are 2.8 mg/kg for infants and 4.8 mg/kg for children
  • the time of onset of neuromuscular block is 1.6 min and the duration is in average 25 mm after injection
  • the adverse experiences found were mild, transient erythema for four subjects and one serious adverse experience (oesophageal obstruction) for one subject. However this oesophageal obstruction occurred six days after surgery and therefore was not considered to be drug-related.
  • composition of intramuscular formulation as used in example 2 is a composition of intramuscular formulation as used in example 2:
  • composition for 1 ml injection fluid temporarily storable after freeze-drying and sealing in ampoules
  • Example 5 Higher dosing of rapacuronium bromide can be reached with the following composition for 1 ml rapacuronium bromide [ 49 81 mg
  • Formulation for intramuscular formulation which is more stable on storage than the freeze dried formulation in example 4 and also containing a local anaesthetic Composition for 1 ml rapacuronium bromide 22 7 mg citric acid monohydrate 7 85 mg disodiumphosphate dihydrate 1 89 mg mannitol to isotonicity 22 9 mg docaine HCI 20 mg
  • compositions of a concentrated rapacuronium bromide for intramuscular administration Compositions of a concentrated rapacuronium bromide for intramuscular administration
  • the product is filled into 3R DIN vials, stoppered with 9310 stoppers and freeze-dned according an appropriate freeze-drying program Before use, the product is reconstituted in 1 ml water for injection
  • Example 7A The composition of example 7A is completed with water for injection containing 10 mg benzylalcohol This component has antimicrobial and local anaesthetic properties
  • composition of solid constituents is enclosed in one compartment of a two-chamber syringe, suitable for fast intramuscular injection
  • the other compartment of the syringe is filled with water for injection
  • a typical example of such a syringe is the Hypak B-D By-PassTM provided with a needle 19G x 2 (diameter x length 0 7 x 50 mm) of the Becton Dickinson company

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a pharmaceutical formulation for intramuscular administration comprising a monoquaternary 2,16-bispiperidinylandrostane derivative having formula (I) or pharmaceutically acceptable salts or solvates thereof. The invention also relates to a method of manufacturing a preparation for intramuscular administration, and to a method of providing muscle relaxation comprising said pharmaceutical formulation.

Description

A pharmaceutical formulation of monoquatemary 2,16- bispiperidinylandrostane for intramuscular administration
The invention relates to an intramuscular formulation comprising a neuromuscular blocking agent. The invention also relates to a method of manufacturing a preparation for intramuscular administration, and to a method of providing muscle relaxation comprising the intramuscular administration of a neuromuscular blocking agent.
Neuromuscular blockers, which have curare-like effects, have acquired an essential position in medical practise. In particular during surgery such drugs are important in order to block unwanted muscle movements and to reduce muscle tension. Often emergency situations require a rapid onset of action of such a drug when administered to patients. For this reason the known drugs are given intravenously in order to reach rapidly the sites of action in the muscles. Intravenous administration has the disadvantage that this route of administration requires meticulous and careful manipulation, which is often difficult in emergency situations. Although there are many compounds available for neuromuscular blockade (alcuronium, atracurium, cisatracurium, doxacurium, gallamine, hexafluorenium, metocurine, mivacurium, rapacuronium, pancuronium, pipecuronium, rocuronium, succinylcholine, tubocurarine, vecuronium), there are only two of those, i.e. succinylcholine and rocuronium, of which pharmaceutical formulations for intramuscular administration were recommended for regular use. The reason for the dearth of such formulations is that it is only on condition of requirements difficult to meet that such a product is useful. Despite said published recommendations, the use of succinylcholine containing formulations is dissuaded because such a serious adverse effect as hyperkalemia can be induced by this compound. The active ingredient for an intramuscular formulation should not only be safe, but it should be extremely rapidly absorbed from the intramuscular depot. This depends on the properties of the active ingredient and of other constituents of the formulation. A combination which causes any painful, allergenic or other local damaging action on the muscle is unsuitable for intramuscular formulation. Rocuronium is sufficiently rapidly absorbed from the intramuscular depot to be useful for intramuscular pharmaceutical formulations. However, the intramuscular administration of rocuronium induces initially vigorous movement in 50 % of the patients. This reaction has been ascribed to local pain, because also with intravenous administration of rocuronium half of the patients experienced pain. This pain is severe in 12 % of the patients. Furthermore, the duration of action of 60-90 min is long which limits its clinical utility.
The present invention gives a solution to the problem of finding a safe and rapidly acting pharmaceutical formulation for intramuscular administration of a neuromuscular blocker with a short duration of action. According to the invention a pharmaceutical formulation for intramuscular administration of a neuromuscular blocker comprising the compound having the formula
Figure imgf000004_0001
Formula
or a pharmaceutically acceptable salt or solvate thereof, is found to have the desired properties.
This compound is described in US 5,418,226, which is incorporated herein by reference. Without further acid or solvate addition the compound is known as rapacuronium bromide or Org 9487.
The compound according to formula I, or a pharmaceutically acceptable salt or solvate thereof, is surprisingly appropriate for an intramuscular pharmaceutical formulation because it is rapidly cleared from the intramuscular depot and consequently has a short onset of action and a short duration of action. Furthermore, it is safe and has a diminished propensity for local irritation.
The invention provides for a pharmaceutical formulation of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof, to be administered into one or more muscles. The term "pharmaceutical formulation" as used here refers to fluid or solid ready for use for intramuscular injections or requiring only a few simple manipulations before being ready for use. The formulation can be used for the preparation of a product aimed at the intramuscular administration of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof. Such a product is characterised in that the manipulations required before the formulation can be injected is at most opening the sterile packaging, mixing or diluting with diluent and filling a syringe up to the desired dosage. The product may have technical provisions in order to facilitate these manipulation steps or to allow omission of one or more of these steps, and the product can comprise instructions for use for generalised neuromuscular blockade via intramuscular administration of rapacuronium bromide, or a pharmaceutically acceptable salt or solvate thereof.
Another aspect of this invention is that it provides for a method of providing neuromuscular blockade in an animal or human that requires neuromuscular blockade, via intramuscular administration of a formulation comprising a compound as defined above. Thus, the invention provides also for the use of a compound according to claim I for the preparation of a product for administration of said compound in order to provide for neuromuscular blockade in vertebrates which administration is carried out intramuscularly.
The formulation may be presented in unit-dose or multi-dose containers for example in prefilled and ready to use injection syringes, sealed ampoules or vials filled with the injectable formulation injection fluid, or ampoules or vials containing the solid formulation to which shortly before use the diluent can be added. The formulation may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use
The formulation, when ready for injection should be isotonic and compatible with the natural constitution of the muscle.
Further additives in the fluid or instant powder of the formulation can be diluents, solubilizers, salts and/or natural sugars for making the injection fluid isotonic, buffers, preservatives, stabilisers, such as antioxidants, inert gases, chelating agents, and a local anaesthetic.
As diluents water and water miscible fluids can be used, for example ethyl alcohol, polyethylene glycol, carboxymethylcellulose, polysorbate and glycerol.
Salt constituents of the formulation are for example NaCI, MgCI2, CaCI2, KCI, and organic salts such as sodium lactate and the like.
Components for osmotic adjustment can be creatinine, glucose, mannitol and other carbohydrates.
Suitable buffers are for example salts of citric acid, acetic acid and phosphoric acid. Preferred is a phosphate buffer.
Suitable antimicrobial agents are for example phenylmercuric nitrate, benzylalcohol, thimerosal, benzethonium chloride and benzalkonium chloride, phenol, cresol and chlorobutanol. Preferred is benzylalcohol.
Chelating agents can be for example sodium salt of ethylenediaminetetraacetic acid or cyclodextrin derivatives like hydrdxypropyl-beta-cyclodextrin.
A local anaesthetic can be lidocaine or xylocaine. The active ingredient in a suitable embodiment of the invention should be present in an amount of 0.5-1000 mg per injection volume, preferably between 1 and 500 mg enabling the administration of the required dosage for an animal or human.
The formulations with these amounts of active ingredient will suffice for one or a limited number of intramuscular injections with a volume of 0.1 - 7 ml each.
In order to provide for muscle blockade the dosage will be between 0.5 and 15 mg/kg of the active ingredient, the exact dose and number of injections of the formulation will vary with the age, size, health condition and fat constitution of the individual subject or animal to whom the neuromuscular blocker is to be administered. Variations of the formulation may also depend on the choice of the muscle or muscles to be injected with the formulation. A total dosage per event for humans should preferably be within the range of 3-10 mg/kg for adults and between 2- 8 mg/kg for children.
Techniques and processes known in the art of preparing pharmaceutical formulations can be used for the manufacture of these specified formulations.
The invention is illustrated further with reference to the following examples.
Example 1 Comparison of rapacuronium bromide, succinylcholine and rocuronium with intramuscular administration.
Female cats are anaesthetised by intraperitoneal administration of a mixture of α-chloralose (80 mg/kg) and sodium pentobarbitone (5 mg/kg). Anaesthesia is maintained by additional doses of α-chloralose as required. The cats are tracheotomized and throughout the experiment artificially ventilated with room air at a rate of 25-28 breaths per minute and a stroke volume of 15 ml/kg. Rectal temperature is maintained between 37 and 38.5°C.
A catheter is placed in the left external jugular vein for the administration of the neuromuscular blocking compounds and additional doses of anaesthetic.
The tibialis anterior muscle in the left hindlimb is dissected free from the surrounding muscles and the cut tendon is tied by a linen thread to a force displacement transducer (for example a Grass FT03). Twitches of the tibialis anterior muscle are induced at 10 sec intervals by stimulating the sciatic nerve with a 25 msec duration rectangular electrical pulse. The stimulus voltage is to be adjusted to approximately twice that required to induce maximal twitches of the muscle. Tibialis anterior muscle twitches are amplified and recorded on an ink-writing recorder (for example Grass 7D).
Succinylcholine is dissolved in a concentration of 2 or 3 mg/ml of water containing 0.9 % NaCI. The other neuromuscular blocking compounds are dissolved in a concentration of 10 mg/ml of phosphate/citrate buffer as described in example 3 and injected intravenously via the jugular vein or intramuscularly using the quadriceps muscle in the right leg. The intramuscular injection volume was 0.27-0.44 ml based on sensitivities and weights of the individual cats. Temperature of the skin surface of the quadriceps muscle is maintained between 36 and 38°C.
The following parameters are measured: Onset time: The time from injection to maximum reduction in twitch tension, or complete block of twitch tension.
Recovery time: The time taken for twitch tension to return from 25 to 75% of the control.
Duration 90: The time elapsing between drug injection and 90% recovery of the twitch response.
100% block duration: The duration of complete neuromuscular block. Results
Dose response data show that the intramuscular dose that produces 100% block within 5 minutes is about 6 x the intravenous dose which produces 50% block of the twitch response. For each cat the intravenous 50% dose is determined first. The intramuscular test dose is 6 x the intravenous 50% effect dose for rapacuronium bromide and 5 x the intravenous 50% effect dose for succinylcholine and rocuronium.
Results with intramuscular dose
Figure imgf000010_0001
These results show that the effect of rapacuronium bromide is similar to the effect of succinylcholine. Rocuronium shows the disadvantage that the duration of action and the recovery times are too long and its onset of action is the slowest of the three compounds.
Example 2:
Determination of the intramuscular dose for obtaining neuromuscular blockade in children and infants undergoing surgery using the up-down dosing scheme. Subjects were stratified in two groups by age, 1 month to <1 year (mean body weight 7.4 kg) and >1 year up to and including 3 years (mean body weight 12.5 kg). Following intubation rapacuronium bromide was administered as an intramuscular injection with the formulation as described in example 3. The time course and intensity of neuromuscular blockade of the adductor pollices muscle (T1 ) was measured by mechanography. Blockade of the respiratory muscles was indirectly estimated by measurements of spontaneous ventilation (Vent. Depr.). The intramuscular dose for the first infant was 3 mg/kg and for the first young child was 5 mg/kg. The dose of the next subject in each group was based on the results with the foregoing subject.
In each age group 12 subjects were enrolled. One child did not receive the drug due to baseline hypercapnia with spontaneous ventilation. Table
Figure imgf000011_0001
The results in this example show that the preferred doses are 2.8 mg/kg for infants and 4.8 mg/kg for children The time of onset of neuromuscular block is 1.6 min and the duration is in average 25 mm after injection The adverse experiences found were mild, transient erythema for four subjects and one serious adverse experience (oesophageal obstruction) for one subject. However this oesophageal obstruction occurred six days after surgery and therefore was not considered to be drug-related.
Example 3
Composition of intramuscular formulation as used in example 2:
Composition for 1 ml:
| rapacuronium bromide 22.7 mg ι
I citric acid monohydrate 7.85 mg |
| disodiumphosphate dihydrate 1.89 mg j i mannitol to isotonicity 27.5 mg | Freeze dried, to be reconstituted with water for injection. pH after reconstitution is 4. Example 4
Composition for 1 ml injection fluid temporarily storable after freeze-drying and sealing in ampoules
Composition for 1 ml rapacuronium bromide 22 66 mg mannitol 21 36 mg
KH2PO4 0 58 mg
Na2HPO4 H2O 5 18 mg
Freeze dried, to be reconstituted with water for injection pH after reconstitution is 7 5
Example 5 Higher dosing of rapacuronium bromide can be reached with the following composition for 1 ml rapacuronium bromide [ 49 81 mg
Figure imgf000012_0001
Freeze dried, to be reconstituted with water for injection pH after reconstitution is 7 2
Example 6
Formulation for intramuscular formulation which is more stable on storage than the freeze dried formulation in example 4 and also containing a local anaesthetic Composition for 1 ml rapacuronium bromide 22 7 mg citric acid monohydrate 7 85 mg disodiumphosphate dihydrate 1 89 mg mannitol to isotonicity 22 9 mg docaine HCI 20 mg
H3PO4 to pH 4
Freeze dried, to be reconstituted with water for injection pH after reconstitution is 4
Example 7
Compositions of a concentrated rapacuronium bromide for intramuscular administration
Figure imgf000013_0001
The product is filled into 3R DIN vials, stoppered with 9310 stoppers and freeze-dned according an appropriate freeze-drying program Before use, the product is reconstituted in 1 ml water for injection
B The composition of example 7A is completed with water for injection containing 10 mg benzylalcohol This component has antimicrobial and local anaesthetic properties
Example 8
In this example the composition of solid constituents is enclosed in one compartment of a two-chamber syringe, suitable for fast intramuscular injection
The other compartment of the syringe is filled with water for injection
A typical example of such a syringe is the Hypak B-D By-Pass™ provided with a needle 19G x 2 (diameter x length 0 7 x 50 mm) of the Becton Dickinson company

Claims

Claims:
1. A pharmaceutical formulation for intramuscular administration comprising a monoquaternary 2,16-bispiperidinylandrostane derivative having the formula
Figure imgf000014_0001
or a pharmaceutically acceptable salt or solvate thereof.
2. A pharmaceutical formulation according to claim 1 , characterised in that it comprises a local anaesthetic
3. The use of a monoquaternary 2,16-bispiperidinylandrostane derivative having the formula according to claim 1 for the preparation of a pharmaceutical formulation for intramuscular administration.
4. A method of providing neuromuscular blockade in vertebrates comprising intramuscular administration of the formulation according to claim 1 or 2.
5. A method of providing neuromuscular blockade in humans comprising intramuscular administration of the formulation according to claim 1 or 2
6. The use of a monoquaternary 2,16-bispiperidinylandrostane derivative having the formula according to claim 1 for the preparation of a product for administration of said compound in order to provide for neuromuscular blockade in vertebrates which administration is carried out intramuscularly
7. A process for the manufacture of a pharmaceutical formulation according to claim 1 or claim 2 comprising dissolving the monoquaternary 2,16- bispiperidinylandrostane derivative in buffered fluid, distributing the buffered fluid in unit-dose or multi-dose containers and optionally freeze-drying the containers before sealing.
PCT/EP1998/007519 1997-11-27 1998-11-23 A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane for intramuscular administration WO1999027914A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU18744/99A AU1874499A (en) 1997-11-27 1998-11-23 A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane forintramuscular administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97203713 1997-11-27
EP97203713.9 1997-11-27

Publications (1)

Publication Number Publication Date
WO1999027914A1 true WO1999027914A1 (en) 1999-06-10

Family

ID=8228981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/007519 WO1999027914A1 (en) 1997-11-27 1998-11-23 A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane for intramuscular administration

Country Status (2)

Country Link
AU (1) AU1874499A (en)
WO (1) WO1999027914A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045741A2 (en) * 1999-12-22 2001-06-28 Glaxo Group Limited Methods for preparing pharmaceutical formulations
US6911455B2 (en) 1999-12-22 2005-06-28 Smithkline Beecham Corporation Methods for preparing pharmaceutical formulations
WO2015001995A1 (en) * 2013-07-01 2015-01-08 丸石製薬株式会社 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5418226A (en) * 1992-04-22 1995-05-23 Akzo N.V. Monoquaternary 2,16-bispiperidinylandrostane derivatives
WO1997034624A1 (en) * 1996-03-20 1997-09-25 Allergan Sales, Inc. Injectable therapy for control of muscle spasms and pain related to muscle spasms

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5418226A (en) * 1992-04-22 1995-05-23 Akzo N.V. Monoquaternary 2,16-bispiperidinylandrostane derivatives
WO1997034624A1 (en) * 1996-03-20 1997-09-25 Allergan Sales, Inc. Injectable therapy for control of muscle spasms and pain related to muscle spasms

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001045741A2 (en) * 1999-12-22 2001-06-28 Glaxo Group Limited Methods for preparing pharmaceutical formulations
WO2001045741A3 (en) * 1999-12-22 2001-12-06 Glaxo Group Ltd Methods for preparing pharmaceutical formulations
JP2003518074A (en) * 1999-12-22 2003-06-03 グラクソ グループ リミテッド Preparation method of pharmaceutical preparation
AU779889B2 (en) * 1999-12-22 2005-02-17 Glaxo Group Limited Methods for preparing pharmaceutical formulations
US6911455B2 (en) 1999-12-22 2005-06-28 Smithkline Beecham Corporation Methods for preparing pharmaceutical formulations
WO2015001995A1 (en) * 2013-07-01 2015-01-08 丸石製薬株式会社 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
CN105431151A (en) * 2013-07-01 2016-03-23 丸石制药株式会社 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
KR20170068624A (en) * 2013-07-01 2017-06-19 마루이시세이야쿠가부시키가이샤 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
KR101803857B1 (en) * 2013-07-01 2017-12-04 마루이시세이야쿠가부시키가이샤 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
CN110251459A (en) * 2013-07-01 2019-09-20 丸石制药株式会社 Improve Rocuronium preparation and its manufacturing method and the inhibition of angialgia using the Rocuronium preparation, mitigation process of angialgia
KR102060160B1 (en) 2013-07-01 2019-12-27 마루이시세이야쿠가부시키가이샤 Rocuronium preparation with improved vascular pain, method for producing same, and method for suppressing and relieving vascular pain using same
US10821119B2 (en) 2013-07-01 2020-11-03 Maruishi Pharmaceutical Co., Ltd. Rocuronium preparation causing less pain, method for producing the same, and method for reducing and/or alleviating vascular pain to be induced using the same

Also Published As

Publication number Publication date
AU1874499A (en) 1999-06-16

Similar Documents

Publication Publication Date Title
Child et al. The pharmacological properties in animals of CT1341—a new steroid anaesthetic agent
CA1038764A (en) Anaesthetic composition containing 2,6-diisopropyl phenol
AU2005295437B2 (en) Use of A2A adenosine receptor agonists
JP6313420B2 (en) Neosaxitoxin combination formulation for sustained local anesthesia
CZ280541B6 (en) Pharmaceutical mixtures of phlorphenicol
AU627610B2 (en) Long active injectable formulations containing triacetin
JP6942182B2 (en) Parenteral drug formulation containing calglumic acid
US6150331A (en) Human growth hormone-containing aqueous pharmaceutical composition
CA2011063C (en) Nicardipine pharmaceutical composition for parenteral administration
DE102004063347A1 (en) Ready-to-use gemcitabine solutions and gemcitabine solution concentrates
JPH0672108B2 (en) Long-term sustained injectable formulation containing hydrogenated castor oil
KR102656841B1 (en) Injectable pharmaceutical formulation of lefamulin
EP2620153B1 (en) 5 alpha-androstane (alkyl)-3 beta,5,6 beta-triol injection and preparation method therefor
Steiness et al. Plasma digoxin after parenteral administration Local reaction after intramuscular injection
US20070015808A1 (en) Pharmaceutical formulations of endo-N-(9-methyl-9-azabicyclo[3,3. 1]non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride
WO1999027914A1 (en) A pharmaceutical formulation of monoquaternary 2,16-bispiperidinylandrostane for intramuscular administration
JPS605567B2 (en) Oxytetracycline preparation
JP3954115B2 (en) Injection and injection kit
EP2804597A1 (en) Aqueous paracetamol composition for injection
JP3051591B2 (en) Anti-adhesion agent for thallium-201 container
JP2012180346A (en) Aqueous composition having improved drug migration property of hydrophilic drug
US20080318919A1 (en) Cefquinome Compositions and Methods of Their Use
HU179942B (en) Process for preparing injectable pharmaceutical compositions against internal parasites,particularly for the treatment and prevention of rot of sheep
EP3632411B1 (en) Improved kit for preparing injectable carmustine solutions
PT100155B (en) USE OF CAMPTOTECIN ANALOG COMPOUNDS IN THE OBTAIN OF A MEDICATION FOR USE IN THE CARCINOMA TREATMENT OF NON SMALL PULMONARY CELLS AND PHARMACEUTICAL COMPOSITIONS

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GE HU ID IL IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO RU SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 09555153

Country of ref document: US

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA