WO1995000148A1 - Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade - Google Patents

Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade Download PDF

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Publication number
WO1995000148A1
WO1995000148A1 PCT/SE1994/000496 SE9400496W WO9500148A1 WO 1995000148 A1 WO1995000148 A1 WO 1995000148A1 SE 9400496 W SE9400496 W SE 9400496W WO 9500148 A1 WO9500148 A1 WO 9500148A1
Authority
WO
WIPO (PCT)
Prior art keywords
ropivacaine
pharmaceutical
manufacture
motor blockade
weight
Prior art date
Application number
PCT/SE1994/000496
Other languages
French (fr)
Inventor
Arne Torsten Eek
Original Assignee
Astra Aktiebolag
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=20390432&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1995000148(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to HU9503692A priority Critical patent/HU218949B/en
Priority to CA002165446A priority patent/CA2165446C/en
Priority to NZ268110A priority patent/NZ268110A/en
Priority to BR9406865A priority patent/BR9406865A/en
Priority to DE69430427T priority patent/DE69430427T2/en
Priority to US08/256,319 priority patent/US5670524A/en
Priority to AU70866/94A priority patent/AU692161C/en
Priority to DE0706395T priority patent/DE706395T1/en
Priority to DK94919912T priority patent/DK0706395T3/en
Priority to SK1646-95A priority patent/SK280111B6/en
Priority to PL94312198A priority patent/PL175518B1/en
Priority to EP94919912A priority patent/EP0706395B1/en
Priority to AT94919912T priority patent/ATE216237T1/en
Priority to JP50268795A priority patent/JP3725541B2/en
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Publication of WO1995000148A1 publication Critical patent/WO1995000148A1/en
Priority to FI956269A priority patent/FI956269A0/en
Priority to NO955313A priority patent/NO955313L/en
Priority to GR970300013T priority patent/GR970300013T1/en
Priority to HK98111303A priority patent/HK1010344A1/en

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the local anaesthetic agent ropivacaine described e.g. in O/85/00599, in form of its hydrochloride can be given to the patient in a dosage which gives pain relief with minimal effect on motor function.
  • This is at a dosage of lower than 0.5% by weight, especially from 0.01% to 0.45% by weight.
  • Such low dosages are normally considered to be ineffective.
  • the normal dosage is from 0.5-2% by weight.

Abstract

Use of a pharmaceutically acceptable salt of ropivacaine for the manufacture of a pharmaceutical preparation with sensoric block and minimal motor blockade.

Description

Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
Field of the invention
The present invention is related to the use of a low concentration of a pharmaceutically acceptable salt of ropivacaine in the manufacture of pharmaceutical preparations for pain relief post operatively and in labour.
Background of the invention
Post operative pain relief is still a problem within modern surgery. According to a newly published study about 70% of all patients treated surgically felt moderate to severe pain after the surgical treatment.
The need for qualified pain relief is greatest during the first 24 hours after the surgical treatment. The traditional method to treat the patients is to give narcotics intramuscularly or intravenously. Such treatment is often insufficient as narcotic analgetics have many negative effects. One disadvantage is depression of the breathing, which may occur even after treatment. This means that the patient must be intensively looked after by specialists.
A patient, who has been treated with morfine is tired, apathetic and is often feeling sick. The patient thus has no interest in things around him. It is thus difficult to take care of the patient and make him participate in respitatory exercises and prophylaxis for thromboses.
One method is administration epidurally, by infusion or intermittent injections of local anaesthetics. Such treatments can only be carried out on patients with epidural catheters being taken care of at an intensive care or post surgical unit by specially trained persons.
There has been a long felt need at ward leval to be able to give a greater group of patients qualified pain relief by epidural infusion of e.g. local anaesthetics instead of opiates.
Normally, with local anaesthetics a good blockade of the pain is obtained. The draw back is the motor blockade in the legs, which is disturbing to the patients, who wants to give up the pain relief treatment in advance. Among other effects the motor blockade means that the patient cannot leave his bed without assistance as the legs will not bear.
Outline of the invention
According to the present invention it has surprisingly been found that the local anaesthetic agent ropivacaine, described e.g. in O/85/00599, in form of its hydrochloride can be given to the patient in a dosage which gives pain relief with minimal effect on motor function. This is at a dosage of lower than 0.5% by weight, especially from 0.01% to 0.45% by weight. Such low dosages are normally considered to be ineffective. The normal dosage is from 0.5-2% by weight.
The local anaesthetic compound used according to the invention is in the form of its pharmaceutically acceptable salts. It is especially preferred to use ropivacaine hydrochloride. The local anaesthetic is incorporated into a solution.
The local anaesthetic composition contains less than 0.5 % by weight of the local anaesthetic compound, preferably from 0.01 up to 0.45% by weight, especially preferred 0.1-0.3% by weight.
Pharmaceutical preparations
Examples 1-3
Solution 5 mg/ml, 3 mg/ml, 2 mg/ l
Examples
I 2. 2
Ropivacaine hydrochloride monohydrate 0.53 kg 0.32 kg 0.21 kg
Sodium hydroxide 2M to pH 5.0-6.0
Purified water qs ad 100 kg 100 kg 100 kg
Ropivacaine is dissolved in the water. Sodium hydroxide is added to pH 5.0-6.0. The resulting solution is autoclaved.
The best mode of carrying out the invention known at present is to use the preparations according to Example 3.
Biological test
A double blind study of sensory and motor blockade with 0.1%, 0.2%, 0.3% ropivacaine and 0.25% bupivacaine during continous epidural infusion in healthy male volunteers. Background
The aim of the study was to find a low concentration of ropivacaine giving a sufficient sensory block but as little or no motor block at all during continous epidural infusion. This study is a first step towards finding a low concentration of ropivacaine which later will be used for treatment of post operative pain in patients. 37 volunteers participated in the study. They were divided into 5 treatment groups, receiving either 0.1%, 0.2% or 0.3% ropivacaine or 0.25% bupivacaine. There was also a control group receiving 0.9% saline. All solutions were first given as a bolus dose of 10 ml, followed by a continous epidural infusion at a rate of 10 ml/hour for 21 hours. During the infusion both motor and sensory blockade was tested using different methods. The postural stability of the volunteers was also evaluated.
Preliminary results
Group 1. No motor and sensory block was acheived in the volunteers receiving saline.
Group 2. Bupivacaine 0.25% gave a good segmental spread (from the lower part of the abdomen to the lower part of the extremities) of sensoric block during the infusion. All of the volunteers had a high degree of motor block and 75% (6/8) could not stand up at any occasion during the infusion.
Group 3. Ropivacaine 0.3% gave an equal duration of sensory blockade compared to bupivaciane 0.25%. The upper segmental spread of sensoric block was somewhat higher than for bupivacaine. The lower segmental spread of sensoric block was, after 10 hours of continous infusion. shifted up to just below the knees compared to bupivacaine and at the end of infusion was found above the knees. The motorblock was somewhat less profound compared to bupivacaine. 5 out of 7 volunteers could not stand at any occasion during the infusion to perform the postural stability tests.
Group 4. Ropivacaine 0.2% gave an equal sensory block compared to bupivacaine 0.25% in the lower part of the abdomen, but showed a less sensory block around the ancles. After 10 hours of continous infusion the sensory block was less than for both ropivacaine 0.3% and bupivacaine. The motor block was less profound compared to the 0.3% ropivacaine as well as to the 0.25% bupivacaine solution. 25% (2/8) of the volunteers could not at any occasion stand up whereas the rest of the volunteers (6/8) could at some point during the infusion make some of the postural tests.
Group 5. Ropivacaine 0.1% gave, during the first 5 hours of the infusion, a more narrow spread of the sensory block compared to the 0.2% ropivacaine solution. Normal sensation returned after 8 hours of the epidural infusion.
No serious or unexpected adverse events could be noted in any of the test groups.
It was found that bupivacaine gives 75% higher motor blockade than ropivacaine, which only gives 25% at comparable dosage levels.
At the dosages 0.3% and 0.2% ropivacaine gives about the same motor blockade. At the dosage 0.1% it is less. Conclusion
From the unique effect of ropivacaine the conclusion can be drawn that said compound is especially useful for administering at low dosage to patients in the need of post surgical and labour pain treatment, with good balance between sufficient sensoric block and a desirable minimal degree of motor block.

Claims

Claims
1. Use of a pharmaceutically acceptable salt of ropivacaine in the manufacture of a pharmaceutical with sensoric block and with minimal motor blockade, wherein the concentration of ropivacaine is lower than 0.5% by weight.
2. Use according to claim 1, wherein ropivacaine is in the form of its hydrochloride.
3. Use according to claim 1, wherein the concentration of ropivacaine is from 0.01 up to 0.45% by weight.
4. Use according to claim 3, wherein the concentration of ropivacaine is 0.2% by weight.
5. A method for the treatment of a person in the need of pain relief with minimal motor blockade, whereby a low effective amount of a pharmaceutically acceptable salt of ropivacaine is being used.
6. A pharmaceutical preparation for the use in acute pain management with minimal motor blockade, wherein the active ingredient is a pharmaceutically acceptable salt of ropivacaine in a concentration lower than 0.5% by weight.
PCT/SE1994/000496 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade WO1995000148A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
DK94919912T DK0706395T3 (en) 1993-06-28 1994-05-26 Analgesic drug with minimal movement blockage
JP50268795A JP3725541B2 (en) 1993-06-28 1994-05-26 Pharmaceutical formulation containing ropivacaine
NZ268110A NZ268110A (en) 1993-06-28 1994-05-26 Use of ropivacaine salt in pharmaceutical compositions for the treatment of pain with sensoric block and minimal motor blockage
BR9406865A BR9406865A (en) 1993-06-28 1994-05-26 Use of a pharmaceutically acceptable salt of ropivacaine in the manufacture of a pharmaceutical process for the treatment of a person in need of pain relief and pharmaceutical preparation
DE69430427T DE69430427T2 (en) 1993-06-28 1994-05-26 USE OF ROPIVACAINE FOR PRODUCING AN ANALGETIC WITH MINIMUM MOTORIC BLOCK
US08/256,319 US5670524A (en) 1993-06-28 1994-05-26 Methods and compositions for the treatment of pain utilizing ropivacaine
AU70866/94A AU692161C (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
PL94312198A PL175518B1 (en) 1993-06-28 1994-05-26 Application of procaine in obtaining a pharmaceutical preparation of analgesic activity with minimum motorial blocking effect
SK1646-95A SK280111B6 (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
HU9503692A HU218949B (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
DE0706395T DE706395T1 (en) 1993-06-28 1994-05-26 USE OF ROPIVACAINE FOR PRODUCING ANALGETIC MUSIC WITH MINIMUM MOTORIC BLOCK
EP94919912A EP0706395B1 (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
AT94919912T ATE216237T1 (en) 1993-06-28 1994-05-26 USE OF ROPIVACAINE TO PRODUCE AN ANALGESIC WITH MINIMAL MOTOR BLOCKADE
CA002165446A CA2165446C (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
NO955313A NO955313L (en) 1993-06-28 1995-12-27 Use of ropivacaine in the preparation of a pharmaceutical with analgesic effect having minimal motor blockage
FI956269A FI956269A0 (en) 1993-06-28 1995-12-27 Use of ropivacaine in the manufacture of a pharmaceutical product having an analgesic effect and a slight lack of motor inhibition
GR970300013T GR970300013T1 (en) 1993-06-28 1997-05-30 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade
HK98111303A HK1010344A1 (en) 1993-06-28 1998-10-19 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9302218-4 1993-06-28
SE19939302218A SE9302218D0 (en) 1993-06-28 1993-06-28 NEW USE

Publications (1)

Publication Number Publication Date
WO1995000148A1 true WO1995000148A1 (en) 1995-01-05

Family

ID=20390432

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1994/000496 WO1995000148A1 (en) 1993-06-28 1994-05-26 Use of ropivacaine in the manufacture of a pharmaceutical with analgetic effect with minimal motor blockade

Country Status (33)

Country Link
US (2) US5670524A (en)
EP (1) EP0706395B1 (en)
JP (1) JP3725541B2 (en)
CN (1) CN1074918C (en)
AT (1) ATE216237T1 (en)
BR (1) BR9406865A (en)
CA (1) CA2165446C (en)
CZ (1) CZ283300B6 (en)
DE (2) DE69430427T2 (en)
DK (1) DK0706395T3 (en)
EE (1) EE03205B1 (en)
ES (1) ES2099048T3 (en)
FI (1) FI956269A0 (en)
GR (1) GR970300013T1 (en)
HK (1) HK1010344A1 (en)
HU (1) HU218949B (en)
IL (1) IL110006A (en)
IS (1) IS4174A (en)
LT (1) LT3449B (en)
LV (1) LV12918B (en)
MY (1) MY119360A (en)
NO (1) NO955313L (en)
NZ (1) NZ268110A (en)
PH (1) PH31258A (en)
PL (1) PL175518B1 (en)
PT (1) PT706395E (en)
RU (1) RU2152215C1 (en)
SA (1) SA94150010B1 (en)
SE (1) SE9302218D0 (en)
SG (1) SG49078A1 (en)
SK (1) SK280111B6 (en)
TW (1) TW285640B (en)
WO (1) WO1995000148A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5945435A (en) * 1997-07-21 1999-08-31 Darwin Discovery Limited Levobupivacaine and its use

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9302218D0 (en) * 1993-06-28 1993-06-28 Ab Astra NEW USE
US20060270708A1 (en) * 2005-05-25 2006-11-30 Navinta Llc Novel process for preparation of isotonic aqueous injection of ropivacaine
US8920843B2 (en) * 2007-11-07 2014-12-30 Svip5 Llc Slow release of organic salts of local anesthetics for pain relief
CA2871821C (en) 2012-05-10 2021-01-12 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
JP2016508956A (en) * 2012-05-10 2016-03-24 セリックスビオ プライヴェート リミテッド Compositions and treatments for the treatment of local pain
US9006462B2 (en) 2013-02-28 2015-04-14 Dermira, Inc. Glycopyrrolate salts
US8558008B2 (en) 2013-02-28 2013-10-15 Dermira, Inc. Crystalline glycopyrrolate tosylate
EP2961734B1 (en) 2013-02-28 2018-09-26 Dermira, Inc. Glycopyrrolate salts

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Publication number Priority date Publication date Assignee Title
ATE40994T1 (en) * 1983-08-01 1989-03-15 Astra Laekemedel Ab L-N-N-PROPYLPIPECOLIC-2,6-XYLIDIDE AND ITS PRODUCTION.
SE9302218D0 (en) * 1993-06-28 1993-06-28 Ab Astra NEW USE

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ACTA ANAESTHESIOL SCAND, Volume 37, 1993, D. ZARIC et al., "Blockade of the abdominal muscles measured by EMG during lumbar epidural analgesia with ropivacaine - a double-blind study", page 274 - page 280, see abstract. *
ANESTHESIA AND ANALGESIA, Volume 70, 1990, M. Concepcion, MD et al., "A New Local Anesthetic, Ropivacaine", page 80 - page 85, see abstract. *
BRITISH JOURNAL OF ANAESTHESIA, Volume 66, 1991, M.S. BROCKWAY et al., "Comparison of extradural ropivacaine and bupivacaine", page 31 - page 37, see abstract. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5945435A (en) * 1997-07-21 1999-08-31 Darwin Discovery Limited Levobupivacaine and its use

Also Published As

Publication number Publication date
DK0706395T3 (en) 2002-07-22
ES2099048T3 (en) 2002-11-16
PH31258A (en) 1998-06-18
HU218949B (en) 2001-01-29
FI956269A (en) 1995-12-27
JP3725541B2 (en) 2005-12-14
LT3449B (en) 1995-10-25
HUT75115A (en) 1997-04-28
GR970300013T1 (en) 1997-05-31
RU2152215C1 (en) 2000-07-10
EE03205B1 (en) 1999-08-16
SA94150010B1 (en) 2006-04-04
CA2165446A1 (en) 1995-01-05
IS4174A (en) 1994-12-29
JPH09500620A (en) 1997-01-21
TW285640B (en) 1996-09-11
CZ283300B6 (en) 1998-02-18
CN1126435A (en) 1996-07-10
NZ268110A (en) 1999-06-29
SK280111B6 (en) 1999-08-06
NO955313D0 (en) 1995-12-27
AU7086694A (en) 1995-01-17
DE69430427T2 (en) 2002-11-14
AU692161B2 (en) 1998-06-04
HK1010344A1 (en) 1999-06-17
ATE216237T1 (en) 2002-05-15
FI956269A0 (en) 1995-12-27
LV12918B (en) 2003-03-20
PT706395E (en) 2002-09-30
HU9503692D0 (en) 1996-02-28
SK164695A3 (en) 1996-07-03
EP0706395B1 (en) 2002-04-17
US5670524A (en) 1997-09-23
LTIP1958A (en) 1995-01-31
SE9302218D0 (en) 1993-06-28
NO955313L (en) 1995-12-27
BR9406865A (en) 1996-03-26
CA2165446C (en) 2005-07-05
CZ336495A3 (en) 1996-06-12
IL110006A (en) 1999-01-26
EP0706395A1 (en) 1996-04-17
MY119360A (en) 2005-05-31
SG49078A1 (en) 1998-05-18
PL312198A1 (en) 1996-04-01
IL110006A0 (en) 1994-11-11
DE69430427D1 (en) 2002-05-23
ES2099048T1 (en) 1997-05-16
PL175518B1 (en) 1999-01-29
CN1074918C (en) 2001-11-21
US5834489A (en) 1998-11-10
DE706395T1 (en) 1997-09-04

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