AU7231291A - Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis - Google Patents
Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresisInfo
- Publication number
- AU7231291A AU7231291A AU72312/91A AU7231291A AU7231291A AU 7231291 A AU7231291 A AU 7231291A AU 72312/91 A AU72312/91 A AU 72312/91A AU 7231291 A AU7231291 A AU 7231291A AU 7231291 A AU7231291 A AU 7231291A
- Authority
- AU
- Australia
- Prior art keywords
- iontophoresis
- ropivacaine
- local anaesthetic
- injection
- manufacture
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 229960005015 local anesthetics Drugs 0.000 title description 15
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims description 16
- 229960001549 ropivacaine Drugs 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 9
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 8
- 229960003150 bupivacaine Drugs 0.000 description 8
- 238000003780 insertion Methods 0.000 description 8
- 230000037431 insertion Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000003444 anaesthetic effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960004194 lidocaine Drugs 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- NDNSIBYYUOEUSV-RSAXXLAASA-N (S)-ropivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCC[NH+]1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C NDNSIBYYUOEUSV-RSAXXLAASA-N 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 229960003691 ropivacaine hydrochloride monohydrate Drugs 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 230000008326 skin blood flow Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000015110 jellies Nutrition 0.000 description 3
- 239000008274 jelly Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960001813 ropivacaine hydrochloride Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Electrotherapy Devices (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis
Field of the invention
The present invention is related to the use of pharmaceutically acceptable salts of ropivacaine in the manufacture of pharmaceutical preparations for iontophoresis.
Background of the invention
The common use of local anaesthetic agents is to apply them onto a tissue surface or inject them into a tissue or a vascular bed in order to inhibit impulse generation and conduction in peripheral nerves. Local anaesthetics are generally used to reduce painful sensations, by blocking the nerves. Freedom from pain is obtained by use for local anaesthesia at surgical operations or when used to reduce pain at different kinds of illnesses. The effect has been obtained by the single application of a local anaesthetic
• composition or when pain relief during a longer period of time is needed by several applications.
Recently a new way of applying local anaesthetics has been developed. This is called iontophoresis. Ionized substances are then introduced into intact tissue such as human skin by an electric current. The equipment consists of one reservoir containing the drug in ionic form and two electrodes, one above the reservoir and one at a distal skin location.
Prior art
Iontophoresis is described e.g. by Gangarosa Louis P. in
Meth and Find Expt. Clin. Pharmacol. 3(2), p. 89-34 (1981) and by Tyle P. in Pharmaceutical Research, Vol. 3, No. 6, 1986.
The local anaesthetic ropivacaine is described e.g. in WO 85/00599.
Outline of the invention
According to the present invention it has surprisingly been found that the local anaesthetic agent ropivacaine in form of its hydrochloride is especially useful for iontophoresis. Earlier other local anaesthetics such as lidocaine and bupivacaine have been used together with ephinephrine. Ephinephrine is necessary in order to make it possible for the earlier used local anaesthetics to penetrate the skin without significant irritation. The local anaesthetic agent defined above need not be combined with ephinephrine as it has a vasoconstrictive effect itself. This is very important as the addition of ephinephrine to hydrochloric solutions of the local anaesthetics gives an insufficient storage stability.
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 jelly or a solution.
The local anaesthetic composition contains between 0.25 and 10% by weight of the local anaesthetic compound, preferably 0.5-2% by weight.
Pharmaceutical preparations
Example 1
Jelly 0.5%
Ropivacaine hydrochloride monohydrate 5.3 kg
Hydroxypropyl methylcellulose 4000 cps 24.5 kg
Water for injection qs ad 1000 1
Ropivacaine hydrochloride monohydrate and hydroxypropyl methylcellulose are dissolved in water for injection. The volume is adjusted to 1000 1 with water. The resulting solution is autoclaved.
Example 2
Jelly 2%
Ropivacaine hydrochloride monohydrate 8.5 kg
Hydroxypropyl methylcellulose 4000 cps 9.8 kg Water for injection qs ad 400 1
Ropivacaine hydrochloride monohydrate and hydroxypropyl methylcellulose are dissolved in water for injection. The volume is adjusted to 400 J. with water. The resulting solution is autoclaved.
Examples 3 - 5
Solution 5 mg/ml, 10 mg/ml, 20 mg/ml Examples
3 4
Ropivacaine hydrochloride monohydrate 0.53 kg 1.06 kg 2.12 Sodium hydroxide 2M to pH 5.0-6.0 Purified water qs ad 100 kg 100 kg 100
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 preparation according to Example 4.
Biological test
In a pilot study it was observed that the insertion of an intrader al needle provoked a marked increase in blood flow as measured by laser Doppler flowmetry. Thus, an intradermal injection might be a suitable test method, elucidating drug effects on skin blood flow, i.e. not only showing an increase but also a decrease in flow, if the effect of the needle insertion, per se, is considered in the evaluation of the net circulatory effect of both needle insertion and the injected drug.
The following test was used to evaluate the skin blood flow changes provoked by the intradermal injection of clinically used local anaesthetic agents. Drugs tested were lidocaine, bupivacaine and a new long-acting local anaesthetic agent, ropivacaine.
Material and methods
The studies were carried out on healthy, young male volunteers. In the test group (n=12, mean age 31.7 years, range 25-45) the effects of needle insertion, "injection of saline, injection of lidocaine, of bupivacaine and of the new local anaesthetic agent, ropivacaine on skin blood flow were studied. An untreated area of skin served as a control.
Six volunteers took part in the test. According to a
randomized pattern the following procedure was carried out at the various test sites.
In this test measurements at an untreated control area, after needle insertion and after injection of local anaesthetic agents (0.1 ml through a needle) as follows; 1 mg lidocaine, 0.25 mg and 0.75 mg bupivacaine, 0.25 mg and 0.75 mg ropivacaine.
The solutions were coded enabling the studies to be double blind as regards the injection of different solutions. The pH of saline was 6.0, of lidocaine 6.7 and of all solutions of bupivacaine and ropivacaine 5.5. All intradermal injections were made by one and the same person. After the original blood flow levels had been determined, intradermal needle insertions or injections were made exactly 2 minutes apart.
Measurements after needle insertion or fluid injection were started at one site within 30 seconds to elucidate their circulatory effect.
Twenty minutes after the first injection at the first site the recording was started. After 2 minutes the recording probe was moved to the next site etc. In this way a recording was made at each site at 20, 40 and 60 minutes in the first two series. In the third series a recording 90 minutes after the needle insertion or injection was also done. An untreated area served as a control.
When the intradermal test procedure described above was applied to bupivacaine and ropivacaine the injection of 0.75 mg bupivacaine produced a marked increase in blood flow, similar to the increase seen after 1 mg lidocaine but longer lasting. The injection of 0.25 mg of bupivacaine showed a smaller increase in skin blood flow, similar to that after the injection of saline. This
finding is in line with earlier studies showing increase in flow more marked with higher concentrations of local anaesthetics compared to weaker concentrations. Injections of ropivacaine, however, caused a decrease in blood flow compared to saline, most marked when injecting 0.25 rag, indicating a unique effect of this new local anaesthetic drug.
Conclusion
From the unique effect of ropivacaine the conclusion can be drawn that said compound is especially useful for iontophoresis. Due to its decrease in the blood flow it can be used without the addition of ephinephrine, which diminishes the storage stability of the local anaesthetic compositions.
Claims (4)
1. Use of a pharmaceutically acceptable salt of ropivacaine in the manufacture of a pharmaceutical preparation for iontophoresis.
2. Use according to claim 1, wherein ropivacaine is in the form of its hydrochloride.
3. A method for the treatment by iontophoresis whereby a by iontophoresis effective amount of a pharmaceutically acceptable salt of ropivacaine is being used.
4. A pharmaceutical preparation for use in iontophoresis wherein the active ingredient is a pharmaceutically acceptable salt of ropivacaine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9000288 | 1990-01-26 | ||
| SE9000288A SE9000288D0 (en) | 1990-01-26 | 1990-01-26 | NEW USE |
| PCT/SE1991/000053 WO1991011182A1 (en) | 1990-01-26 | 1991-01-24 | Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU7231291A true AU7231291A (en) | 1991-08-21 |
| AU650002B2 AU650002B2 (en) | 1994-06-09 |
Family
ID=20378368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU72312/91A Ceased AU650002B2 (en) | 1990-01-26 | 1991-01-24 | Use of local anaesthetic agents in the manufacture of pharmaceutical preparations for iontophoresis |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0597833A1 (en) |
| JP (1) | JPH05503704A (en) |
| KR (1) | KR927003530A (en) |
| AU (1) | AU650002B2 (en) |
| CA (1) | CA2073028A1 (en) |
| HU (1) | HU210322B (en) |
| SE (1) | SE9000288D0 (en) |
| WO (1) | WO1991011182A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6295469B1 (en) | 1997-11-14 | 2001-09-25 | Alza Corporation | Formulation for electrically assisted delivery of lidocaine and epinephrine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60502054A (en) * | 1983-08-01 | 1985-11-28 | アストラ・レケメデル・アクチボラグ | L-N-n-propylpipecolic acid-2,6-xylidide and its manufacturing method |
-
1990
- 1990-01-26 SE SE9000288A patent/SE9000288D0/en unknown
-
1991
- 1991-01-24 JP JP3503925A patent/JPH05503704A/en active Pending
- 1991-01-24 KR KR1019920701761A patent/KR927003530A/en not_active Withdrawn
- 1991-01-24 CA CA002073028A patent/CA2073028A1/en not_active Abandoned
- 1991-01-24 EP EP91903251A patent/EP0597833A1/en not_active Withdrawn
- 1991-01-24 AU AU72312/91A patent/AU650002B2/en not_active Ceased
- 1991-01-24 WO PCT/SE1991/000053 patent/WO1991011182A1/en not_active Ceased
- 1991-01-24 HU HU9202444A patent/HU210322B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU650002B2 (en) | 1994-06-09 |
| HU9202444D0 (en) | 1992-10-28 |
| KR927003530A (en) | 1992-12-18 |
| JPH05503704A (en) | 1993-06-17 |
| WO1991011182A1 (en) | 1991-08-08 |
| EP0597833A1 (en) | 1994-05-25 |
| HU210322B (en) | 1995-03-28 |
| CA2073028A1 (en) | 1991-07-27 |
| HUT65098A (en) | 1994-04-28 |
| SE9000288D0 (en) | 1990-01-26 |
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