WO1997042955A1 - Compositions contenant des activateurs des canaux sodiques et des anesthesiques locaux - Google Patents

Compositions contenant des activateurs des canaux sodiques et des anesthesiques locaux Download PDF

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Publication number
WO1997042955A1
WO1997042955A1 PCT/US1997/008196 US9708196W WO9742955A1 WO 1997042955 A1 WO1997042955 A1 WO 1997042955A1 US 9708196 W US9708196 W US 9708196W WO 9742955 A1 WO9742955 A1 WO 9742955A1
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WO
WIPO (PCT)
Prior art keywords
composition
bupivacaine
sodium channel
veratridine
channel activator
Prior art date
Application number
PCT/US1997/008196
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English (en)
Inventor
Gary R. Strichartz
Marina Vladimirov
Original Assignee
Brigham And Women's Hospital
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 Brigham And Women's Hospital filed Critical Brigham And Women's Hospital
Priority to AU32059/97A priority Critical patent/AU3205997A/en
Publication of WO1997042955A1 publication Critical patent/WO1997042955A1/fr

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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

Definitions

  • the present invention is directed to compositions and methods that are useful in relieving pain and providing anesthesia. More particularly, it relates to compositions containing a combination of a sodium channel activator and a local anesthetic. The invention is also directed to an improved method for relieving pain by concurrently administering these agents.
  • Sodium channel activators have been the subject of considerable research aimed at the development of new analgesic and anesthetic agents.
  • the activators studied are the veratrum alkaloids, an abundant group of steroid-like polycyclic nitrogen-containing ring structures found in liliaceous plants.
  • Krayer, et al. Physiol. Rev. 26:336-446 (1946);
  • Krayer, et al. "Veratrum Alkaloids” in Pharmacology in Medicine, V.A. Drill, ed., (1958).
  • One of these alkaloids, veratridine has been widely used as a neuropharmacological tool for studying the electrical properties of nerve and muscle fibers. Ulbricht, W., Rev. Physiol.
  • Veratridine has been reported to inhibit nerve impulses and to act preferentially on C-fibers in mammalian peripheral nerves in vitro.
  • the present invention is based upon the discovery that sodium channel activators and local anesthetics act synergistically to induce analgesia.
  • the effect produced by the combination is surprising in three different respects.
  • nerve impulses are inhibited by the combination for a duration that is greater than would be expected based upon adding the individual effects of the agents.
  • analgesia is potentiated by the combination to a much greater extent than motor system blockade. This selective action is particularly desirable in that it should permit treated patients to move with minimal pain and discomfort after surgery.
  • the combination exhibits little or no systemic toxicity and is therefore well suited for the long-term treatment of chronic pain.
  • the present invention is directed to a pharma ⁇ ceutical composition
  • a sodium channel activator and a local anesthetic.
  • Either natural or synthetic sodium channel activators may be used, with members of the veratrum alkaloids, such as veratridine, being generally preferred.
  • Other sodium channel activators may also be used including aconitine and members of the grayanotoxins or pyrethroids.
  • composition is useful in relieving pain in a subject, preferably a human, when administered in one or more unit doses.
  • a preferred composition would contain the sodium channel activator veratridine and the local anesthetic is bupivacaine.
  • veratridine will be adrninistered at a dosage of between about 0.10 mM and 1.0 mM in a volume of between 1 cc and 50 cc, depending upon the nerve to be anesthetized.
  • Bupivacaine will typically be present at a concentration of about 0.5 mM to 20 mM, with lower doses (0.5 mM to 5.0 mM) being preferred.
  • epinephrine may be included in the composition as an agent to help to protect against systemic toxicity.
  • the composition may be formulated in a manner suitable for any route of administration, but preferred routes are parenteral administration, topical administration and transdermal administration.
  • the present invention is also directed to a kit containing, in close confinement, two or more components, e.g. vials, bottles or packets.
  • the first component contains a sodium channel activator (e.g., veratridine or other members of the veratrum alkaloids) and the second component contains a local anesthetic (e.g., bupivacaine).
  • epinephrine may be included in the kit as a third component.
  • the present invention is directed to an improved method for relieving pain in a subject, preferably a human, by administering a composition comprising a sodium channel activator and a local anesthetic.
  • veratridine and bupivacaine are among the agents preferred.
  • concentration of veratridine in the administered composition will be between about 0.10 mM and about 1.0 mM.
  • the preferred concentration of bupivacaine is between about 0.5 and about 5.0 mM, although higher dosages can also be used.
  • epinephrine may also be administered as part of the method and such administration will be preferred in cases where systemic tocxicity may be a problem.
  • the preferred routes for administering agents are parenterally, topically and transdermally.
  • Figure 1 Relative Effects of Bupivacaine and a Combination of Bupivacaine and Veratridine:
  • Figure 1 shows the results of experiments in which solutions of bupivacaine (BUPI) or bupivacaine and veratridine (VTD) were injected near the sciatic nerve of rats.
  • Experimental groups contained 6 rats each and were injected with: 0.25 mM veratridine; 7.7 mM bupivacaine; 15.3 mM bupivacaine; and 7.7 mM bupivacaine + 0.25 mM veratridine.
  • nociceptive block (138 +/- 6.4 min.) became significantly longer compared to administration of 7.7 mM bupivacaine alone (81.7 +/- 1.7 min.).
  • the effect of injecting bupivacaine with the vehicle used for veratridine (4% DMSO in saline) did not produce an effect statistically different from that seen with the injection of bupivacaine alone.
  • 0.1 ml was injected near the sciatic notch of test animals.
  • Figures 2 A and 2B Duration of Motor and Nociceptive Block: Figure 2 shows a comparison of the durations of motor and nociceptive block produced by injecting rats with bupivacaine, veratridine, or a combination of bupivacaine plus veratridine. The results were obtained from the experiments described in connection with Figure 1.
  • Figures 3 A and 3B Effects of Low Dose Administration of Bupivacaine and a Combination of Bupivacaine and Veratridine:
  • the experimental model described above in connection with Figure 1 was also used in experiments designed to determine the effect of low (threshold) doses of bupivacaine and veratridine. Specifically, experiments were conducted to determine whether it is possible to obtain selective nociceptive block after co-injection of a low dose of bupivacaine with veratridine, similar to the results which were obtained after co- injection of an "anesthetic" dose of bupivacaine. Solutions (0.1 ml) were injected near the sciatic nerve of rats in the same manner as described for Figure 1.
  • mice were injected with: 1.925 mM bupivacaine; 3.85 mM bupivacaine; 0.0625 mM veratridine; and 1.925 mM bupivacaine + 0.0625 mM veratridine.
  • the non-injected hind limb of each animal served as a control.
  • bupivacaine alone at a dosage of 1.925 mM, it was found that complete motor block lasted for 15.17 +/- 6.07 minutes and complete nociceptive block lasted for 27.0 +/- 4.05 minutes.
  • Figure 3 shows the changes in motor (3A) and nociceptive (3B) functions of the sciatic nerve observed after the administration of either bupivacaine alone or bupivacaine in combination with veratridine.
  • the results of this study confirmed that the addition of a low dose of veratridine is able to potentiate preferentially the nociceptive component of the regional block induced by bupivacaine.
  • a subthreshold dose of bupivacaine (1.925 mM) itself led to a preferential inhibition of nociception, i.e. complete motor blockade lasted for a shorter duration than complete nociceptive block and, in some rats, complete motor blockade was never observed.
  • the present invention is directed to a composition for alleviating pain which comprises a combination of a sodium channel activator and a local anesthetic.
  • Sodium channel activators that may be used include, without limitation, the veratrum alkaloids, the grayanotoxins, the pyrethroids and aconitine.
  • the preferred veratrum alkaloid is veratridine which is a commercially available natural product derived from a mixture of compounds called veratrine. A monograph on veratridine can be found in The Merck Index, 11th edition (1989) under reference no. 9855.
  • Local anesthetics that are presently available and which are suitable for compositions include bupivacaine, ropivacaine, mepivacaine, tocainide, etc.
  • the preferred local anesthetic is bupivacaine.
  • Veratrum alkaloids and local anesthetics can be used in the form of a free base or, alternatively, in the form of a non-toxic pharmaceutically acceptable salt.
  • the particular form of the agents used in the composition will depend, in part, on the route of administration. For example, in transdermal formulations a free base would generally be preferred whereas parenteral solutions would generally use water-soluble salts.
  • compositions may be formulated for any route of administration but parenteral administration will generally be preferred. Suitable compositions for such administration will include aqueous solutions in which agents are used in water-soluble form, for example, water- soluble salts.
  • oily suspensions of the active compounds may be administered. Suitable lipophilic solvents or vehicles include fatty oils (e.g. sesame oil) or synthetic fatty acid esters (e.g. ethyl oleate or triglycerides).
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.
  • injections will be made in close proximity to the nerve or nerves where anesthesia is desired.
  • extended release formulations of agents e.g. microsphere carriers or lipid-based emulsions
  • Other formulations and dosage forms that are preferred include those suitable for topical and transdermal administration. Methods for preparing these are well known in the art (see e.g. U.S. Patent No. 5,387,615; 5,192,550; 4,868,218; 5,128, 145; and foreign patent documents EP-A404807; EP-A509761 ; and EP-A593807).
  • veratridine When veratridine is used in compositions, it will typically be present at a concentration of between about 0.10 and 1.0 mM. Bupivacaine will typically be present at a concentration of between about 0.5 mM and 20 mM, with lower doses (0.5 to 5.0 mM) being preferred. In some instances, it may be desirable to include an agent that reduces the likelihood of systemic toxicity. Epinephrine is suitable for this purpose and may be included in preparations at a ratio of about 1:200,000 mass to volume. The dosage of the composition to be administered will depend upon factors specific to individual patients and can be determined using procedures well known in the art. In the case of veratridine, therapeutically effective amounts include 0.027 to 0.63 mg/kg of body weight and, more preferably, 0.027 to 0.27 mg/kg of body weight.
  • kits comprising a carrier (e.g. a box or bag) compartmentalized to receive one or more components (bottles, vials, packets, etc.) in close confinement.
  • a carrier e.g. a box or bag
  • components such as a kit
  • the agents provided in the kit may be mixed immediately before administration to a patient or, they may be administered in immediate succession.
  • Other agents besides sodium channel activators and local anesthetics that may be provided in the kit include agents that mitigate systemic toxicity such as epinephrine.
  • the present invention is also directed to a method for relieving pain in a patient, typically a human, in need of such relief.
  • the method may be performed before a surgical procedure or for the purpose of relieving pain either after surgery or at other times.
  • the method entails administering compositions such as those described above, i.e. compositions that include a sodium channel activator such as veratridine and a local anesthetic such as bupivacaine.
  • compositions such as those described above, i.e. compositions that include a sodium channel activator such as veratridine and a local anesthetic such as bupivacaine.
  • the combined administration of these agents allows lower doses of anesthetic to be used to achieve the same degree of pain relief which reduces the likelihood that unwanted side effects such as systemic toxicity will be experienced.
  • any dosage form and route of administration is compatible with the method but parenteral, topical and transdermal administration will generally be preferred.
  • the method may include the administration of other therapeutic agents or agents designed to protect against systemic toxicity, e.g. epinephrine.
  • the duration of administration will depend upon clinical conditions and the nature of the pain experienced by the patient. Such considerations will also be largely dete ⁇ ninative of the dosage form used. For example, patients experiencing long-term chronic pain can probably best be treated using dosage forms or formulations designed for the slow release of therapeutic agent.

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

Abstract

Cette nouvelle composition sert à soulager la douleur et contient une association d'un activateur des canaux sodiques, et d'un anesthésique local. L'activateur des canaux sodiques préféré est un alcaloïde de vératre. L'invention concerne également un méthode améliorée de traitement de la douleur par l'administration de ces compositions et une trousse dont les éléments contiennent les substances décrites.
PCT/US1997/008196 1996-05-16 1997-05-15 Compositions contenant des activateurs des canaux sodiques et des anesthesiques locaux WO1997042955A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32059/97A AU3205997A (en) 1996-05-16 1997-05-15 Compositions comprising sodium channel activators and local anesthetics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1772896P 1996-05-16 1996-05-16
US60/017,728 1996-05-16

Publications (1)

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WO1997042955A1 true WO1997042955A1 (fr) 1997-11-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125676B2 (en) 2002-02-25 2006-10-24 Vanderbilt University Expression system for human brain-specific voltage-gated sodium channel, type 1

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288723A (en) * 1991-09-06 1994-02-22 Brigham And Women's Hospital A composition and a method of using veratridine and epinephrine as a local anesthetic

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288723A (en) * 1991-09-06 1994-02-22 Brigham And Women's Hospital A composition and a method of using veratridine and epinephrine as a local anesthetic

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIPTON E.A.: "TECHNOLOGICAL ADVANCES IN REGIONAL ANAESTHESIA", S.AFR.MED.J., vol. 84, no. 3, March 1994 (1994-03-01), (SOUTH AFRICA), pages 128 - 129, XP002037837 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7125676B2 (en) 2002-02-25 2006-10-24 Vanderbilt University Expression system for human brain-specific voltage-gated sodium channel, type 1

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Publication number Publication date
AU3205997A (en) 1997-12-05

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