JP2006298934A - Method for treating pain of headache by using topical local anesthetic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for treating pain of headache by using a topical coating of a local anesthetic on the affected host. <P>SOLUTION: The method for treating the pain of the headache by treating the affected host by blocking the transmission at the target nerve accompanying the pain of the headache involves a step for topically coating the local anesthetic composition containing an effective amount of the local anesthetic combined with eucalyptol as a penetration enhancer on a keratinized skin site at the vicinity of the target nerve. As a result, the local anesthetic rapidly penetrates the surface of the skin at the skin site to block the transmission at the target nerve. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

(Field of Invention)
The field of the invention is the treatment of headache pain.

(background)
Headache is a common problem that affects most of the population. Headaches such as tension and migraine can occur both intermittently and chronically and can result in responses to various stimuli, including stress, injury, environmental toxins, and the like.

  Various therapeutic agents have been developed for use in the treatment of patients suffering from headache pain. Several drugs are administered systemically, such as aspirin, acetaminophen, vasoconstrictors, and NSAIDs (eg, ibuprofen and naprosyn). Despite the prevalence of this form of treatment for headache pain, systemic administration is not recommended in some cases. For example, oral administration of aspirin can cause stomach upset and patient discomfort. Furthermore, the drug can exert host systemic toxicity, which can be more significant than any therapeutic benefit provided by the drug. Finally, since the drug is administered systemically, its effect is also systemic, which may not be desired.

  In view of the above problems and disadvantages associated with systemically administered therapeutics, local administration of a local anesthetic that selectively blocks transmission in the target nerve is a desirable alternative for the treatment of headache pain . The use of local anesthetics is desirable because neurotransmission can be selectively blocked only in those nerves associated with headache pain. While the use of local anesthetics in the treatment of headache pain is desirable, administration of an effective amount of local anesthetic to the target nerve is difficult and / or inconvenient.

  For example, local anesthetics can be injected directly at nerve sites associated with headache pain (eg, the occipital and supraorbital nerves) to produce nerve blocks, thereby providing pain relief. See Non-Patent Document 1. This method is effective in providing headache pain relief, but since a local anesthetic is injected, it must be administered by trained personnel. Furthermore, the patient must tolerate the discomfort associated with local anesthetic injections.

  Because of these disadvantages of administration by injection, local administration of a local anesthetic is a desirable alternative to the mode of administration. However, local anesthetics from them do not readily penetrate the stratum corneum of the skin. See Non-Patent Document 2. Therefore, the use of intranasal application of local anesthetics in the treatment of headache pain has been found. See Non-Patent Document 3.

  For local administration of the local anesthetic to the keratinized skin surface, further treatment must be taken to provide penetration of the local anesthetic across the keratinized skin surface. One means of providing penetration of the local anesthetic across its skin surface is to employ iontophoretic techniques, where an electric field is applied to the local local anesthetic composition. Local anesthetics penetrate the keratinized skin surface under the influence of an applied electric field.

  Another means of providing keratinized skin penetration is to employ formulations that promote local anesthetic penetration. While such formulations are available and have been adopted for a variety of applications, currently available local local anesthetic formulations are widely used for the treatment of headache pain. Not found. One reason that currently available formulations have not found widespread use for the treatment of headache pain is that an effective amount of anesthetic provides pain relief in a sufficiently short period of time. Does not penetrate the skin quickly enough. For example, if EMLA (a eutectic mixture of lidocaine and prilocaine) is applied topically to the keratinized skin surface, it must be applied under a closed bandage for at least 1 hour before analgesia is experienced by the host. See Non-Patent Document 4.

  Accordingly, there is continued interest in identifying local local anesthetic formulations suitable for use in the treatment of headache pain. Such topical formulations should provide rapid penetration through the skin surface of an effective amount of local anesthetic and thereby provide rapid pain relief.

(Related literature)
U.S. Patent No. 6,057,049 describes topical application containing eucalyptol as an enhancer. Patents for other purposes include: Patent Document 2; Patent Document 3; Patent Document 4; Patent Document 5; Patent Document 6;

Non-Patent Document 5 reports the application of 4% lidocaine solution to the sphenopalantine fossa to treat nitrate-induced cluster headache pain.
U.S. Pat.No. 4,440,777 U.S. Pat.No. 4,588,580 U.S. Pat.No. 4,911,707 U.S. Pat.No. 5,069,909 U.S. Pat.No. 5,070,084 U.S. Pat.No. 5,330,452 U.S. Pat.No. 5,368,860 Garron, “Relieving Pain with Nerve Blocks”, Geriatrics (1978) 33: p. 49-57 Review of Medical Pharmacology (Edited by Meyers et al., 1978) p. 217-226 Brandt et al., “Cluster headache and chronic paroxysmal hemicrania: current therapy”, Nervenarzt (1991) 62: p. 329-339 Physician's Desk Reference, 1994, p. 544 Kittrelle et al., “Cluster Headache. Local Anesthetic Abortive Agents”, Arch. Neurol. (1985) 42: p. 496-498

(Summary of the Invention)
Methods are provided for the treatment of a host suffering from headache pain using a local local anesthetic composition. The local local anesthetic composition employed in the method of the present invention comprises an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancer. The local anesthetic composition is applied to the keratinized skin site proximal to the target nerve with headache pain. In application, the local anesthetic rapidly penetrates the skin surface to reach the target nerve, blocks transmission in the target nerve, and provides rapid pain relief.

The present invention provides the following.
(Item 1)
A method for treating a host suffering from headache pain by blocking transmission in a target nerve associated with the headache pain, the method comprising:
Applying a local local anesthetic composition at a keratinized skin site proximal to the target nerve comprising: an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancer;
Thereby, the local anesthetic quickly penetrates the skin surface at the skin site and blocks transmission in the target nerve.
(Item 2)
The method of claim 1, wherein the local local anesthetic composition further comprises an additional penetration enhancer.
(Item 3)
Item 2. The method according to Item 1, wherein the target nerve is selected from the group consisting of the occipital and supraorbital nerves.
(Item 4)
A method for treating a host suffering from headache pain by blocking transmission in a target nerve associated with the headache pain, the method comprising:
Applying at the keratinized skin site proximal to the target nerve a local local anesthetic composition comprising: (a) an effective amount of the local anesthetic, wherein the local anesthetic is via a connecting group An amine linked to an aromatic group; (b) eucalyptol as a penetration enhancer; and (c) an additional penetration enhancer, wherein the target nerve is selected from the group consisting of the occipital and supraorbital nerves; Including
Thereby, the local anesthetic quickly penetrates the skin at the skin site and blocks transmission in the target nerve.
(Item 5)
Item 5. The method according to Item 4, wherein the local anesthetic is bupivacaine.
(Item 6)
Item 5. The method of item 4, wherein the additional penetration enhancer is N, N-diethyl-m-toluamide.
(Item 7)
A method for treating a host suffering from headache pain by blocking transmission in a target nerve selected from the group consisting of the occipital and supraorbital nerves, the method comprising:
Applying at the keratinized skin site proximal to the target nerve a topical local anesthetic composition comprising: (a) an effective amount of benzocaine, (b) eucalyptol, and (c) N, N-diethyl -m-toluamide;
Thereby, the bupivacaine rapidly penetrates the skin at the skin site to block transmission in the target nerve.
(Item 8)
8. A method according to item 7, wherein the benzocaine is present in the composition in an amount ranging from 20 to 40% by weight.
(Item 9)
8. The method of item 7, wherein the ratio of eucalyptol to N, N-diethyl-m-toluamide in the composition is 1: 2.
(Item 10)
8. A method according to item 7, wherein the composition is formulated as a gel.
(Item 11)
8. A method according to item 7, wherein the gel is coated with a dressing.
(Item 12)
8. The method of item 7, wherein the composition is formulated in a plaster adhesive.

(Description of specific embodiments)
A method is provided for the treatment of a host suffering from headache pain through the application of a local local anesthetic composition. The local anesthetic composition employed in the method of the present invention comprises an effective amount of a local anesthetic in combination with eucalyptol as a penetration enhancer and rapid penetration of the local anesthetic through the keratinized skin surface. I will provide a. In the method of the invention, the local anesthetic composition is applied topically to the skin site proximal to the target nerve associated with headache pain. In application, the local anesthetic agent penetrates the skin, blocks transmission in the target nerve, and provides host pain relief.

  The topical composition employed in the methods of the present invention includes a local anesthetic as the active agent. Although more than one local anesthetic agent may be present in the composition of the present invention, generally the composition of the present invention comprises a single local anesthetic agent. The local anesthetic employed in the method of the present invention is anesthetic, which, when administered in a topical formulation, quickly penetrates the keratinized skin surface and blocks transmission in nerves that are in the skin surface. To do. Local anesthetics have molecular weights and melting points that are compatible with transport across the keratinized skin surface. In general, the molecular weight of a local anesthetic does not exceed about 300 dal, and more usually does not exceed about 250 dal. The melting point of the local anesthetic is less than about 100 ° C. In general, a local anesthetic is a compound consisting of a secondary or tertiary amine linked to an aromatic group via a connecting group. Local anesthetics are alkanyl compounds consisting of about 9 to 20 carbon atoms. Because the composition is applied topically, local anesthetics are generally present in the composition as the free base to facilitate penetration of the drug across the skin surface. A number of local anesthetics are known in the art, many of which are suitable for topical applications. Suitable local anesthetics include: lidocaine, butamben, butanilicine, ethyl aminobenzoate, fomocaine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine, octacaine, paretoxycaine, pyridocaine, prilocaine, procaine Lysokine, tricaine, trimecamine, especially ethyl aminobenzoate (benzocaine). The amount of local anesthetic present in the composition of the invention is sufficient to provide an effective amount of the drug when administered locally by the method of the invention. The exact amount of anesthetic present in the topical formulation depends on the particular drug employed, but is generally in the range of 5-50% by weight, usually about 10-40% by weight.

  Critical to the topical application employed in the method of the present invention is eucalyptol, which acts as a penetration enhancer for local anesthetics. Eucalyptol (1,3,3-trimethyl-2-oxabicyclo [2,2,2] -octane) is the major component of eucalyptus oil and is also known as cineole and cajeputol. Eucalyptol is known in the art and has found use as an insect repellent and as a flavoring agent. The amount of eucalyptol present in the composition ranges from about 10-80%, usually about 10-50%, and more usually about 20-40% by weight of the composition.

  If desired, the compositions of the present invention may further comprise one or more additional penetration enhancers that are textured in combination with eucalyptol and provide rapid penetration of local anesthetics. Additional penetration enhancers can penetrate the skin rapidly and are pharmaceutically acceptable, i.e., non-toxic to the host at the level at which they are present in the composition. Examples of additional penetration enhancers that may be used in the compositions of the present invention include: propylene glycol and N-methyl-2-pyrrolidone. An additional penetration enhancer that finds particular use in combination with eucalyptol in the compositions of the present invention is N, N-diethyl-m-toluamide (DEET). When present, the amount of this additional penetration enhancer in the composition of the invention will vary depending on the particular drug as well as the local anesthetic present in the composition. The amount of additional penetration enhancer (s) in the composition of the present invention ranges from 10 to 80% by weight, usually about 30 to 60% by weight. In general, the ratio of eucalyptol to additional penetration enhancer in the composition of the present invention is 0.25: 1 to 2: 1, usually about 1: 2 to 1: 1.

  A composition comprising a local anesthetic, eucalyptol, and any additional penetration enhancers employed in the methods of the present invention is formulated in a manner convenient for topical application. Thus, the compositions of the present invention can be formulated as stable eucalyptol solutions or suspensions of local anesthetics. Alternatively, local anesthetics and eucalyptol can be combined with one or more carrier materials to form solutions, suspensions, gels, lotions, creams, ointments, aerosol sprays, etc., as is known in the art.

  Gel vehicles in which the local anesthetics and eucalyptol of the present invention can be formulated to make topical applications useful in the methods of the present invention are physiologically acceptable and generally include a solvent in combination with a thickening agent. In general, the solvent is an alkanol such as an alcohol or polyol, including: ethanol, isopropanol, propylene glycol, glycerol and the like. These alcohols and polyols can be used separately or in combination. In gel vehicles, the solvent is generally present at about 1-80%, more usually 10-40% by weight of the topical composition.

  Conventional gelling or thickening agents can be employed to provide formulations that can be conveniently applied to the skin. An exemplary gelling agent that has been found to be effective and commonly used for skin application is Carbomer 940 (neutralized with diisopropanolamine), neutralizing poly Contains acrylic acid. The gelling agent is used in an amount sufficient to provide a suitable viscosity and generally ranges from about 0.1 to 5% by weight of the formulation.

  Nonionic surfactants can be included in the composition, where the nonionic surfactant is in addition to eucalyptol and any additional penetration enhancers described above, as a co-solvent and epidermal penetration enhancer. Can work. Conventional surfactants such as sorbitan esters may be employed and are physiologically acceptable. When present, generally the nonionic surfactant is present in an amount of about 2-20% by weight of the formulation.

  Topical compositions can also include other physiologically acceptable excipients or other small amounts of additives, particularly those related to sensory receptive properties, such as perfumes, dyes, emulsifiers, buffers, cooling agents (e.g. Menthol), antibiotics, stabilizers and the like. Excipients and minor additives are present in conventional amounts in the range of about 0.001 to 5% by weight, more typically 0.001 to 2% by weight, and generally do not exceed 10% by weight.

  Conveniently, the topical application is covered with an occlusive dressing (which can be porous or non-porous) so as to protect the gel from mechanical removal during the treatment, for example using a gel formulation. obtain. Various inert coatings can be employed, including various materials that may find use in the plaster described below. Alternatively, non-woven or woven coatings, particularly elastomeric coatings, that allow heat or steam transfer may be employed. These coatings provide greater comfort while allowing the aching site to cool and protecting the gel from mechanical removal.

Instead of a gel, a plaster can be employed, where a composition containing a local anesthetic and eucalyptol, and any additional penetration enhancers, can be formulated in the adhesive of the plaster. For plasters, coatings include the following: polyvinyl chloride, polyvinylidene chloride, ^{(SARAN (R)),} polyethylene, synthetic rubber, woven or nonwoven polyester fabric. Local anesthetics and eucalyptol can be combined with the adhesive with the aid of a co-solvent (eg, propylene glycol, glycerin, methyl salicylate, glycol salicylate, etc.) or in combination with a co-solvent. The specific choice of adhesive is not important and there are a wide range of physiologically acceptable adhesives that maintain local anesthetics, eucalyptol, and any additional penetration enhancers in contact with the skin Can do.

  Of particular interest are the local local anesthetic compositions described in US Pat. No. 4,440,777 (the disclosure of which is hereby incorporated by reference).

  In the method of the present invention, a topical composition comprising a local anesthetic is applied to the keratinized skin site of the host, proximal to the target nerve with headache pain. The nerves usually associated with headache pain are the occipital and supraorbital nerves. The skin site to which the composition is applied is close enough to the target nerve so that the local anesthetic can easily reach the target nerve and exert anti-transmitter activity upon contact with the skin surface of the composition (For example, the skin site covers an area dominated by the target nerve). Of particular interest as topically applied skin sites are the orbital and occipital regions.

  The composition of the present invention is applied to the skin site for a period ranging from 0.25 to 6 hours, usually about 0.5 to 5 hours, during which time the host reduces pain due to local anesthetic activity on the target nerve. experience. If headache pain recurs following removal of the topical composition, a new topical composition may be applied. The process can be repeated as necessary and desirable to achieve pain relief. Due to the nature of the local local anesthetic composition employed in the method of the invention, local anesthetic penetration is rapid. Therefore, patients experience pain relief within a short time after application. Typically, the patient experiences at least some relief of headache pain in about 0.25-30 minutes following application of the topical composition and usually about 0.5-30 minutes following application of the topical composition.

  Typically, the amount of applied composition is the majority of the skin overlying the target nerve to ensure that transmission is blocked at a sufficient percentage of the target nerve so that the host experiences pain relief. Cover well. The exact amount of topical composition applied can be determined empirically. For example, if a topical application is applied to the epiorbital region of the head, the amount of composition applied is sufficient to cover at least about 50%, more usually at least about 75% of the region. For solutions, dispersions, gels, lotions, creams, etc., the composition is spread over the area and a coating is applied to it as required. For the patch, an appropriately sized patch is applied over the entire area including the skin site.

  Conveniently, the composition may be provided in unit dosage form, which is known in the art.

  In applying the topical composition, the local anesthetic quickly penetrates the surface of the skin and blocks transmission of target nerves proximal to the skin site. As a result, the patient may experience at least partial sedation in headache pain intensity and in some cases may experience complete cessation of pain. Thus, application of a local local anesthetic composition by the method of the present invention results in the treatment of a host suffering from headache pain.

  The following examples are presented by way of illustration and not limitation.

(Experiment)
A mixture of DEET (N, N-diethyl-m-toluamide) and eucalyptol (1,3,3-trimethyl-2-oxabicyclo [2,2,2] -octane) was prepared in a 2: 1 ratio. A sufficient amount of benzocaine free base (about 30% by weight) was dissolved in the mixture to produce a saturated solution of local anesthetic.

  The solution was applied topically to female patients who suffered from acute migraine without aura. The solution was applied directly to the region of the patient's head where the supraorbital and occipital nerves were closest to the skin (the same area where the needle was inserted to perform local anesthesia on these nerves). Prior to application of the solution, the patient assessed her headache pain as “moderate” with “moderate” nausea and “moderate” light sensitivity.

  After 15 minutes, the headache pain sedated to a level described by the patient as "very mild". Furthermore, the patient reported no nausea or photosensitivity. In addition, patients have traditionally not experienced any noise sensitivity that typically becomes heavy during previous migraine attacks.

  The patient's relief from pain and other migraine symptoms lasted more than 2 hours. The patient was able to continue working following the application of a local local anesthetic solution. This was a favorable result compared to other forms of treatment that the patient had previously employed (despite the treatment, the patient had to stop working).

  It is clear from the above results and discussion that a new and effective method of treating host headache pain is provided. The nature of the topical application employed provides for rapid penetration of the local anesthetic into the skin surface. As a result, patients experience pain relief immediately after application of the composition. Furthermore, because the local anesthetic composition is local, this method is convenient for the patient and well tolerated.

  All documents and patent applications cited herein are hereby incorporated by reference, with each individual document or patent application being shown in detail and separately incorporated by reference. .

  Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims. This will be readily apparent to those skilled in the art in view of the teachings of the present invention.

Claims (11)

  Blocks headache pain for application at the keratinized skin site proximal to the occipital and supraorbital nerves in the occipital and supraorbital regions, and blocks transmission in the occipital and supraorbital nerves with the headache pain A local local anesthetic composition for treating by comprising an effective amount of a local anesthetic combined with eucalyptol as a penetration enhancer, wherein the local anesthetic is aromatic via a connecting group A local local anesthetic composition which is an amine linked to a group.   The composition of claim 1 further comprising an additional penetration enhancer.   Topical for treating headache pain for application at a keratinized skin site proximal to the occipital and supraorbital nerves by blocking transmission in the occipital and supraorbital nerves associated with the headache pain A local anesthetic composition comprising: (a) an effective amount of a local anesthetic, wherein the local anesthetic is an amine linked to an aromatic group via a linking group; (b) as a penetration enhancer A local local anesthetic composition comprising eucalyptol; and (c) an additional penetration enhancer.   4. The composition of claim 3, wherein the local anesthetic is bupivacaine.   4. The composition of claim 3, wherein the additional penetration enhancer is N, N-diethyl-m-toluamide.   Topical topical for treating headache pain for application at a keratinized skin site proximal to the target nerve by blocking transmission in the target nerve selected from the group consisting of the occipital nerve and supraorbital nerve An anesthetic composition comprising (a) an effective amount of benzocaine, (b) eucalyptol, and (c) N, N-diethyl-m-toluamide.   7. A composition according to claim 6, wherein the benzocaine is present in the composition in an amount ranging from 20 to 40% by weight.   The composition of claim 6, wherein the ratio of eucalyptol to N, N-diethyl-m-toluamide in the composition is 1: 2.   7. A composition according to claim 6 formulated as a gel.   10. The composition of claim 9, wherein the gel is coated with a dressing.   7. A composition according to claim 6 formulated in a plaster adhesive.