Formulations for the treatment of pain

Abstract

Formulations and methods are provided for the treatment of pain, and neuropathic pain in particular. The formulations are eutectic mixtures of a capsaicinoid and a local anesthetic agent and/or an anti-pruritic agent.

Claims

1. A substantially nonaqueous therapeutic formulation comprising a binary eutectic mixture of: (a) a capsaicinoid having the structure of formula (I) ##STR00005## wherein R.sup.1 is hydrogen, hydroxyl or methoxy, R.sup.2 is hydroxyl or C.sub.2-C.sub.6 alkoxycarbonyl, X is selected from ##STR00006## and R is selected from C.sub.5-C.sub.11 alkyl, C.sub.5-C.sub.11 alkenyl, C.sub.11-C.sub.23 cis-alkenyl, C.sub.11-C.sub.23 alkynyl, and C.sub.11-C.sub.23 alkadienyl, provided that the capsaicinoid is other than capsaicin, wherein the capsaicinoid represents about 10 wt. % to about 70 wt. % of the formulation; and (b) a second active agent effective to decrease at least one side effect associated with capsaicin monotherapy, said second agent existing as a solid at 25 C., and wherein said second agent is a local anesthetic agent selected from the group consisting of amylocaine, articaine, benzocaine, bupivacaine, butacaine, 2-chloroprocaine, cinchocaine, dexivacaine, diamocaine, dibucaine, etidocaine, ketocaine, lidocaine, mepivacaine, oxybuprocaine, parethoxycaine, prilocaine, procaine, propanocaine, proparacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, ropivacaine, tetracaine, and combinations thereof; and wherein the formulation contains less than 5 wt. % water.

2. The formulation of claim 1, wherein the capsaicinoid is selected from resiniferatoxin, N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, N-vanillyl-monounsaturated alkenamides, N-vanillylsulfonamides, and hydroxyphenylacetamides.

3. The formulation of claim 2, wherein the capsaicinoid is an N-vanillyl monounsaturated alkenamide.

4. The formulation of claim 1, wherein the local anesthetic agent is lidocaine.

5. The formulation of claim 1, wherein the local anesthetic agent is tetracaine.

6. The formulation of claim 1, wherein the capsaicinoid represents about 40 wt. % to about 70 wt. % of the formulation.

7. A method for treating a patient suffering from pain, comprising administering to the patient a therapeutically effective amount of the formulation of claim 1.

8. The method of claim 7, wherein the formulation is administered topically.

9. The method of claim 8, wherein the pain is caused by inflammation of joints, tendons, nerves, or muscle.

10. The method of claim 7, wherein the pain is caused by cancer.

11. The method of claim 7, wherein the pain is neuropathic pain.

12. The formulation of claim 1, wherein the formulation contains less than 1 wt. % water.

13. The formulation of claim 1, wherein the formulation is substantially free of additional components other than the capsaicinoid and the local anesthetic agent.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) Unless otherwise indicated, the invention is not limited to specific active agents, pharmaceutical formulations, modes of administration, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

(2) As used in the specification and the appended claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an active agent encompasses a combination or mixture of different active agents as well as a single active agent, and the like. In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:

(3) As used herein, the phrase having the formula or having the structure is not intended to be limiting and is used in the same way that the term comprising is commonly used.

(4) The term alkyl as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like. If not otherwise indicated, the term alkyl includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl.

(5) The term alkenyl as used herein refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like. If not otherwise indicated, the term alkenyl includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl.

(6) The term alkynyl as used herein refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. If not otherwise indicated, the term alkynyl includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkynyl.

(7) When referring to an active agent, applicants intend the term to encompass not only the specified molecular entity but also its pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.

(8) The terms treating and treatment as used herein refer to reduction in severity and/or frequency of pain, elimination of pain, prevention of pain, and/or prevention of pain.

(9) By the terms effective amount and therapeutically effective amount of a formulation of the invention is meant a nontoxic but sufficient amount of the formulation to provide the desired effect. The amount that is effective will vary from subject to subject, depending on the age and general condition of the individual, the particular active agents. and the like. Thus, it is not always possible to specify an exact effective amount. However, an appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. For example, a therapeutically effective amount of capsaicin is that quantity needed to treat or prevent pain, e.g., neuropathic pain. A therapeutically effective amount of an anesthetic agent is that concentration needed to prevent burning or discomfort from capsaicin at the site of administration.

(10) By pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term pharmaceutically acceptable is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing of that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. Pharmacologically active (or simply active) as in a pharmacologically active derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.

(11) Accordingly, in a first embodiment, a therapeutic formulation is provided that is substantially nonaqueous, i.e., contains less than 5 wt. %, preferably less than 2.5 wt. %, and most preferably less than 1 wt. % water, and is composed of a binary eutectic mixture of a capsaicinoid and a second active agent. The term binary eutectic mixture refers to a mixture of two components that has a melting point that lower than the melting point of either component. In the present context, the two components of the binary eutectic mixture are solid at 25 C. but the eutectic mixture itself is preferably a liquid at 25 C. The term capsaicinoid refers to an analgesic agent, generally used as a topical analgesic agent, having the structure of formula (I)

(12) ##STR00003##
wherein R.sup.1 is hydrogen, hydroxyl or methoxy, R.sup.2 is hydroxyl or C.sub.2-C.sub.6 alkoxycarbonyl, X is selected from

(13) ##STR00004##
and R is selected from C.sub.5-C.sub.11 alkyl, C.sub.5-C.sub.11 alkenyl, C.sub.11-C.sub.23 cis-alkenyl, C.sub.11-C.sub.23 alkynyl, and C.sub.11-C.sub.23 alkadienyl.

(14) Generally, the capsaicinoid is selected from resiniferatoxin, N-vanillyl-alkadienamides, N-vanillyl-alkanedienyls, N-vanillyl-monounsaturated alkenamides, N-vanillylsulfonamides, and hydroxyphenylacetamides. In a preferred embodiment, the capsaicinoid is an N-vanillyl-monounsaturated alkenamide (i.e., R.sup.1 is methoxy, R.sup.2 is hydroxyl, X is NH(CO), and R is an alkene chain), and in a particularly preferred embodiment, the N-vanillyl-monounsaturated alkenamide is capsaicin (R is (CH.sub.2).sub.4CHCHCH(CH.sub.3).sub.2).

(15) The second active agent may be a local anesthetic agent that can alleviate the pain and discomfort associated with capsaicin monotherapy (i.e., administration of capsaicin without a second active agent) or may be an anti-pruritic agent, which can alleviate the itching and irritation associated with administration of capsaicin. Any local anesthetic agent or anti-pruritic agent that is a solid at 25 C. can be used in the formulations of the invention. The term solid is intended to include hygroscopic compounds and other solids that, under certain conditions, take a semisolid form.

(16) The local anesthetic agent is a drug that provides local numbness or pain relief by producing a reversible loss of sensation by inhibiting or by decreasing pain at the site of application, without resulting in a loss of nerve control. Representative local anesthetic agents include amylocaine, articaine, benzocaine, bupivacaine, butacaine, 2-chloroprocaine, cinchocaine, dexivacaine, diamocaine, dibucaine, etidocaine, ketocaine, lidocaine, mepivacaine, oxybuprocaine, parethoxycaine, prilocaine, procaine, propanocaine, proparacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, ropivacaine, tetracaine, and combinations thereof. Preferred local anesthetic agents for use in the present formulations are lidocaine and tetracaine.

(17) Exemplary anti-pruritic agents include, by way of illustration and not limitation, camphor, phenol, and menthol.

(18) The active agents may be incorporated into the formulation in the form of a salt, ester, amide, prodrug, active metabolite, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite, or analog is pharmaceutically acceptable and pharmacologically active in the present context. Salts, esters, amides, prodrugs, active metabolites, analogs, and other derivatives of the active agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). In a preferred embodiment, however, the free base form of the local anesthetic agent is used since, typically, the free base form has a lower melting point than the equivalent salt.

(19) The binary eutectic mixture enables incorporation of the capsaicinoid into the formulation at higher levels than previously possible. In the aforementioned formulations, the capsaicinoid represents about 10 wt. % to about 70 wt. % of the formulation, preferably about 40 wt. % to about 70 wt. % of the formulation. Ideally, the formulation is substantially free of components other than the two active agents (i.e., the active agents represent at least 90 wt. % of the formulation, preferably at least 95 wt. % of the formulation, and optimally at least 99 wt. % of the formulation), and therefore does not contain carriers, excipients, enhancers, or other additives. Pharmaceutically acceptable carriers can, however, be included if desired, and the invention thus encompasses those embodiments wherein the capsaicin and secondary agents are admixed with one or more pharmaceutically acceptable carriers suited to the particular type of formulation, i.e., solution, gel, cream, lotion, ointment, suppository, or the like.

(20) In another embodiment, a therapeutic formulation is provided that is composed of a capsaicinoid having the structure of formula (I) and two additional active agents, wherein the formulation is substantially nonaqueous as defined above. Each of the two additional active agents is effective to decrease at least one side effect associated with capsaicin monotherapy, e.g., pain, discomfort, itching, or irritation. In a preferred embodiment, one of the additional active agents is a local anesthetic agent as described above, and the other of the additional active agents is an anti-pruritic agent as also described above. Preferred capsaicinoids are N-vanillyl-monounsaturated alkenamides, with capsaicin per se particularly preferred.

(21) In the ternary eutectic mixture, the capsaicinoid generally, although not necessarily, represents about 10 wt. % to about 50 wt. % of the formulation, with the two active agents together representing about 50 wt. % to about 90 wt. % of the formulation. In a particularly preferred embodiment, the weight ratio of the two additional active agents, e.g., the local anesthetic agent and the anti-pruritic agent, is approximately 1:1. Thus, in the latter case, the three active agents, the capsaicinoid, the local anesthetic agent, and the anti-pruritic agent, will be in an approximately 10:45:45 to 50:25:25 ratio by weight.

(22) To prepare the formulations of the invention, the solid components are mixed together. After about 30 minutes, a moist mixture is formed, and subsequently, for example over a 24-hour period, a liquid is formed and the ingredients remain in the liquid state. The mixture may be warmed to expedite formation of the liquid, although this is not required.

(23) Because the formulations of the invention are primarily or even entirely composed of active agents, and furthermore because the capsaicinoid represents a substantial fraction of the formulation, extremely high doses of the capsaicinoid can be delivered with a relatively small amount of the formulation. The incorporation of the additional active agents, e.g., the local anesthetic agent and/or the anti-pruritic agent, will facilitate patient compliance since the side effects of capsaicin are substantially reduced. In addition, there is no need to further formulate the capsaicin into cream or gel because the liquid can be packaged as is, for example, in a roll-on type applicator.

(24) The formulations of the invention find utility in pain caused by inflammation of joints, tendons, nerves, muscle, and other soft tissues, including arthritic pain; back pain; headache pain; pain caused by cancer; and neuropathic pain, the latter of which is of particular interest. Examples of neuropathic pain, for which the formulations of the invention are particularly well-suited, include, post-herpetic neuralgia, neuropathic pain related to HIV-associated neuropathy, pain associated with diabetic neuropathy, and neuropathic pain associated with trigeminal neuralgia.

(25) Administration of a formulation of the invention may be carried out using any appropriate mode of administration. Typically, administration will be carried out topically rather than systemically, although systemic administration, generally parenteral administration, is possible.

(26) It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the foregoing description as well as the examples that follow, are intended to illustrate and not limit the scope of the invention. It should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention, and further that other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains.

Example 1

(27) Capsaicin (Cap) and lidocaine (Lido) were mixed in the various ratios set forth in Table 1. Some of the formulations spontaneously became partially liquid. All of the formulations were mildly heated to form a uniform solution. The solutions were allowed to crystallize and/or separate at room temperature. The mixtures were also analyzed by DSC.

(28) TABLE-US-00001 TABLE 1 Composition Observations Cap:Lido Immediately 24 hours Melt/48 hours 96 hours 100 Solid Solid Solid Solid 90:10 Solid Wet mass Wet mass Wet mass 80:20 Solid Wet mass Wet mass Wet mass 70:30 Wet mass Wet mass Liquid Liquid 60:40 Wet mass Wet mass Liquid Liquid 50:50 Wet mass Wet mass Liquid Liquid 40:60 Wet mass Wet mass Liquid Liquid 30:70 Solid Wet mass Wet mass Wet mass 20:80 Solid Wet mass Wet mass Wet mass 10:90 Solid Wet mass Wet mass Wet mass 0:100 Solid Solid Solid Solid

Example 2

(29) Capsaicin, menthol, and lidocaine were mixed in the ratios given in Table 2. As in Example 1, some of the formulations spontaneously became partially liquid. All of the formulations were mildly heated to form a uniform solution. The solutions were allowed to crystallize and/or separate at room temperature.

(30) TABLE-US-00002 TABLE 2 Composition Observations Cap:Menthol:Lido Immediately 24 hours Melt/(over 2 weeks) 100 Solid Solid Solid 10:45:45 Solid Wet mass Liquid 30:35:35 Solid Wet mass Liquid 40:30:30 Wet mass Wet mass Liquid 50:25:25 Wet mass Wet mass Liquid 60:20:20 Wet mass Wet mass Wet mass 70:15:15 Wet mass Wet mass Wet mass 90:5:5 Wet mass Wet mass Wet mass

Example 3

(31) Capsaicin (Cap) and tetracaine (Tetra) were mixed in the ratios set forth in Table 3. As in Example 1, some of the formulations spontaneously became partially liquid. All of the formulations were mildly heated to form a uniform solution. The solutions were allowed to crystallize and/or separate at room temperature.

(32) TABLE-US-00003 TABLE 3 Composition Observations Cap:Tetra Immediately 24 hours Melt/(over 2 weeks) 100 Solid Solid Solid 10:90 Solid Wet mass Liquid 30:70 Solid Wet mass Liquid 40:60 Wet mass Wet mass Liquid 50:50 Wet mass Wet mass Liquid 60:40 Wet mass Wet mass Wet mass 70:30 Wet mass Wet mass Wet mass 90:10 Wet mass Wet mass Wet mass

Example 4

(33) Capsaicin (Cap) and menthol were mixed in the different ratios set forth in Table 4. Some of the formulations spontaneously became partially liquid. All of the formulations were mildly heated to form a uniform solution. The solutions were allowed to crystallize and/or separate at room temperature.

(34) TABLE-US-00004 TABLE 4 Composition Observations Cap:Menthol Immediately 24 hours Melt/(1 week) Over 2 weeks 100 Solid Solid Solid Solid 10:90 Solid Wet mass Wet mass Wet mass 30:70 Solid Wet mass Wet mass Wet mass 40:60 Wet mass Wet mass Liquid Wet mass 50:50 Wet mass Wet mass Liquid Wet mass 60:40 Wet mass Wet mass Liquid Wet mass 70:30 Wet mass Wet mass Wet mass Wet mass 90:10 Solid Wet mass Wet mass Solid