ZA200100443B

ZA200100443B - Methods and transdermal compositions for pain relief.

Info

Publication number: ZA200100443B
Application number: ZA200100443A
Authority: ZA
Inventors: Robert W Murdock; C Donald Williams
Original assignee: Pharmaceuticals Applic Associa
Priority date: 1998-06-29
Filing date: 2001-01-16
Publication date: 2001-10-31

Description

>] . ! © WO 00/00120 PCT/US99/14653

METHODS AND TRANSDERMAL COMPOSITIONS FOR PAIN RELIEF

: i : >

Field Of The Invention ’

The present invention is directed to methods and compositions for transdermal administration. In particular, the present invention is directed to methods and : : compositions for the transdermal administration of an amine containing compound Le oo having biphasic solubility and/or an agent which enhances the activity of the amine = containing compound having biphasic solubility, e.g., a muscle relaxant, to relieve pain. rT

Background Of The Invention =

It is believed that damage to somatic sensory nerves causes a somatic sensory : loss. Such damage can be caused by a variety of means including trauma, diseases such. Lu as diabetes, herpes zoster and late-stage cancer, chemotherapy, or by a chemical injury. EE

It is believed that neural pain circuits rewire themselves, both anatomically and, a. CL } 15 biochemically, after nerve injury. In many patients suffering from damage to somatic ~~ ., BRT sensory nerves, negative symptoms such as numbness are joined by positive sensations, So : involving a sort of false sensation of pain. The experience canrange from mild aoe

Co dysesthesia to excruciating pain, rendering some patients unable to work, walk or do. SL other daily activities. : FE EY i 20 In the past, patients were generally treated by administration of analgesicsto

EI relicve pain. A vast majority of such patients receive doses of these agents orally. . ©. +. . oo . " Unfortunately, in some situations, oral administration of such agents has been associated . ~~. .

ER with a variety of side effects, such as liver damage, kidney damage, gastrointestinal side =~ ~~ © effects, addiction, sedation, and/or weight gain which cannot be tolerated well by the . ~~ patient. In other cases, malabsorption of oral preparations have resulted in Ce > Lh subtherapeutic plasma levels. In other cases, the agents have relatively short plasma ~~ Ca half-lives, necessitating inconveniently frequent dosing. In general, oral delivery RET . : ~ "involves a time delay as the analgesic is absorbed via the digestive system before CL entering the bloodstream. A number of agents which have traditionally been oo

Co 30 © administered orally or by injection have been inappropriate or suboptimal for some . a oo patients when so-administered. There are a number of medications which, in at least : oo some patients, are not tolerated well when orally administered (e.g. which cause RB

Co undesirable gastrointestinal or other side effects) and/or which provide undesirably high © or low concentrations or delayed concentrations in a target tissue. In some cases,

Co 35. dosages which are appropriate for oral administration, upon being distributed more or less uniformly throughout the body, are undesirably low in a particular area, e.g., tissue, to achieve desired results. Oral or injection administration may result in too slow or too rapid increase in blood plasma levels, e.g., may involve an undesirably long time delay

© WO 00/00120 PCTIUSIIASSS ) . as the analgesic is absorbed by the digestive system before entering the bloodstream, or . may result in a "spike" in blood plasma levels followed by an undesirably low level, } . where a more constant level would be preferable. Some analgesics are particularly . prone to cause or contribute to kidney or liver damage when administered orally.

Although other forms of delivery of pharmaceuticals agents are known, each has. its drawbacks. Parenteral (i.e., intravenously or intramuscularly injected) administration is inconvenient and expensive, and is rarely used outside the hospital. Inhalation is - believed to be not feasible with many analgesic agents currently in use.

Therefore, there is a need for an analgesic delivery system which provides effective and acceptable levels, while preferably avoiding or reducing undesired effects such as liver damage or gastrointestinal side effects.

Summary Of The Invention

The present invention provides a transdermal composition for the treatment of pain in a subject, particularly a human subject. The transdermal composition for the treatment of pain in a subject includes an amine containing compound having biphasic - solubility in an amount effective to treat pain in a subject and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound, : e.g, a lecithin organogel carrier. In a preferred embodiment, the transdermal : 20 composition further includes an agent which enhances the activity of the amine : containing compound having biphasic solubility, e.g., a muscle relaxant, such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof. Preferably, the agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., the muscle relaxant, also has a biphasic solubility.

In one embodiment of the present invention, the amine containing compound having biphasic solubility is an antidepressant compound, such as a tricyclic antidepressant compound, e.g., doxepin or trimipramine.

In another embodiment of the present invention, the amine containing compound having biphasic solubility is a sodium channel blocker, an anti-epileptic compound, or an anti-convulsant compound.

Another embodiment of the invention fearures a transdermal composition which includes an amine-containing compound as described herein and an anti-inflammatory compound, such as a nonsteroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx®, and combinations thereof. Such a composition can further include an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant such as guaifenesin. —

In another aspect, the invention features a transdermal composition for the ‘ ) treatment of pain in a subject including an amine containing compound having biphasic ] solubility in an amount effective to treat pain in a subject; a muscle relaxant in an ’ amount effective to enhance the activity of the amine containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal ; delivery of the amine containing compound having biphasic solubility and the muscle vr relaxant. : - .

In yet another aspect, the invention features a transdermal composition for the TT treatment of pain in a subject including doxepin in an amount effective to treat pain in a n : 10 subject; guaifenesin in an amount effective to enhance the activity of doxepin; and a EE pharmaceutically acceptable carrier suitable for transdermal delivery of the doxepin and the guaifenesin. LT * Other aspects of the invention feature methods for treating pain in a subjectin ~~ +. which the subject is contacted with a transdermal composition including an amine CL EY containing compound having biphasic solubility in an amount effective to treat painin . .. FE the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery EE a - of the amine containing compound to thereby treat pain in the subject. In a preferred © a

B + embodiment, the transdermal composition is applied to the skin of the subject. CL " Eo . © Another aspect of the invention features a method for selecting a compound ~~ &

EXE ~~ 20. suitable for treating pain in a subject. The method includes transdermally administering . PET

BO . ‘an amine containing compound having biphasic solubility to a subject; and determining", Ce

AA whether pain is treated in the subject to thereby select a compound suitable for treating Co - SE pain in a subject. In a preferred embodiment, the method can further include modeling ~~ 5 iS

BC the compound using a computer equipped with a three-dimensional chemical structure. 1. - 25 modeling program; and determining whether the three-dimensional chemical structure of ~~. the compound possesses sufficient characteristics to be useful as a sodium channel |. CL blocker, thereby selecting a compound suitable for treating pain in a subject. Cy : In another aspect, the invention features a transdermal composition suitable for. ~~ . "transdermal delivery, which includes a therapeutically effective amount of a : Co © 30 pharmaceutical compound-(e.g., a serotonin specific reuptake inhibitor, a mood : oo stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and © akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the : pharmaceutical compound, e.g., a lecithin organogel carrier. .

In yet another aspect, the invention features a transdermal composition for treatment of pain in a subject which includes a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a N subject; and a pharmaceutically acceptable catrier suitable for transdermal delivery of

Co the compound. . Ce a oo 7 . Other features and advantages of the invention will be apparent from the following detailed description and claims. }

Brief Description Of The Drawings .

Figure 1 is an evaluation form used in evaluating an embodiment of the present invention. ° Figure 2 is a table depicting the results from clinical experiments using compositions of the invention.

Detailed Description Of The Invention ” The present invention provides a transdermal composition suitable for treatment “of pain in a subject. The transdermal composition includes an amine containing ) ‘compound having biphasic solubility in an amount effective to treat pain in a subject; “and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine “containing compound having biphasic solubility.

Bh As used herein, the term “subject” includes a mammal, such as a human, a horse, ’ 20 “a pig, a cow, a mouse, a rat, a rabbit, or a goat. In preferred embodiment, the subject is a human.

As used herein, the term “pain” is art recognized and includes a bodily sensation elicited by noxious chemical, mechanical, or thermal stimuli, in a subject, e.g., a mammal such as a human. The term “pain” includes chronic pain, such as lower back pain; pain due to arthritis, e.g., osteoarthritis; joint pain, e.g., knee pain or carpal tunnel syndrome; myofascial pain, and neuropathic pain. The term “pain” further includes acute pain, such as pain associated with muscle strains and sprains; tooth pain; headaches; pain associated with surgery; or pain associated with various forms of tissue injury, e.g., inflammation, infection, and ischemia.

As used herein, the term “amine containing compound having biphasic solubility” includes compounds having at least one amine moiety and having sufficient lipid solubility (e.g., solubility in polar solvents such as ethanol, ethoxydiglycerol, ethoxydiglycol, chloroform, benzene, and the like) such that the compound passes through the stratum corneum, and has sufficient aqueous solubility to be active in the aqueous environment of the dermis and the underlying tissue.

Transdermal compositions of the present invention include an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject. +

\ : . TT WO 00/00120 © PCT/US99/14653

As used herein, the terms “amount effective to treat pain in a subject” and "effective : . amount" are used interchangeably herein and include an amount effective, at dosages ) Bh and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat : pain in a subject. An effective amount of an amine containing compound or a pharmaceutical compound as defined herein may vary according to factors such as the : disease state, age, and weight of the subject, and the ability of the amine containing compound or pharmaceutical compound to elicit a desired response in the subject. .

Dosage regimens may be adjusted to provide the optimum therapeutic response. An oT effective amount is also one in which any toxic or detrimental effects of the amine | : containing compound having biphasic solubility or pharmaceutical compound are oo outweighed by the therapeutically beneficial effects. a

The transdermal compositions of the invention can further include an agent is EE . : which enhances the activity of the amine containing compound having biphasic a : solubility. As used herein, an “agent which enhances the activity of the amine =. _- EE Ol containing compound having biphasic solubility” includes an agent which enhances the . E pharmacological activity of the amine containing compound having biphasic solubility FF : (e.g., the ability of the amine containing compound to treat pain), or enhances the oo ER i .

SE transdermal delivery of the amine containing compound having biphasic solubility (e.g., .. ~~ - % oo the ability of the amine containing compound to cross the stratum corneum), or... io © 20- enhances both the pharmacological activity and the transdermal delivery of the amine .... —. Co

N containing compound. Examples of agents which enhance the activity of the amine =. . Co IEE i containing compound having biphasic solubility, include muscle relaxants, described in . =; further detail below. Co Ey : As used herein, the term “transdermal” composition includes compositions . oo o 25 capable of passing through the stratum corneum of a subject. The term transdermal - . NE further includes compositions capable of passing through the epidermis of a subject,. =~ . = - compositions capable of passing through the dermis of a subject, and compositions TRE ~~ capable of passing through the hypodermis of a subject. In preferred embodiments, the IER : "term transdermal includes compositions capable of passing through the skin of a subject and reaching the underlying tissues and organs. :

As used herein, the term “transdermal delivery” includes delivery of, for : example, a compound through the stratum corneum of a subject. The term transdermal delivery further includes delivery of, for example, a compound through the epidermis of a subject, delivery of, for example, a compound through the dermis of a subject, and E Co delivery of, for example, a compound through the hypodermis of a subject. In preferred embodiments, the term transdermal delivery includes delivery of, for example, a Co : compound through the skin of a subject to the underlying tissues and organs. Cl

© WO 00/0120 PCT/USIOIAESS ~The present invention further features a transdermal composition for treatment of ) pain in a subject which includes a compound capable of blocking afferent neuron ’ i transmission in an amount effective to block afferent neuron transmission in a subject; : and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.

Co As used herein, the term “compound capable of blocking afferent neuron * transmission” includes a compound which is capable of blocking the ability of an = - afferent neuron, i.e., a sensory neuron, to carry an impulse toward the central nervous system. : 10

Various aspects of the invention are described in further detail in the following subsections: . . Amine Containing Compounds Having Biphasic Solubility = Amine containing compounds having biphasic solubility for use in the - transdermal compositions of the invention include antidepressant compounds, : - antiepileptic compounds, anticonvulsant compounds, and sodium channel blockers. : As used herein, the term “antidepressant compounds” includes compounds capable of alleviating the symptoms of depression. Examples of antidepressant compounds include : 20 - all tricyclic antidepressants (e.g., amitriptyline, dothiepin, or lofepramine), bupropion ~ (sold under the trade name Wellbutrin), reboxetine (sold under the trade name Edronax), nefazodone (sold under the trade name Serzone) and trazodone (sold under the trade name Desyrel). Antidepressant compounds are described in, for example, the 1998

SIGMA catalogue and the "The Merck Index”, 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, the contents of which are incorporated herein by reference.

In one embodiment of the present invention, the antidepressant compounds of the present invention contain a tricyclic moiety. Therefore, in a preferred embodiment, a transdermal composition of the present invention includes a tricyclic antidepressant compounds. Exemplary tricyclic antidepressants include adinazolam, amitriptylinoxide, amoxapine, clomipramine, demexiptiline, dimetacrine, dothiepin, doxepin, imipramine

N-oxide, iprindole, lofepramine, melitracen, metapramine, noxiptilin, pizotyline, propizepine, quinupramine, tianeptine, and trimipramine. A particularly preferred tricyclic antidepressant for use in the compositions of the invention is doxepin.

Tricyclic antidepressant compounds are described in, for example, “Guide to

Clinical Neurology” by J.P. Mohr et al.(Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

7 WO 00/00120 © PCT/US99/14653 -

Preferably, the tricyclic antidepressant compound is selected from the group consisting of doxepin, trimipramine, other tricyclics having biphasic solubility, and } combinations thereof. When combined with other compounds, such as an agent which enhances the activity of the amine containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound, as : discussed below, the tricyclic antidepressant preferably constitutes from about 1 % by : weight (% by wt.) to about 30 % by wt. of the total amount of the pharmaceutical, more - preferably from about 3 % by wt;. to about 15 % by wt., and most preferably from about : = 5 % by wt. to about 13 % by wt.

The amine containing compounds having biphasic solubility used in the transdermal compositions of the invention further include antiepileptic compounds. As N used herein, the term “antiepileptic compound” includes compounds capable of : alleviating the symptoms of epilepsy. Exemplary antiepileptic compounds for use in the oe N "compounds of the invention include lamotrigine, felbamate, and carbamazepine. [ER

Preferably, the anticpileptic compound is selected from the group consisting of = - To Sa lamotrigine, felbamate, carbamazepine, and combinations thereof. When combined with oo other compounds, such as an agent which enhances the activity of the amine containing Co compound, e.g.,a muscle relaxant, and/or an anti-inflammatory compound, e.g., a Ce "nonsteroidal anti-inflammatory compound as discussed below, the antiepileptic... pl Ce 20° compound constitutes from about 1 % by wt. to about 30 % by wt: of the total amount of, . "the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt. and .- most preferably from about 5 % by wt. to about 15 % by wt. Antiepileptic compounds - - CL are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h.. | BE + Ed. Budavari et al., eds., Merck & Co, Inc., Rahway, N.J., 1996, and the “Guide to, - = = [*

Clinical Neurology” by J.P. Mohr et al. (Churchill Livingstone, 1995) the contents of ~~. ) : which are incorporated herein by reference. SRT SP Co

In another aspect of the present invention, the amine containing compounds oo CL having biphasic solubility of the present invention include anticonvulsant compounds. . EER "As used herein, the term “anticonvulsant compound” includes compounds capable of - alleviating the symptoms of convulsion, i.e., the violent involuntary tetanic contractions: - : Lo "of an entire group of muscles. Exemplary anticonvulsant compounds which forusein . the compositions of the invention include felbamate, lamotrigine and carbamazepine.

Preferably, the anticonvulsant compound is selected from the group consisting of SEE felbamate, lamotrigine, and combinations thereof. When combined with other Co compounds, such as an agent ‘which enhances the activity of the amine containing . oo compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a: nonsteroidal anti-inflammatory compound as discussed below, the anticonvulsant compound constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of :

© WO 00/00120 PCT/US99/14653 i , the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most preferably from about 5 % by wt. to about 15 % by wt. Anticonvulsant . compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck .

Index", 12t:h Ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J.,, 1996, and the

S “Guide to Clinical Neurology” by J.P. Mohr ef al.(Churchill Livingstone, 1995) the “contents of which are incorporated herein by reference.

In yet another aspect of the present invention, the amine containing compounds ~ having biphasic solubility of the present invention include adrenergic agonist ~compounds. Preferably, the adrenergic agonist compound is tizanidine. When : 10 .combined with other compounds, such as a muscle relaxant and/or nonsteroidal anti-inflammatory compound as discussed below, the adrenergic agonist compound constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 20 % by wt., and most - preferably from about 5 % by wt. to about 15 % by wt. Adrenergic agonist compounds are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h 'Ed., Budavari et al., eds., Merck & Co., Inc, Rahway, N.J., 1996, and the “Guide to «Clinical Neurology” by J.P. Mohr ez al.(Churchill Livingstone, 1995) the contents of which are incorporated herein by reference. . The amine containing compounds having biphasic solubility used in the transdermal compositions of the invention further include sodium channel blockers. As used herein, the term “sodium channel blockers includes compounds which are capable of blocking the activity of a sodium channel. Examples of sodium channel blockers include tetrodoxin, flecainide, disopyramide, and terfenadine. Sodium channel blockers are described in, for example, the 1998 SIGMA catalogue, the "The Merck

Index", 12t:h Ed., Budavari et al., eds., Merck & Co, Inc., Rahway, N.J., 1996, and the “Guide to Clinical Neurology” by J.P. Mohr ef al.(Churchill Livingstone, 1995) the contents of which are incorporated herein by reference. .

Whenever nerves are damaged, for example, by trauma, by diseases such as diabetes, herpes zoster, or late-stage cancer, or by chemical injury (e.g, as an untoward consequence of agents including the false-nucleoside anti-HIV pharmaceuticals), neural pain circuits rewire themselves, anatomically and/or biochemically. Thus, following an injury, new sodium channels are formed which is believed to constitute the basis for chronic pain development. Through a similar action in the dorsal root ganglia, chronic regional pain syndromes may develop. Each time one of these sodium channels depolarizes, a nerve impulse originates. Because there are so many sodium channels, there may be a constant cascade of nerve impulses, causing allodynia, burning sensations, and/or dysesthesias. It is believed that some chronic pains may be mediated through sodium channels in nerve cells. Thus, it is believed that amine containing

. . 7 ‘Wo 00/00120 © PCT/US99/14653 compounds having biphasic solubility which can block sodium channels may also be ; ) used in the transdermal compositions of the invention. So Co ]

In one embodiment of the invention, the-amine moicty of the amine containing : compounds having biphasic solubility of the present invention may function similar to a N sodium ion upon entry into the sodium channel of a nerve cell membrane: A non-polar . : moiety, which is preferably present in the amine containing compound having biphasic solubility of the present invention may interact with the nerve cell membrane, perhaps - through Van der Waals forces. In such cases, it is believed that the presence of the. oo non-polar moiety prevents or inhibits a complete uptake of the amine containing compound having biphasic solubility through the nerve cell membrane. It is believed “ that one or more these interactions prevent or reduce the amount and/or the rate of g depolarization and ion exchange involved in stimulus conduction, thereby decreasing o - pain sensation. ’ "The amount of an amine containing compound having biphasic solubility useful . : A ; in relieving pain transdermally may be determined by methods known in the art, and RN - : typically ranges from about 1 mg to about 300 mg per subject per dose, preferably from h oo about 5 mg to about 100 mg per subject per dose, and:more preferably from about 10 mg J . to about 50 mg per subject per dose, depending on a variety of factors including the aE : . particular amine containing compound having biphasic solubility used, whether the area ER : : 20 of transdermal application is the site of action, and the intended size'of the-site of action... ol . . & foo In a preferred embodiment, the amount of an amine containing compound having. .. UE biphasic solubility useful in relieving pain transdermally, is 5, 10, 15, 20, 25, 30, 35, 40, Ce eo 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, 150 mg, 200 mg, 250 mg, or 300mg - : per subject per dose. Co Ce = i 25 . | N in } 0 Muscle Relaxants . Co

Transdermal compositions of the present invention may also include a muscle relaxant. As used herein, the term “muscle relaxant” includes compounds which J RB “facilitate or enhance the relaxation of muscles (e.g., provide relief from muscle spasm) “and, thus, facilitate or enhance the transdermal delivery of the transdermal compositions- : : * of the invention. Exemplary muscle relaxants include both skeletal muscle relaxants and smooth muscle relaxants such as anticholinergics, antispasmodics, bronchodilators, and Co vasodilators. Muscle relaxants are described in, for example, the 1998 SIGMA catalogue, the "The Merck Index", 12t:h Ed., Budavari er al., eds., Merck & Co., Inc.,

Rahway, N.J., 1996, pp. THER-1 to THER-28, and the “Guide to Clinical Neurology” by J.P. Mohr ef al.(Churchill Livingstone, 1995) the contents of which are incorporated herein by reference. Preferably, the muscle relaxant is selected from the group : consisting of guaifenesin, benzodiazepines (e.g., clozapine or diazopam),

CT WO 00/00120 PCT/US99/14653 ‘ chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, other muscle relaxants k having biphasic solubility, and combinations thereof. More preferably, the muscle oo relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, and : ) - . combinations thereof. A preferred muscle relaxant for use in the compositions of the invention is guaifenesin. oe Preferably the muscle relaxant has biphasic solubility. Preferably the muscle » relaxant, when present in the pharmaceutical composition, constitutes from about 1 % ~ by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably ~from about 3 % by wt. to about 20% by wt., and most preferably from about 5 % by wt. 10 .-to about 15 % by wt.

Anti-Inflammatory Compounds

The transdermal compositions of the present invention may also include an _anti-inflammatory compound. As used herein, the term “anti-inflammatory compound” . 15 includes a compound which is capable of reducing cell migration, caused by ischemic and trauma associated events, and therefore reduces edema formation to thereby provide : pain relief. Preferably, the anti-inflammatory compound is a nonsteroidal : anti-inflammatory compound (i. e., NTHE) including ketoprofen. Anti-inflammatory compounds, e.g., NTHEs, are described in, for example, the 1998 SIGMA catalogue, the : 20 "The Merck Index". 12t:h Ed., Budavari er al., eds., Merck & Co., Inc., Rahway, N.J,, 1996, pp. THER-1 to THER-28, and the “Guide to Clinical Ncurology” by J.P. Mohr er al.(Churchill Livingstone, 1995) the contents of which are incorporated herein by reference. Preferably, the NTHE is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx®, COX-2 NTHEs having biphasic solubility, and combinations thereof.

More preferably, the NTHE is selected from the group consisting of celecoxib, etodolac, naproxen, COX-2 NTHEs having biphasic solubility, and combinations thereof. Preferably, the NTHE has biphasic solubility. The NTHE, when present in the transdermal composition, preferably, constitutes from about 1 % by wt. to about 30 % by wt. of the total amount of the pharmaceutical, more preferably from about 3 % by wt. to about 30 % by wt., and most preferably from about 5 % by wt. to about 30 % by wt.

Dosages

The concentration as well as the quantity of the amine containing compounds having biphasic solubility, the agents which enhance the activity of the amine containing compounds, ¢.g., the muscle relaxants, and the anti-inflammatory compounds can be varied independently in order to achieve the desired effect. For example, higher concentrations of the amine containing compounds having biphasic solubility, the

" : “ 7 WO 00/00120 PCT/US99/14653 : muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of : . decreased viscosity may result in an analgesic with fast onset and short duration. High ) concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of increased viscosity may result in potent analgesic with fast-onset and long duration. . "Low concentrations of the amine containing compounds having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds in‘a‘dosage form'of decreased a x viscosity may result in mild analgesic with longer onset and short duration. Low - concentrations of the amine containing compounds having biphasic solubility, the ©. 10 muscle relaxants, and the anti-inflammatory compounds contained in a dosage form of Co } oe increased viscosity may have mild analgesic properties with longer onset and longer oo duration. The ability to vary the concentration of the amine containing compounds ETRE "having biphasic solubility, the muscle relaxants, and the anti-inflammatory compounds oo : : "from very low to high of the total composition, combined with the ability to coat thin : (about 0.1 mm) or thick (about 0.5 mm) enables the practitioner of the invention to vary : Co ~ : the dosage of the system as needed for particular level of pain and anatomical sites of : oo . interest. It should be appreciated, however, that onset time as well as duration of © : Co : } analgesic effect of the transdermal composition of the present invention will vary from ~~... . subject to subject as well as on the basis of the site of application, and properties of the Le a : ' 20 amine containing compounds having biphasic solubility, the muscle relaxants, and the < Co i i “anti-inflammatory compounds. SH - : SEE Co : | . - ‘Generally, the concentration of the amine containing compounds having biphasic . .. . : | So “solubility, the muscle relaxants, and the anti-inflammatory compounds can range, ona. “ : ‘weight basis, from about 1 % to about 30 % of the total composition, preferably from ee ! } : 25 about 3 % to about 20 %, and more preferably from about 5 % to about 15%. = © ©. .

Lo _ Pharmaceutically Acceptable Carriers Co a oo "The transdermal compositions of the present invention also includes a- — : . : pharmaceutically acceptable carrier which is capable of transdermal delivery of the amine containing compound having biphasic solubility. As used herein, the term Eu } Co . ) “pharmaceutically acceptable carrier suitable for transdermal delivery” includes a carrier ] capable of delivering the amine containing compound transdermally as defined above. oo ) Suitable carriers for transdermal delivery of pharmaceuticals are described in U.S. oo

Patent No. 5,446,070, the contents of which are incorporated herein by reference. : 35 Briefly, pharmaceutically acceptable carriers of the present invention include any - : : suitable finite (i. e, solid) or non-finite (i. e., non-solid, such as liquid or semi-liquid) : carrier including liquids, semi-liquids or solid carriers, such as a bioadhesive. Thus, the amine containing compounds having biphasic solubility may be admixed with a : | SERS a.

pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, salve, paste, ) plaster, ointment, spray solution, or any other "non-finite" carrier known in the art of Co pharmaceutical delivery. For example, the base of a non-finite carrier may be lipid : including phospholipids such as lecithins; fatty oils; lanolin; vasoline; paraffins; glycols; higher fatty acids; and higher alcohols. : : The term "bioadhesive" as used herein includes an adhesive which attaches to a - biological surface such as skin or mucosal tissue. Preferably, the bioadhesive of the = present invention is self-adhesive in that it attaches to the site of interest without the need to reinforce its attachment by way of another adhesive. Suitable bioadhesive = include natural or synthetic polysaccharides such as cellulose derivatives including ~ methylcellulose, cellulose acetate, carboxymethylcellulose, hydroxyethylcellulose and the like; pectin; a mixture of sulfated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums including natural plant exudates, such as karaya gum, ghatti gum, tragacanth gum, xanthan gum, jaraya gum and the like; seed gums including guar gum, . 15 .z locust bean gum, psillium seed gum and the like; and lecithins such as soya jecithin. .+ In addition to the above ingredients, compositions of the present invention may also : += include other ingredients such as various pharmaceutically acceptable additives : available to those skilled in the art. These additives include binders, stabilizers, ~ preservatives, flavorings, fragrances, and pigments. : 20 = -In another embodiment, the pharmaceutically acceptable carrier of the present z invention includes van pen cream (cetyl alcohol, stearyl alcohol, steric acid, gllycerol monosterate, isopropyl myristate, soya lecithin, BHT alcohol 95%, simethicone, sodium hydroxide 30% solution, polyoxyl stearate, edetate disodium 5%, purified water, urea).

Other Pharmaceutical Compounds "In another aspect, the invention features a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (e.g., a serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for treating attention deficit hyperactivity disorder, a compound suitable for treating hypertension and akathisia, an analgesic compound, or a compound used in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound.

As used herein, the term “pharmaceutical compound” includes compounds suitable for treating a targeted condition and capable of being delivered in active form, in vivo. Examples of pharmaceuticals include drugs, enzymes, chemical compounds, combinations of chemical compounds, biological macromolecules and analogs thereof.

Examples of pharmaceutical compounds are described in detail below.

Claims

WHAT IS CLAIMED IS:

1. A transdermal composition for treatment of pain in a subject comprising: (a) an amine containing compound having biphasic solubility in an 5S amount effective to treat pain in a subject; and (b) apharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound. ~

2. The transdermal composition of claim 1, further comprising an agent which enhances the activity of the amine containing compound having biphasic solubility.

3. The transdermal composition of claim 2, wherein the agent which enhances the activity of the amine containing compound having biphasic solubility is a muscle relaxant.

4, The transdermal composition of claim 1, wherein the amine containing : compound is an antidepressant compound.

5. The transdermal composition of claim 4, wherein the antidepressant compound is a tricyclic antidepressant compound.

: 6. The transdermal composition of claim 1, wherein the amine containing compound is doxepin. :

CT. The transdermal composition of claim 1, wherein the amine containing compound is trimipramine.

8. The transdermal composition of claim 1, wherein the amine containing compound is a sodium channel blocker.

9. The transdermal composition of claim 1, wherein the pharmaceutically acceptable carrier is a lecithin organogel.

10. The transdermal composition of claim 3, wherein the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.

B WO 00/00120 PCT/US99/14653 ‘

11. The transdermal composition of claim 10, wherein the muscle relaxant is guaifenesin. Co

. .

12. The transdermal composition of claim 3, wherein the muscle relaxant is a ~ 5 benzodiazepine.

- . ag

13. The transdermal composition of claim 12, wherein the benzodiazepineis clozapine. - 10 =

14. The transdermal composition of claim 12, wherein the benzodiazepine . -is diazopam.

15. The transdermal composition of claim 1, further comprising an - _anti-inflammatory compound.

16. The transdermal composition of claim 15, wherein the anti-inflammatory w scompound is a nonsteroidal anti-inflammatory compound.

17. The transdermal composition of claim 16, wherein the nonsteroidal z 20 anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx®, and combinations thereof.

18. A transdermal composition for treatment of pain in a subject comprising: (a) an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; (b) a muscle relaxant in an amount effective to enhance the activity of the amine containing compound having biphasic solubility; and (c) a pharmaceutically acceptable carrier suitable for transdermal ’ 30 delivery of the amine containing compound and the muscle relaxant.

19. The transdermal composition of claim 18, wherein the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.

20. The transdermal composition of claim 18, wherein the muscle relaxant is guaifenesin.

21. The transdermal composition of claim 18, wherein the muscle relaxant has biphasic solubility.

22. The transdermal composition of claim 18, wherein the amine containing compound is an antidepressant compound. :

23. The transdermal composition of claim 22, wherein the antidepressant ~ compound is a tricyclic antidepressant compound.

24. The transdermal composition of claim 22, wherein the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and combinations thereof.

25. The transdermal composition of claim 18, wherein the amine containing compound is doxepin.

26. The transdermal composition of claim 18, wherein the amine containing compound is a sodium channel blocker.

27. The transdermal composition of claim 18, wherein the pharmaceutically acceptable carrier is a lecithin organogel.

28. The transdermal composition of claim 18, further comprising an anti-inflammatory compound.

29. The transdermal composition of claim 28, wherein the anti-inflammatory compound is a nonsteroidal anti-inflammatory compound.

30. The transdermal composition of claim 29, wherein the nonsteroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx®, and combinations thereof.

31. A transdermal composition for treating pain in a subject comprising: (a) doxepin in an amount effective to treat pain in a subject; (b) guaifenesin in an amount effective to enhance the activity of doxepin; and

32. The transdermal composition of claim 31, wherein the pharmaceutically acceptable carrier is a lecithin organogel.

33. The transdermal composition of claim 31, further comprising an anti- inflammatory compound.

34. The use of a transdermal composition comprising: (a) an amine containing compound having biphasic solubility in an amount effective to treat pain in a subject; and (b) a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine containing compound, in the manufacture of a medicament for use in a method of treating pain in a subject.

35. The use of claim 34, wherein the transdermal composition further comprises an agent which enhances the activity of the amine containing compound having biphasic solubility.

36. The use of claim 35, wherein the agent which enhances the activity of the amine containing compound having biphasic solubility is a muscle relaxant.

37. The use of claim 34, wherein the amine containing compound is an antidepressant compound.

38. The use of claim 37, wherein the antidepressant compound is a tricyclic antidepressant compound.

39. The use of claim 37, wherein the antidepressant coumpound is selected from the group consisting of doxepin, trimipramine, and combinations thereof.

40. The use of claim 37, wherein the antidepressant compound is doxepin.

41. The use of claim 34, wherein the amine containing compound is a sodium channel blocker. 54 AMENDED SHEET —- DATED 31 JANUARY 2002

42. The use of claim 34, wherein the pharmaceutically acceptable carrier is a lecithin organogel.

43. The use of claim 36, wherein the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof.

44. The use of claim 43, wherein the muscle relaxant is guaifenesin.

45. The use of claim 36, wherein the muscle relaxant is a benzodiazepine.

46. The use of claim 45, wherein the benzodiazepine is clozapine.

47. The use of claim 45, wherein the benzodiazepine is diazopam.

48. The use of claim 34, wherein the transdermal composition further comprises an anti-inflammatory compound.

49. The use of claim 48, wherein the anti-inflammatory compound is a nonsteroidal anti-inflammatory compound.

50. The use of claim 49, wherein the nonsteroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx®, and combinations thereof.

51. A method for selecting a compound suitable for treating pain in a subject comprising: (a) transdermally administering an amine containing compound having biphasic solubility to a subject; and (b) detecting whether pain is treated in the subject to thereby select a compound suitable for treating pain in a subject.

52. A transdermal composition for treatment of pain in a subject comprising: (a) a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and (b) a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound. 55 AMENDED SHEET - DATED 31 JANUARY 2002

53. The transdermal composition of claim 52, further comprising an agent which enhances the activity of the compound suitable for blocking afferent neuron transmission.

54. A transdermal composition comprising a psychopharmaceutical and guaifenesin in an amount effective to treat pain, and lecithin organogel.

55. The composition of claim 54, wherein said psychopharmaceutical is selected from the group consisting of sertraline, fluoxetine, carbamazepine, amitriptyline, trazodone, fluvoxamine, pemoline, pergolide, bromocriptine mesylate, propranolol, buproprion, reboxetine, valproic acid, nefazodone and doxepin.

56. The composition of claim 54, wherein said psychopharmaceutical is doxepin.

57. A transdermal composition comprising doxepin and guaifenesin in an amount effective to treat pain, and lecithin organogel.

58. The composition of claim 57, further comprising Pluronic F127. N

59. A transdermal composition comprising doxepin and guaifenesin in an amount effective to treat pain, Pluronic F127, and lecithin organogel. .

60. The composition of any one of claims 54, 57, or 59, comprising about wt % doxepin.

61. The composition of any one of claims 54, 57, or 59, comprising about wt % guaifenesin. :

62. The composition of any one of claims 54, 57, or 59, comprising about : 5 wt % doxepin and about 10 wt % guaifenesin.

63. A transdermal composition suitable for treating pain comprising about 5 wt % doxepin, about 10 wt % guaifenesin, and lecithin organogel. 56 AMENDED SHEET 11/06/2002

64. A transdermal composition suitable for treating pain comprising about wt % doxepin, about 10 wt % guaifenesin, Pluronic F127, and lecithin organogel.

65. A transdermal composition according to claim ! substantially as herein described with reference to any one of the illustrative Examples. 57 AMENDED SHEET 11/06/2002