CZ20004823A3 - Methods and Transdermal Agents for Pain Relief - Google Patents

Abstract

One embodiment relates to methods and compositions for transdermally administering an amine-containing compound having a biphasic solubility and / or agents that enhance the activity of an amine-containing compound, e.g., a myorelaxant, for pain relief.

Description

Technical field

The present invention relates to methods and compositions for transdermal administration. More particularly, the present invention relates to methods and compositions for transdermal administration of an amine-containing compound having biphasic solubility and/or an agent that enhances the activity of an amine-containing compound with biphasic solubility, e.g., a muscle relaxant, for alleviating pain.

State of the art

Damage to somatic sensory nerves is thought to cause loss of somatic sensation. Such damage can be caused by a variety of causes, including trauma, diseases such as diabetes, herpes zoster, and advanced cancer, chemotherapy, or chemical damage. It is thought that neural pain pathways become interconnected, both anatomically and biochemically, after nerve injury. In many patients with somatic sensory nerve injury, negative symptoms, such as decreased sensation, are associated with positive sensations, including a false sense of pain. This can range from mild dysesthesia to excruciating pain that prevents patients from working, walking, and other daily activities.

Recently, patients have been routinely treated with analgesics for pain relief. The vast majority of such patients receive these agents orally. Unfortunately, in some situations, oral administration is associated with various side effects such as liver damage, kidney damage, gastrointestinal side effects, habituation, sedation, and/or weight gain, which may not be well tolerated by the patient. In other cases, malabsorption of oral agents results in subtherapeutic plasma concentrations. In other cases, the agents have relatively short plasma half-lives, requiring inconveniently frequent dosing. A common feature of oral administration is a delay in onset of action because the analgesic is absorbed through the digestive system before reaching the circulation. Many of the agents that are traditionally administered orally or by injection are inconvenient or suboptimal for patients when administered in this manner. There are many medications that are not well tolerated by oral administration, at least in some patients (for example, they cause undesirable gastrointestinal or other side effects) and/or cause undesirably high or low concentrations in target tissues or such concentrations are delayed. In some cases, the dose that is suitable for oral administration, after more or less uneven distribution in the body, is too low in a particular area, for example a tissue, to achieve the desired results. Oral or injectable administration may lead to a rise in plasma concentration that is too slow or too rapid, for example, an undesirable delay in the onset of action because the analgesic is absorbed through the digestive system before reaching the circulation, or a peak in plasma concentration followed by an undesirable decrease to a concentration that is too low in a situation where a more constant concentration is desired. Some analgesics are more likely than others to cause liver or kidney damage when administered orally.

Although other forms of administration of pharmaceutical agents are known, each has its own disadvantages. Parenteral (i.e., intravenous or intramuscular injection) administration is inconvenient and expensive and is rarely used outside of the hospital. Inhalation is considered unsuitable for many currently used analgesics. Therefore, there is a need for an analgesic delivery system that delivers effective and acceptable concentrations without or with reduced adverse effects such as liver damage or gastrointestinal side effects.

The essence of the invention

The present invention provides a transdermal composition for the treatment of pain in a subject, particularly in a human subject. The transdermal composition for the treatment of pain in a subject comprises an amine-containing compound having biphasic solubility in an amount effective to treat pain in the subject and a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound, for example a lecithin organogel carrier. In a preferred embodiment, the transdermal composition further comprises an agent enhancing the activity of the amine-containing compound having biphasic solubility, for example a muscle relaxant such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol and combinations thereof. Preferably, the agent enhancing the activity of the amine-containing compound having biphasic solubility, for example a muscle relaxant, also has 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, for example, doxepin or trimipramine.

In another embodiment of the present invention, the biphasic solubility amine-containing compound is a sodium channel blocker, an antiepileptic compound, or an anticonvulsant compound.

• « • · · · • *

Another embodiment of the present invention relates to a transdermal composition comprising an amine-containing compound as described herein and an anti-inflammatory compound, such as a nonsteroidal anti-inflammatory compound, such as celecoxib, etociolac, mefanamic acid, nabumetone, salsalate, naproxen, vioxx3> and combinations thereof. Such composition may further comprise an agent enhancing the activity of the amine-containing compound, for example a muscle relaxant such as guaifenesin.

In another aspect, the invention relates to a transdermal composition for treating pain in a subject, comprising a compound comprising a biphasic amine in an amount effective to treat pain in the subject; a muscle relaxant in an amount effective to enhance the activity of the compound comprising a biphasic amine; and a pharmaceutically acceptable carrier suitable for transdermal administration of the compound comprising a biphasic amine and the muscle relaxant.

In another aspect, the invention relates to a transdermal composition for treating pain in a subject, comprising doxepin in an amount effective to treat pain in the subject; guaifenesin in an amount effective to enhance the activity of doxepin; and a pharmaceutically acceptable carrier suitable for transdermal administration of doxepin and guaifenesin.

Other aspects of the invention relate to methods for treating pain in a subject, wherein the subject is contacted with a transdermal composition comprising an amine-containing compound with biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound, resulting in treatment of pain in the subject. In a preferred embodiment, the transdermal composition is applied to the skin of the subject.

• · ·

In another aspect, the invention relates to a method for selecting a compound suitable for treating pain in a subject. The method comprises transdermally administering a compound comprising an amine with biphasic solubility to the subject; and determining whether the subject is suffering from pain, and accordingly, a compound suitable for treating pain in the subject can be selected. In a preferred embodiment, the method may further comprise modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program; and determining whether the three-dimensional chemical structure of the compound has satisfactory characteristics for use as a sodium channel blocker, thereby enabling the selection of a compound suitable for treating pain in the subject.

In another aspect, the invention relates to a transdermal composition suitable for transdermal administration, comprising a therapeutically effective amount of a pharmaceutical compound (e.g., a specific serotonin reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for the treatment of attention deficit hyperactivity disorder, a compound suitable for the treatment of hypertension and akathisia, an analgesic compound, or a compound suitable for the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal administration of the pharmaceutical compound, e.g., a lecithin organogel carrier.

In another aspect, the invention relates to a transdermal composition for treating pain in a subject, comprising a compound capable of blocking afferent neuronal transmission in an amount effective to block afferent neuronal transmission in the subject; and a pharmaceutically acceptable carrier suitable for transdermal administration of the compound.

• · · ·

Other features and advantages of the present invention will become apparent from the following detailed description and the appended claims.

Description of images in the attached drawings

Fig. 1 is a form used to evaluate the implementation of the present invention.

Fig. 2 is a table showing results from clinical trials using the compositions of the present invention.

Detailed description of the invention

The present invention provides a transdermal composition suitable for treating pain in a subject. The transdermal composition comprises an amine-containing compound having biphasic solubility in an amount effective for treating pain in a subject; a. a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound having biphasic solubility.

The term individual, as used herein, refers to a mammal, such as a human, horse, pig, cow, mouse, rat, rabbit, or goat. In a preferred embodiment, the individual is a human.

The term pain, as used herein, is known in the art and refers to the sensations induced in an individual, e.g., a mammal such as a human, by noxious chemical, mechanical, or thermal stimuli. The term pain includes chronic pain, such as low 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 a muscle strain or sprain; toothache; headache; pain associated with surgery; or pain associated with various forms of tissue damage, such as inflammation, infection, and ischemia.

The term amine-containing compound having biphasic solubility, as used herein, refers to compounds containing at least one amine group and having sufficient lipid solubility (e.g., solubility in polar solvents such as ethanol, ethoxydiglycerol, ethoxydiglycol, chloroform, benzene, and the like) to penetrate the stratum corneum, and having sufficient water solubility to be active in the aqueous environment of the dermis and deeper tissues.

The transdermal compositions of the present invention comprise an amine-containing compound having biphasic solubility in an amount effective for treating pain in a subject. The terms an amount effective for treating pain in a subject and an effective amount are interchangeable and refer to an amount effective, at dosages and for a period of time necessary, to achieve the desired effect, e.g., sufficient to treat pain. An effective amount of an amine-containing compound or pharmaceutical compound, as defined herein, may vary depending on factors such as the stage of the disease, the age and weight of the subject, and the ability of the amine-containing compound or pharmaceutical compound to elicit the desired response in the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response. An effective amount is also that amount at which any toxic or deleterious effects of the amine-containing compound having biphasic solubility or pharmaceutical compound are outweighed by the therapeutically beneficial effects.

The transdermal compositions of the present invention may further comprise an agent enhancing the activity of the amine-containing compound having biphasic solubility. The term "agent enhancing the activity of the amine-containing compound having biphasic solubility", as used herein, refers to an agent that enhances the pharmacological activity of the amine-containing compound having biphasic solubility (e.g., the ability of the amine-containing compound to act as an analgesic), or that enhances the transdermal penetration of the amine-containing compound having biphasic solubility (e.g., the ability of the amine-containing compound to penetrate the stratum corneum), or that enhances both the pharmacological activity and the transdermal penetration of the amine-containing compound. Examples of agents enhancing the activity of the amine-containing compound having biphasic solubility are muscle relaxants, as described in more detail below.

The term transdermal means refers to means capable of penetrating the stratum corneum of an individual. The term transdermal further refers to means capable of penetrating the epidermis of an individual, means capable of penetrating the dermis of an individual, and means capable of penetrating the hypodermis of an individual.

In preferred embodiments, the term refers to transdermal devices capable of penetrating the skin of an individual and reaching deeper tissues and organs.

The term transdermal administration, as used herein, refers to the administration of, for example, a compound through the stratum corneum of an individual. The term transdermal further refers to the administration of a compound through the epidermis of an individual, the administration of a compound through the dermis of an individual, and the administration of a compound through the hypodermis of an individual. In preferred embodiments, the term transdermal administration refers to the administration

ΦΦΦ compounds through the individual's skin into deeper tissues and organs.

The present invention further relates to a transdermal composition for treating pain in a subject, comprising a compound capable of blocking afferent neuronal transmission in an amount effective to block afferent neuronal transmission in the subject; and a pharmaceutically acceptable carrier suitable for transdermal administration of the compound.

The term compound capable of blocking afferent neuronal transmission refers to a compound that can block the ability of afferent neurons, i.e. sensory neurons, to transmit an impulse to the central nervous system.

Various aspects of the invention are further described in the following sections:

Amine-containing compounds having two-phase solubility

Amine-containing compounds having biphasic solubility for use in transdermal compositions of the present invention include antidepressant compounds, antiepileptic compounds, anticonvulsant compounds and sodium channel blockers. The term antidepressant compounds as used herein refers to compounds capable of alleviating the symptoms of depression. Examples of antidepressant compounds are: 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, for example, in the catalog • · · »

SIGMA and in The Merck Index, 12th edition, Budavari et al., ed., 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 group. Therefore, in a preferred embodiment, the transdermal composition of the present invention contains tricyclic antidepressant compounds. Examples of tricyclic antidepressants are adinazolam, amitriptyline oxide, amoxapine, clomipramine, demexiptillin, dimethacrine, dothiepin, doxepin, imipramine N-oxide, iprindol, lofepramine, melitracen, metapramine, noxiptilin, pizotyline, propizepine, quinupramine, tianeptine and trimipramine. A particularly preferred tricyclic antidepressant for use in the compositions of the present invention is doxepin.

Tricyclic antidepressant compounds are described, for example, in Guide to Clinical Neurology, J.P. Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

Preferably, the tricyclic antidepressant compound is selected from the group consisting of doxepin, trimipramine, other tricyclic compounds having biphasic solubility, and combinations thereof. When combined with other compounds, such as compounds enhancing the activity of amine-containing compounds, e.g., muscle relaxants, and/or anti-inflammatory compounds, e.g., nonsteroidal anti-inflammatory compounds, as described below, the tricyclic antidepressant preferably comprises from about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 15% by weight, and most preferably from about 5% by weight.

by weight to approximately 13% by weight.

The amine-containing compounds having biphasic solubility for use in transdermal compositions of the present invention further include antiepileptic compounds. The term antiepileptic compound, as used herein, refers to a compound capable of alleviating the symptoms of epilepsy. Examples of antiepileptic compounds for use in the present invention are lamotrigine, felbamate, and carbamazepine. Preferably, the antiepileptic compound is selected from the group consisting of lamotrigine, felbamate, carbamazepine, and combinations thereof. When combined with other compounds, such as compounds that enhance the activity of amine-containing compounds, for example muscle relaxants, and/or anti-inflammatory compounds, for example nonsteroidal anti-inflammatory compounds, as described below, the antiepileptic compound preferably comprises from about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 20% by weight, and most preferably from about 5% by weight to about 15% by weight. Antiepileptic compounds are described, for example, in the SIGMA catalog and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co., Inc., Rahway, N.J., 1996, and in Guide to Clinical Neurology, J.P. Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

The amine-containing compounds having biphasic solubility according to the present invention further include anticonvulsant compounds. The term anticonvulsant compound, as used herein, refers to a compound capable of alleviating the symptoms of convulsions, i.e., painful involuntary tetanic contractions of entire muscle groups. Examples of anticonvulsant compounds for use in the present invention are lamotrigine, • · · · · * 4 4

44 felbamate and carbamazepine. Preferably, the anticonvulsant compound is selected from the group consisting of lamotrigine, felbamate and combinations thereof. When combined with other compounds, such as compounds that enhance the activity of amine-containing compounds, e.g., muscle relaxants, and/or anti-inflammatory compounds, e.g., nonsteroidal anti-inflammatory compounds, as described below, the anticonvulsant compound preferably constitutes from about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 20% by weight, and most preferably from about 5% by weight to about 15% by weight. Anticonvulsant compounds are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co., Inc., Rahway, N.J., 1996, and in the Guide to Clinical Neurology, J.P.

Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

In yet another embodiment, the biphasic solubility amine-containing compound of the present invention is a compound that is an adrenergic agonist. Preferably, the adrenergic agonist is tizanidine. When combined with other compounds, such as muscle relaxants, and/or nonsteroidal anti-inflammatory compounds as described below, the adrenergic agonist preferably comprises from about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 20% by weight, and most preferably from about 5% by weight to about 15% by weight. Compounds that are adrenergic agonists are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co., Inc., Rahway, N.J., 1996, and in the Guide to Clinical Neurology, J.P. Mohr et 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 present invention further include sodium channel blockers. The term sodium channel blockers, as used herein, refers to compounds capable of blocking sodium channel activity. Examples of sodium channel blockers are tetrodoxin, flecainide, disopyramide, and terfenadine. Sodium channel blockers are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co., Inc., Rahway, N.J., 1996, and in the Guide to Clinical Neurology,

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

When nerves are damaged, for example due to trauma, diseases such as diabetes, herpes zoster or advanced cancer, or chemical damage (for example due to administration of agents such as nucleotide analogues in anti-HIV pharmaceuticals), the pain conduction circuits become interconnected with each other, anatomically and/or biochemically. Thus, after injury, new sodium channels are formed, which are thought to be responsible for the development of chronic pain. The same process can occur in the dorsal root ganglia of the spinal cord, resulting in regional pain syndromes. With each depolarization of these sodium channels, a nerve impulse is generated, and since there are many sodium channels, there is a constant cascade of nerve impulses that cause allodynia, burning sensations and/or dysesthesia. It is believed that chronic pain may be mediated by sodium channels in nerve cells. Therefore, it is believed that amine-containing compounds having biphasic solubility, which can block sodium channels, can also be used in

·· ·

• · • 99 transdermal devices according to the present invention

invention.

In one embodiment of the invention, the amine group of the amine-containing compound having biphasic solubility according to the present invention can act in the same way as a sodium ion upon entry into the sodium channel of the nerve cell membrane, the non-polar group, which is preferably present in the amine-containing compound having biphasic solubility according to the present invention, can interact with the nerve cell membrane, perhaps through Van der Waals forces. In such cases, the presence of the non-polar group is believed to prevent or inhibit the complete uptake of the amine-containing compound having biphasic solubility by the nerve cell membrane, it is believed that one or more of these interactions prevents or reduces the number and/or degree of depolarizations and ion exchanges involved in the conduction of the stimulus, thereby reducing the sensation of pain.

The dose of an amine-containing compound having biphasic solubility useful for transdermal pain relief can be determined by methods known in the art and is typically in the range of about 1 mg to about 300 mg per dose per subject, more preferably in the range of about 5 mg to about 100 mg per dose per subject, and most preferably in the range of about 10 mg to about 50 mg per dose per subject, depending on various factors such as the particular amine-containing compound having biphasic solubility used, whether the site of transdermal application is a site of action, and the intended size and site of action. In a preferred embodiment, the dose of the amine-containing compound having biphasic solubility useful for transdermal pain relief is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, 150 mg,

200 mg, 250 mg or 300 mg per dose and individual.

4 4 • ··· • 4 • 44 4·

Muscle relaxants

The transdermal compositions of the present invention may also contain muscle relaxants. The term muscle relaxant, as used herein, refers to compounds that facilitate or enhance muscle relaxation (e.g., cause relaxation of muscle spasms) and thus facilitate or enhance transdermal delivery of the transdermal composition of the present invention. Examples of muscle relaxants are skeletal muscle and smooth muscle relaxants, such as anticholinergics, spasmolytics, bronchodilators, and vasodilators. Muscle relaxants are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co., Inc., Rahway, N.J., 1996, pp. THER-1 to THER-28, and in the Guide to Clinical Neurology, J.P. Mohr et 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 diazepam), chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, other muscle relaxants having biphasic solubility, and combinations thereof. Most preferably, the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, and combinations thereof. A preferred muscle relaxant for use in the compositions of the present invention is guaifenesin.

Preferably, the muscle relaxant has biphasic solubility. Preferably, the muscle relaxant, when present in the pharmaceutical composition, constitutes from about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 20% by weight, and most preferably from about 5% by weight to about 15% by weight.

Anti-inflammatory compounds

The transdermal compositions of the present invention may also contain an anti-inflammatory compound. The term anti-inflammatory compound, as used herein, refers to a compound that is capable of reducing cell migration caused by ischemic and traumatic events and thus reduces the formation of edema, which causes pain relief. Preferably, the anti-inflammatory compound is a nonsteroidal anti-inflammatory compound (i.e., NTHE), including ketoprofen. Anti-inflammatory compounds, such as NTHE, are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, 12th edition, Budavari et al., ed., Merck & Co. , lne., Rahway, N.J., 1996, pp. THER-1 and THER-28, and in the Guide to Clinical Neurology, J.P. Mohr et 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, melfanamic acid, nabumetone, salsalate, naproxen, Vioxx®, COX-2 NTHE having biphasic solubility, and combinations thereof.

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

Dosage

The concentrations, as well as the amounts, of the amine-containing compounds having biphasic solubility, of the agents enhancing the activity of the amine-containing compounds, e.g., muscle relaxants, and of the anti-inflammatory agents, may vary depending on the desired effect. For example, higher concentrations of the amine-containing compound having biphasic solubility, the muscle relaxant, and the anti-inflammatory compound in a dosage form with reduced viscosity may result in an analgesic with a faster onset and shorter duration of action. High concentrations of the amine-containing compound having biphasic solubility, the muscle relaxant, and the anti-inflammatory compound in a dosage form with increased viscosity may result in an effective analgesic with a fast onset and long duration of action. Low concentrations of the amine-containing compound having biphasic solubility, the muscle relaxant, and the anti-inflammatory compound in a dosage form with reduced viscosity may result in a weaker analgesic with a slow onset and short duration of action. Low concentrations of an amine-containing compound having biphasic solubility, a muscle relaxant, and an anti-inflammatory compound in a dosage form with increased viscosity may result in a weaker analgesic with a slow onset and long duration of action.

The ability to vary the concentrations of the amine-containing compound having biphasic solubility, the muscle relaxant and the anti-inflammatory compound from very low to very high in the composition, together with varying the thickness of the coating (from 0.1 mm to 0.5 mm), allows the dosage in the system to be varied according to the level of pain and according to the anatomical sites of action. However, it should be appreciated that the onset as well as the duration of the analgesic effect of the transdermal composition of the present invention varies both between individuals and according to the site of application, the properties of the

amine-containing compounds having biphasic solubility, muscle relaxants and anti-inflammatory compounds.

Typically, the concentration of the amine-containing compound having biphasic solubility, the muscle relaxant, and the anti-inflammatory compound is in the range of about 1% by weight to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% by weight to about 20% by weight, and most preferably from about 5% by weight to about 15% by weight.

Pharmaceutically acceptable carriers

The transdermal compositions of the present invention also comprise a pharmaceutically acceptable carrier that enables transdermal administration of the amine-containing compound having biphasic solubility. The term pharmaceutically acceptable carrier suitable for transdermal administration, as used herein, refers to a carrier that enables transdermal administration of the amine-containing compound as defined above. Suitable carriers for transdermal administration of pharmaceutical compositions are described in U.S. Patent No. 5,446,070, the contents of which are incorporated herein by reference. Briefly, pharmaceutically acceptable carriers of the present invention include suitable solid (i.e., solid) or non-solid (i.e., other than solid, e.g., liquid or semi-liquid) carriers, including liquid, semi-liquid or solid carriers, such as bioadhesive agents. Thus, the amine-containing compound having biphasic solubility can be mixed with a pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, paste, patch, ointment, spray or any other non-solid carrier known in the pharmaceutical composition art, for example, the non-solid carrier can be a lipid base, including phospholipids such as lecithins; fatty oils;

• ·· lanolin; vasolin; paraffins; glycols; higher fatty acids; and higher alcohols.

The term bioadhesive as used herein refers to an adhesive that adheres to biological surfaces such as skin or mucous membranes. Preferably, the bioadhesive of the present invention is self-adhesive in the sense that it adheres to a selected area without the need for the use of another adhesive. Suitable bioadhesives include natural or synthetic polysaccharides, such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymethylcellulose, hydroxyethylcellulose, and the like; pectin; mixtures of sulfated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums, including natural plant gums such as karaya, ghatti'' gum, tragacanth, xanthan gum, jaraya gum, and the like; fruit gums such as guar gum, breadfruit gum, psyllium seed gum, and the like; and lecithins such as soy lecithin. In addition to the above-mentioned ingredients, the compositions of the present invention may further comprise other ingredients, such as various pharmaceutically acceptable ingredients known in the art. Such ingredients include binders, stabilizers, preservatives, flavor enhancers, fragrance modifiers, and pigments.

In another embodiment, the pharmaceutically acceptable carrier of the present invention is a cream carrier (cetyl alcohol, stearyl alcohol, stearic acid, glycerol monostearate, isopropyl myristate, soy lecithin, BHT alcohol 95%, simethicone, 30% sodium hydroxide solution, polyoxyl stearate, 5% disodium edetate, purified water, urea).

Other pharmaceutical compounds

« · · * • · · ··

In another aspect, the invention relates to a transdermal composition suitable for transdermal administration comprising a therapeutically effective amount of a pharmaceutical compound (e.g., a specific serotonin reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for the treatment of attention deficit hyperactivity disorder, a compound suitable for the treatment of hypertension and akathisia, an analgesic compound, or a compound suitable for the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal administration of the pharmaceutical compound.

The term pharmaceutical compound, as used herein, refers to a compound useful for treating a given condition that can be administered in an active form in vivo. Examples of pharmaceutical compounds include drugs, enzymes, chemical compounds, combinations of chemical compounds, biological macromolecules, and analogs thereof. Examples of pharmaceutical compounds are described in detail below.

In one embodiment of the invention, the pharmaceutical compound is a specific serotonin reuptake inhibitor (SSRI). SSRIs are commonly prescribed for patients with mood disorders, some forms of anxiety (particularly panic attacks), obsessive-compulsive disorders, some forms of menopausal disorders, and eating disorders (particularly bulimia nervosa). Examples of such SSRIs are sertraline (sold under the trade name Zoloft), paroxetine (sold under the trade name Paxil), fluoxetine (sold under the trade name Prozac), venlafaxine (sold under the trade name Effexor), and fluvoxamine (sold under the trade name Luvox).

In another embodiment, the pharmaceutical compound is a mood stabilizing compound, such as carbamazepine (sold under the brand name

• · • · · · · f« ·* ·« ····

·· * under the trade name Tegretol) and valproic acid (sold under the trade name Depakote). These agents are often used in psychiatric practice either as adjunctive medication (to enhance the effect of antidepressants) or as antimanic medication for the treatment of bipolar psychosis. Mood stabilizing drugs are also used in neurological practice for the treatment of seizure disorders and for the treatment of certain types of pain.

In yet another embodiment, the pharmaceutical compound is a compound used to treat attention deficit hyperactivity disorder (ADHD), an example of which is permoline, sold under the trade name Cylert. Permoline is a drug used to treat attention deficit hyperactivity disorder in adults and children. It is practically insoluble in water, but soluble in ethylene glycol and lipids, making it a good candidate for transdermal administration.

In another embodiment, the pharmaceutical compound is a dopamine compound used for the treatment of Parkinson's disease, where examples of such a compound are pergolide, sold under the trade name Permax, and bromocriptine mesylate, sold under the trade name Parlodel.

In another embodiment, the pharmaceutical compound is a compound used for the treatment of hypertension and akathisia, where one example of such a compound is propranolol, sold under the trade name Inderal.

In another embodiment, the pharmaceutical compound is a compound used for the treatment of impotence, an example of such a compound being sildenafil, sold under the trade name Viagra. It is believed that transdermal administration of sildenafil may be more advantageous, at least in some individuals, than oral administration, since oral administration has been found to be associated with gastrointestinal side effects in some situations.

Methods of preparing transdermal preparations

Another embodiment of the present invention provides a method of preparing the above transdermal compositions by mixing a therapeutically effective amount of an amine-containing compound having biphasic solubility, optimally an agent enhancing the activity of the amine-containing compound, for example a muscle relaxant, optimally an anti-inflammatory compound, with a carrier suitable for transdermal administration of the amine-containing compound.

In one embodiment of the present invention, the transdermal composition is prepared by dispersing or dissolving crushed tablets, capsules, or other preparations of an amine-containing compound having biphasic solubility, a muscle relaxant, and an anti-inflammatory compound, which are intended for oral administration, in a gel formed of soy lecithin and isopropyl palmitate or isopropyl myristate, alcohol, or ethoxydiglycol.

In another embodiment of the present invention, a Pluronic gel prepared from Pluronic, such as Pluronic F127, potassium sorbate, and water is used.

In a particular embodiment of the present invention, a transdermal composition comprising a combination of doxepin and guaifenesin is used for the treatment of pain. It is believed that transdermal administration of such a combination may be advantageous, at least in some individuals, over oral administration, as high local pharmaceutical concentrations can be achieved at the site of, e.g., injury, allowing for a better therapeutic response without systemic side effects such as weight gain, lethargy, gastrointestinal distress, and/or other known side effects of these pharmaceutical agents.

Ways of use

In one embodiment, the invention relates to methods for treating pain in a subject, wherein the subject is contacted with a transdermal composition comprising an amine-containing compound with biphasic solubility in an amount effective to treat pain in the subject; and a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound, resulting in treatment of pain in the subject. In a preferred embodiment, the transdermal composition is applied to the skin of the subject as often as necessary to relieve pain. For example, the transdermal composition may be applied daily, weekly, monthly, annually, for a period of time sufficient to relieve pain.

Detailed examples of the preparation are given below, together with examples of results obtained with transdermal administration in human patients. Preferably, the gel composition is applied to the skin at the site or sites of pain. Patients are assessed using a structured assessment form, completed at least once a week. Symptoms are assessed, as well as any adverse effects. This allows changes to be recorded over time.

The compositions of the present invention may be doses intended for administration by a patient in the form of a gel applied to the skin, or may be prepared in the form of a pre-determined dose transdermal compositions, preferably in conjunction with an adhesive or other surface or patch that can be applied to the patient's skin. Although some embodiments of the invention are described with the example of application of the pharmaceutical gel to the patient's arm, other sites of application to the skin may also be used.

Because, depending on the nature of the composition, the rate or duration of transdermal delivery may vary depending on the location of application on the skin, in one embodiment, the area of skin to which the pharmaceutical composition is applied is selected to relatively increase or decrease the delay, rate, or duration of delivery of the pharmaceutical composition, either to a particular tissue or to the systemic circulation.

for example, if a rapid increase in serum concentrations is desired, a location that increases the rate of delivery, such as behind the ear, may be used. If a local increase in dose or rate of delivery is desired, the transdermal device may be placed adjacent to the treatment area. Membranes or matrices, such as polymer matrices, may be used to limit or control the rate of delivery. In addition to administration in a transdermal gel or patch, administration in a transdermal or aerosolized device, such as nasal drops, ear drops, eye drops, and/or suppositories, may also be used.

In one embodiment, the drug in the transdermal gel forms a dosage unit, as is the case with blister packs. In such a case, the gel is extruded from the blister pack and spread at the site of administration. The dose is adjusted by the number of dosage units applied. This ensures accurate measurement of the dose and eliminates contamination of the gel.

Methods for selecting a compound suitable for treating pain

In another aspect, the invention relates to a method for selecting a compound suitable for treating pain in a subject. The method comprises transdermally administering to the subject a compound comprising an amine with biphasic solubility; and determining whether the subject is • ·» · · ···· ·

pain is being treated, and a compound suitable for treating pain in the individual can be selected accordingly. In a preferred embodiment, the method can further comprise modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program (e.g., Molecules-3D Professional Edition, version 2.60, copyright 1991-1998, Molecular Arts Corp., © 1994-1998 WCB/McGraw Hill); and determining whether the three-dimensional chemical structure of the compound has satisfactory characteristics for use as a sodium channel blocker, thereby enabling the selection of a compound suitable for treating pain in the individual.

The efficacy of administering an amine-containing compound having biphasic solubility for the treatment of pain can be tested in vitro or in vivo. An animal model of pain, such as the model described in Král, M.G. et al. (1999), pain 81(1-2): 15-24, can be used to test such compounds, for example.

The invention will now be illustrated by the following examples, which are not intended to limit the scope of the present invention. The contents of all references, patents and published patent applications cited in this invention, as well as the drawings, are hereby incorporated by reference.

Examples of embodiments of the invention

Example 1

100 g of soy lecithin (granular) and 0.66 g of sorbic acid (NF-FCC powder) are dispersed in 100 g (117 ml) of isopropyl palmitate NF and the mixture is allowed to stand overnight. Approximately 220 ml of lecithin-isopropyl palmitate is obtained in the form of a syrupy liquid.

»« ·

4 · 4 * β · 4 4 4 • · · · · · 4

4 4 4 « 4 »44 4

4 4 4 4 4 4

44 44 44 4

Example 2

100 g of soy lecithin (granular) and 0.66 g of sorbic acid (NF-FCC powder) are dispersed in 100 g (117 ml) of isopropyl myristate NF and the mixture is allowed to stand overnight. Approximately 220 ml of lecithin-isopropyl myristate is obtained in the form of a syrupy liquid.

Example 3

A beaker is prepared by measuring a volume of 100 ml. It is considered important to measure the volume accurately rather than using the markings on the beaker. A batch of Pluronic F127 NF (20 g for 20% gel, 30 g for 30% gel and 40 g for 40% gel) is mixed with 0.3 g of potassium sorbate NF. Chilled purified water is added in an amount sufficient to bring the volume to 100 ml. When all the granules are moistened, the gel is cooled. A solution forms on cooling over a period of 12 to 24 hours. The resulting 100 ml of Pluronic gel is left to cool as the gel solidifies at ambient temperature.

Example 4 g of carbamazepine in tablet form are crushed in a mortar. 4.3 ml of ethoxydiglycol are added and mixed to form a creamy paste. 13.2 ml of soy lecithin are added and mixed until a smooth mixture is obtained. 24 cm ³ of the resulting solution is drawn into a 60 cm ³ syringe. Approximately 36 cm ^{3 of} 20% Pluronic F127 gel (prepared in Example 3) is drawn into another syringe. The material in the syringes is mixed well with each other, obtaining 60 cm ³ of carbamazepine organogel with a strength of 150 mg per ml. In some cases, the mixture is processed in a fat mill to reduce the particle size.

Example 5

Sixty 100 mg buproprion tablets were crushed and sieved to obtain a fine powder. The buproprion powder was dissolved in approximately 30 cm ³ of purified water, placed in a filter and washed with 10 to 20 cm ³ of purified water. The filtrate was used to prepare a 20% Pluronic gel using the procedure of Example 3, exchanging the filtrate for an equal volume of water and storing in the refrigerator. 13 ml of soy lecithin was mixed with one half of the buproprion Pluronic gel and mixed between syringes to obtain the first batch. 13 ml of soy lecithin was mixed with the other half of the buproprion Pluronic gel and mixed between syringes to obtain the second batch. Sufficient Pluronic F127 gel (prepared according to Example 3) is added to each batch to yield a total of two 60 cm ³ batches of 15 mg/ml buproprion HCl organogel.

Example 6

600 mg of fluoxetine HCl (in the form of thirty 20 mg capsules) are placed in a beaker and dissolved in approximately 18 cm ^{3 of} 95% ethyl alcohol. The solution is filtered through a filter funnel using fine filter paper. The residue is washed with 95% alcohol. The filtrate is heated, maintaining the temperature below 85 °C, to evaporate the alcohol and concentrate to 1-2 ml. 600 mg of isopropyl palmitate is mixed with 600 mg of soy lecithin (granular) and the mixture is allowed to liquefy. After liquefaction, a thick syrup is obtained. 1.2 g of the mixture is drawn into a 10 ml syringe and the alcoholic solution of fluoxetine HCl is drawn into another syringe. The two syringes are connected with a Luer-Luer connector and the gel is mixed thoroughly. All the organogel is then transferred to one syringe and the empty syringe is disconnected. 20% Pluronic F127 gel (prepared • 4 44 ···· ·· • · · · · 4 · • · · · · · · • 4 4 · 4 4 4 · 4 4 » · 4 · 4 · ·

4» 44 44 44 syringe coupling and .:.

in example 3) to obtain - after mixing with the second a total volume of 6 ml. The contents of the two syringes are connected again by Luer-Luer and mixed until a fine creamy mixture is obtained. All the material is transferred to one syringe, the empty syringe is disconnected and the Luer-Luer connector is also disconnected.

A Luer-oral connector is attached to the syringe containing the mixture and the mixture is transferred into six 1 ml oral syringes, which then contain 1 ml of gel. Thus, each syringe contains five 20 mg doses or ten 10 mg doses, for a total of 60 doses of fluoxetine in lecithin organogel at a strength of 10 mg/ml.

Example 7

250 mg nefazadone tablets are crushed in a mortar and the material is sieved through a sieve. 4.8 ml of ethoxydiglycol (8%) is added and the mixture is mixed. If all the particles are not dissolved, 2 ml of Pluronic is added and the mixture is mixed. 13.6 ml of soy lecithin is added and the mixture is mixed. The resulting mixture is drawn into Luer-lock syringes and mixed thoroughly. Pluronic F127 gel, prepared according to Example 3, is added in an amount sufficient to achieve a volume of 60 cm ³ and the mixture is mixed to obtain 60 cm ^{3 of} nefazadone organogel with a strength of 50 mg/ml.

Example 8

Thirty 40 mg tablets containing paroxetine were crushed and the resulting material was sieved to remove the green coating material. 4.8 ml of ethoxydiglycol was added to the powder and the mixture was mixed in a mortar. 40 ml of 20% Pluronic F127 gel, prepared in Example 3, was added in gradually increasing amounts to the powder and the mixture was mixed using a spatula.

Φ φ · φ ♦ φ φ φφφ φ • · «φφφ φφ φφφφ* φφ φφ φφ φ

13.2 ml of soy lecithin and the mixture is mixed and the resulting material is drawn into syringes and Pluronic gel is added in an amount sufficient to increase the volume to 60 ml.

In cases where the particle size of the obtained material is too large, the cream is processed in an ointment mill to obtain 60 ml of paroxetine organogel with a strength of 20 mg/ml.

Example 9

Thirty 100 mg tablets containing sertraline were crushed to a fine powder and the resulting material was sieved through a sieve to remove the yellow coating material. 20% Pluronic F127 gel (prepared according to Example 3) was added in an amount sufficient to increase the volume to 38 ml and the mixture was mixed in a mortar to obtain a fine cream. This material was drawn into syringes and mixed between syringes to obtain a compact cream. 13.2 ml of soy lecithin was added and the mixture was mixed well between syringes by approximately 20 piston strokes. 20% Pluronic F127 gel was added in an amount sufficient to increase the volume to 60 ml to obtain 60 ml of a 15 mg/ml sertraline gel.

Example 10

Venlafaxine hydrochloride has a water solubility of 572 mg/mL (adjusted to ionic strength of 0.2 M sodium chloride). Twenty-five 100 mg venlafaxine tablets were crushed and sieved. The powder was dissolved in approximately 15 cm ³ of purified water, the solution was placed in a filter and washed with 10 cm ³ of purified water. The filtrate was used to prepare a 20% Pluronic gel using the procedure of Example 3 (replacing the filtrate with an equal volume of water) and placed in the refrigerator overnight. 13.2 mL of soy lecithin was drawn into a syringe fitted with a Luer lock.

• *9 »····» 99 · *· · 9 · 9 · 9999 • 99 99· 999

99999 9 999 9 9 • 9 9999 999

999 <9 99 99 99 «9»

Venlafaxine Pluronic gel is drawn into a second syringe connected to the first syringe and the contents of both syringes are mixed. Sufficient Pluronic F127 gel is added to obtain 60 ^cm3 of 75 mg/ml strength.

Example 11 g of sodium valproate (Depakote) is ground in a mortar. 4 ml of ethoxydiglycol is added and the material is mixed thoroughly to obtain a creamy paste. 19.8 ml of soy lecithin is added and the mixture is mixed until smooth. The 24 cm ³ solution obtained is drawn into two syringes with a Luer tip and mixed thoroughly. The mixture is divided so that half of the mixture is in each syringe. Using another 60 cm ³ syringe, 30% Pluronic gel is added to each syringe in such an amount that each syringe contains a volume of 45 ml.

Example 12

Paroxetine hydrochloride has a water solubility of 5.4 mg/ml. Paroxetine (Paxil) gel was prepared according to the procedure of Example 8. A dose of 40 mg per day was applied to the skin by a 59 year old male, each time for at least one hour. No skin irritation was reported. After 210 days, blood was collected and the serum concentration of Paxil was determined to be 0 ng per ml, when typical reference values are 49 ± 26 ng/ml, indicating possible poor absorption or laboratory error. Clinical evaluation of the patient during the 210 day period of such transdermal administration showed clinical benefit to the patient without the adverse gastrointestinal (GI) effects observed with oral administration.

Example 13

Sertraline hydrochloride is sparingly soluble in water and isopropyl alcohol and slightly soluble in ethanol. Sertraline (Zoloft) gel was prepared according to the procedure of Example 9. A dose of 100 mg per day was applied to the skin by a 54-year-old woman, each time for at least one hour. No skin irritation was reported. After 19 days, blood was collected and the serum concentration of Zoloft was determined to be 5 ng per ml, when typical reference values are 30-200 mg/ml, indicating possible limited absorption or laboratory error.

Example 14

Fluoxetine hydrochloride has a water solubility of 14 mg/ml. Fluoxetine (Prozac) gel was prepared according to the procedure of Example 6. A dose of 20 mg per day was applied to the skin by a 54-year-old woman, each time for at least one hour. No skin irritation was reported. After 7 days, blood was collected and the serum concentration of fluoxetine was determined to be 45 ng/ml and the plasma concentration of the primary active metabolite norfluoxetine was also 45 ng/ml. Clinical evaluation showed improvement in the patient's condition.

Example 15

Carbamazepine is practically insoluble in water and soluble in alcohol and acetone. Carbamazepine (Tegretol) gel was prepared according to the procedure of Example 4. A dose of 400 mg per day was applied to the skin by a 55-year-old man, each time for at least one hour. No skin irritation was reported. After 120 days, blood was collected and the serum concentration of Tegretol was determined to be 4.6 pg per ml, while typical therapeutic values are 4-10 μρ/ιηΐ, indicating good absorption. No GI side effects were observed and the patient showed clinical improvement.

Example 16

Carbamazepine (Tegretol) gel was prepared according to the procedure of Example 4. A dose of 200 mg per day was applied to the skin by a 53-year-old man, each time for at least one hour. No skin irritation was reported. After 60 days, blood was collected and the serum concentration of Tegretol was determined to be 10.8 μς per ml, while typical therapeutic values are 4-10 μg/ml, indicating excellent absorption. No GI side effects were observed and the patient showed clinical improvement.

Example 17

Sertraline (Zoloft) gel was prepared according to the procedure of Example 9. A dose of 50 mg per day was applied to the skin by a 53-year-old man, each time for at least one hour. No skin irritation was reported. After 63 days, blood was collected and the serum concentration of Zoloft was determined to be 23 ng per ml, while typical therapeutic values are 30-200 mg/ml. The patient showed a good clinical response without adverse GI effects.

Example 18

Carbamazepine (Tegretol) gel was prepared according to the procedure of Example 4. A dose of 200 mg per day was applied to the skin by a 47-year-old man, each time for at least one hour. No skin irritation was reported. After 91 days, blood was collected and the serum concentration of Tegretol was determined to be less than 0.5 μg per ml, while typical therapeutic values are 4-10 μg/ml, indicating poor absorption, laboratory error or patient non-compliance.

·· ·♦·· 44 • · · #

Example 19

Buproprion is highly soluble in water. Buproprion (Wellbutrin) gel was prepared according to the procedure of Example 5. A dose of 100 mg per day was applied to the skin by a 47-year-old man, each time for at least one hour. No skin irritation was reported. After 44 days, blood was collected and the serum concentration of Wellbutrin was determined to be less than 0.5 ng/ml, while typical therapeutic values are 10-30 ng/ml, indicating poor absorption, laboratory error, or patient non-compliance.

Example 20

Fluoxetine gel was prepared according to the method of Example 6. Typically, the daily dose of fluoxetine for an adult applied to the skin by the method of the present invention is between about 20 mg and 200 mg, more preferably between about 120 mg and about 200 mg. Doses for children and/or non-human mammals must be adjusted, for example proportionally to body weight. A dose of 20-60 mg per day was applied to the skin by 5 patients, including the patient of Example 13 and also a 44-year-old man, a 53-year-old woman, a 47-year-old man and a 36-year-old woman, each for a period of at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during a 30-180 day period of such transdermal administration showed a clinical response ranging from complete remission to mild improvement in symptoms.

Example 21

Fluoxetine gel was prepared according to the procedure of Example 6. A dose of 80-160 mg per day was applied to the skin by a 50-year-old woman, • · · · ··· each time for at least one hour. No skin irritation was reported. After 7 days at a dose of 80 mg, blood was collected and serum concentrations of fluoxetine were determined to be 34 ng/ml and norfluoxetine to be 25 ng/ml, while typical reference values are 50-480 ng/ml, indicating good absorption.

Clinical evaluation showed improvement in the patient's condition. The dose was then increased to 160 mg per day and the application was carried out in the same manner. After 7 days, blood was collected and the serum concentration of fluoxetine was determined to be 90 ng/ml and norfluoxetine to be 25 ng/ml, indicating good absorption.

The clinical evaluation showed greater improvement in the patient's condition at the higher dose, which positively correlates with higher plasma levels. The patient received the medication continuously for 5 months.

Example 22

Fluoxetine gel was prepared according to the procedure of Example 6. A dose of 80-160 mg per day was applied to the skin by a 38-year-old woman, each time for at least one hour. No skin irritation was described. After 7 days at a dose of 80 mg, blood was collected and the serum concentration of fluoxetine was determined to be 25 ng/ml and that of norfluoxetine to be 25 ng/ml. Clinical evaluation showed an improvement in the patient's condition. The dose was then increased to 160 mg per day and the application was carried out in the same way.

Example 23

Sertraline (Zoloft) gel was prepared as described in Example 9. A dose of 50-200 mg per day was applied to the skin of 6 patients, including the patients of Examples 12 and 16, and a 60-year-old man, a 53-year-old man, a 48-year-old man, a 38-year-old man, and a 47-year-old man, each for at least one hour. No adverse effects were observed.

4 4 4 4 4 4 4 4 4 4 4 • 4 4 4 4 · · 4 4 • 444 · 4 · 4 « * 4 • 4 4 4 4 · · 4

444 44 44 44 44 no skin irritation or gastrointestinal side effects. Clinical evaluation of patients over a 7-90 day period of such transdermal administration has shown clinical response ranging from complete remission of depression to no response.

Example 24

Carbamazepine (Tegretol) gel was prepared as described in Example 4. A dose of 200-400 mg per day was applied to the skin of 6 patients, including the patients in Examples 14, 15, and 17, as well as a 48-year-old woman, a 48-year-old man, and a 54-year-old woman, for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients over a 30-300 day period of such transdermal administration showed a clinical response ranging from moderate improvement to no positive clinical response.

Example 25

Paroxetine (Paxil) gel was prepared as described in Example 8. A dose of 20 mg per day was applied to the skin of the patient from Example 12 and a 15-year-old female, each for at least one hour. No skin irritation was observed.

Clinical evaluation of patients over a 30-210 day period of such transdermal administration has shown inconclusive clinical improvement in depression that may (or may not) be related to transdermally administered Paxil.

Example 26

Five 150 mg tablets containing amitriptyline are crushed and the material is sieved. The powder is drawn into Luer-lock syringes and mixed thoroughly with 2 ml

•9 9999 ethoxydiglycol. Add approximately 6 ml of 20% Pluronic gel and mix well. Add approximately 6.6 ml of soy lecithin and mix well. The resulting mixture is concentrated to a total volume of 30 ml with 20% Pluronic gel and mix thoroughly. The resulting mixture, having a strength of 25 mg/ml, is placed in a suitable dosing device.

Example 27

Amitriptyline (Elavil) gel was prepared as described in Example 26. A dose of 25 mg per day was administered to a 47-year-old male. The formulation was applied to the skin, each time for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of the patient during a 100-day period of such transdermal administration showed a good clinical response, comparable to that of oral formulations.

Example 28

Trazodone (Desyrel) gel was prepared in a manner similar to that of Example 7. A dose of 50-150 mg per day was administered to 2 patients, including a 36-year-old woman and a 47-year-old man. The composition was applied to the skin, each for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during a 42-90 day period of such transdermal administration showed good to excellent clinical response.

Example 29

Venlafaxine (Effexor) gel was prepared in a manner similar to that of Example 9. A dose of 150-225 mg per day was

9

9 99

9 9

9 9

9 9

99 9 was applied to 2 patients, including a 54-year-old woman and a 55-year-old man. The composition was applied to the skin, each for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during a 15-160 day period of such transdermal administration showed clinical responses ranging from no improvement to mild improvement.

Example 30

Propranolol (Inderal) gel was prepared in a manner similar to that of Example 8, yielding a gel containing 40 mg propranolol per ml of gel. A dose of 80 mg per day was administered to 2 patients, including a 36-year-old woman and a 47-year-old man. The composition was applied to the skin, each time for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during a 100-day period of such transdermal administration showed results comparable to oral administration.

Example 31

Buproprion (Wellbutrin) gel was prepared in a manner similar to that of Example 5. A dose of 150-200 mg per day was administered to 3 patients, including the patient in Example 18, a 38-year-old man, and a 53-year-old woman. The composition was applied to the skin, each for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients over a 5-45 day period of such transdermal administration showed equivocal results.

Example 32 *9 *··· •9 9 9 9 9 9 ·· · ♦ 9 9 999 9 9 • 9999 99 9 ·· ·* 99 99 999

A gel containing valproic acid (Depakote) was prepared in a manner similar to that of Example 4. A dose of 1000 mg per day was administered to a 37-year-old male. The composition was applied to the skin, each time for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of the patient during a 30-day period of such transdermal administration showed results comparable to oral administration.

Example 33

A gel containing valproic acid (Depakote) was prepared in a manner similar to that of Example 11. A dose of 500-1000 mg per day was applied to 2 male patients, aged 41 and 49 years. The composition was applied to the skin, each for at least one hour. Significant skin irritation was observed in one patient, but no gastrointestinal side effects were observed. Clinical evaluation of the patients over a two-month period showed improvement, but on long-term follow-up it appeared that other factors were responsible for this improvement. After 28 days, blood was drawn and a serum valproic acid concentration of 26 pg/ml was found in the 49-year-old patient (who was taking 250 mg twice daily), when the therapeutic range is 50-150 pg/ml. This indicated poor absorption and the dose was therefore increased to 500 mg twice daily, with further improvement in clinical response. A 41-year-old patient showed a good clinical response at an initial dose of 250 mg twice daily, but the serum valproic acid concentration was only 1 pg/mL. The dose was increased to 500 mg twice daily, and similar serum valproic acid concentrations were obtained. The discrepancy between clinical response and plasma concentration may be explained by either laboratory error or a placebo effect.

ΦΦ ·

Example 34

A gel containing reboxetine (sold under the trade name Edronax) is prepared in a manner similar to that used in Example 5, but using reboxetine instead of boproprion. The resulting mixture is applied to the skin by patients for at least one hour. No skin irritation or gastrointestinal side effects are expected. It is anticipated that clinical evaluation of patients over a 5-45 day period of such transdermal administration will demonstrate a good response to the treatment.

Example 35

Nefazodone (Serzone) gel was prepared according to the method of Example 7. A dose of 100 mg per day was applied to 61-year-old patients (male, female). The composition was applied to the skin, each time for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during a 21-day period of such transdermal administration showed a good response to the treatment.

Example 36 g of permoline tablets are crushed in a mortar and then dissolved in propylene glycol in an amount sufficient to dissolve. 3 ml of propylene glycol or 95% ethyl alcohol are added to form a paste. 6.6 ml of soy lecithin is added to the mixture in the mortar. The mixture is drawn into two Luer-lock syringes and mixed thoroughly. Each syringe is filled with 30 ml of 20% Pluronic F127 gel and the contents of the syringes are mixed to obtain a mixture with a strength of 33 mg/ml. The mixture is placed in a suitable dosing • 9

of the means.

Example 37

A 16-year-old female with a diagnosis of attention deficit hyperactivity disorder was successfully treated with oral permoline (Cylert) for 6 months. To potentially reduce the risk of liver damage associated with long-term use of permoline, permoline prepared according to the procedure of Example 36 was administered transdermally by application to the skin in the area behind the ear for at least one hour, at two sites, twice daily. Skin irritation was not expected. Clinical results were expected to be comparable to those obtained with oral agents, although the dose may need to be increased to achieve appropriate plasma concentrations and more frequent applications may be necessary to achieve appropriate plasma concentrations.

Psychiatric patients sometimes receive two or more psychotropic drugs, and in some cases two or more of the above examples describe different assessments for the same period of psychotropic drug administration.

Of the patients prescribed any medication as described in the above examples, each had demonstrated significant intolerance to an oral medication prior to initiating transdermal application. Laboratory measurements of plasma concentrations described above for transdermally administered fluoxetine and carbamazepine demonstrate good transdermal absorption using a lecithin organogel matrix as a vehicle. Valproic acid and sertraline do not appear to be well and reliably absorbed. Valproic acid has caused skin irritation in some patients requiring discontinuation of treatment. Both laboratory measurements ·* ·· 4444 4· * • 4 44 · 4444 •44 4 · 4 4444 * * 4444 44 4 ·* ·· 44 44 444 for buproprion and clinical patient responses indicate poor or equivocal absorption and outcomes. Patient tolerance of transdermal administration was good to excellent. The patients described in the examples above who had severe GI side effects with oral administration tolerated the uncomfortable spreading of the gel much better than the patients who had only mild to moderate side effects with oral administration. In general, better motivated and compliant patients also have a higher degree of long-term compliance.

The patients in the examples described above were evaluated using the structured questionnaires shown in Fig. 1 , which were completed at least once a week for each patient with the transdermal medication of the present invention.

Patients were assessed for both the presence of psychiatric symptoms and any side effects of medication. It is generally believed that patients with the most clearly defined and uncomplicated diagnosis of major depression have the best outcomes. In general, patients with a severe personality disorder or substance abuse disorder have the worst outcomes.

Example 38

1800 mg of gabapentin powder is dissolved in 1 ml of propylene glycol in a Luer-lock syringe. 6.6 ml of soy lecithin is added and the mixture is mixed thoroughly between the syringes. The resulting material is placed in a device for administration of a predetermined dose.

Example 39

2% and 4% gabapentin mixtures are prepared by replacing 1200 mg

4444 * ·· ·· · » · · • · · · · • ··# « · · • · « · • vr «· 44 • · · · • 4 4

4 4 4

4 4 • 4« 4 gabapentin or 600 mg gabapentin instead of 1800 mg gabapentin in Example 38.

Example 40

Gabapentin, prepared according to Example 38 or 39, is mixed with 3% or 5% lidocaine in various ratios.

Example 41

4% gabapentin, prepared according to Example 38 or 39, is mixed with 7% carbamazepine and 7% amitriptyline.

Example 42

2% gabapentin, prepared according to Example 38 or 39, is mixed with 2% carbamazepine and 1% Piroxicam, which is expected to lead to better penetration into muscle tissue.

Example 43

Gabapentin, prepared according to Example 38 or 39, at concentrations ranging from 2%-6%, is mixed with clonidine at concentrations between 2% and 3%.

Example 44

A 56-year-old woman had painful spasms of the upper and lower extremities due to spastic paraparesis following injury. Oral gabapentin, an anticonvulsant agent, had been administered previously but had produced a feeling of being drugged, a common adverse effect of this agent. It is believed that the use of transdermal gabapentin may provide local improvement by achieving high local tissue concentrations near the site of application, without increasing plasma concentrations. Other anticonvulsants, such as carbamazepine, are known to be useful for reducing neurogenic pain. The solubility of gabapentin in water exceeds 10%, making systemic absorption unlikely. Gabapentin prepared according to the method of Example 38 was applied to the skin in the painful area. The patient described moderate relief from spasms within one week, with no systemic side effects and no skin irritation.

Example 45 g of amitriptyline powder is added to 40 ml of 33% Pluronic F127 gel and the mixture is placed in the refrigerator for dissolution. 2 ml of ethoxydiglycol is added to 4.8 g of carbamazepine and the mixture is mixed to form a fine paste. 16.4 g of soy lecithin is added to the resulting paste and the mixture is mixed thoroughly. The dissolved amitriptyline preparation is added to the carbamazepine preparation and sufficient Pluronic F127 is added to make a volume of 120 ml and the resulting mixture is mixed to obtain a preparation containing 5% amitriptyline and 4% carbamazepine.

Example 46 g of doxepin is added to 20 ml of 33% Pluronic F127 mixture and placed in the refrigerator for dissolution. 24 g of ketoprofen and 12 g of guaifenesin are added to 10 ml of 95% alcohol and the mixture is mixed thoroughly. 26.4 ml of soy lecithin is added and the mixture is mixed and the doxepin composition is mixed with the ketoprofen/guaifenesin composition. The resulting mixture is added to 33% Pluronic, which is in an amount sufficient to reach a volume of 120 ml. The resulting mixture is mixed to obtain a composition containing approximately 20% ketoprofen, 5% doxepin and 10% guaifenesin.

• ·

Example 47 g of doxepin is added to 26 ml of 33% Pluronic F127 gel and the mixture is placed in the refrigerator for dissolution. 2 ml of ethoxydiglycol is added to 4.8 g of carbamazepine and the mixture is mixed. The resulting mixture is added to 24 g of ketoprofen and 6 ml of alcohol and the resulting mixture is mixed. 26.4 ml of soy lecithin is added to the ketoprofen preparation and the mixture is mixed well. The doxepin preparation is mixed with the carbamazepine/ketoprofen preparation and 33% Pluronic is added in an amount sufficient to reach a volume of 120 ml. The resulting mixture is mixed to obtain a preparation containing approximately 20% ketoprofen, 4% carbamazepine and 5% doxepin.

Example 48

0.15 g of sildenafil is crushed and sieved and dissolved in 5 ml of 20% Pluronic F127 and the contents are mixed between syringes. 2.2 ml of soy lecithin is added and the mixture is mixed. 20% Pluronic is added in an amount sufficient to make a volume of 10 ml and the resulting material is mixed thoroughly to give a composition with a strength of 15 mg/ml.

Example 49

A 15 mg/ml sildenafil mixture was applied to the penis and scrotum of a 51-year-old man. After sexual stimulation, an immediate and strong erection occurred, without any irritation or burning. The composition is expected to have the therapeutic effects of orally administered sildenafil, without any delay in effect, without any systemic GI side effects, and perhaps without any interaction with nitrates used in heart disease. It is expected that this will contribute to both the acceptability of the use of this pharmaceutical agent and its safety.

Example 50

The compositions of Examples 45 to 47, 53, 55 were applied transdermally to a number of patients for the treatment of pain, including other examples, and the results are summarized in Table 1 below. The significance of some of the values in Table 1 are given in Table 2. A blank space indicates that the patient was not treated at the respective site. If a given row of Table 1 reports more than one value, the best (most significant pain relief) result is reported in bold.

• ·

= c. -r -r, *-r. m m - r> C C3 3 > Patient ο <5 here what here OC what •Ji ~~i •her -u ·_/» X- 3\ About about ’Ul O Age — here IU here I'.» here here — —· here Gender — — here here here here here ru *“* ^— — here Cl· lir. performance here here tJ here here — here Hey here here Pain here — — About ketoprolene oP S Zf O 3 0- O H- X. X. 4- X- — X- X. here (jabapenum r+ . fU Ω <J <t> here — here — here Xx 1’iroxicam to treat •u« — •Her •Her doxepin H· 0 O < Φ' 3 0 h (D Z> 0 iQ 4X X. 4_ •Her X- X. enrbaniazepim •Her amitriptyline •Her — guaifenesin el X- í> X- here here — here About here X. here Duration JU here here c here shoulder here here here here about back = here about neck Result (most here IU O here Elbow .easier better: •Her knee c *<' ω — wrist saltpeter — •Her arms bold ankle (D< hip — foot

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1- — — — Patient ·_/ι X. C X. C Age — — — Gender — — *- C hir. performance oh UJ Pain χ Cetoprolene dp £ ►-r (D 3 Ø at 7 year O <<n> η- (D 0 H· lips H- 3 0 < Φ' 3 O TO iQ PJ 3 0 iQ (D H ' & X. Gabapentin X. 'ο Piroxicam ·_Λ doxepin '_Λ X. carbamazepine *-Λ amitriptyline C suifenesin NJ κ; Duration shoulder n ____i* Results (best result in bold) ι ίη ΐ back 1 ί neck i I elbow knee κ> wrist arms ankle hip foot

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From From 2 Γ* Γ 7: from: Patient Π x. •-j X. *-j Oh oh LA L/i La LA X. b Age NJ —* NJ AJ — Gender “ bJ SJ t-J 2hir. performance NJ here —· Kj ř-J Lu Pain X kj About 77 keioprolcn dp s p· (P 3 0- OH· ct ?r • 0) Ω <J Φ H ⁴ (D Ω H- r+ H- P O <(D' 3 0 li tO 0 P 0 tfl Φ H' 0 ιυ x- Gabapentin — LU lu 1’iroxicam X- •-A 0 LA doxepin LA carbamazepine 'jr\ amitriptyline guaifenesin t-J UJ fsj CA ooo X- Duration b Gj b 0» X. shoulder Lu Love back X-. neck: High (no elbow salted butter best result in bold) b knee ru O b wrist about about arms ankle _a ; hip tsj b foot

Table 1 (continued) • ·

< X <. < <= —ί C/> 73 c ~c c c Patient X. 00 OO X. Cb here here ’-Λ •U in ~u X. in 'Ul ga ga GJ GA here GA GA ’-A I know -u y> -u Age ru — — — here tU — tU — here here here here Gender —* — tU — *—* here here — — — here here — :hir. performance here here here 1U here here — here here here here here here here Pain = About about about here '.A about here Keioproln Medication %wt in lecithin organogel 4- X» 4- X At X. •ui X. X. Gabapentin — here — — here Piroxcam ga He knows GA GA doxcpin X. About X carbamazepine In» Amitriptyline guitenesin X. X- ooo ooo CU OO here about Cb — about — here here -U here X. Duration here about 7* here shoulder Results (best result in bold) here JU about here jU about back here In» neck •Her here about elbow· Γ Gi o here about = — ia knee Oh — wrist arms here about ankle about hip foot

Table 1 (continued)

4

ο α -π η ΓΓ Π r~ n r' r*\ c » 3 > Patient U4 CZ ©0 •λ Ό •about •j\ V» OO gj Age — bJ — — r·-» bJ Gender - bJ “· — — — KJ Ch ir. performance here M M kj řJ Hey — Pain bJ Ο ο ο c About = UJ about Keloprofen Φ 3 QO Hrt • ft> O < φ H (D O w· ft H- P O <p O* 3 O TO iQ OH P O cQ ID H C «U i- X. 4- X* X. X. X. Gabapenlin Oh GJ ’-Λ — Piroxicam doxcpin X» carbamazepine Band 1 i Amitriptyline guaifenesin •U b-> bJ X» bJ — b© C ooo — Duration t-J ’-Λ shoulder Results (best result in bold) r bj back 5 tJ κ» neck ο elbow u« l+t t j knee ο bJ wrist arms LU O b-> o ankle ro hip . leg

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• ·

Γ r r 7* 7Š I = X X Q O Ω O Ω Ώ e> o Patient t-Λ La X» UJ -U .u x- o X* o -U. about Lu La Lu La LU LA LU LA Age — U Gender — — here here — here here — “ c :hir. performance Lu LU here here LU LU here LU LU LU LU Pain About about About i i _ about here About here About Ketoprofen <* £ cr íd 3 CL O H· X» -U -U X- X. LA Gabapentin rt • o < Φ LU — LU LU LU Piroxicam to treat LA LA La La LA doxcpin H· 3 O < -U La LA carbamazepine Φ' 3 o h LA LA amitriptyline< e ganog About guaifenesin Φ H a tU C\ 00 here OO oc X- here here here OO Duration shoulder about About here about LA About back neck About About elbow Result (not eating About About Γ knee Φ CL Ό w< »< H' here LA here About About About wrist <l M arms sdk ankle bold hip LA foot

Table 1 (continued) ·»·

Z z 2 2 2 ? of 2 Patient X. X- Xx w Xx IU Age t-J isJ Gender ru — c iner. performance and Lu LU LU In Pain ' about 1 ° í 1 Ketoprofen ÓP £ ΣΤ Φ 3 CL Gabapentin rt· • cu 0 < Φ ! LU LU Piroxicam heal LA doxepin tin Xx Xx carbamazepine O 3 0 TO i0 p.j d O iQ Φ H th amitriptyline, > guaifenesin NJ -u- F3 cc Duration shoulder· About = about back 4- neck'< - < elbow result best knee Ό !V ω< H' · <j wrist ω φ CL φ κ c+ Ivj o NJ Oh arms ankle & a< 3 a>< hip 1 i Oh foot

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• ·

Table 2

Gender: 1 = male Surgical procedure: Pain: 1 = mild = female = one or more 2 = moderate = none = severe - sufficient to cause observable tears

Duration: length of treatment in weeks

Results: 0 = no effect = mild effect = moderate effect (more than 25% pain relief) = . significant effect (more than 40-45% pain relief) = almost complete disappearance of pain (more than 80% pain relief)

Some results from the data presented in Table 1 are summarized in Tables 3 and 4.

Table 3 - Percentages of reported pain relief

Place N (number of dates) no effect mild effect mild - medium effect medium effect significant effect Complete relief Wrist 13 16.7 33.3 8.3 41.7 Arm 14 7.1 21, 4 14.3 42.9 7.1 7.1 Elbow 5 40 20 20 20 Back 25 24 32 8 28 8 Arms 7 28, 6 14.3 14.3 28.6 14.3 Neck 11 9, 1 18.2 45, 5 9.1 18.2 Knee 13 15.4 46.2 15.4 7.7 15.4

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ROTT,RUZICKA,GOTMAN @ OOÍ

Table 4 - Percentages of reported pain relief

N no effect mild effect mild - medium effect medium effect significant effect Complete relief Best result without tricyclic compound 36 16.7 " 36.1 8.3 27.8 8.3 2.8 BEST result with any tricyclic compound 20 10 10 20 '35 15 10 Tri cyclic agent in monotherapy 7 14.3 14.3 42.9 14.3 14.3 Best results with ketoprofen, gabapentin, piroxicam 25 16 44 4 28 8 The best results without doxepin 43 18.6 32, 6 14 23.3 7 4.7 The best results with doxepin 13 7.7 7.7 53.8 23.1 7.7

Example 51

A 51-year-old woman applied a composition prepared according to Example 46 containing 20% ketoprofen, 5% doxepin and 10% guaifenesin to her back for 2 weeks. She reported moderate pain relief lasting several hours after each application. She reported no skin irritation or any other adverse effects. Oral medication produced no improvement and caused severe GI adverse effects.

Example 52

A 34-year-old man applied a preparation containing 20% ketoprofen, 4% carbamazepine and 5% doxepin to a very severe

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ROTT,RUZICKA,GUTMAN @00 scarred wrist, on which he had undergone 4 operations for carpal tunnel syndrome. He described moderate improvement in pain, lasting several hours after each application. No other treatment, including oral opioid analgesic medication, produced even modest improvement in pain.

Example 53 g of ketoprofen and sufficient guaifenesin to give a final concentration of 10% guaifenesin are mixed thoroughly with 10 ml of 95% alcohol. 1200 mg of gabapentin is dissolved in 1 ml of propylene glycol in a syringe with a Luer lock. 26.4 ml of soy lecithin is added to the ketoprofen-guaifenesin-alcohol mixture and the mixture is mixed thoroughly. The resulting mixture is added to the gabapentin-propylene glycol mixture and mixed thoroughly. 4.8 g of carbamazepine is mixed with the resulting mixture and the mixture is mixed thoroughly to form a fine paste. The resulting paste is mixed with the ketoprofen-guaifenesin-alcohol-gabapentin mixture and thoroughly mixed with a sufficient amount of Pluronic to obtain 120 ml of a composition containing 20% ketoprofen, 4% carbamazepine, 4% gabapentin and 10% guaifenesin.

Example 54

A 58-year-old woman with a cervical spinal cord injury resulting in spastic quadriparesis reported moderate relief of pain and muscle spasms after application of a mixture of Example 53 containing 20% ketoprofen, 4% carbamazepine, 4% gabapentin, and 10% guaifenesin, applied to her back and hips for 8 weeks. She did not tolerate oral administration of carbamazepine and gabapentin due to systemic side effects, including skin rash after carbamazepine and dizziness and sedation after gabapentin. When applied as a transdermal

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ROTT,RUZICKA,GUTMAN @004 did not describe any side effects or skin irritation.

Example 55 g of doxepin powder is mixed with 26 ml of pluronic and the mixture is placed in the refrigerator until liquefied. 1200 mg of gabapentin is mixed with 1 ml of propylene glycol and placed in a syringe with a Luer lock. 6.6 ml of soy lecithin is added and the mixture is mixed thoroughly between the syringes. 24 g of ketoprofen and 8 ml of alcohol are mixed thoroughly between two syringes with a Luer lock. The doxepin mixture is mixed thoroughly with the gabapentin mixture and then the ketoprofen mixture is added and the resulting material is mixed thoroughly. 20% Pluronic (approximately 54 ml) is added in an amount sufficient to obtain 60 ml of a composition containing 20% ketoprofen, 4% by weight gabapentin and 5% by weight doxepin.

Example 56

A 57-year-old woman applied the mixture of Example 55, containing 20% ketoprofen, 4% gabapentin and 5% doxepin, to her neck for 8 weeks and reported significant relief. She also applied the same mixture to her shoulder and reported moderate relief. The mixture containing piroxicam instead of doxepin produced only a slight improvement in the shoulder area.

Example 57

A 35-year-old man with a history of a knee injury with vascular disruption and 3 surgical procedures applied the mixture of Example 45, containing 4% carbamazepine and 5% amitriptyline, to his knee and reported mild to moderate improvement in pain, without skin irritation or other adverse effects.

Example 57A

A 41-year-old woman with a history of spinal surgery applied a mixture of Example 45, containing 4% carbamazepine and 5% gabapentin, to her back for 2 weeks. She reported mild pain relief.

Example 58

A 53-year-old man with a history of bilateral knee replacements applied the mixture of Example 45, containing 4% carbamazepine and 5% amitriptyline, to both knees for 4 weeks. He reported no relief of pain.

Example 58A

A 54-year-old man with a history of 7 spinal surgeries applied the mixture of Example 45, containing 4% carbamazepine and 5% amitriptyline, to his back for 2 weeks. He described mild to moderate pain relief, longer and better than with transdermal opioids (Duragesic). He reported no adverse effects, particularly skin irritation.

Example 59

A 38-year-old man with a history of shoulder ligament strain applied the mixture of Example 45, containing 4% carbamazepine and 5% amitriptyline, to his shoulder for 2 weeks. He reported mild to moderate pain relief, with no skin irritation or other adverse effects.

4· ««*·

Example 61

Sufficient amounts of carbamazepine and gabapentin are added to a combination of soy lecithin and pluronic to obtain a lecithin organogel containing approximately 4% carbamazepine and 5% gabapentin.

Example 62

A 42-year-old woman with a history of 3 spinal surgeries and cervical degenerative disc disease applied the mixture of Example 61, containing 4% carbamazepine and 5% gabapentin, to her neck and reported relief of pain, without skin irritation or other adverse effects. At the same time, she noted rapid relief of migraine headaches. When the same mixture was applied to her arms and wrists, affected by reflex sympathetic dystrophy, she reported moderate improvement in pain.

Example 63

3.6 g of gabapentin is dissolved in 5.4 ml of ethoxydiglycol in a mortar, 9.6 g of ketoprofen and 2.7 g of piroxicam are added and the resulting mixture is mixed thoroughly. 19.8 ml of soy lecithin is added and the resulting mixture is mixed thoroughly and added to a sufficient amount of 20% Pluronic gel to obtain 90 ml of a composition containing approximately 10% ketoprofen, 4% gabapentin and 3% piroxicam.

Example 64

3.6 g of gabapentin is dissolved in 5.4 ml of ethodioxyglycol in a mortar, 9 g of ketoprofen and 0.9 g of piroxicam are added and the resulting mixture is mixed thoroughly. 19.8 ml of soy ·« ♦ · » · lecithin is added and the resulting mixture is mixed thoroughly and 20% Pluronic gel is added in an amount sufficient to obtain 90 ml of a composition containing approximately 10% ketoprofen, 4% gabapentin and 1% piroxicam.

Example 65 g of doxepin is mixed with 50 ml of 33% Pluronic F127 and the mixture is placed in the refrigerator to dissolve. 12 g of gabapentin is dissolved in 9 ml of ethoxydiglycol and mixed to form a fine paste. 52.8 ml of soy lecithin is added and the mixture is mixed. The doxepin/pluronic mixture is added and the resulting material is mixed well. 20% Pluronic F 127 gel is added in an amount sufficient to obtain 240 ml of a composition containing approximately 5% by weight of gabapentin and 5% by weight of doxepin.

Example 66

A 36-year-old man with a knee injury involving the articular surfaces and compromising vascular supply applied the mixture prepared according to Example 65 to his knee several times a day. He reported moderate to significant (40%) pain relief that persisted for 4 to 6 hours. No relief was reported with previous application of carbamazepine-amitriptyline gel to this knee.

Example 67 g of doxepin is mixed with 18 ml of 33% Pluronic and the mixture is placed in the refrigerator for dissolution. 6 g of gabapentin is ground in a mortar to a fine powder which is added to 6 ml of ethoxydiglycol and mixed to form a fine paste. 12 g of guaifenesin is added and the mixture is mixed. 26.4 ml of soy lecithin is added and the mixture is mixed. The doxepin/pluronic mixture is added and the resulting material is mixed well. Pluronic gel (25.2 ml of 33% pluronic, but 30% or 20% pluronic can also be used) is added in an amount sufficient to obtain 120 ml of a composition containing about 5% by weight of gabapentin, about 5% by weight of doxepin, and about 10% by weight of guaifenesin.

Example 68

A 55-year-old woman with a spinal and shoulder injury applied the mixture prepared according to Example 67 to her back three times a day for 2 weeks and significant pain relief was achieved. She applied the same mixture to her hip and leg and reported moderate to significant improvement. The mixture containing only doxepin caused only a slight improvement in back pain and a slight to moderate improvement in hip and leg pain. The mixture containing only ketoprofen, gabapentin and piroxicam caused only a slight improvement in back pain.

Example 69

A 59-year-old woman with cervical and thoracic spine strain applied a mixture prepared according to Example 51, but without ketoprofen, containing approximately 5% by weight of doxepin and approximately 10% by weight of guaifenesin to her neck for 2 weeks, two to four times daily, and achieved complete relief of pain. She applied the same mixture to her back and achieved significant to complete relief of pain.

• ·« ·

Example 70

4.5 g of doxepin HCl is dissolved with 2.5 ml of 95% alcohol and the material is mixed thoroughly between two syringes. It is also possible to mix doxepin with 5 ml of 20% Pluronic and place the mixture in the refrigerator for dissolution. Then 20% Pluronic F127 is added in an amount sufficient to obtain 90 ml of a composition containing approximately 5% by weight of doxepin. Preferably, this and other compositions described are protected from light.

Example 71

A 61-year-old man with back, neck and arm injuries applied the mixture prepared according to the procedure of Example 7 to his neck four times a day and achieved significant relief. He applied the same mixture to his elbow and achieved moderate relief.

Example 72

A composition containing 7% antidepressant and approximately 10% muscle relaxant is prepared by dissolving 3.15 g trimipramine and 4.5 g guaifenesin in a mixing vessel using

2.7 ml of ethoxydiglycol. Add approximately 9.9 ml of soy lecithin and mix thoroughly. Add Pluronic F127 NF (20%) in an amount sufficient to make a total volume of 45 ml and mix.

Example 73

A gel containing 30% NTHE is prepared from 36 g of celecoxib, 7.2 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (20%) in an amount sufficient to achieve a total volume of 120 ml.

44 444444 4* *

444 4 44 4 4444 • 44 444 444

44444 4 444 4 ·

4 4444 444 • 44 44 44 44 444

Example 74

A gel containing approximately 7% antidepressant and approximately 13% muscle relaxant is prepared from 14.4 g doxepin, 31.2 g guaifenesin, 12 ml ethoxydiglycol, 52.8 ml soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 240 ml.

Example 75

A gel containing 5% antiepileptic drug is prepared from 6 g of lamotrigine, 6 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 76

A gel containing 10% adrenergic agonist is prepared from 12 g of crushed tizanidine, 6 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 77

A gel containing 10% muscle relaxant is prepared from 12 g of crushed metaxolone, 6 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 78

A gel containing 10% muscle relaxant is prepared from 12 g

44 444444 44

4444 44 4 444

44444 4 444 4 4

4 4444 444

444 44 44 44 44 444 crushed carisoprodol, 6 mL ethoxydiglycol, 26.4 mL soy lecithin, and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 mL.

Example 79

A gel containing 10% methocarbamol is prepared from 12 g of crushed methocarbamol, 6 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 80

A gel containing 10% muscle relaxant is prepared from 12 g of crushed dantrolene sodium, 6 ml of ethoxydiglycol, 26.4 ml of soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 81

A gel containing 7% antiperspirant, 10% muscle relaxant is prepared from 8.4 g crushed doxepin, 12 g chlorzoxazone, 6 ml ethoxydiglycol, 26.4 ml soy lecithin and Pluronic F127 NF (33%) in an amount sufficient to achieve a total volume of 120 ml.

Example 82

A series of human trials were conducted using various combinations of pharmaceutical agents. The results are shown in Fig. 2.

Pain relief assessment is provided as described ·«·· • 4 »·

4 4 « · • •4 4 4 • 4 • 44 ♦· patients for different parts of the body to which medication was applied. The scale used in Fig. 2 is as follows:

= no effect (no or uncertain effect) = moderate effect (less than 15% pain relief)

1.5 = mild-moderate effect (15-25% pain relief)

2.0 = moderate effect (25-33% pain relief)

2.5 = moderate-strong effect (33-45% pain relief)

3.0 = strong effect (45-60% pain relief)

3.5 = strong-complete effect (60-80% pain relief)

4.0 = complete effect (more than 80% pain relief)

For each body part and for the percentage composition of each medication, individual ratings are given as well as means, which are statistical averages of the scores according to the scale above. For example, 3 patients were given 5% doxepin on their backs and the average pain relief score was 2.333.

Conversely, 13 patients were administered a 5%/10% combination of doxepin/guaifenesin and their mean pain relief score was 2.885. Results for the 7/10 and 10/10 doxepin/guaifenesin formulations are also presented, and the mean for the entire dox-guai sample in all combinations is given at the end of the section and is equal to 2.722.

The abbreviations used in Fig. 2 are as follows:

Abbreviations c-dox-gu c-gab-do carb carb-ami

Generic pharmaceutical names carbamazepine carbamazepine carbamazepine carbamazepine doxepin guaifenesin gabapentin doxepin amitriptyline ·« «···

65 carb-gab carbamazepine gabapentin dox doxepin dox-chl doxepin chlorzoxazone dox-guai doxepin guaifenesin g-dox-gu gabapentin doxepin guaifenesin gab-dox gabapentin doxepin k-ca-dox ketoprofen carbamazepine doxepin to-car-pi ketoprofen carbamazepine piroxicam k-dox-ch ketoprofen doxepin chlorzoxazone k-dox-gu ketoprofen doxepin guaifenesin k-dox-pi ketoprofen doxepin piroxicam k-g-do-g ketoprofen gabapentin doxepin guay k-gab ketoprofen gabapentin to-gab-ami ketoprofen gabapantin amitriptyline to-gab-do ketoprofen gabapantin doxepin to-gab-gu ketoprofen gabapantin guaifenesin k-gab-pi ketoprofen gabapantin piroxicam to-fi ketoprofen piroxicam la-li-gu lamotrigine lidocaine guaifenesin lam-chl lamotrigine chlorzoxazone n-dox-ch naproxen doxepin chlorzoxazone naproxen naproxen tri-chl trimipramir chlorzoxazone

• ·· · · ·

·· 1

According to the results described herein, doxepin appears to be effective in the treatment of pain when administered transdermally and further appears to be almost free of undesirable side effects when administered transdermally.

Doxepin appears to produce approximately a three-fold better response compared to at least some of the pharmaceutical agents described herein, regardless of whether these other agents are

• ·· • 9 · ·» ···· • ·· 9 • * • • ··· « • • • · • • • 9 (9 • • · • • ·· ·· ··

pharmaceutical agents administered alone or in combination. Doxepin appears to be significantly more effective than amitriptyline as an analgesic when administered transdermally, for example in the treatment of neuropathic pain. This appears to be true regardless of whether doxepin is administered as a single agent or in combination with other pharmaceutical agents as described herein.

Carbamazepine appears to have positive effects in the treatment of pain, such as neuropathic pain, at least in appropriately selected patients. Carbamazepine causes a rash in some patients, requiring discontinuation of its use.

These adverse effects are similar to those seen with oral carbamazepine. Gabapentin does not appear to have any adverse effects when administered transdermally. Although some patients appear to benefit from the transdermal combination of ketoprofen, gabapentin, and piroxicam, these positive effects are relatively weak compared to those of doxepin.

Guaifenesin appears to be of benefit as an adjunctive treatment for painful muscle spasms. For the patient population described here, amitriptyline appears to have limited analgesic efficacy when administered transdermally. Combining gabapentin with doxepin appears to be of additional benefit. Adding guaifenesin to doxepin may be of benefit, particularly when muscle spasms are present.

It is clear from the results presented above that the invention provides a treatment for patients for whom oral administration is suboptimal, such as patients with gastrointestinal or other side effects, patients with poor absorption of orally administered pharmaceuticals, and/or patients for whom prolonged administration or relatively rapid administration or a higher rate of increase in plasma concentrations is desirable. The present invention provides a method for administering therapeutic amounts of pharmaceutical agents, at least to a certain patient population, substantially free of any of the skin irritation, gastrointestinal or other adverse effects associated with oral administration of pharmaceutical agents, particularly psychotropic drugs, and with a clinical effect comparable to or greater than that observed with oral administration of the respective pharmaceutical agents. For these reasons, the most effective medications for the treatment of pain are the medications described in Examples 65, 67, 69 and 70.

Many variations and modifications of the present invention may be used. It is contemplated that plasma concentrations may be increased by performing two or more transdermal applications per day and/or applying the transdermal compositions to two or more sites.

In at least one case, twice-daily application of Prozac gel appears to increase plasma concentrations by approximately twofold. It is anticipated that twice-daily application of Prozac gel to two sites will result in therapeutic concentrations of approximately 140-250 ng/mL. Based at least in part on the results reported for fluoxetine, olanzapine (marketed under the trade name Zyprexa) or a mixture of fluoxetine/olanzapine in a lecithin organogel is expected to be useful.

Another type of psychotropic or psychopharmaceutical medication for which transdermal delivery may be used is the administration of psychostimulant agents. One example of a psychostimulant agent is Methylphenidate (sold under the trade name Ritalin), which is used in the treatment of attention deficit hyperactivity disorder (ADHD). Methylphenidate has a duration of action of typically 2-4 hours, requiring frequent dosing, which is particularly difficult for school-age children.

Transdermal administration is expected to provide a prolonged duration of action throughout the day, eliminating the need for frequent oral administration. Transdermal administration is also expected to eliminate peaks and troughs in plasma concentrations, allowing for better clinical efficacy. Similar results are expected to be obtained for other pharmaceutical agents, such as dextroamphetamine (sold under the trade name Dexedrine), for which the benefits will be less pronounced because a sustained-release form is available, with a duration of action typically of 5-6 hours. Another group of psychotropic drugs that will benefit from transdermal administration are antipsychotics, such as those used in the treatment of schizophrenia.

Embodiments of the present invention include, for example, use in patients with intestinal malabsorption.

Many equivalent embodiments of the specific embodiments of the invention described herein will be apparent to those skilled in the art.

Such equivalent embodiments fall within the scope of the following claims.

Claims (53)

PATENT CLAIMS What is claimed is: 1. A transdermal composition for treating pain in an individual comprising: (a) an amine-containing compound having biphasic solubility in an amount effective to treat pain in an individual; and (b) a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound. 2. The transdermal composition of claim 1, further comprising an activity enhancing agent for the amine-containing compound having biphasic solubility. The transdermal composition of claim 2, wherein the amine-enhancing agent of the amine-containing compound having biphasic solubility is a myorelaxant. The transdermal composition of claim 1, wherein the amine-containing compound is an antidepressant compound. 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. 7. 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 myorelaxant is selected from the group consisting of guaifenesin, chlorzoxazone, sodium dantrolene, metaxalone, carisoprodol, and combinations thereof. 11. The transdermal composition of claim 10, wherein the muscle relaxant is guaifenesin. 12. The transdermal composition of claim 3, wherein the myorelaxant is benzodiazepine. 13. The transdermal composition of claim 12 wherein the benzodiazepine is clozapine. 14. The transdermal composition of claim 12 wherein the benzodiazepine is diazopam. 15. The transdermal device of claim 1, further comprising: - a - - - - - - - - - - - - - - - - - - - - - - - - - - - - An anti-inflammatory compound. 16. The transdermal composition of claim 15, wherein the anti-inflammatory compound is a non-steroidal anti-inflammatory compound. 17. The transdermal composition of claim 16 wherein the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalat, naproxen, vioxx®, and combinations thereof. 18. A transdermal composition for treating pain in an individual comprising: (a) an amine-containing compound having biphasic solubility in an amount effective to treat pain in an individual; (b) a myorelaxant in an amount effective to increase the activity of the amine-containing compound having biphasic solubility; and (c) a pharmaceutically acceptable carrier suitable for transdermal administration of an amine-containing compound and a muscle relaxant. 19. The transdermal composition of claim 18 wherein the myorelaxant is selected from the group consisting of guaifenesin, chlorzoxazone, sodium dantrolene, 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 myorelaxant has a 4 .4... 4 4... 4 4. 44444 4,444 4 • 4 4 4 4 4 4 44 44 4-4 44 4 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 agent 4 4 4 4 · · · 4 4 The compound is a non-steroidal anti-inflammatory compound. 4 The compound is a non-steroidal anti-inflammatory compound. 30. The transdermal composition of claim 29, wherein the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalat, naproxen, vioxx®, and combinations thereof. 31. A transdermal composition for treating pain in an individual comprising: (a) doxepin in an amount effective to treat pain in an individual; (b) guaifenesin in an amount effective to enhance doxepin activity; and (c) a pharmaceutically acceptable carrier suitable for transdermal administration of doxepin and guaifenesin. 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. A method of treating pain in an individual comprising contacting the individual with a transdermal composition comprising: (a) an amine-containing compound having biphasic solubility, in an amount effective to treat pain in an individual; and (b) a pharmaceutically acceptable carrier suitable for transdermal administration of the amine-containing compound. 35. The method of claim 34, wherein the transdermal composition further comprises an activity-enhancing agent of the amine-containing compound having biphasic solubility. 36. The method of claim 35, wherein the activity enhancing agent of the amine-containing compound having biphasic solubility is a myorelaxant. The method of claim 34, wherein the amine-containing compound is an antidepressant compound. 38. The method of claim 37 wherein the antidepressant compound is a tricyclic antidepressant compound. 39. The method of claim 37 wherein the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and combinations thereof. 40. The method of claim 37, wherein the antidepressant compound is doxepin. 41. The method of claim 34, wherein the amine-containing compound is a sodium channel blocker. 42. The method of claim 34 wherein the pharmaceutically acceptable carrier is a lecithin organogel. 43. The method of claim 36 wherein the myorelaxant is selected from the group consisting of guaifenesin, chlorzoxazone, sodium dantrolene, metaxalone, carisoprodol, and combinations thereof. 44. The method of claim 43, wherein the myorelaxant is guaifenesin. by 45. The method of claim 36, wherein the muscle relaxant is benzodiazepine. 46. The method of claim 45 wherein the benzodiazepine is clozapine. 47. The method of claim 45 wherein the benzodiazepine is diazepam. so that 48. The method of claim 34, wherein the transdermal composition further comprises a compound. It is said to contain anti-inflammatory 49. The method of claim 48, wherein the anti-inflammatory compound is a non-steroidal anti-inflammatory compound. 50. The method of claim 49 wherein the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalat, naproxen, vioxx®, and combinations thereof. 51. A method for selecting a compound suitable for treating pain in an individual comprising: (a) transdermally administering to the subject an amine-containing compound having biphasic solubility; and (b) detecting whether the pain in the individual is being treated, thereby allowing the selection of a compound suitable for treating pain in the individual. 52. Transdermal composition for treating pain in an individual 9 9 9 characterized by comprising: (a) a compound capable of blocking afferent neuron signal transduction in an amount effective to block afferent neuron signal transduction in an individual; and (b) a pharmaceutically acceptable carrier suitable for transdermal administration of the compound. 53. The transdermal composition of claim 52, further comprising an agent enhancing the activity of the compound suitable for blocking the transmission of signal by afferent neurons.