SK20012000A3 - Methods and transdermal compositions for pain relief - Google Patents

Abstract

The present invention features methods and compositions for transdermal administration. In one embodiment, the invention features methods and compositions for transdermal administration of an amine containing compound having biphasic solubility and/or agent which enhances the activity of the amine containing compound having biphasic solubility, e.g., a muscle relaxant, to relieve pain.

Description

Technical field

The present invention relates to methods and compositions for transdermal administration. More specifically, the present invention relates to methods and compositions for transdermally administering an amine-containing compound having biphasic solubility and / or an agent that enhances the activity of an amine-containing compound having biphasic solubility, for example, a myorelaxant, to alleviate pain.

BACKGROUND OF THE INVENTION

Damage to somatic sensory nerves is believed to cause loss of somatic sensitivity. Such damage can be caused by a variety of causes including injury, diseases such as diabetes, herpes zoster, and advanced stage tumors, chemotherapy, or chemical damage. Neural pain pathways are believed to interconnect, both anatomically and biochemically, after nerve injury. In many patients with somatic sensory nerve damage, negative symptoms, such as decreased sensitivity, are associated with positive sensations, including a false sense of pain. It can be mild dysesthesia to unbearable pain that prevents patients from working, walking and other daily activities.

Recently, patients have generally been treated with analgesics to relieve pain. 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, addiction, sedation and / or weight gain, which may not be well tolerated by the patient. In other cases, malabsorption of oral formulations results in subtherapeutic plasma concentrations. In other instances, the reagents have relatively short plasma bbe < b &gt; &lt; - &gt; &lt; - &gt; &lt; - &gt; B BBBBBB Half-life, which requires an uncomfortable dose. A general feature of oral administration is delaying the effect because the analgesic is absorbed through the digestive system before it reaches the circulation. Many of the agents that are traditionally administered orally or by injection are inappropriate or suboptimal for the patient. There are many medications that, at least in some patients, are not well tolerated by oral administration (for example, they cause undesirable gastrointestinal or other side effects) and / or cause undesirable high or low concentrations in the target tissues or 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 certain area, such as tissue, to achieve the desired results. Oral or injection may result in too slow or too rapid a rise in plasma concentration, for example, an undesired delay in onset of action, because the analgesic is absorbed through the digestive system before it reaches circulation, or peak plasma concentration followed by undesirable reduction to too much. low concentration in a situation where it is desirable to achieve a more constant concentration. Some analgesics more easily than others cause liver or kidney damage when administered orally.

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

SUMMARY OF THE INVENTION

The present invention provides a transdermal composition for treating pain in a subject, particularly a human subject. The transdermal composition for treating pain in a subject comprises an amine-containing compound having a biphasic solubility in an amount effective to treat pain in the subject and a pharmaceutically acceptable carrier suitable for transdermal administration of an amine-containing compound, such as a lecithin organogel carrier. In a preferred embodiment, the transdermal composition further comprises an activity-enhancing agent of the amine-containing compound having biphasic solubility, for example, a muscle relaxant such as guaifenesin, chlorzoxazone, sodium dantrolene, metaxalone, carisoprodol, and combinations thereof. Preferably, the activity-enhancing agent of the amine-containing compound having biphasic solubility, for example a myorelaxant, 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 amine-containing compound having biphasic solubility 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 non-steroidal anti-inflammatory compound such as celecoxib, etodolac, mefanamic acid, nabumetone, salsalat, naproxen, vioxx®, and combinations thereof. Such a 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 an amine-containing compound having biphasic solubility in an amount effective to treat pain in the subject; a myorelaxant in an amount effective to increase the activity of the amine-containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal administration of an amine-containing compound having biphasic solubility and a muscle relaxant.

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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 increase doxepin activity; and a pharmaceutically acceptable carrier suitable for transdermal administration of doxepin and guaifenesin.

Other aspects of the invention pertain to methods for treating pain in a subject, wherein the subject is contacted with a transdermal composition comprising an amine-containing compound having a 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 the 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 useful for treating pain in an individual. The method comprises transdermally administering to the subject an amine-containing compound having biphasic solubility; and determining whether pain is being treated in the individual, and accordingly, the compound of choice may be suitable for treating pain in the individual. In a preferred embodiment, the method may further comprise modeling the compound using a computer equipped with a three-dimensional modeling chemical structure program; and determining whether the three-dimensional chemical structure of the compound has satisfactory characteristics for use as a sodium channel blocker, allowing selection of a compound suitable for treating pain in an individual.

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 serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound useful for treating attention deficit hyperactivity, a compound useful for treating hypertension and akathathisia, an analgesic compound, or a compound useful in the treatment of impotence) and a pharmaceutically acceptable carrier suitable for transdermal administration of a pharmaceutical compound, for example, a lecithin organogel carrier.

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In another aspect, the invention relates to a transdermal composition for treating pain in an individual 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 be apparent from the following detailed description and the appended claims.

Description of the figures in the attached drawings

Fig. 1 is a form used to evaluate an embodiment 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 to treat pain in an individual; and a pharmaceutically acceptable carrier suitable for transdermal administration of an 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 subject is a human.

The term pain as used herein is known in the art and refers to sensations induced in an individual, for example a mammal such as a human, by harmful chemical, mechanical or thermal stimuli. The term pain includes chronic pain, such as cross pain, arthritis pain, such as osteoarthritis arthritis; joint pain such as knee pain or carpal canal syndrome; myofascial pain and neuropathic pain. The term pain further includes acute pain, such as pain associated with muscle stretching 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 fat solubility (e.g. solubility in polar solvents such as ethanol, ethoxydiglycerol, ethoxydiglycol, chloroform, benzene, and the like) to they could penetrate through the stratum corneum, and having sufficient water solubility to be active in the aqueous environment of the dermis and deeper embedded tissues.

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

The transdermal compositions of the present invention may further comprise an activity enhancing agent for the amine-containing compound having biphasic solubility. The term amine-enhancing agent having a biphasic solubility, as used herein, refers to an amine-containing compound having a biphasic solubility as used herein.

7 an agent that enhances the pharmacological activity of an amine-containing compound. having a biphasic solubility (e.g., the ability of an amine-containing compound to counteract pain), or which enhances the transdermal penetration of an amine-containing compound having a biphasic solubility (e.g., the ability of the amine-containing compound to cross the stratum corneum), or enhances both pharmacological activity and transdermal penetration of the amine-containing compound. Examples of agents that increase the activity of an amine-containing compound having biphasic solubility are myorelaxants, as described in more detail below.

The term transdermal composition refers to compositions capable of penetrating the stratum corneum of an individual. The term transdermal further refers to agents capable of penetrating the epidermis of the subject, agents capable of penetrating the dermis of the subject, and agents capable of penetrating the hypodermis of the subject. In preferred embodiments, the term transdermal pro-class means capable of penetrating an individual's skin and reaching deeper embedded tissues and organs.

The term transdermal administration as used herein refers to the administration, for example, of a compound through the stratum corneum of an individual. The term transdermally further refers to administering the compound through the epidermis of the subject, administering the compound through the dermis of the subject, and administering the compound through the hypodermis of the subject. In preferred embodiments, the term transdermal administration refers to the administration of the compounds through the skin of an individual to deeper tissues and organs.

The present invention further relates to a transdermal composition for treating pain in an individual 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, B B, BBBB

B B BBBBBBB

B · ·· ·· ·· ·····

i sensory neurons, transmitting impulse to the central nervous system.

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

Amine-containing compounds having biphasic solubility

Amine containing compounds having biphasic solubility for use in the 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, dotiepine or iofepramine), bupropion (sold under the trade name Wellbutrin), reboxetine (sold under the trade name Edronax), nefazodone (sold under the trade name Serzone) and trazodine (sold under the trade name Serzone) Desyrel). Antidepressant compounds are described, for example, in the SIGMA catalog and in The Merck Index, "12th edition, Budavari et al., Eds., Merck &amp; 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 comprise a tricyclic group. Therefore, in a preferred embodiment, the transdermal composition of the present invention comprises tricyclic antidepressant compounds. Examples of tricyclic antidepressants are adinazolam, amitriptyline oxide, amoxapine, clomipramine, demexiptiline, dimethacrine, dotiepine, doxepine, imipramine N-oxide, iprindole, Iofepramine, melitracene, metapramine, noxiptilin, pisotyline, pizotyline, pizotyline, pizotyline, pizotyline, pizotyline, pisotyline. 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 Neuroogy, J.P. Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

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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 that increase the activity of amine-containing compounds, such as myorelaxants, and / or anti-inflammatory compounds, such as non-steroidal anti-inflammatory compounds, as described below, the tricyclic antidepressant preferably constitutes from about 1% to about 30% % of the pharmaceutical composition, preferably from about 3% to about 15%, and most preferably from about 5% to about 13%.

Amine containing compounds having biphasic solubility for use in the transdermal compositions of the present invention further include anti-epileptic 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 increase the activity of amine-containing compounds, such as myorelaxants, and / or anti-inflammatory compounds, such as non-steroidal anti-inflammatory compounds, as described below, the antiepileptic compound preferably constitutes from about 1% to about 30% preferably from about 3% to about 20% by weight, and most preferably from about 5% 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., Eds., Merck &amp; 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 the biphasic solubility of the present invention further include anticonvulsant compounds. The term anticonvulsant compound, as used herein, refers to a compound capable of reconciliation. 9 9 9

9

99 9999 e., To avoid symptoms of convulsions, i. painful involuntary tetanic contractions of whole muscle groups'. Examples of anticonvulsant compounds for use in the present invention are lamotrigine, 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 increase the activity of amine-containing compounds, for example myorelaxants, and / or anti-inflammatory compounds, for example non-steroidal anti-inflammatory compounds, as described below, the anticonvulsant compound preferably constitutes from about 1% to about 30% preferably from about 3% to about 20% by weight, and most preferably from about 5% 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., Eds., Merck & Co., Inc., Rahway, NJ, 1996, and in the Guide to Clinical Neurology, JP Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

In yet another embodiment, the amine-containing compound having the biphasic solubility 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 myorelaxants and / or non-steroidal anti-inflammatory compounds, as described below, the adrenergic agonist preferably constitutes from about 1% to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% to about 20% by weight and most preferably from about 5% by weight to about 15% by weight. Compounds which are adrenergic agonists are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, "12th edition, Budavari et al., Eds., Merck & Co., Inc., Rahway, NJ., 1996, and in Guide to Clinical Neurology, JP Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

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., Eds., Merck & Co., Inc., Rahway, NJ, 1996, and in Guide to Clinical Neurology. , JP Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference.

In nerve damage, for example as a result of trauma, diseases such as diabetes, herpes zoster or an advanced stage of cancer, or chemical damage (e.g. due to the administration of agents such as nucleotide analogues in anti-HIV pharmaceuticals), the pain management circuits are interconnected , anatomically and / or biochemically. Thus, upon injury, new sodium channels are formed which are believed to form the basis for chronic pain. The same action in the spinal ganglion ganglia may result in regional pain syndromes. Each depolarization of these sodium channels produces a nerve impulse. 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. It is therefore contemplated that amine-containing compounds having biphasic solubility that can block sodium channels may also be used in the transdermal compositions of the present invention.

In one embodiment of the invention, the amine group of the amine-containing compound having the biphasic solubility of the present invention may act as a sodium ion upon entry into the sodium channel of a nerve cell membrane. The non-polar group, which is preferably present in the amine-containing compound having the biphasic solubility of the present invention, may interact with the nerve cell membrane, perhaps through Van der Waals forces. In such cases, it is assumed that the presence of the product is considered to be present. · · · ·· ··

The nonpolar group prevents or inhibits the complete uptake of the amine-containing compound having biphasic solubility through the nerve cell membrane. It is believed that one or more of these interactions prevent or reduce the number and / or degree of depolarizations and ion exchanges involved in stimulating the stimulus, thereby reducing the sensation of pain.

The dose of the amine-containing compound having biphasic solubility useful for transdermal pain relief can be determined by methods known in the art and is usually in the range of about 1 mg to about 300 mg per dose and subject, preferably in the range of about 5 mg to about 100 mg per dose and the subject and preferably in the range of about 10 mg to about 50 mg per dose and subject, depending on various factors, such as the particular amine-containing compound used having biphasic solubility, whether the site of transdermal application is the 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 per subject.

muscle relaxants

The transdermal compositions of the present invention may also contain myorelaxant agents. The term myorelaxant as used herein refers to compounds that facilitate or enhance muscle relaxation (e.g., cause muscle spasms) and thus facilitate or improve the transdermal delivery of the transdermal composition of the present invention. Examples of myorelaxants are both skeletal muscle and smooth muscle, such as anticholinergic, spasmolytic, bronchodilatory and vasodilating agents. Myorelaxant agents are described, for example, in the SIGMA catalog, 1998 and in The Merck Index, "12th edition, Budavari et al., Eds., Merck &amp; Co., Inc., Rahway, N.J., 1996, p. THER-1 to THER-28, ·· ····

• e · · · · ·······

and in Guide to Clinical Neurology, J.P. Mohr et al. (Churchill Livingstone, 1995), the contents of which are incorporated herein by reference. Preferably, the myorelaxant is selected from the group consisting of guaifenesin, benzodiazepines (e.g. clozapine or diazepam), chlorzoxazone, sodium dantrolene, metaxalone, curry zoprodol, other myorelaxants having biphasic solubility, and combinations thereof. Most preferably the myorelaxant is selected from the group consisting of guaifenesin, chlorzoxazone and combinations thereof. A preferred myorelaxant for use in the compositions of the present invention is guaifenesin.

Preferably, the myorelaxant has biphasic solubility. Preferably, the muscle relaxant, when present in the pharmaceutical composition, forms from about 1% to about 30% by weight of the total weight of the pharmaceutical composition, more preferably from about 3% to about 20% by weight, and most preferably from about 5% 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 thereby decreasing swelling formation, thereby relieving pain. Preferably, the anti-inflammatory compound is a non-steroidal 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., Eds., Merck & Co., Inc., Rahway, N.J., 1996, p. THER-1 and THER-28, and in 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, melphanamic acid, nabumetone, salsalate, naproxen, Vioxx®, COX-2 NTHE having biphasic solubility, and combinations thereof.

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

batching

Concentrations, as well as the amount of amine-containing compounds having biphasic solubility, activity-enhancing agents of amine-containing compounds, for example myorelaxants, and anti-inflammatory agents, may vary depending on the desired effect. For example, higher concentrations of an amine-containing compound having biphasic solubility, a myorelaxant, and an anti-inflammatory compound in a reduced viscosity dosage form can result in analgesics with faster onset and shorter duration of action. High concentrations of an amine-containing compound having biphasic solubility, a myorelaxant, and an anti-inflammatory compound in a dosage form with increased viscosity may result in the formation of an effective analgesic with rapid onset and long duration of action. Low concentrations of an amine-containing compound having biphasic solubility, a myorelaxant, and an anti-inflammatory compound in a reduced viscosity dosage form 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 myorelaxant, and an anti-inflammatory compound in a dosage form with increased viscosity may result in a weaker analgesic with slow onset and long duration of action. The ability to vary the concentrations of the amine-containing compound having biphasic solubility, the myorelaxant and the anti-inflammatory compound from very low to very high concentrations in the composition, together with varying the coating thickness (from 0.1 mm to 0.5 mm) and according to ana ·· ······ It will be appreciated, however, 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 the site of application, the properties of the amine-containing compound having biphasic solubility, the myorelaxant and the anti-inflammatory compound.

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

Pharmaceutically acceptable carriers

The transdermal compositions of the present invention also contain a pharmaceutically acceptable carrier that allows 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 enabling transdermal administration of an amine-containing compound as defined above. Suitable carriers for transdermal administration of pharmaceutical compositions are described in U.S. Pat. U.S. Patent No. 5,768,516; 5446070, 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. non-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 admixed 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 art. For example, the non-solid carrier may be based on a lipid, including phospholipids such as lecithins; fatty oils; lanolin; vazolín; paraffins; glycols; higher fatty acids; and higher alcohols.

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The term bioadhesive agent as used herein refers to an adhesive agent that adheres to biological surfaces such as the skin or mucosa. Preferably, the bioadhesive agent of the present invention is self-adhesive in the sense that it adheres to the selected area without the need for any other adhesive. Suitable bioadhesive agents include natural or synthetic polysaccharides such as cellulose derivatives including methylcellulose, cellulose acetate, carboxymethylcellulose, hydroxyethylcellulose and the like; pectin; mixtures of sulphated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums (including natural vegetable gums such as karaya, ghatti gum, tragacanth, xanthan gum, jaray gum and the like; fruit gums such as guar gum, breadfruit gum, psillium seed gum and the like; and lecithins In addition to the above ingredients, the compositions of the present invention may further comprise other ingredients, such as various pharmaceutically acceptable ingredients known in the art, including binders, stabilizers, preservatives, flavoring agents, flavoring agents 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 serotonin specific reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound useful for treating attention deficit hyperactivity, a compound useful for treating hypertension and akatathisia, an analgesic compound or a compound of value 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 suitable for the treatment of a given condition, which can be administered in active form in vivo. Examples of pharmaceutical compounds are 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 serotonin specific reuptake inhibitor (SSRI). SSRIs are commonly prescribed to patients with mood disorders, some forms of anxiety (especially panic attacks), obsessive-compulsive diseases, some forms of menopausal disorders, and eating disorders (especially 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 trade name Tegretol) and valproic acid (sold under the trade name Depakote). These agents are often used in psychiatric practice either as adjunctive medications (to enhance the effect of antidepressants) or as antimanic medications to treat bipolar psychoses. Mood stabilizing drugs are also used in neurological practice to treat seizure disorders and to treat a certain type of pain.

In yet another embodiment, the pharmaceutical compound is a compound used to treat attention deficit hyperactivity disorder (ADHD), exemplified by permoline, sold under the tradename Cylert. Permoline is a medicine 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.

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

In another embodiment, the pharmaceutical compound is a compound used to treat hypertension and akathathisia, wherein one example of such a compound is propranalol, sold under the tradename Inderal.

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

Methods of preparing transdermal compositions

Another embodiment of the present invention provides a process for the preparation of the above transdermal compositions by mixing a therapeutically effective amount of an amine-containing compound having biphasic solubility, optimal reagents for increasing the activity of the amine-containing compound, for example a myorelaxant, optimally an anti-inflammatory compound.

In one embodiment of the present invention, the transdermal composition is prepared by dispersing or dissolving crushed tablets, capsules or other formulations of an amine-containing compound having a biphasic solubility, a myorelaxant and an anti-inflammatory compound for oral administration in a soy lecithin and isopropyl palmitate or isopropyl palmitate gel. 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.

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t »··· · · · · • ······ · ··· · • · · t · · · 19 ·· ·· ·· ·· ·· · In particular An embodiment of the present invention is transdermal

a composition comprising a combination of doxepin and guaifenesin used to treat pain. It is believed that transdermal administration of such a combination may be

more preferably, at least u some individuals like oral administration because they can

high local pharmaceutical concentrations at the site (s) e.g. injuries, allowing to achieve 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.

Methods 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 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 resulting in the 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 alleviate pain. For example, the transdermal composition may be administered daily, weekly, monthly, annually, for a period of time sufficient to alleviate pain.

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

The compositions of the present invention can be dosages to be administered to patients in the form of a gel applied to the skin, or they can be prepared in the form of a transdermal formulation with a predetermined dose, preferably

9 9 9 9 9 9 9 9 9 9 9

9

99 9999

9

99 hours together with the adhesive or other surface or patch, so that the dose can be administered e.g. applying an adhesive patch to the skin of the patient. Although some embodiments of the invention are described by way of example of applying a pharmaceutical gel to the arm of a patient, other sites of application to the skin of the patient may also be used. Because, depending on the nature of the composition, the rate or duration of transdermal transmission may vary depending on the site of application to the skin, in one embodiment the skin area to which the pharmaceutical composition is applied is selected to relatively increase or decrease the delay, rate or duration of transmission. a pharmaceutical composition, either into a particular tissue or into the systemic circulation.

For example, if a rapid increase in serum concentrations is desired, a rate-increasing location such as a placement behind the ear may be used. When a local increase in dose or rate of administration is desired, the transdermal composition may be placed adjacent to the treatment area. Membranes or matrices, such as polymer matrices, can be used to limit or control the transfer rate. In addition to administration in a transdermal gel or patch, administration in a transdermal or aerosol formulation may also be performed in the form of, for example, nasal drops, ear drops, eye drops and / or suppositories.

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

Methods of selecting a compound suitable for the treatment of pain

In another aspect, the invention relates to a method for selecting a compound useful for treating pain in an individual. The method comprises transdermally administering to the subject an amine-containing compound having biphasic solubility; and determining whether the subject is being treated for pain, and accordingly the compound may be selected.

• • • • • • • • • • • • • • • • • • Suitable for treating pain in an individual. In a preferred embodiment, the method may further comprise modeling the compound using a computer equipped with a three-dimensional modeling chemical structure 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, allowing selection of a compound suitable for treating pain in an 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 pain model, such as that described by Kral, M.G. et al. (1999), Pain 81 (1-2): 15-24, can be used, for example, to test such compounds.

The invention will be further illustrated by the following examples, which in no way limit the scope of the present invention. The contents of all references, patents and published patent applications cited herein, as well as in the drawings, are incorporated herein by reference.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

100 g of soya 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 Iecithin isopropyl palmitate is obtained as a syrup-like liquid.

Example 2

100 g of soya 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 as a syrup-like liquid.

Example 3

Prepare the beaker by measuring the volume of 100 ml. It is considered important to measure the volume exactly instead of using the beaker marking. A dose 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 increase the volume to 100 ml. When all the granules are wetted, the gel cools. The solution is formed with cooling for 12 to 24 hours. The obtained 100 ml Pluronic gel is allowed to cool because the gel solidifies at ambient temperature.

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

Example 5

Sixty 100 mg buproprion tablets are crushed and sieved to give a fine powder. The buproprion powder is 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 <RTIgt; as described in </RTI>. · Replace the filtrate with an equal volume of water and store in a refrigerator. 13 ml of soya lecithin is mixed with one half of the buproprionic Pluronic gel and mixed between the syringes to form a first batch. 13 ml of soya lecithin is mixed with the other half of the buproprionic Pluronic gel and mixed between the syringes to form a second batch. Sufficient Pluronic F127 gel (prepared according to Example 3) is added to each batch to form a total of two 60 cm ³ batches of 15 mg / ml buproprionic HCl organogel.

Example 6

600 mg of fluoxetine HCl (in the form of thirty 20 mg capsules) is placed in a beaker and dissolved in approximately 18 cm ^{3 of} 95% ethyl alcohol. Filter the solution through a filter funnel using fine filter paper. The residue was washed with 95% alcohol. The filtrate was heated, maintaining the temperature below 85 ° C, to evaporate the alcohol and concentrate to 1-2 mL. 600 mg of isopropyipalmitate is mixed with 600 mg of soya lecithin (granular) and allowed to liquefy. A thick syrup is obtained after liquefaction. 1.2 g of the mixture is withdrawn into a 10 ml syringe and the alcohol solution of fluoxetine HCl is withdrawn into another syringe. The two syringes are connected with a Luer-Luer coupling and the gel is thoroughly mixed. All organogel is then transferred to one syringe and the empty syringe is disconnected. A 20% Pluronic F127 gel (prepared in Example 3) is loaded into an empty syringe to obtain - after mixing with the second syringe - a total volume of 6 ml. The Luer-Luer coupling is reconnected and the contents of the two syringes are mixed until a fine creamy mixture is obtained. All material is transferred to one syringe, the empty syringe is disconnected, and the Luer-Luer coupling is also disconnected.

The luer-oral connection is connected to a syringe containing the mixture and the mixture is transferred to 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, giving a total of 60 doses of fluoxetine in the lecithin organogel at a strength of 10 mg / ml.

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Example 7

Twenty 250 mg of nefazadone tablets are crushed in a mortar and sieved through a sieve. 4.8 ml of ethoxydiglycol (8%) are added and the mixture is stirred. If not all of the particles are dissolved, add 2 ml of Pluronic and mix. 13.6 ml of soya lecithin are added and the mixture is mixed. The resulting mixture is withdrawn into a Luer-tip syringe and mixed thoroughly. Pluronic F127 gel, prepared according to Example 3, is added in an amount sufficient to reach a volume of 60 cm ³ and mixed to give 60 cm ³ of a 50 mg / ml non-phazodone organogel.

Example 8

Thirty 40 mg of paroxetine-containing tablets are crushed and the resulting material is sieved through a sieve to remove the green coating material. 4.8 ml of ethoxydiglycol are added to the powder and the mixture is stirred in a mortar. 40 ml of the 20% Pluronic F127 gel prepared in Example 3 is added in successively increasing amounts to the powder and the mixture is stirred with a paddle. 13.2 ml of soya lecithin is added and the mixture is mixed and the obtained 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 grinder to give 60 ml of paroxetine organogel with a force of 20 mg / ml.

Example 9

Thirty 100 mg sertraline-containing tablets are crushed to a fine powder and the resulting material is sieved through a sieve to remove the yellow coating material. 20% Pluronic F127 gel (prepared according to Example 3) is added in an amount sufficient to increase the volume to 38 ml and mixed in a mortar to form a fine cream. This material is pulled into the syringes and mixed between the syringes to form a compact syringe. ····································· 13.2 ml of soya lecithin is added and the mixture is mixed thoroughly between the syringes with about 20 plunger movements. 20% Pluronic F127 gel is added in an amount sufficient to increase the volume to 60 ml to give a 60 ml sertraline gel with a strength of 15 mg / ml.

Example 10

Venlafaxine hydrochloride has a solubility in water of 572 mg / ml (adjusted to an ionic strength of 0.2 M with sodium chloride). Twenty-five 100 mg venlafaxine tablets are crushed and sieved through a sieve. The powder is dissolved in approximately 15 cm ^{3 of} purified water, the solution is added to the filter and washed with 10 cm of purified water. The filtrate was used to prepare a 20% Pluronic gel using the procedure of Example 3 (exchanging the filtrate with an equal volume of water) and placed in a refrigerator overnight. 13.2 ml of soya lecithin is withdrawn into a syringe equipped with a Luer tip. The Venlafaxine Pluronic gel is drawn into a second syringe connected to the first syringe and the contents of the two syringes are mixed. Sufficient Pluronic F127 gel is added to form 60 cm ³ with a force of 75 mg / ml.

Example 11 g of sodium valproate (Depakote) is crushed in a mortar. 4 ml of ethoxydiglycol are added and the material is mixed thoroughly to form a creamy paste. 19.8 ml of soya lecithin are added and mixed until smooth. The 24 cm ^{3 of} solution obtained are drawn into two Luer-tip syringes and mixed thoroughly. The mixture is divided so that each syringe has half the mixture. Using another 60 cm ³ syringe, 30% Pluronic gel is added to each syringe in such a quantity that each syringe contains a volume of 45 ml.

Example 12 ·· ·· • · · ·

Paroxetine hydrochloride has a solubility in water of 5.4 mg / ml. A 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 man for at least one hour. No skin irritation has been reported. After 210 days, blood was collected and the serum concentration of Paxil was determined to be 0 ng per ml, while typical reference values are 49 ± 26 ng / ml, indicating a possible poor absorption or laboratory error. Clinical evaluation of the patient over a 210 day period of such transdermal administration has shown clinical benefit to the patient without the undesirable GI (gastrointestinal) effects observed with oral administration.

Example 13

Sertraline hydrochloride is poorly soluble in water and isopropyl alcohol and sparingly soluble in ethanol. A sertraline (Zoloft) gel was prepared as described in Example 9. A dose of 100 mg per day was applied to the skin by a 54-year-old woman for at least one hour. No skin irritation has been reported. After 19 days, blood was collected and the serum concentration of Zoloft was determined to be 5 ng per ml, while 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. A 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 for at least one hour. No skin irritation has been 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. The clinical evaluation showed an improvement in the patient's condition.

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Example 15

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

Example 16

Carbamazepine (Tegretol) gel was prepared as described in the Example

4. A dose of 200 mg per day was applied to the skin by a 53-year-old man for at least one hour. No skin irritation has been reported. After 60 days, blood was collected and the serum concentration of Tegretol was determined to be 10.8 µg / ml, while typical therapeutic values are 4-10 µg / ml, indicating excellent absorption. No GI side effects were observed and clinical improvement was evident in the patient.

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 for at least one hour. No skin irritation has been 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 as described in the Example

4. A dose of 200 mg per day was applied to the skin by a 47-year-old man for at least one hour. No skin irritation has been reported. After 91 days, blood was collected and the serum concentration of Tegretol was determined to be less than 0.5 gg per ml, while typical therapeutic values are 4-10 µg / ml, indicating poor absorption, laboratory failure, or non-cooperation of the patient.

Example 19

Buproprion is highly soluble in water. A buproprion (Wellbutrin) gel was prepared as described in Example 5. A 47-year-old male was applied to the skin at a dose of 100 mg per day for at least one hour. No skin irritation has been reported. After 44 days, blood was drawn 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 non-cooperation of the patient.

Example 20

The fluoxetine gel is prepared by the method of Example 6. Typically, the daily adult fluoxetine dose applied to the skin by the method of the present invention is between about 20 mg and 200 mg, preferably between about 120 mg and about 200 mg. Dosages for children and / or non-human mammals must be adjusted, for example, in proportion to body weight. A dose of 20-60 mg per day was administered to the skin by 5 patients, including the patient of Example 13 and a 44-year-old man, a 53-year-old, a 47-year-old, and a 36-year-old, for 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. φφ φφφ showed a clinical response ranging from complete remission to slight 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, for at least one hour each. No skin irritation has been reported. After 7 days at a dose of 80 mg, blood was collected and serum fluoxetine concentration was determined to be 34 ng / ml and norfluoxetine 25 ng / ml, while typical reference values are 50480 ng / ml, indicating good absorption. The clinical evaluation showed an improvement in the patient's condition. Thereafter, the dose was increased to 160 mg per day and administered 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 was 25 ng / ml, indicating good absorption. Clinical evaluation showed a greater improvement in the patient's condition at a higher dose, which correlates positively with a higher plasma level. The patient received the medication continuously for 5 months.

Example 22

The fluoxetine gel was prepared as described in Example 6. A dose of 80-160 mg per day was applied to the skin by a 38-year-old woman, for at least one hour. No skin irritation has been reported. 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 norfluoxetine was 25 ng / ml. The clinical evaluation showed an improvement in the patient's condition. Thereafter, the dose was increased to 160 mg per day and administered in the same manner.

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Example 23

A sertraline (Zoloft) gel was prepared as described in Example 9. A dose of 50-200 mg per day was administered by 6 patients, including those of Examples 12 and 16, and a 60-year-old male, 53-year-old male, 48-year-old male and a 47-year-old man, on the skin, for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients over a 7-90 day period of such transdermal administration showed a clinical response ranging from complete remission of depression to no apparent response.

Example 24

Carbamazepine (Tegretol) gel was prepared as described in the Example

4. A dose of 200-400 mg per day was administered to the skin by 6 patients, including those of Examples 14, 15 and 17, and 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

A paroxetine (Paxil) gel was prepared as described in Example 8. A dose of 20 mg per day was applied to both the patient of Example 12 and a 15-year-old woman on the skin 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 an ambiguous improvement in depression, which may or may not be related to transdermally administered Paxil.

φ φφ φφφφ

ΦΦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ Φ

Example 26

Five 150 mg amitryptyline-containing tablets are crushed and sieved through a sieve. The powder is drawn into the Luer-tip syringes and mixed thoroughly with 2 ml of ethoxydiglycol. Approximately 6 ml of 20% Pluronic gel is added and mixed thoroughly. Approximately 6.6 ml of soya lecithin is added and mixed thoroughly. The resulting mixture is concentrated to a total volume of 30 ml with a 20% Pluronic gel and mixed thoroughly. The resulting mixture having a strength of 25 mg / ml is placed in a suitable dosage formulation.

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 man. The composition was applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of the patient over 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 Example 7. A dose of 50-150 mg per day was administered by 2 patients, a 36-year-old woman and a 47-year-old man. The composition was applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients over a 42-90 day period of such transdermal administration showed a good to excellent clinical response.

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Example 29

Venlafaxine (Effexor) gel was prepared in a manner similar to that described in Example 9. A dose of 150-225 mg per day was administered by 2 patients, a 54 year old woman and a 55 year old man. The composition was applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients over a 15-160 day period of such transdermal administration showed a clinical response ranging from no improvement to a slight improvement.

Example 30

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

Example 3 1

Buproprion (Wellbutrin) gel was prepared in a manner similar to that of Example 5. A dose of 150-200 mg per day was administered by 3 patients, including the patient of Example 18 and a 38-year-old male and a 53-year-old female. The composition was applied to the skin 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 has shown ambiguous results.

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Example 32

A valproic acid gel (Depakote) was prepared by a method similar to that of Example 4. A 37-year-old man was given a 1000 mg daily dose. The composition was applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of the patient over a 30 day period of such transdermal administration showed results comparable to oral administration.

Example 33

The valproic acid gel (Depakote) was prepared in a manner similar to Example 11. A dose of 500-1000 mg per day was administered to 2 male patients, aged 41 and 49 years. The composition was applied to the skin for at least one hour. Significant skin irritation was observed in one patient but no gastrointestinal side effects were observed. Clinical evaluation of patients over a two-month period showed an improvement, but in long-term follow-up, other factors appeared to be responsible for this improvement. After 28 days, blood was collected and serum valproic acid concentration of 26 pg / ml was detected in a 49-year-old (250 mg twice daily), while the therapeutic range is 50-150 gg / ml. This indicates 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 concentration of valproic acid was only 1 pg / ml. The dose was increased to 500 mg twice daily and a similar serum concentration of valproic acid was obtained. The mismatch between the clinical response and the plasma concentration may be explained by either a laboratory error or a placebo effect.

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Example 34

The gel containing reboxetine (sold under the trade name Edronax) was prepared in a manner similar to the method used in Example 5 but using reboxetine instead of boproprion. The obtained mixture is applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects are expected. Clinical evaluation of patients over a 5-45 day period of such transdermal administration is expected to show a good response to treatment.

Example 35

A non-azodone (Serzone) gel was prepared as described in Example 7. A dose of 100 mg per day was administered by 61-year-old patients (male, female). The composition was applied to the skin for at least one hour. No skin irritation or gastrointestinal side effects were observed. Clinical evaluation of patients during the 21 day period of such transdermal administration showed a good response to 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 soya lecithin are added to the mixture in a mortar. The mixture is withdrawn into two syringes with a Luer tip and mixed thoroughly. Each syringe is filled with 30 ml of a 20% Pluronic FI27 gel and the contents of the syringes are mixed to form a mixture with a force of 33 mg / ml. The mixture is placed in a suitable dispensing means.

·· ····

Example 37

A 16 year old woman with attention deficit disorder was successfully treated with oral permoline (Cylert) for 6 months. To potentially reduce the risk of liver damage associated with prolonged use of permoline, the permoline prepared by the procedure of Example 36 was administered transdermally by application to the skin behind the earlobe for at least one hour, two sites, twice daily. Skin irritation was not expected. It was expected that the clinical results would be comparable to those achieved with oral formulations, although the dose may be increased to achieve appropriate plasma concentrations and more frequent administration may be required to achieve appropriate plasma concentrations.

Psychiatric patients sometimes receive two or more psychopharmaceuticals, and in some cases two or more of the above examples describe different assessments for the same periods of psychopharmaceutical administration.

Of the patients prescribed some medication, as described in the above examples, each prior to initiating transdermal administration showed significant intolerance to some medication by oral administration. The laboratory measurements of plasma concentrations described above for transdermally administered fluoxetine and carbamazepine demonstrate good transdermal absorption using the lecithin organogel matrix as vehicle. Valproic acid and sertraline do not appear to be absorbed well and reliably. Valproic acid causes skin irritation in some patients, which requires discontinuation of treatment. Both laboratory measurements for buproprion and clinical responses of patients show poor or ambiguous absorption and results. Patients' tolerance to transdermal administration was good to excellent. The patients described in the examples above, who had severe G1 adverse reactions when administered orally, tolerated uncomfortable gel spreading much better than those who had only mild to moderate adverse events when administered orally. In general, better motivated and treatment-conscious patients also have a higher degree of long-term cooperation.

·· ····

Patients in the examples described above were evaluated using the structured questionnaires shown in FIG. 1, which have been completed at least once a week for each transdermal medication patient according to the present invention. Patients were evaluated for all psychiatric symptoms present and for any side effects of the medication administered. It is generally considered that patients with the clearest and uncomplicated diagnosis of major depression show the best results. In general, patients with severe personality disorder or addictive disease show worse results.

Example 38

800 mg of gabapentin powder are dissolved in 1 ml propylene glycol in a Luer-tip syringe. Add 6.6 ml of soya lecithin and mix thoroughly between the syringes. The obtained material is placed in a composition for administration of a predetermined dose.

Example 39

2% and 4% gabapentin mixtures were prepared by swapping 1200 mg 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.

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Example 42

2% gabapentin, prepared according to Example 38 or 39, is mixed with 2% carbamazepine and 1% piroxicam, which is believed to result in 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 limbs as a result of spastic quadruparesis after injury. Oral gabapentin, an anticonvulsant agent, has been administered before, but has caused a feeling of overdose, which is a common adverse effect of this agent. It is believed that the use of transdermal gabapentin can cause 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 in reducing neurogenic pain. The water solubility of gabapentin exceeds 10%, making systemic absorption less likely. Gabapentin prepared by the method of Example 38 was applied to the skin in the pain area. The patient reported moderate spasm relief for one week, without systemic side effects and without skin irritation.

Example 45 g of amitriptyline powder is loaded into 40 ml of a 33% Pluronic F127 gel and the mixture is placed in a refrigerator to dissolve. 2. ml ethoxydiglycol is added

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they are added to 4.8 g of carbamazepine and the mixture is mixed to form a fine paste. 16.4 g of soya lecithin are added to the resulting paste and mixed thoroughly. The dissolved amitriptyline preparation is added to the carbamazepine preparation and Pluronic F127 is added in an amount sufficient to reach a volume of 120 ml and the resulting mixture is mixed to form a preparation containing 5% amitriptyline and 4% carbamazepine.

EXAMPLE 46 g of doxepin are placed in 20 ml of 33% Pluronic F127 and placed in a refrigerator to dissolve. 24 g of ketoprofen and 12 g of guaifenesin are added to 10 ml of 95% alcohol and mixed thoroughly. 26.4 ml of soya lecithin are added and the mixture is mixed and the doxepin formulation is mixed with the ketoprofen / guaifenesin formulation. The resulting mixture was added to a sufficient amount of 33% Pluronic to give a volume of 120 mL. The resulting mixture is mixed to form a formulation containing about 20% ketoprofen, 5% doxepin and 10% guaifenesin.

EXAMPLE 47 g of doxepin are placed in 26 ml of 33% Pluronic and placed in a refrigerator to dissolve. 2 ml of ethoxydiglycol are added to 4.8 g of carbamazepine and mixed. The mixture is added to 24 g of ketoprofen and 6 ml of alcohol and the mixture is stirred. 26.4 ml of soya lecithin is added to the ketoprofen formulation and mixed thoroughly. The doxepin formulation is mixed with the carbamazepine / ketoprofen formulation and sufficient 33% Pluronic is added to reach a volume of 120 ml. The resulting mixture is mixed to form a formulation containing about 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 mixed between syringes. 2.2 ml of soya lecithin are added and the mixture is mixed. 20% Pluronic is added in an amount sufficient to reach a volume of 10 ml, and the resulting material is thoroughly mixed to form a composition having a strength of 15 mg / ml.

Example 49

The sildenafil mixture of 15 mg / ml was applied to the penis and scrotal of a 51-year-old male. After sexual stimulation there was an immediate and strong erection without any irritation or burning. The composition is believed to have therapeutic effects inherent to orally administered sildenafil, without any delay in action, without any systemic GI side effects, and possibly without interaction with nitrates used in heart disease. This is believed to contribute both to the acceptability of the use of the pharmaceutical agent and to its safety.

Example 50

The compositions of Examples 45 to 47, 53, 55 have been transdermally administered to many patients for the treatment of pain, including other examples, and the results are summarized in the following Table 1. The significance of some of the inputs in Table 1 is shown in Table 2. was not performed in the patient. If a given row of Table 1 lists more than one site, the best result (most notable pain relief) is in bold.

• IB • 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

TABLE 1

The results (best result bold) eqou ABOUT oipoq J [OU8H B? Ed O m T about apssttyz = 0118 (03 ( in. q n ra e> IN e ri O rí W O rí e WP ri e 5 ri with ouamtti e ri Ä o ri C, ♦ N e ri ERU & m IN Ν ' ri •about and _r - IN IN TO -r «c • r medication % wt. in lecithin organogel upranajrenž IA a ^ duirare ir. ujdgzEttretyttf N Ν ' »A N N ajdaxop ir. ABOUT lA tupfixoiid n m m upiradBqno m N · n- * T · * N • r -r • r ugpudomx about C about XX = Q ΓΝ 9 «188 (00 rn r » m ÍN rn r * ·. m r * i m N m UO ^ ajAjtutqO and M » IN r * m ΓΝ n ri 9TA * lW (N rN rl n IN n r · 3ΡΛ ABOUT W) FROM 3 • PART m IT. r · K. r * ir. 90 n 90 »*» 90 m Ή 3 íuapsj < ÍR Q and U and OJ ¼ u. □ -

• •about

TABLE 1 (continued)

The results (best result bold) eqon cupsq 1 J (OUOR B? Bd 2I) W 0 n about e * 6 0119 (03 ( , WI w 1 1 WP 2 ousutei βΤΠΕΛίχ m rs rs medication % wt. in lecithin organogel ujzsnsjienS about ujjÁjduinire W. ujdazmuBqmsf • r. T «R« ujdaxop W tmpfixoiid m • T ujnisdnqeg T upjcudo] 9) and X jsops m «» m m ποχ ^ Λ. amnqo 9iABp [ ⁰ d 3ΡΛ * r O τ Ο »’ T -r in *. lUOIOBd

· ·

TABLE 1 (continued)

The results (best result bold) Bqou e CN ojpaq • Λ X0U3R B? Ed p p opsgdpz about c M ΟΠΟ [Ο5 [ p W »l W 9 C H WF p r * i ouaurei • à 9th p Irish. p »* ΐ ABOUT OTUBAJJ. * r 00 CM f *> ABOUT IN cia vom organogéli 1 UJZOU ^ IBtď U *-íjíujiure «Λ ujtfozBtrrecpBjf ! /> Ά O ä 5 * 5 S ® > ujdaxop ITB tupjpxaiij f b * m A «O g Λ WITH? upuadBqBQ * r ri TT η & ακίσρχ 9 about About CN e jsapg F *} m n n IN ΓΝ U05 $ A • SMtmiO n (N ri fN n n FN fN n 'PA FROM * F ΙΛ m In M 00 r * • y r * prism LZ LZ -J 5 from from

· · ·

TABLE 1 (continued)

The results (best result bold) Bqou oipsq q xotrai? O H W apsgd ^ z q UK ouapx ΙΛ q q Γ4 ABOUT ** I q 0 ri IN. W ABOUT "*" O ÍN W about Ä • à q r4 q q q q ÍN q IN ouet s> rš q O IN araEAJj; «Ν * r aí rM _with «0 Ό ΓΝ oo R 1 oo QQ » * s o o o o u s Q Ot S  r. O o> upauajrenŽ about uitôduiiure in. ujcfozBUiEqmx T «0 Ό · * <eo • ä e • W ^73. «« S «> ujdaxop * n in. IN. IN" urppxojTj r » m e g 31 upnadBqET) * r IN IN" in «t * r T n T o ^ · upjoidojsx and in ABOUT • r. Γ4 e about ABOUT about WITH about with e ^ sapa and IN n ÍN IN FN IN . rN m m r *> m r b * UO ^ A • 3ΛΗΠ13 ΓΜ IN _ IN M (N ouwiW IN IN (N ÍN ΓΜ IN IN ri 3ΡΛ rV » r * V. • r, V> K. r *> Vb r *> m V, © V » * R. • T r * V / r * Vi V »r *» Ό V OO Vŕ oa JUSIOBJ about ABOUT a. ABOUT ac Q £ (/) j Rev > > with X > >

· «·

O · o · o · o o · f ···

TABLE 1 (continued)

The results (best result bold) MPU ojpoq about N JfOUOR O rí O rn B? Ud APS & tyz ri about The q ousjojf O pi 9 H Q n wl q W ΓΜ ri q q w q O ri about ouauiBi ιη e M ANRE / Jj, T 90 C4 o ΓΜ - «r ΓΜ O ΓΜ in medication % wt. in lecithin organogel i ujzonojrenž ujíÄjdinnire R® with qdezuureqflq • r ujdoxop A tnyjpxanj in. m m m upuoduqBO 't -r • t T F 't * r n? ^ jojdaja ABOUT About CM = ABOUT ABOUT ABOUT 9 o PM jsajog • * 1 n iM n n PM m cn • amittO ΓΝ __ _{I '} PM atABjqod ΓΜ _ ΓΝ CN V | sa • r ·. CÁ * r. 9> <A 0 * Vi PO IA • A • y -T • y «Α rn jnaiOBj < < CC U » U u n o XI u L · U. 8

······················· · f · ·· ·· · ·· ··

TABLE 1 (continued)

: thanks edok tučné) uqou T n ojpaq XOUOR BZEd opsgdpz 9 J < s S < 9 ' rí < λ M Results The (best result 0U9 0J {[ s> I 9 9 T => < 9 w 1 1 lyqitp 9 in· and o ri about iM about ouamei anreAJj. oo Ο » 04 04 00 oo I 4 00 Ό 04 • wM * M Q S bO H o o s • m o u> 3 S Ή £ “s« > p S a £ ttjzauajrenž ABOUT ttlpúdujiure m tn ujdozEureqítij ΜΊ tn ^ · ujdaxop m tn <n m tn urpiixand m m ΠΊ m upuadtqBQ tn T -r • 'T T u ^ x-joidoia about 04 About CM about 1- Io I " ABOUT about about JsqoH m m m n m m 04 04 m m & rtUtqo - 04 04 - 04 04 81AB [C [0J rs wl vn m m m tn m m m o rf O * T O * r m T r * m «n tn JUaiOBJ o o □ □ c ΰ o □ x x M * -J -1 J J

·· ···· ··

TABLE 1 (continued)

The results (best result bold) eqou about oipaq VU0R iE? ed O bi O bi apsgdpz onojajf seems © -t WP about © about ohouibi aiuBAii 00 b · -t bl medication % by weight, in a lecithin organogel ujzonajreng uftAjdujnire njdazmietpfôf * 0- rr ujtfaxop * R> uippxojid m m upnodBqBT) ujgaidojax © about «jsoioH «*) m m bl UO ^ ÄA • Sjttnqo M. M r » OIAVIW n Γ4 n ^ PA ri * T b | bl * T rr juoiobj s z Σ Σ Σ Σ z z

φ φ

TABLE 2

ΦΦ φ ΦΦ φ Φ ΦΦ ΦΦ

ΦΦ φφ

Φ

Φ ΦΦΦ

Φ ΦΦ • φΦ φ φ φ φ φΦ

Φ · ·· φφ ΦΦ

Φ φΦ φΦ φΦ φφ Φ

Gender: 1 = male = female

Surgery: 1 = one or more = no surgery

Pain: 1 = mild 2 = moderate = severe - sufficient to induce observable tears

Duration: duration of treatment in weeks

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

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

TABLE 3 percent of reported pain relief

The place N (data count) no effect slight effect Slight-medium effect medium effect considerable effect Total relief wrist 13 16.7 33.3 8.3 41.7 shoulder 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 varlet 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

· 99 9 9 99 9 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99 99

TABLE 4 (percentages of pain relief reported)

N no effect slight effect slight medium effect medium effect considerable effect Total 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 Tricyclic 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 result without doxepin 43 18.6 32.6 14 23.3 7 4.7 The best result with doxepin 13 7.7 7.7 53.8 23.1 7.7

Example 51

A 51-year-old woman applied the composition of Example 46, which contained 20% ketoprofen, 5% doxepin, and 10% guaifenesin to the back for 2 weeks. She reported moderate pain relief lasting several hours after each administration. It reported no skin irritation or any other side effects. Oral medication produced no improvement and caused serious GI side effects.

···················································

Example 52

A 34-year-old man applied a formulation containing 20% ketoprofen, 4% carbamazepine, and 5% doxepin to a very difficult scarred wrist over which he had 4 surgeries due to carpal tunnel syndrome. He reported moderate pain relief lasting several hours after each administration. No other treatment, including opioid analgesic oral medication, caused a slight pain relief.

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

Example 54

A 58-year-old spinal cord injury resulting in spastic quadruparesis reported moderate relief from pain and muscle spasms following administration of the Example 53 composition containing 20% ketoprofen, 4% carbamazepine, 4% gabapentin, and 10% guaifenezine. applied over 8 weeks to the back and hips. She did not tolerate oral administration of carbamazepine and gabapentin due to systemic side effects, including carbamazepine skin rash and dizziness and gabapentin sedation. It did not report any side effects or skin irritation when applying the transdermal formulation.

EXAMPLE 55 g of doxepin powder are mixed with 26 ml of pluronic and placed in a refrigerator until liquefied. 1200 mg of gabapentin is mixed with 1 ml of propylene glycol and placed in a Luer-tip syringe. Add

6.6 ml of soya lecithin and mix thoroughly between syringes. Mix 24 g of ketoprofen and 8 ml of alcohol thoroughly between two Luer-tip syringes. The doxepin mixture is thoroughly mixed with the gabapentin mixture and then the ketoprofen mixture is added and the resulting material is thoroughly mixed. 20% pluronic (about 54 ml) is added in an amount sufficient to provide 60 ml of a composition comprising 20% ketoprofen, 4% gabapentin and 5% doxepin.

Example 56

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

Example 57

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

·· ····

·· ···

Example 57A

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

Example 58

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

Example 58A

A 57-year-old man with a history of 7 surgical procedures on his spine applied a mixture of Example 45 containing 4% carbamazepine and 5% amitriptyline to his back for 2 weeks. He reported mild to moderate pain relief, longer and better than transdermal opioid administration (Duragesic). He did not report side effects, especially not skin irritation.

Example 59

A 38-year-old man with a history of shoulder ligament stretching applied the composition of Example 45 containing 4% carbamazepine and 5% amitriptyline to the shoulder for two weeks. He reported mild to moderate pain relief, without skin irritation or other side effects.

·· ························

Example 61

Sufficient carbamazepine and gabapentin are added to the combination of soy lecithin and pluronic to form a lecithin organogel containing about 4% carbamazepine and 5% gabapentin.

Example 62

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

Example 63

Dissolve 3.6 g of gabapentin in 5.4 ml of ethoxydiglycol in a mortar, add 9.6 g of ketoprofen and 2.7 g of piroxicam and mix thoroughly. 19.8 ml of soya lecithin is added and the resulting mixture is thoroughly mixed and added to a sufficient amount of 20% Pluronic gel to obtain a 90 ml formulation containing about 10% ketoprofen, 4% gabapentin and 3% piroxicam.

Example 64

Dissolve 3.6 g of gabapentin in 5.4 ml of ethoxydiglycol in a mortar, add 9 g of ketoprofen and 0.9 g of piroxicam and mix thoroughly. Add 19.8 ml of soya lecithin and mix thoroughly and add 20% Pluronic gel in a quantity sufficient to give 90%. ·· ·· ······

999 ml of a formulation containing about 10% ketoprofen, 4% gabapentin and

1% piroxicam.

Example 65 g of doxepin are mixed with 50 ml of 33% Pluronic F127 and placed in a refrigerator to dissolve the mixture. 12 g of gabapentin are dissolved in 9 ml of ethoxydiglycol and mixed to form a fine paste. 52.8 ml of soya lecithin are added and the mixture is mixed. Doxepin / Pluronic is added and the material is mixed well. 20% Pluronic F127 is added in an amount sufficient to provide 240 ml of a composition comprising about 5% by weight gabapentin and 5% by weight doxepin.

Example 66

A 36-year-old man with knee damage affecting joint surfaces and disrupting vascular supply applied the composition prepared as described in Example 65 to his knee several times a day. He reported moderate and significant (40%) pain relief that persisted for 4 to 6 hours. No relief has been reported with prior application of the carbamazepine-amitriptyline gel to this knee.

Example 67 g of doxepin are mixed with 18 ml of 33% Pluronic. place in the refrigerator to dissolve the mixture. 6 g of gabapentin are crushed 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 are added and the mixture is mixed. 26.4 ml of soya lecithin are added and the mixture is mixed. Doxepin / Pluronic is added and the material is mixed well. Pluronic gel (25.2 ml 33% Pluronic, but 30% or 20% Pluronic may also be used) is added in an amount sufficient to provide a 120 mi composition containing about 5% gabapentin, about 5% doxepin and about 10% by weight of guaifenesin.

Example 68

A 55-year-old woman with spinal and shoulder damage applied the composition 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 a moderate to significant improvement. The doxepin-only mixture produced only slight relief from back pain and mild to moderate relief of back and leg pain. A mixture containing only ketoprofen, gabapentin and piroxicam caused only a slight reduction in back pain.

Example 69

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

Example 70

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

·· ····

Example 71

A 61-year-old man with back, neck, and hand injections applied the compound prepared as described in Example 7 four times a day to the neck and achieved significant pain relief. He applied the same mixture to the elbow and achieved moderate pain relief.

· · · · · · · · • · · · · · · · · · · · · · · ·

Example 72

A composition containing 7% antidepressant and about 10% myorelaxant is prepared by dissolving 3.15 g of trimipramine and 4.5 g of guaifenesin in a mixing vessel using 2.7 ml of ethoxydiglycol. Approximately 9.9 ml of soya lecithin is added and mixed thoroughly. Pluronic F127 NF (20%) is added in an amount sufficient to give a total volume of 45 ml and mixed.

Example 73

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

Example 74

A gel formulation containing about 7% antidepressant and about 13% myorelaxant is prepared from 14.4 g of doxepin, 31.2 g of guaifenesin, 12 ml of ethoxydiglycol, 52.8 ml of soya lecithin and Pluronic F127 NF (33%) in amounts. sufficient to give a total volume of 240 ml.

····································· · · · · · 9 999 9 9 9 99999 • 9 9 9999 999 «· ·· ·· ·· * · ·

Example 75

A gel formulation containing 5% antiepileptic is prepared from 6 g of lamotrigine, 6 ml of ethoxydiglycol, 26.4 ml of soya lecithin and Pluronic F127.

NF (33%) in an amount sufficient to give a total volume of 120 mL.

Example 76

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

Example 77

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

Example 78

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

Example 79

A gel formulation containing 10% metocarbamol is prepared from 12 g of crushed metocarbamol, 6 ml of ethoxydiglycol, 26.4 ml of soya lecithin and

I ο · ············

Pluronic F127 NF (33%) in an amount sufficient to provide a total volume of 120 mL.

Example 80

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

Example 81

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

Example 82

A series of human experiments were performed using various combinations of pharmaceutical agents. The results are shown in FIG. Second

An assessment of pain relief is presented, as reported by patients for the various parts of the body to which the medication has been applied. The range used in FIG. 2 is as follows:

= no effect (no or ambiguous effect) = mild effect (less than 15% pain reduction)

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

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

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

9 ······· * * «99 99 99 99 999

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

3.5 = strong-complete effect (60-80% pain reduction) 4.0 = full-effect (more than 80% pain reduction)

For each part of the body and for the percentage composition of each medication, individual ratings are given as well as averages that are statistical averages of values according to the scale above. For example, 3 patients were given 5% doxepin on the back and the median pain relief was 2.333. In contrast, 13 patients received a 5% / 10% doxepine / guaifenesin combination and had an average pain relief value of 2.857. Also shown are results for 7/10 and 10/10 formulations containing doxepin / guaifenesin, and the mean for the whole dox-guai sample in all combinations is shown at the end of the section and is equal to 2.722.

The abbreviations used in FIG. 2 are as follows:

abbreviations Generic pharmaceutical names c-dox-gu carbamazepine doxepine guaifenesin c-gab-do carbamazepine gabapentin doxepin carb carbamazepine carb-ami carbamazepine amitriptyline carb-gab carbamazepine gabapentin dox doxepin dox-chl doxepin chlorzoxazone dox-guai doxepin guaifenesin g-dox-gu gabapentin doxepin guaifenesin gab-dox gabapentin doxepin a-ca-dox ketoprofen carbamazepine doxepine k-car-pi ketoprofen carbamazepine piroxicam a-dox-ch ketoprofen doxepin chlorzoxazone a-dox-gu ketoprofen doxepin guaifenesin k-dox-pi ketoprofen doxepin piroxicam a-g-to-g ketoprofen gabapentin doxepin guaifenesin

K-gab k-gab-a k-gab-do k-gab-g k-gab-pi k-pi ia-li-gu lam-chlor n-dox-ch naproxen tri-chlor ketoprofen gabapentin ketoprofen gabapentin amitriptyline ketoprofen gabapentin doxepin ketoprofen gabapentin guaifenesin ketoprofen gabapentin piroxics ketoprofen piroxics lamotrigine lidocaine guaifenesin lamotrigine chlorzoxazone naproxen oxzoxazone naproxen doxazone

Based on the results described herein, doxepine is effective in the treatment of pain by transdermal administration and further shows that it is virtually free of unwanted side effects with said transdermal administration.

Doxepine appears to produce approximately three times better response compared to at least some of the pharmaceutical agents described herein, regardless of whether these other pharmaceutical agents are administered alone or in combination. Doxepin appears to be significantly more potent than amitriptyline as an analgesic for transdermal administration, for example in the treatment of neuropathic pain. This seems to be true regardless of whether doxepin is administered as a single agent or in combination with other pharmaceutical agents as described herein.

Carbamazepine has been shown to have positive effects in the treatment of pain, e.g. Carbamazepine causes a rash in some patients that requires discontinuation.

These side effects are similar to those seen with oral carbamazepine. It has been shown that gabapentin has no adverse effects when administered transdermally. Although some patients have been shown to benefit from transdermal administration of a combination of ketoprofen, gabapentin and piroxicam, these positive effects are relatively weak compared to doxepin.

················ I · · ·

Guaifenesin has been shown to be beneficial as an auxiliary treatment for painful muscle spasms. For the patient population described herein, amitriptyline appears to have a limited analgesic effect when administered transdermally. It has been shown that combining gabapentin with doxepin may be an additional benefit. The addition of guaifenesin to doxepin may be beneficial especially when muscle spasms are present.

From the results above, it is clear that the invention provides treatments for patients in which oral administration is suboptimal, such as patients with gastrointestinal or other side effects, patients with poor absorption of orally administered pharmaceutical compositions, and / or patients in need of long-term administration. or a relatively rapid administration or a higher rate of increase in plasma concentrations. The present invention provides a method for administering therapeutic amounts of pharmaceutical agents, at least to a certain patient population, substantially free of any skin irritation, gastrointestinal or other adverse reactions associated with oral administration of pharmaceutical agents, particularly psychopharmaceuticals, and clinical effects comparable to or greater than administration of appropriate pharmaceutical agents. For these reasons, the most effective medications for treating pain are those described in the examples

65, 67, 69 and 70.

It is reasonably contemplated that plasma concentrations may be increased by providing two or more transdermal applications per day and / or by applying transdermal formulations to two or more sites.

In at least one case, twice daily dosing of Prozac gel formulation appears to increase plasma concentrations to approximately 2-fold. It is expected that application of the Prozac gel composition at two sites twice daily will result in therapeutic concentrations of approximately 140-250 ng / ml. At least partially based on the results described for fluoxetine, it is assumed that olanzepine (sold under the trade name • 9 9)

9 0 0 09O 90 • o o 9 * 9 000090 OOOO O

Ä1. ········· ie 1 ·· ·· ·· ·· 90990

Zyprexa) or a fluoxetine / olanzepine mixture in a lecithin organogel will be useful.

Another type of psychotropic or psychopharmaceutical medication for which transdermal administration can be used is the administration of psychostimulatory agents. One example of a psychostimulatory agent is methylphenidate (marketed under the trade name Ritalin), which is used in the treatment of attention deficit hyperactivity disorder (ADHD). Methylphenidate usually lasts for 2-4 hours, requiring frequent dosing, which is particularly difficult in school children. Transdermal administration is believed to provide a prolonged effect over the entire day, eliminating the need for frequent oral administration. Transdermal administration is also expected to exclude peaks and decreases in plasma concentration, allowing better clinical performance. It is anticipated that similar results will also be obtained for other pharmaceutical agents such as dextroamphetamine (marketed under the trade name Dexedrine) for which the benefits will be less pronounced, since there is a controlled release form, the duration of action is usually 5-6 hours . Another group of psychopharmaceuticals that will benefit from transdermal administration are antipsychotics, such as those used to treat schizophrenia.

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

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 (1)

PATENT CLAIMS ·· ···· 8 8 8 · 18 ·· 88 «I 8 B 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. 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 activity 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. The transdermal composition of claim 1, wherein the amine-containing compound is doxepin. The transdermal composition of claim 1, wherein the amine-containing compound is trimipramine. The transdermal composition of claim 1, wherein the amine-containing compound is a sodium channel blocker. • · ·· ···· 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, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof. The transdermal composition of claim 10, wherein the myorelaxant is guaifenesin. 12. The transdermal composition of claim 3, wherein the myorelaxant is benzodiazepine. 13. The transdermal formulation of claim 12 wherein the benzodiazepine is clozapine. 14. The transdermal formulation of claim 12 wherein the benzodiazepine is diazopam. 15. The transdermal composition of claim 1, further comprising an anti-inflammatory compound. 16. The transdermal composition of claim 15, wherein the anti-inflammatory 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 the amine-containing compound and a muscle relaxant. 19. The transdermal formulation of claim 18 wherein the myorelaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof. 20. The transdermal composition of claim 18 wherein the myorelaxant is guaifenesin. 21. The transdermal composition of claim 18, wherein the myorelaxant has biphasic solubility. 22. The transdermal composition of claim 18, wherein the amine-containing compound is an antidepressant compound. 23. The transdermal composition of claim 22, wherein the antidepressant compound is a tricyclic antidepressant compound. 24. The transdermal composition of claim 22, wherein the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and combinations thereof. 25. The transdermal composition of claim 18, wherein the amine-containing compound is doxepin. 26. The transdermal composition of claim 18, wherein the amine-containing compound is a sodium channel blocker. ·· ···· ·· 27. The transdermal composition of claim 18, wherein the pharmaceutically acceptable carrier is a lecithin organogel. 28. The transdermal composition of claim 18, further comprising an anti-inflammatory compound. 29. The transdermal composition of claim 28, wherein the anti-inflammatory compound is a 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 a subject; (b) guaifenesin in an amount effective to increase 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. • · ··· · The method of claim 34, wherein the transdermal composition further comprises an activity enhancing agent for 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. The method of claim 37, wherein the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and combinations thereof. 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. · B B e B B B B · · · · · · · · · B ·· ··· B B 'B B · · · ·· B f B B 9 B WB 9 B WB The method of claim 36, wherein the myorelaxant is benzodiazepine. 46. The method of claim 45, wherein the benzodiazepine is clozapine. 47. The method of claim 45, wherein the benzodiazepine is diazepam. 48. The method of claim 34, wherein the transdermal composition further comprises an anti-inflammatory compound. 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 of selecting a compound suitable for treating pain in an individual, the method comprising: (a) transdermally administering to the subject an amine-containing compound having biphasic solubility; and (b) detecting whether the pain is being treated in the subject, allowing selection of a compound suitable for treating pain in the subject. 52. A transdermal composition for treating pain in an individual comprising: (a) the 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 a compound suitable for blocking afferent neuron signal transmission.