HRP20000905A2 - Methods and transdermal compositions for pain relief - Google Patents

Description

Field of invention

The proposed invention relates to methods and preparations for transdermal application. In particular, the proposed invention relates to methods and preparations for transdermal application of an amine-containing compound having biphasic solubility and/or an agent that enhances the action of an amine-containing compound having biphasic solubility, e.g. a muscle relaxant, for pain relief.

Background of the invention

Injury to somatic sensory nerves is believed to cause loss of somatic sensation. Such an injury can be caused by a variety of means including trauma, diseases such as diabetes, herpes zoster and late stage cancer, chemotherapy, or chemical injury. It is believed that after a nerve injury, the pain of the nerve circulates around itself, both automatically and biochemically. In many patients suffering from somatic sensory nerve injuries, negative symptoms, such as numbness, are associated with positive sensations, which include a type of false sensation of pain. This sensation can range from mild dysesthesia to excruciating pain, which makes some patients unable to work, walk or perform other daily activities.

Previously, patients were generally treated with analgesics for pain relief. The vast majority of such patients received doses of these agents orally. Unfortunately, in some situations, oral administration of such agents has been associated with various side effects, such as liver damage, kidney damage, gastrointestinal side effects, habituation, sedation, and/or weight gain that the patient cannot tolerate well. In other cases, deficient absorption of oral preparations has resulted in plasma levels that are below therapeutic levels. In other cases, the agents have a relatively short plasma residence time, necessitating unusually frequent dosing. In general, oral administration involves a time delay while the analgesic is absorbed through the digestive tract, before it reaches the bloodstream. A number of agents traditionally administered orally, or by injection, were not suitable for some patients or were suboptimal when administered in such a manner. There are numerous drugs that some patients do not tolerate well when given orally (eg, causing unwanted gastrointestinal or other side effects) and/or that produce undesired high or low target tissue concentrations. In some cases, the dosage suitable for oral administration, after more or less uniform distribution in the body, is undesirably low to achieve the desired results, especially in the area of, for example, tissues. Oral or injection administration may result in plasma levels that are too low or rise too rapidly, eg, may involve an undesirably long lag time while the analgesic is absorbed through the gastrointestinal tract before entering the bloodstream, or may result in "high" values and then an unwanted low level, while a more stable level would be more favorable.Some analgesics in particular are known to cause or contribute to kidney or liver damage when given orally.

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

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

Summary of the invention

The proposed invention provides a transdermal preparation for the treatment of pain in a subject, especially a human. A transdermal composition for treating pain in a subject comprises an amine-containing compound having biphasic solubility in an amount effective to treat the subject's pain and a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine-containing compound, eg, a lecithin organogel carrier. In a preferred embodiment, the transdermal preparation further comprises an agent that enhances the action of an amine-containing compound having biphasic solubility, eg, a muscle relaxant, such as guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and combinations thereof. Preferably, an agent that enhances the action of an amine-containing compound that has biphasic solubility, eg, a muscle relaxant, also has biphasic solubility.

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

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

In an embodiment of the invention, a transdermal composition comprising an amine-containing compound, as described herein, and an anti-inflammatory compound, such as a non-steroidal anti-inflammatory compound, e.g., celecoxib, etodolac, mefanamic acid, nubemetone, salsalate, naproxen, Vioxx® , and their combinations. Such a composition may further include an agent that enhances the action of the amine-containing compound, eg, a muscle relaxant such as guaifenesin.

In another aspect, the invention provides a transdermal composition for treating pain in a subject, which composition includes an amine-containing compound having biphasic solubility in an amount effective to treat pain in the subject; a muscle relaxant in an amount effective to enhance the action of the amine-containing compound having biphasic solubility; and a pharmaceutically acceptable carrier suitable for transdermal delivery of an amine-containing compound having biphasic solubility and a muscle relaxant.

Also, in another aspect, the invention provides a transdermal preparation for treating pain in a subject, which preparation includes doxepin in an amount effective to treat pain in the subject, guaifenesin in an amount effective in enhancing the action of doxepin; and a pharmaceutically acceptable carrier suitable for transdermal delivery of doxepin and guaifenesin.

Other aspects of the invention are methods for treating pain in a subject, by which methods 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 delivery of the amine-containing compound, thereby treating the subject's pain. In a preferred embodiment, the transdermal composition is applied to the skin of the subject.

Another aspect of the invention is a method for selecting a compound suitable for treating pain in a subject. The method involves transdermal application to a subject of an amine-containing compound having biphasic solubility; and determining whether the subject's pain has been cured, thereby selecting a compound suitable for treating the subject's pain. In a preferred embodiment, the method may further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program; and determining whether the three-dimensional chemical structure of the compound has characteristics sufficient to act as a sodium channel blocker, thereby selecting a compound suitable for treating pain in the subject.

In another aspect, the invention provides a transdermal composition suitable for transdermal delivery, which includes a therapeutically effective amount of a pharmaceutical compound (eg, a serotonin reuptake inhibitor, a mood stabilizing compound, a dopamine compound, a compound suitable for the treatment of attention deficit hyperactivity disorder, a compound suitable for the treatment of hypertension and akathisia, an analgesic compound, or a compound used to treat impotence) and a pharmaceutically acceptable carrier suitable for transdermal delivery of the pharmaceutical compound, eg, a lecithin organogel carrier.

Also, in another aspect, the invention provides a transdermal composition for treating pain in a subject that includes a compound suitable for blocking afferent neuronal transmission in an amount effective to block afferent neuronal transmission in the subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery.

Other forms and advantages of the invention will be apparent from the following detailed description and patent claims.

Short description of the pictures

Figure 1 shows the evaluation method applied to evaluate the performance of the proposed invention.

Figure 2 shows a table with results from clinical trials in which the invention was applied.

Description of the invention in detail

The proposed invention provides a transdermal preparation 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 a subject; and a pharmaceutically acceptable carrier for transdermal delivery of the amine-containing compound having biphasic solubility.

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

As used herein, the term "pain" is professionally recognized and includes a bodily sensation induced by a noxious chemical, mechanical or thermal cause in a subject, eg, a mammal such as a human. The term "pain" includes chronic pain, such as lower back pain; pain due to arthritis, eg osteoarthritis, joint pain, eg knee pain or carpal tunnel syndrome; myofascial pain, and neuropathic pain. The term "pain" further includes acute pain, such as that associated with a muscle strain or dislocation; toothache; headache; pain associated with surgery; or pain associated with various forms of tissue injury, eg, inflammation, infection, and ischemia.

As used herein, the term "amine-containing compound having biphasic solubility" includes compounds having at least one amino group and having sufficient lipid solubility (eg, solubility in polar solvents such as ethanol, ethoxy-diglycerol, ethoxydiglycol, chloroform, benzene, and the like ), so that this compound passes through the stratum corneum, and has sufficient water solubility to be active in the aqueous environment of the dermis and the tissue that is located below it.

The transdermal compositions of the present invention comprise an amine-containing compound having biphasic solubility in an amount effective to treat pain in a subject.

As used herein, the terms "an amount effective for the treatment of pain" and "an effective amount" are used interchangeably herein and include an amount that, by dosage and time period required to achieve the desired result, is effective, e.g., for the treatment of pain in a subject. An effective amount of an amine-containing compound or pharmaceutical compound, as defined herein, may be varied according to factors such as the disease state, age and weight of the subject, and the ability of the amine-containing compound or pharmaceutical compound to elicit the desired response in the subject. Dosage regimens can be adjusted to obtain an optimal therapeutic response. An effective amount is also one at which any toxic or deleterious effect of the amine-containing compound having biphasic solubility, or of the pharmaceutical compound, is balanced against the therapeutically beneficial effects.

The transdermal preparations according to the invention may further include an agent that enhances the action of an amine-containing compound that has biphasic solubility. As used herein, an "agent that enhances the activity of an amine-containing compound having biphasic solubility" includes an agent that enhances the pharmacological activity of an amine-containing compound having biphasic solubility (eg, the ability of the amine-containing compound to treat pain), or enhances transdermal release of an amine-containing compound that has biphasic solubility (eg, the ability of the amine-containing compound to pass through the stratum corneum), or enhances both the pharmacological action and the transdermal release of the amine-containing compound. Examples of agents that enhance the action of an amine-containing compound having biphasic solubility include the muscle relaxants described in detail further below.

As used herein, the term "transdermal" composition includes compositions that can pass through the stratum corneum of a subject. The term "transdermal" further includes compositions that can pass through the epidermis of a subject, compositions that can pass through the dermis of a subject, and compositions that can pass through the hypodermis of a subject. In preferred embodiments, the term "transdermal" includes compositions that can pass through the skin of a subject and reach tissues and organs located beneath the skin.

As used herein, the term "transdermal delivery" refers, for example, to the delivery of a compound through the stratum corneum of a subject. The term transdermal delivery further includes delivery of, for example, a compound through the epidermis of a subject, delivery of, for example, a compound through the dermis of a subject, and delivery of, for example, a compound through the hypodermis of a subject. In preferred embodiments, the term transdermal delivery includes delivery, for example, of a compound through the skin of a subject to a tissue and organ located beneath the skin.

The present invention further provides transdermal compositions for the treatment of pain comprising a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound.

As used herein, the term "compound that can block afferent neuron transmission" refers to a compound that can block an afferent neuron, i.e., a sensory neuron, from transmitting impulses to the central nervous system.

Various aspects of the invention are further described in detail in the following paragraphs.

Amine-containing compounds having biphasic solubility

Amine-containing compounds having biphasic solubility that are used in the transdermal compositions of the invention include antidepressant compounds, antiepileptic compounds, anticonvulsant compounds, and sodium channel blockers. As used herein, the term "antidepressant compounds" includes compounds that can alleviate the symptoms of depression. Examples of antidepressant compounds include all tricyclic antidepressants (eg, amitriplyline, dothiepine, or lofepramine), bupropion (sold under the trade name Wellbutrin), reboxetine (sold under the trade name Edronax), nefazodone (sold under the trade name Serzone) and trazodone (sold under the trade name Desyrel). Antidepressant compounds are described, for example, in the 1998 SIGMA Catalog and in "The Merck Index", 12th edition, Budavari et al., published by Merck & Co., Inc. Rahway, N. J. 1996, the contents of which are incorporated herein by reference.

In one embodiment of the proposed invention, the antidepressant compounds of the proposed invention contain a tricyclic group. Therefore, in a portable version, the transdermal preparation of the proposed invention contains tricyclic antidepressant compounds. Examples of tricyclic antidepressants include adinazolam, amitriptyline oxide, amoxapine, clomipramine, demexiptyline, dimethacrine, dothiepin, doxepin, imipramine N-oxide, iprindole, lofepramine, melitracene, metapramine, noxiptiline, pizotiline, propizepine, quinupramine, tianeptine, and trimipramine. A particularly preferred tricyclic antidepressant for use in the compositions of this invention is doxepin.

Tricyclic antidepressant compounds are described, for example, in "Guide to Clinical Neurology" by J.P. Mohre et al. (Churchill Livingstone, 1995) whose content is included here as a literature source.

First of all, the tricyclic antidepressant compound is selected from the group consisting of doxepin, trimipramine, other tricyclics having biphasic solubility and combinations thereof. When combined with other compounds, such as an agent that enhances the action of an amine-containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a nonsteroidal anti-inflammatory compound, as described below, the tricyclic antidepressant is advantageously approx. 1 wt. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 15 wt. % and best of approx. 5 wt. % to approx. 13 mass. %.

Compounds containing amine and having biphasic solubility, used in transdermal preparations according to the invention, include antiepileptic compounds. As used herein, an "antiepileptic compound" includes compounds that can alleviate the symptoms of epilepsy. Examples of antiepileptic compounds for use in the compositions of the invention include lamotrigine, felbamate and carbamazepine. Advantageously, the antiepileptic compound is selected from the group consisting of lamotrigine, felbamate, carbamazepine and combinations thereof. When combined with other compounds, such as an agent that enhances the action of an amine-containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a non-steroidal anti-inflammatory compound as described below, the antiepileptic compound represents from approx. 1 wt. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 20 wt. % and best of approx. 5 wt. % to approx. 15 wt. %. Antiepileptic compounds are described, for example, in the 1998 SIGMA Catalog, "The Marck Index", 12th edition, Budavari et al., eds. Merck & Co., Inc., Rahway, N.J., 1996, and in the "Guide to Clinical Neurology" by J.P. Mohr et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference.

In another aspect of the present invention, the amine-containing compounds having biphasic solubility according to the present invention include anticonvulsant compounds. As used herein, the term "anticonvulsant compound" refers to compounds that can alleviate the symptoms of a convulsion, i.e., violent involuntary tetanic contractions of an entire group of muscles. Examples of anticonvulsant compounds used in the compositions of the invention include felbamate, lamotrigine and carbamazepine. Preferably, the anticonvulsant compound is selected from the group consisting of felbamate, lamotrigine and mixtures thereof. When combined with other compounds, such as an agent that enhances the action of an amine-containing compound, e.g., a muscle relaxant, and/or an anti-inflammatory compound, e.g., a non-steroidal anti-inflammatory compound as described below, the anticonvulsant compound represents from approx. l mass. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 20 wt. % and best of approx. 5 wt. % to approx. 15 wt. %. Anticonvulsant compounds are described, for example, in the 1998 SIGMA Catalog, "The Marck Index," 12th ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and in the "Guide to Clinical Neurology " by J.P. Mohr et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference.

Also in another aspect of the proposed invention, compounds containing amine and having biphasic solubility according to the proposed invention include adrenergic agonist compounds. Preferably, the adrenergic agonist compound is tizanidine. When combined with other compounds, such as a muscle relaxant, and/or a non-steroidal anti-inflammatory compound as described below, the adrenergic agonist compound represents from approx. 1 wt. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 20 wt. % and best of approx. 5 wt. % to approx. 15 wt. %. Adrenergic agonist compounds are described, for example, in the 1998 SIGMA Catalog, "The Marck Index," 12th ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and in the "Guide to Clinical Neurology" by J.P. Mohra et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference.

The amine-containing compounds having biphasic solubility used in the transdermal compositions of the invention further include sodium channel blockers. As used herein, "sodium channel blockers" include compounds capable of blocking the action of sodium channels. Examples of sodium channel blockers include tetrodoxine, flecainide, disopyramide, and terfenadine. Sodium channel blockers are described, for example, in the 1998 SIGMA Catalog, "The Marck Index," 12th ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and in "Guide to Clinical Neurology" by J.P. Mohra et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference.

Whenever nerves are injured, for example by trauma, disease such as diabetes, herpes zoster, or late-stage cancer, or by chemical injury (eg, as a side effect of agents containing fake nucleoside anti-HIV drugs), nerve pain circles around itself. , anatomical and/or biochemical. This is why new sodium channels are formed after an injury, which are believed to form the basis for the development of chronic pain. With a similar action as in the root of the dorsal ganglia, chronic regional pain syndromes can develop. Each time one of these sodium channels is depolarized, a pain impulse is generated. As there are many sodium channels, they can be a constant cascade of nerve impulses causing allodynia, burning sensation and/or dysesthesia. It is believed that some chronic pain may be mediated by sodium channels and nerve cells. Therefore, it is believed that amine-containing compounds with biphasic solubility, which can block sodium channels, can also be used in transdermal preparations and rush.

In one embodiment of the invention, the amine group in the amine-containing compounds having the biphasic solubility of the proposed invention can act similarly to sodium ion upon entering the sodium channel of the nerve cell membrane. The non-polar group, which is preferably present in the amine-containing compound having the biphasic solubility of the present invention, can interact with the nerve cell membrane, possibly by means of van der Waals forces. In this case, the presence of the non-polar group is believed to prevent or inhibit the complete uptake of the amine-containing compound having biphasic solubility across the nerve cell membrane. One or more such interactions are believed to prevent or reduce the amount and/or rate of depolarization and ion exchange in the conduction of stimuli, thereby reducing the sensation of pain.

The amount of an amine-containing compound having biphasic and solubility that can be used for transdermal pain relief can be determined by methods known in the art, and is typically from approx. 1 mg to approx. 300 mg per subject and dose, preferably from approx. 5 mg to approx. 100 mg per subject and dose, and the most favorable of approx. 10 mg to approx. 50 mg per subject and dose, depending on various factors including whether the amine-containing compound in question has biphasic solubility, whether the area of transdermal application is the site of action, and the anticipated size of the site of action. In a preferred embodiment, the amount of an amine-containing compound having biphasic solubility that can be used for pain relief transdermally 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 subject and dose.

Muscle relaxants

The transdermal preparations of the proposed invention may also contain a muscle relaxant. As used herein, the term "muscle relaxant" refers to compounds that facilitate or enhance muscle relaxation (eg, provide relief of muscle spasm) and thereby facilitate or enhance transdermal delivery of a transdermal composition of the invention. Examples of muscle relaxants include skeletal muscle relaxants and smooth muscle relaxants, such as anticholinergics, antispasmodics, bronchodilators, and vasodilators. Muscle relaxants are described, for example, in the 1998 SIGMA Catalog, "The Marck Index," 12th ed., Budavari et al., eds., Merck & Co., Inc., Rahway, N.J., 1996, and in "Guide to Clinical Neurology" by J.P. Mohra et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference. The preferred muscle relaxant is selected from the group consisting of ganifenesine, benzodiazepines (eg, clozapine or diazopam), chlorzoxazone, dantrolone sodium, metaxalone, carisoprodol, and other muscle relaxants having biphasic solubility, and combinations thereof. More specifically, the muscle relaxant is selected from the group consisting of ganifenesin, chlorzoxazone, and combinations thereof. A preferred muscle relaxant for use in the compositions of the invention is guaifenesin.

First of all, the muscle relaxant has biphasic solubility. Advantageously, the muscle relaxant when present in the pharmaceutical preparation represents from approx. 1 wt. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 20 wt. % and best of approx. 5 wt. % to approx. 15 wt. %.

Anti-inflammatory compounds

The transdermal preparations of the proposed invention may also contain an anti-inflammatory compound. As used herein, the term "anti-inflammatory compound" refers to a compound that can reduce cell migration caused by an event associated with ischemia and trauma, and therefore reduces edema formation thereby achieving pain relief. Preferably, the anti-inflammatory compound is a non-steroidal anti-inflammatory compound (ie, NTHE) including ketoprofen. Anti-inflammatory compounds, eg, NTHE, are described, for example, in the 1998 SIGMA Catalog, "The Marck Index", 12th edition, Budavari et al., ed. Merck & Co., Inc., Rahway, N.J., 1996 , p. THER-1 through THER-28 and in "Guide to Clinical Neurology" by J.P. Mohra et al., (Churchill Livingstone, 1995), the contents of which are included here as a reference. Advantageously, the NTHE is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx®, COX-2, which have biphasic solubility, and combinations thereof.

More specifically, NTHE is selected from the group consisting of celecoxib, etodolac, naproxen, COK-2, NHTE compounds having biphasic solubility and combinations thereof. First of all, NTHE has biphasic solubility. NTHE, when present in a transdermal preparation, represents primarily from approx. l mass. % to approx. 30 wt. % of the total amount of medicine, even better than approx. 3 wt. % to approx. 20 wt. % and best of approx. 5 wt. % to approx. 15 wt. %.

Dosage

To achieve the desired effect, the concentration as well as the amount of the amine-containing compound having biphasic solubility, the agent that enhances the action of the amine-containing compound having biphasic solubility, e.g., the muscle relaxant, and the anti-inflammatory compound can be independently varied. For example, a higher concentration of an amine-containing compound having biphasic solubility, a muscle relaxant, and an anti-inflammatory compound contained in a reduced viscosity dosage form may result in a rapid onset of action and a short duration of action. A high concentration of an amine-containing compound with biphasic solubility, a muscle relaxant and an anti-inflammatory compound contained in a dosage form of increased viscosity can result in a rapid, strong analgesic effect with a rapid onset and long-lasting effect. A low concentration of an amine-containing compound with biphasic solubility, a muscle relaxant and an anti-inflammatory compound, contained in a dosage form of increased viscosity may result in a rapid mild analgesic effect with a longer onset and short duration of action. A low concentration of an amine-containing compound having biphasic solubility, a muscle relaxant and an anti-inflammatory compound, contained in a dosage form of increased viscosity can result in a rapid mild analgesic effect with a longer onset and longer duration of action. Concentrations of an amine-containing compound having biphasic solubility, a muscle relaxant and an anti-inflammatory compound, which can be varied from very high to high contents in the total composition, combined with the possibility of coating thin (approx. 0.1 mm) or thick (approx. , 0.5 mm) layer, allow the practitioner of the invention to vary the dosage of the system as needed for the individual level of pain and the anatomical site in question. However, it should be appreciated that the time of onset of action as well as the duration of the analgesic effect of the transdermal preparation proposed by the invention varies from subject to subject, as well as depending on the site of application, and the properties of the compound containing the amine and having biphasic solubility, the muscle relaxant and the anti-inflammatory compound .

In general, the concentration of amine-containing compounds having biphasic solubility, muscle relaxant and anti-inflammatory compound can range, on a mass basis, from approx. 1% to approx. 30% of the total composition, primarily from approx. 3% to approx. 20% and best of approx. 5% to approx. 15%.

Pharmaceutically acceptable carrier

The transdermal compositions of the present invention also comprise a pharmaceutically acceptable carrier capable of transdermally delivering an amine-containing compound having biphasic solubility. As used herein, the term "pharmaceutically acceptable carrier suitable for transdermal delivery" refers to a carrier capable of delivering an amine-containing compound transdermally, as defined above. Suitable carriers for transdermal drug delivery are described in U.S. Pat. patent no. 5,446,070, the contents of which are incorporated herein by reference. Briefly, the pharmaceutically acceptable carriers of the present invention include any suitable finished (ie, solid) or unfinished (ie, non-solid, such as liquid or semi-liquid) carrier, including liquids, semi-liquids or solid carriers such as bioadhesives. Thus, the amine-containing compounds having biphasic solubility can be mixed with a pharmaceutically acceptable carrier such as a cream, gel, emulsion, lotion, ointment, paste, patch, ointment, spray, solution, or any "unfinished" carrier known in the art. profession for pharmaceutical delivery. For example, the base for the unfinished carrier can be a lipid, including phospholipids such as lecithins; fatty oils; lanolin; vasoline; paraffins; glycols; more fatty acids; and higher alcohols.

The term "bioadhesive" as used herein includes adhesives that bond to a biological surface such as skin or mucosal tissue. First of all, the bioadhesive of the proposed invention is self-adhesive in that it adheres to the site in question without the need to reinforce this adhesion with another adhesive. Suitable bioadhesive includes natural or synthetic polysaccharides as cellulose derivatives, including methyl cellulose, cellulose acetate, carboxymethyl cellulose, hydroxyethyl cellulose and the like; pectin; a mixture of sulfated sucrose and aluminum hydroxide; hydrophilic polysaccharide gums, including natural plant extracts, such as gum karaja, gati gum, tragacanth gum, xanthan gum, jaraja gum and the like; seed gums such as guar gum, carob seed gum, psyllium seed gum and the like; and lecithins such as soy lecithin. Additionally, in addition to the above ingredients, the compositions of the proposed invention may also contain other ingredients, such as various pharmaceutically acceptable additives available to a person skilled in the art. These additives include binders, stabilizers, preservatives, spices, fragrances and pigments.

In another embodiment, the pharmaceutically acceptable carrier of the proposed invention includes van pen cream (cetyl alcohol, stearyl alcohol, stearic acid, glycerol monostearate, isopropyl myristate, soy lecithin, BHT alcohol 95%, simethicone, 30% sodium hydroxide solution, polyol stearate, edetate disodium 5%, purified water, etc.).

Other pharmaceutical compounds

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

As used herein, "XN pharmaceutical compound" includes compounds suitable for the treatment of a target condition that can be delivered in an active form in vivo. Examples of pharmaceutical drugs include enzymes, chemical compounds, combinations of chemical compounds, biological macromolecules, and analogs thereof. Exemplary pharmaceutical compounds are described in continuation.

In one embodiment of the invention, the pharmaceutical compound is a specific serotonin reuptake inhibitor (SSRI). SSRIs are generally prescribed to patients diagnosed with mood disorders, some forms of anxiety disorders (especially panic disorder), obsessive compulsive disorders, some forms of menopausal disorders, and eating disorders (especially bulimia nervosa). Examples of such SSRIs include 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 ( which is sold under the commercial name Luvox).

In another embodiment of the invention, the pharmaceutical compound is a mood stabilizer such as carbamazepine (sold under the trade name Tegretol) and valproic acid (sold under the trade name Depakote). These agents are often used in psychiatry as complementary drugs (to obtain a better effect of antidepressants) or as anti-manic drugs in the treatment of bipolar mood disorder. Mood stabilizers are also used in neurological practice to treat panic attacks and to treat certain pain disorders.

Also, in another embodiment of the invention, the pharmaceutical compound is a compound used for the treatment of attention deficit hyperactivity disorder (ADHD), one example of which is permoline (sold under the commercial name Cylert). Permoline is a drug used to treat attention deficit hyperactivity disorder in children and adults. It is particularly insoluble in water, but soluble in ethylene glycol and lipids, making it a good candidate for transdermal application.

In a further embodiment of the invention, the pharmaceutical compound is a dopamine compound used for the treatment of Parkinson's disease, examples of which are pergolide (sold under the commercial name Permax) and bromocriptine mesylate (sold under the commercial name Parlodel).

Also, in another embodiment of the invention, the pharmaceutical compound is a compound for the treatment of hypertension and akathisia, a particular example of which is propranalol (sold under the commercial name Inderal).

Also in another embodiment of the invention, the pharmaceutical compound is a compound used to treat impotence such as sildenafil, (sold under the commercial name Viagra). Transdermal administration of sildenafil is believed to be beneficial in at least some subjects, compared to oral administration, which has been found to be associated with gastrointestinal side effects in at least some situations.

Methods for preparing transdermal preparations

In another embodiment of the proposed invention, there is provided a method for preparing the above-described transdermal preparations by mixing a therapeutically effective amount of an amine-containing compound that has biphasic solubility, as needed, an agent that enhances the action of the amine-containing compound, e.g., a muscle relaxant, as needed, an anti-inflammatory compound with a carrier suitable for transdermal delivery of the amine-containing compound.

In one embodiment of the proposed invention, the transdermal preparation is produced by dispersing or dissolving crushed tablets, capsules, or other preparations of amine-containing compounds that have biphasic solubility, e.g., muscle relaxants, as needed, anti-inflammatory compounds, which are intended for oral application, in a gel formulated from soy lecithin and isopropyl palmitate or isopropyl myristate, alcohol or ethoxy dichlorochol. Another embodiment of the proposed invention uses a Pluronic gel made from a Pluronic such as Pluronic F127, potassium sorbate and water.

In a special embodiment of the proposed invention, the transdermal preparation includes a combination of doxepin with guaifenesin used for the treatment of pain. It is believed that transdermal application of such a combination may be advantageous, at least in some patients, compared to oral administration, as a higher local concentration of the drug at the site(s), e.g., injury, can be achieved, thereby yielding an improved therapeutic response without systemic side effects. , such as weight gain, drowsiness, gastrointestinal disturbances and/or other known side effects of these drugs.

Methods for use

In one embodiment, the invention provides 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 delivery of the amine-containing compound, thereby treating pain in the subject. In a preferred embodiment, the transdermal composition is applied to the subject's skin at a frequency necessary to relieve pain. For example, the transdermal preparation can be applied daily, weekly, monthly, annually for a long period of time sufficient to relieve pain.

Below is a description of exemplary formulations in detail together with exemplary results obtained with transdermal applications in humans. First of all, the preparation in the form of a gel is applied to the skin, to the place or places of pain. Patients can be assessed by a structured form of assessment, which is carried out, for example, with a frequency of at least once a week. Patients are evaluated for the presence of symptoms as well as side effects from the current medication regimen. This allows changes made to this basis to be recorded.

The preparations according to the invention can be in dosages for self-administration in the form of a gel applied to the skin of the patient, or they can be incorporated by administering a transdermal preparation in pre-measured doses preferably associated with an adhesive or covering or patch so that the dose can be administered, for example, by placing adhesive patch on the patient's skin. Although some embodiments of the invention have been described in connection with the application of the pharmaceutical gel to the patient's hand, a different application to the patient's skin can also be applied. Since, depending on the formulation, the rate or duration of transdermal drug release can vary as a function of the site on the skin, in one embodiment the site on the skin where the drug is applied is selected according to a relative increase or decrease in the delay, rate, duration or rate of release of the drug, either with regard to a particular tissue or systemically.

For example, when a rapid rise in serum levels is desired, a site that enhances the rate of release, such as behind the ear, can be used. When it is desired to locally increase the dose or speed of release, the transdermal formulation can be placed directly next to the desired treatment area. Membranes or matrices, such as polymer matrices, can be used to limit or control the release rate. In addition to delivery with a transdermal gel or patch, the release of a transdermal or aerosol formulation can be achieved, for example, by administration as nose drops, ear drops, eye drops and/or suppositories.

In one embodiment, the medicaments provided in the form of a transdermal gel are administered in metered unit doses, such as blister packs. The gel is squeezed out of the blister pack and rubbed on the application site. The dosage is adjusted by changing the number of applied unit doses. This ensures accurate dosing and avoids contamination of the gel.

Methods for selecting a compound suitable for the treatment of pain

In a further aspect, the invention provides a method for selecting a compound suitable for treating pain in a subject. The method involves transdermally applying an amine-containing compound having biphasic solubility to a subject and determining whether the subject's pain is cured and whether the compound selected thereby is suitable for treating the subject's pain. In a preferred embodiment, the method may further include modeling the compound using a computer equipped with a three-dimensional chemical structure modeling program (eg, Molecules-3D Professional Edition. Version 2.60, Copyright 1991-1998, Molecular Arts Corp., © 1994-1998 WCB /McGraw Hill) and determining whether the compound's three-dimensional chemical structure has sufficient characteristics to be used as a sodium channel blocker, and thus whether the choice of the compound is suitable for the treatment of pain in the patient.

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

The invention is further illustrated by the following examples which should not be construed as limiting. The contents of all literature sources, patents and published patent publications, which are listed in this description, as well as images, are included here as a literature source.

EXAMPLES

Example 1

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

Example 2

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

Example 3

A glass for a measured volume of 100 ml is used. It is considered important to measure the volume accurately and not to use the markings on the cup. A quantity of Pluronica F127 NF (20 grams for 20% gel, 30 grams for 30% gel, 40 g for 40% gel) is mixed with 0.3 grams of potassium sorbate NF. Add enough water purified by freezing to obtain a volume of 100 ml. When all the granules are moistened, the gel cools down. The solution is prepared after cooling for 12 to 24 hours. The obtained 100 ml of Pluronic gel is kept cold, because the gel solidifies at room temperature.

Example 4

9 grams of carbamazepine in tablet form are crushed in a tablet. Add 4.3 ml of ethoxy diglycol and mix to obtain a creamy paste. Add 13.2 ml of soy lecithin and mix until smooth. The resulting 24 ml of solution is placed in a 60 ml bottle. In the second bottle of 60 ml, put approx. 36 ml of 20% Pluronica F127 gel (prepared as in example 3). The material is mixed well between the vials, resulting in 60 ml of carbamazepine organogel containing 150 mg per milliliter. In some cases, the mixture is passed through a grease mill to reduce the particle size.

Example 5

Sixty tablets of 100 mg of buproprion are ground and crushed into a fine powder. Buproprion powder is dissolved in 30 ml of purified water, placed on a filter and washed with 10 to 20 ml of purified water. A 10% Pluronic gel is made from the filtrate using the procedure as in example 3, with the equivalent volume of water being replaced with the filtrate, and stored in the refrigerator. 14 ml of soy lecithin is mixed with half of the buproprion Pluronic gel and mixed between the vials, resulting in the first mixture. 14 ml of the lecithin salt is mixed with the other half of the buproprion Pluronic gel and mixed between the vials, resulting in a second mixture. Sufficient Pluronic gel F127 (prepared as in Example 3) is added to each mixture to give a total of two mixtures of 60 ml of buproprion HC1 organogel containing 15 mg per milliliter.

Example 6

600 mg of fluoxetine HCl (in the form of 20 mg capsules) is placed in a beaker and dissolved in approximately 18 ml of 95% ethyl alcohol. The solution is filtered through a funnel with fine filter paper. The rest is washed with 95% alcohol. The filtrate is heated, kept at a temperature below 85°C to evaporate the alcohol and concentrated to 1 to 2 ml. 600 mg of isopropyl palmitate is mixed with 600 mg of soy lecithin (granulated), set aside and allowed to liquefy. When it becomes a liquid, a thick syrup is obtained. 1.2 grams of the mixture is poured into a 10 ml vial, and an alcoholic solution of fluoxetine HC1 is poured into another vial. The two vials are connected with a Luer-Luer adapter and the gel is mixed thoroughly. Then all the organogel is transferred into one vial and the empty vial is separated. A sufficient amount of 20% Pluronic F127 (prepared as in Example 3) is placed in the empty vial to give a total of 6 ml when added to the volume in the second vial. The Luer-Luer adapter is attached and the contents of the two vials are mixed again until a smooth creamy mixture is obtained. All the mixture is transferred into one vial, the empty vial is separated and the Luer-Luer adapter is removed.

The Luer-Luer adapter is attached to the mixture and transferred to 6 oral vials of 1 ml, which are filled with 1 ml of gel. In this way, each vial contains a dose of 20 mg, or 10 mg per dose, resulting in a total of 60 doses of fluoxetine in lecithin organogel with a concentration of 10 mg in 0.1 ml.

Example 7

Twenty tablets of 250 milligrams of nefazadone are crushed in a sieve and passed through a sieve. Add 4.8 ml of ethoxy diglycol (8%) and mix. If all the particles do not dissolve, add 2 ml of Pluronic and mix. Add 13.6 ml of soy lecithin and mix. The resulting mixture is placed in vials with a Luer adapter and mixed well. Sufficient Pluronica F127 gel, prepared as in Example 3, is added so that a volume of 60 ml is obtained and mixed well, thereby obtaining 60 ml of nefazadone organogel containing 50 mg per ml.

Example 8

30 tablets of 40 milligrams of paroxetine are crushed and passed through a sieve. The green coating material is discarded. Add 4.8 ml of ethoxy diglycol to the powder and mix in a mixer. 40 ml of 20% Pluronica F127 gel, prepared as in example 3, is gradually added to the powder with a spoon and mixed until it becomes smooth. 13.2 ml of soy lecithin is added and mixed well and the resulting material is placed in vials and a sufficient amount of Pluronic gel is added to obtain a volume of 60 ml. In the event that the particle size of the obtained material is too large, the cream is passed through a grease mill, so that 60 ml of paroxetine organogel containing 20 mg per ml is obtained.

Example 9

30 tablets of 100 mg sertraline are crushed into a fine powder and ground, the yellow coating material is discarded. A sufficient amount of 20% Pluronica F127 gel (prepared as in example 3) is added so that a volume of 38 ml is obtained and mixed well in a blender until a smooth cream is obtained. This material is placed in vials and mixed between vials to obtain a compact cream. 13.2 ml of soy lecithin is added and mixed well between the vials so that it is pumped approximately 20 times. Sufficient amount of 20% Pluronic F127 gel is added to obtain 60 ml of sertraline gel containing 15 mg per ml.

Example 10

Venlafaxine hydrochloride has a solubility in water of 572 mg/ml (adjusted to an ion concentration of 0.2 M with sodium chloride). 45 tablets of 100 mg of venlafaxine are crushed and ground in a mill. The powder is dissolved in 15 ml of purified water, the solution is placed on a filter and washed with 10 ml of purified water. The filtrates are used to prepare a 20% Pluronic gel by the procedure as in example 3 (replacing the filtrate with an equivalent amount of water) and are placed in the refrigerator overnight. 13.2 ml of soy lecithin is placed in a vial with a Luer attachment. Venlafaxine Pluronic gel is placed in a second vial connected to the first vial and mixed well. Sufficient Pluronic F127 gel is added, so that a volume of 60 ml containing 75 mg per ml is obtained.

Example 11

15 grams of sodium valproate (Depakote) is crushed in a tablet. Add 4 ml of ethoxy diglycol and mix well to obtain a creamy paste. Add 19.8 ml of soy lecithin and mix until smooth. The resulting 24 ml of solution is placed in 2 vials with a Luer attachment and mixed well. The mixture is divided so that there is one half in each bottle. Using another 60 ml bottle, add 30% Pluronic gel to each bottle, so that a volume of 45 ml is obtained in each bottle.

Example 12

Paroxetine hydrochloride has a solubility in water of 5.4 mg/ml. Paroxetine (Paxil) gel is prepared as in example 8. The patient, a 59-year-old woman, self-administered a dose of 40 mg per day over a period of at least 1 hour. There were no reports of skin irritation. After 210 days, blood was taken and the amount of Paxil in the serum was found to be 0 nanograms (0 ng) per ml, whereas values of 49±26 ng/ml are typically reported, indicating possible poor absorption or laboratory error. A clinical trial of a patient over a period of 210 days with such transdermal application showed improvement for the patient without GI side effects similar to those observed with the oral preparation.

Example 13

Sertraline hydrochloride is sparingly soluble in water and isopropyl alcohol and moderately soluble in ethanol. Sertraline (Zoloft) gel was prepared using the same procedure as in example 9. The patient, a 54-year-old woman, self-administered a dosage of 100 mg per day for a period of at least 1 hour. There were no reports of skin irritation. After 19 days, blood was taken and the amount of Zoloft in the serum was found to be 5 nanograms per ml, whereas levels of 30-200 mg/ml are typically reported, indicating possible poor absorption or laboratory error.

Example 14

Fluoxetine hydrochloride has a solubility in water of 14 mg/ml. Fluoxetine (Prozac) gel was prepared using the same procedure as in example 6. The patient, a 54-year-old woman, self-administered a dosage of 20 mg per day for a period of at least 1 hour. There were no reports of skin irritation. After 7 days, blood was taken and it was determined that the amount of fluoxetine in the serum was 45 ng/ml, while the amount of the primary active metabolite of norfluoxetine was also 45 ng/ml. The patient's improvement was evident from the clinical assessment.

Example 15

Carbamazepine is practically insoluble in water, and soluble in alcohol and acetone. A carbamazepine gel (Tegretol) was prepared by the procedure as in example 4. The patient, a 55-year-old man, self-administered a dose of 400 mg per day on the skin over a period of at least 1 hour. There were no reports of skin irritation. After 120 days, blood was taken and the amount of Tegretol in the serum was determined to be 4.6 μg/ml, while typical therapeutic levels range from 4-10 ng/ml, indicating good absorption. There were no GI side effects and the patient showed clinical improvement.

Example 16

Carbamazepine (Tegretol) gel was prepared by the procedure as in example 4. The patient, a 53-year-old man, self-administered a dose of 200 mg per day on the skin over a period of at least 1 hour. There were no reports of skin irritation. After 60 days, blood was drawn and serum Tegretol was found to be 10.8 µg/ml, whereas typical therapeutic levels range from 4-10 μg/ml, indicating excellent absorption. There were no GI side effects and the patient showed clinical improvement.

Example 17

Sertraline (Zoloft) gel was prepared as in Example 9. The patient, a 53-year-old male, self-administered a dose of 50 mg per day to the skin over a period of at least 1 hour. There were no reports of skin irritation. After 63 days, blood was taken and the amount of Zoloft in the serum was determined to be 23 ng/ml, while typical therapeutic levels range from 30-200 mg/ml. The patient showed a good clinical response with no GI side effects.

Example 18

Carbamazepine (Tegretol) gel was prepared as in Example 4. The patient, a 47-year-old man, self-administered a dose of 50 mg per day to the skin over a period of at least 1 hour. There were no reports of skin irritation. After 91 days, blood was drawn and serum Tegretol was found to be 0.5 μg/ml, while typical therapeutic levels range from 4-10 μg/ml, indicating modest absorption, laboratory error, or patient non-compliance.

Example 19

Buproprion has a high solubility in water. Buproprion (Wellbutrin) gel was prepared as in Example 5. The patient, a 47-year-old male, self-administered a dose of 100 mg daily to the skin over a period of at least 1 hour. There were no reports of skin irritation. After 44 days, blood was drawn and serum Wellbutrin was found to be 0.5 ng/ml, whereas typical therapeutic levels range from 10-30, indicating modest absorption, laboratory error, or patient non-compliance.

Example 20

Fluoxetine gel is prepared by the procedure as in example 6. A typical total daily dose of fluoxetine applied to the skin according to the proposed invention is between approx. 20 mg and 200 mg. Even better is between approx. 120 mg and approx. 200 mg. Dosage for non-adult and/or non-human mammals may be adjusted as necessary, eg in proportion to body weight. 5 patients self-administered a dose of 20-60 mg per day, including example 13, and also included a patient, a 44-year-old man, a 53-year-old woman, a 47-year-old man and a 36-year-old woman, at for which the application on the skin lasted at least one hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical examination of patients during a period of 30-180 days of such transdermal application showed a clinical reaction ranging from complete disappearance of symptoms to moderate improvement.

Example 21

Fluoxetine gel was prepared using the same procedure as in example 6. A 50-year-old woman applied a dose of 80-160 mg daily to her skin for a period of at least 1 hour. There were no reports of skin irritation. After 7 days, blood was taken and the amount of fluoxetine in the serum was determined to be 34 ng/ml and 25 ng/ml norfluoxetine, while typically levels are reported to be 50-480 ng/ml, indicating good absorption. The patient's improvement was evident from the clinical examination. Then the dosage was increased to 160 mg per day and was administered using the same method. After 7 days at a dosage of 160 mg per day, blood was taken and the amount of fluoxetine in the serum was determined to be 90 ng/ml and 25 ng/ml of norfluoxetine, which shows good absorption. At this higher dosage level, the patient showed increased improvement, which coincided with the higher plasma level. The patient received the drug continuously for a period of 5 months.

Example 22

Fluoxetine gel was prepared by the procedure from example 6. A 38-year-old woman self-administered a dose of 80-160 mg/day to her skin over a period of at least 1 hour. There were no reports of skin irritation. After 7 days at a dosage of 80 mg, blood was taken and the amount of 25 ng/ml fluoxetine and 25 ng/ml norfluoxetine was determined in the serum. Clinical trials have proven improvement in the patient. Then the dosage was increased to 160 mg per day and the same method was applied.

Example 23

Sertraline (Zoloft) gel was prepared by the procedure of Example 9. 6 patients, including those of Examples 12 and 16, also including a 60-year-old male, a 53-year-old male, a 48-year-old male, a 47-year-old male, self-administered on the skin a dose of 50-200 mg per day for a period of at least 1 hour. There were no reports of irritation or gastrointestinal side effects. Clinical tests of patients during a period of 7-90 days of such transdermal application showed reactions ranging from the complete disappearance of depression to an invisible reaction.

Example 24

Carbamazepine (Tegretol) gel was prepared by the procedure as in example 4. 6 patients only applied a dose of 200-400 mg per day to their skin for a period of at least 1 hour, including those from examples 14, 15 and 17, and also included a 48-year-old woman, a 48-year-old man, and a 54-year-old woman. There were no reports of irritation or gastrointestinal side effects. Clinical trials of patients during a period of 30-300 days of such transdermal application showed reactions ranging from moderate improvement to a clinical reaction that was not positive.

Example 25

Paroxetine (Paxil) gel was prepared by the procedure as in example 8.

The patient from example 12, as well as the patient, a 15-year-old female, applied a dose of 20 mg per day to their skin over a period of at least 1 hour. There were no reports of skin irritation. Clinical trials of patients during periods of 30-210 days of such transdermal application showed unreliable clinical improvement in depression that may (or may not) have been associated with transdermal application of Paxil.

Example 26

5 tablets of 150 mg of amitriptyline are crushed in a mortar and passed through the mill. The powder is placed in a vial with a Luer attachment and mixed well with 2 ml of ethoxy diglycol. Add approx. 6 ml of 20% Pluronic gel and mix well. Add 6.6 ml of soy lecithin and mix well. This mixture is diluted to a total volume of 30 ml with 20% Pluronic gel Gel 20% and mixed well. The obtained mixture, which contains 25 mg/ml, is placed in a suitable device for taking.

Example 27

Amitriptyline (Elavil) gel was prepared by the procedure as in example 26. The patient, a 47-year-old man, self-applied a dose of 25 mg per day to the skin over a period of at least 1 hour. There were no reports of irritation or gastrointestinal side effects. Clinical tests of the patient during a period of 100 days of such transdermal application clearly showed a good clinical response compared to oral application of the drug.

Example 28

Trazodone (Desyrel) gel was prepared by the procedure as in example 7. 2 patients, including a 36-year-old woman and a 47-year-old man, self-administered a dose of 50-150 mg per day for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical trials of patients during a period of 42-90 days of such transdermal application showed good to excellent clinical reactions.

Example 29

Venlafaxine (Effexor) gel was prepared as in Example 9. 2 patients, including a 54-year-old woman and a 55-year-old man, self-administered a dose of 150-225 mg per day for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical trials of patients during a period of 15-165 days of such transdermal application showed a reaction ranging from no clinical improvement to moderate clinical improvement.

Example 30

Propranolol (Inderal) gel was prepared by the procedure as in Example 8, which produced a gel containing 40 mg of propranolol per ml of gel. 2 patients, including a 36-year-old woman and a 47-year-old man, self-administered a dose of 150-225 mg per day for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical trials of patients during a period of 100 days of such transdermal application showed results comparable to those achieved with oral treatment.

Example 31

Buproprion (Wellbutrin) gel was prepared by the procedure described in Example 5. 3 patients, including the one from Example 18, a 38-year-old man and a 53-year-old woman, self-administered a dose of 150-200 mg daily for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical trials of patients during a period of 5-45 days of such transdermal application showed indeterminate results.

Example 32

Valproic acid gel (Depakote) was prepared by the procedure as in example 4. The patient, a 38-year-old man, applied a dose of 1000 mg daily to his skin for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical tests of the patient during a period of 30 days of such transdermal application showed results that can be compared to those achieved with oral treatment.

Example 33

Valproic acid gel (Depakote) was prepared by the procedure as in example 11. The patients, two men aged 41 and 49, applied a dose of 500-1000 mg daily to their skin for a period of at least 1 hour. One patient experienced significant skin irritation, but there were no reports of gastrointestinal side effects. Clinical tests of patients over a period of two months showed improvement, but after a longer period of time it became clear that this could be due to other factors. After 28 days, blood was taken and in a 49-year-old patient, an amount of 26 μg/ml of valproic acid was obtained in the plasma (who was taking 250 mg twice a day), while the therapeutic range is stated to be from 50 to 150 μg/ml. This showed modest absorption and the dosage was increased to 500 mg daily, with further improvement in clinical response. A 41-year-old patient had a good clinical response with an initial dose of 250 mg twice daily, but the serum valproic acid level was only 1 ng/ml. The dosage was increased to 500 mg twice daily and the same serum valproic acid levels were obtained. The difference between the clinical response and the plasma level may be explained by laboratory error or the placebo effect.

Example 34

A gel containing reboxetine (sold under the trade name Edronax) was prepared as described in Example 5, but using reboxetine instead of boproprion. The patients themselves applied the resulting mixture to their skin for a period of at least 1 hour. As expected, there were no skin irritations or gastrointestinal side effects. Clinical trials of patients during a period of 5-45 days of such transdermal application showed, as expected, a good reaction to the treatment.

Example 35

Nefazodone (Serzone) gel was prepared by the procedure described in example 7. The patient (man, woman) applied a dose of 100 mg daily to his skin for a period of at least 1 hour. There were no reports of skin irritation or gastrointestinal side effects. Clinical tests of the patient during a period of 21 days of such transdermal application showed a good reaction to the treatment.

Example 36

Tablets of 1 gram of permoline are crushed in a mortar and then dissolved in an amount of propylene glycol that is just sufficient for dissolution. To obtain a paste, add 3 ml of propylene glycol or 95% ethyl alcohol. Add 6.6 ml of soy lecithin to the mixture in the bowl. The mixture is placed in two vials with a Luer attachment and thoroughly mixed. Each vial is filled with 30 ml of 20% Pluronic F127 gel and mixed between the vials, so that a mixture containing 33 mg/ml is obtained. The mixture is then placed in a suitable intake device.

Example 37

A 16-year-old female with a confirmed diagnosis of Attention Deficit Disorder was successfully treated orally with pemoline (Cylert) for approx. 6 months. To reduce the potential risk of liver damage associated with long-term use, permoline was prepared as in Example 36 and applied transdermally to the skin behind the ear for a period of at least one hour, at two sites, twice daily. Skin irritation was not expected. Clinical results comparable to those obtained with oral treatment were expected, although dosing had to be adjusted to appropriate plasma levels, which may be required multiple times to achieve satisfactory plasma levels.

Some psychiatric patients received two or more psychopharmaceuticals, and in some cases, two or more of the examples described above were examined during the same period of psychopharmaceutical application.

Of the patients, two received one or more of the prescribed drugs, as described in the examples above, each of whom showed significant intolerance to the oral administration of one or more of the drugs, before the transdermal application was started. It is believed that the above-described laboratory measurements of the amounts in blood plasma for transdermally applied fluoxetine and carbamazepine show good absorption of the transdermal application of the lecithin organogel matrix as a carrier. Valproic acid and sertraline do not appear to be absorbed well or reliably. Valproic acid appears to cause irritation in some patients and they request discontinuation. Laboratory measurements of Buproprion and clinical response of the patient show modest or equivocal absorption and results. Tolerability of transdermal application in patients was good to excellent. The patients in the above example, who suffer from very serious GI side effects from oral use of the preparations, were much more tolerant of inappropriate rubbing of the gel than the patients who experienced only mild to moderate side effects. In general, more motivated patients who consent to treatment are also quicker to give permanent consent.

The patients of the above examples were evaluated using the structured tests shown in Figure 1, which were performed at a frequency of at least once a week for each patient receiving a transdermal drug in accordance with the present invention. The patients were evaluated in terms of all present psychiatric symptoms as well as in terms of any of the side effects from the currently administered drugs. In general, patients with clear and simple diagnoses of major depression are believed to show the best results. In general, patients with severe personality disorders or with covert substance abuse disorders are less successful.

Example 38

1800 mg of gabapentin powder is dissolved in 1 ml of propylene glycol in vials with Luer fittings. Add 6.6 ml of soy lecithin and mix well between the vials. The obtained material is placed in a device for taking measured quantities.

Example 39

The 2% and 4% gabapentin mixtures were prepared by substituting 1200 mg of gabapentin or 600 mg of gabapentin for the 1800 mg of gabapentin in Example 38.

Example 40

Gabapentin, prepared as in example 38 or 39, is mixed with 3% or with 5% Lidocaine in different proportions.

Example 41

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

Example 42

2% Gabapentin, prepared as in Example 38 or 39, is mixed with 2% Carbamazepine and 1% Piroxicam, which is expected to penetrate muscle tissue better.

Example 43

Gabapentin, prepared as in Example 38 or 39, at concentrations ranging from 2-6%, is mixed with clonidine at concentrations of .2% and .3%.

Example 44

A 56-year-old woman had painful spasms in her upper and lower limbs as a result of spastic quadriparesis, which was the result of an injury. Gabapentin, an anticonvulsant, had previously been administered orally, but it caused a feeling of "intoxication", one of the commonly reported side effects with this agent. It is believed that transdermal application of gabapentin may provide local relief achieved by high concentration in local tissue near the site of application without a corresponding increase in blood plasma levels. It is known that other anticonvulsants, such as carbamazepine, can be used to reduce neurogenic pain. The solubility of gabapentin in water exceeds 10%, making systemic absorption less likely. Gabapentin, prepared by the procedure as in example 38, was applied by the patient herself to the skin in the area of pain. The patient reported moderate relief from spasms over a period of one week, with no systemic side effects and no skin irritation.

Example 45

Six grams of amitriptyline powder is placed in 40 ml of 33% Pluronica F127 gel and then placed in the refrigerator to dissolve. 2 ml of ethoxy diglycol is added to 4.8 grams of carbamazepine and mixed to form a smooth paste. Add 16.4 grams of soy lecithin to the resulting paste and mix well. The prepared dissolved amitriptyline is added to the carbamazepine mixture and enough 20% Pluronic F127 is added to make 120 ml. The resulting mixture is mixed well, resulting in a preparation containing 5% amitriptyline and 4% carbamazepine.

Example 46

6 grams of doxepin are added to 20 ml of 33% Pluronic F127 and put in the fridge to melt. 24 grams of ketoprofen and 12 grams of guaifenesin are added to 10 ml of 95% alcohol and mixed well. 26.4 ml of soy lecithin was added and mixed well and the doxepin mixture was mixed with the ketoprofen/guaifenesin mixture. The resulting mixture is added to enough 33% Pluronic to make 120 ml. The resulting mixture is mixed well, resulting in a preparation containing approx. 20% ketoprofen, 5% doxepin and 10% guaifenesin.

Example 47

6 grams of doxepin are added to 26 ml of 33% Pluronic and put in the fridge to melt. 2 ml of ethoxy diglycol is added to 4.8 grams of carbamazepine and mixed. The obtained mixture is added to 24 grams of ketoprofen and 6 ml of alcohol and the obtained mixture is mixed well. 26.4 ml of soy lecithin is added to the ketoprofen mixture and mixed well. The doxepin mixture was mixed with the carbamazepine/ketoprofen mixture and enough 33% Pluronic was added to make 120 ml. The resulting mixture is mixed well, resulting in a preparation containing approx. 20% ketoprofen, 4% carbamazepine and 5% doxepin.

Example 48

15 grams of sildenafil is crushed, passed through a mill and dissolved in 5 ml of 20% Pluronic F127 and mixed between the vials. Add 2.2 ml of soy lecithin and mix. Sufficient 20% Pluronic is added to make 10 ml and the resulting mixture is mixed well to obtain a preparation containing approx. 15 mg/ml.

Example 49

A sildenafil mixture of 15 mg/ml was applied to the penis and scrotum of a 51-year-old man. Sexual stimulation resulted in an immediate and strong erection without any irritation or burning. It is believed that the formulation will have the therapeutic results sought from oral Sildenafil without any time delay and without any systemic GI side effects and probably without any opportunity for the drug to interact with nitrates used in cardiac disease. It is believed that this will contribute to the consent for the use of the medicine and its safety.

Example 50

The compositions of Examples 45 through 47, 53, 55 have been applied transdermally to a number of patients for the treatment of pain, including the other examples described herein, with results summarized below in Table I.

The meaning of individual columns in Table I is given below in Table 2. Empty fields indicate that there was no treatment at a site suitable for that patient. Where a given line in Table I shows more than one site, the single, best result (greatest pain relief) is shown in black.

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TABLE II

Gender: 1 = male 2 = female

Operation: 1 = one or more operations 2 = no operations

Pain: 1 = mild 2 = moderate 3 = severe, enough to cause tears

Duration: length of experimental treatment in weeks Result:

0 = no improvement

1 = slight improvement

2 = moderate improvement (pain reduction greater than 25%)

3 = great improvement (pain reduction greater than 40-45%)

4 = almost complete relief (pain reduction greater than 80%)

Certain results obtained from the information given in Table I are summarized in Tables III and IV.

Table III - Percentage of reported pain reduction

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Table IV. Percentage of reported pain reduction.

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Example 51

A 51-year-old woman applied to her back a preparation prepared as in example 46, which contained 20% ketoprofen, 5% doxepin and 10% guaifenesin over a period of 2 weeks. She reported moderate pain relief, lasting several hours after each application. She had no skin irritation or any other side effects. Oral treatment did not induce pain relief and caused significant GI side effects.

Example 52

A 34-year-old man applied a preparation containing 20% ketoprofen, 4% carbamazepine and 5% doxepin to a very seriously injured wrist, which had undergone 4 operations for carpal tunnel syndrome. (e. carpel tunnel). He reported moderate pain relief lasting several hours after each application. No other treatment, including oral opiates, was effective in achieving even modest pain relief.

Example 53

24 grams of ketoprofen and a sufficient amount of guaifenesin, to obtain a 10% final concentration of guaifenesin, are mixed well with 10 ml of 95% alcohol. 1200 mg of gabapentin is dissolved in 1 ml of propylene glycol in a vial with a Luer cap. Add 26.4 ml of soy lecithin to the mixture of ketoprofen, guaifenesin and alcohol and mix well. The resulting mixture is added to the mixture of gabapentin and propylene glycol and mixed well. 4.8 g of carbamazepine was mixed with the resulting mixture and everything was mixed well to obtain a smooth paste. The resulting paste is mixed with a mixture of ketoprofen, guaifenesin, alcohol and gabapentin and mixed well with enough pluronic to produce 120 ml of a preparation containing 20% ketoprofen, 4% carbamazepine, 4% gabapentin and 10% guaifenesin.

Example 54

A 58-year-old woman with cervical spinal cord injury resulting in spastic quadriparesis reported moderate relief of pain and muscle spasms when she administered a mixture prepared generally according to Example 53, containing 20% ketoprofen, 4% carbamazepine, 4% gabapentin and 10% guaifenesin over a period of 8 weeks on the back and flank. She was intolerant of oral carbamazepine and oral gabapentin due to systemic side effects, including pruritus with carbamazepine and dizziness, and sedation with gabapentin. She experienced no skin irritation or other side effects with the transdermal formulation.

Example 55

Six grams of doxepin powder are mixed with 26 ml of pluronic and put in the fridge until it melts. 1200 mg of gabapentin is mixed with 1 ml of propylene glycol and placed in a vial with a Luer attachment. Add 6.6 ml of soy lecithin and mix well between the vials. 24 gm of ketoprofen and 8 ml of alcohol are mixed well between two vials with a Luer attachment. The doxepin mixture is mixed well with the gabapentin mixture, then the ketoprofen mixture is added and mixed well. Add enough 20% Pluronic (approx. 54 ml) to obtain 60 ml of the preparation containing approx. 20% ketoprofen, 4 wt. % gabapentin and 5 wt. % doxepin.

Example 56

A 57-year-old woman applied a mixture prepared generally according to Example 55, containing 20% ketoprofen, 4% gabapentin and 5% doxepin over a period of 8 weeks to her neck and reported great relief. She applied the same mixture to her shoulder and reported moderate relief. The mixture in which piroxicam was replaced by doxepin produced only mild relaxation in the shoulder.

Example 57

A 35-year-old man with a vascular knee injury and 3 surgeries applied a mixture prepared generally according to Example 45 containing 4% carbamazepine and 5% amitriptyline to his knee and reported mild to moderate pain relief without skin irritation and other side effects.

Example 57A

A 41-year-old woman who had back surgery applied to her back a mixture prepared generally according to Example 45 containing 4% carbamazepine and 5% gabapentin over a period of 2 weeks. She reported mild pain relief.

Example 58

A 53-year-old woman with two bilateral total knee replacements applied a mixture prepared generally according to Example 45, containing 4% carbamazepine and 5% amitriptyline to both knees for a period of 4 weeks. She reported that there was no relief of pain.

Example 58A

A 54-year-old man who had 7 back surgeries applied to his back a mixture prepared generally according to Example 45 containing 4% carbamazepine and 5% amitriptyline over a 2-week period. He reported mild to moderate pain relief. He reported mild to moderate pain relief, and in addition received a transdermal and opiate medication (Duragesic). He reported no side effects, and specifically no skin irritation.

Example 59

A 38-year-old man with a sprained shoulder applied to his shoulder a mixture prepared generally according to Example 45 containing 4% carbamazepine and 5% amitriptyline over a period of 2 weeks. He reported mild to moderate pain relief and had no skin irritation or other side effects.

Example 61

Sufficient carbamazepine and gabapemin are added to the mixture of lecithin and pluronic strain to obtain a lecithin organogel containing approx. 4% carbamazepine and 5% gabapentin.

Example 62

A 42-year-old woman with 3 back surgeries and cervical disc degeneration applied a mixture prepared according to Example 61 containing 4% carbamazepine and 5% gabapenline to her neck and reported total pain relief. She reported no side effects and no skin irritation. At the same time, she noted the complete and rapid disappearance of a migraine-like headache. Applying the same mixture to her shoulder and wrist, attacked with a diagnosed condition of reflex sympathetic dystrophy, achieved moderate pain relief.

Example 63

3.6 grams of gabapentin are dissolved with 54 ml of ethoxy diglycol in a pestle and mortar. 9.6 grams of ketoprofen and 2.7 grams of piroxicam are added and the resulting mixture is mixed well. 19.8 ml of soy lecithin is added, the resulting mixture is mixed well and added to a sufficient amount of 20% pluronic to obtain 90 ml of the preparation containing approx. 10% ketoprofen, 4% gabapentin and 3% piroxicam.

Example 64

3.6 grams of gabapentin were dissolved with 5.4 ml of ethoxy diglycol using a pestle and mortar. Add 9 grams of ketoprofen and 0.9 grams of piroxicam and mix well. Add 19.8 ml of soy lecithin to the resulting mixture and mix well. A sufficient quantity of 20% pluronic gel is added to obtain 90 ml of a preparation containing approximately 10% ketoprofen, 4% gabapenline and 1% prioxicam.

Example 65

12 g of doxepin is mixed with 50 ml of 33% Pluronic F 127 and placed in the refrigerator to melt. 12 g of gabapentin are dissolved in 9 ml of ethoxy diglycol and mixed to form a smooth paste. Add 52.8 ml of soy lecithin and mix well. Add the mixture of doxepin and Pluronic and mix well. A sufficient amount of 20% Pluronic F 127 20% is added to obtain 240 ml of the preparation containing approx. 5 wt. % gabapenlin and 5% doxepin.

Example 66

A 36-year-old male with an injured knee, including articular surface injury and vascular injury, applied a mixture prepared generally according to Example 65 to his knee several times a day. He reported great (40%) pain relief lasting 4 to 6 hours. An earlier trial with carbamazepine-amcriptiline gel, applied to his knee, did not relieve the pain.

Example 67

6 g of doxepin is mixed with 18 ml of 33% Pluronic and placed in the refrigerator to dissolve. 6 g of gabapentin are crushed in a mortar and pestle into a fine powder, added to 6 ml of ethoxy diglycol and mixed to obtain a smooth paste. Add 12 g of guaifenesin and mix well. Add 26.4 ml of soy lecithin and mix well. Add the mixture of doxepin and Pluronic, and mix well. A sufficient amount of Pluronic gel (25.2 ml of 33% Pluronic, although 30% or 20% Pluronic can also be used) is added to prepare 120 ml of the preparation containing approx. 5 wt. % gabapentin, approx. 5 wt. % doxepin and approx. 10 wt. % guaifenesin.

Example 68

A 55-year-old woman with a back and shoulder injury, who needed the help of others, applied to her back a mixture prepared generally according to Example 67 three times a day for a period of two weeks and achieved great relief. She applied the same mixture to her hip and leg and reported moderate to great relief. The mixture, which contained only doxepin, produced only moderate improvement in her back and mild to moderate relief in her hip and leg. A mixture containing only ketoprofen, gabapentin and piroxicam produced only mild improvement in her back.

Example 69

A 59-year-old woman with cervical and back sprains applied to her neck a mixture prepared generally as in Example 51 (but without the steps involving ketoprofen) containing approx. 5 wt. % doxepin and approx. 10 wt. % guaifenesin over a period of two weeks, two to four times a day and she achieved complete pain relief. She applied the same mixture to her back and achieved great to complete pain relief.

Example 70

4.5 g of doxepin HC1 is dissolved in 2.5 ml of 95% alcohol and mixed well between vials. Doxepin can also be mixed with 5 ml of 20% Pluronic 20% and put in the fridge to melt. A sufficient amount of 20% Pluronic F127 is added to produce 90 ml of the preparation containing approx. 5 wt. % doxepin. First of all, this and other described preparations are kept protected from light.

Example 71

A 61-year-old man with back, neck, and arm injuries applied a mixture prepared generally as in Example 70 to his neck four times a day and found great relief. He applied the same mixture to his elbow and found moderate relief.

Example 72

Formulation with 7% antidepressants and approx. A 10% muscle relaxant was prepared by dissolving 3.15 g of trimipramine and 4.5 g of guaifenesin in a mixer using 2.7 ml of ethoxy diglycol. Add approx. 9.9 ml of soy lecithin and mix well. Sufficient amount of Pluronica F127 NF (20%) is added to obtain a total volume of approx. 45 ml and mix well.

Example 73

A gel formulation with 30% NTHE was prepared from 36 g of celecoxib, 7.2 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica K127 NF (20%) to obtain a total volume of 120 ml.

Example 74

Gel formulation containing 7% antidepressant and approx. A 13% muscle relaxant was prepared from 14.4 g of doxepin, 31.2 g of guaifenesin, 12 ml of ethoxy diglycol, 52.8 ml of soy lecithin and sufficient amount of Pluronic F127 NF (33%) to give a total volume of 240 ml.

Example 75

A gel formulation containing 5% antiepileptic was prepared from 6 g of lamotrigine, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) to obtain a total volume of 120 ml.

Example 76

A gel formulation containing 10% adrenergic agonist was prepared from 12 g of crushed tizanidine, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) so that a total volume of 120 ml was obtained.

Example 77

A gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed metaxalone, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) so that a total volume of 120 ml was obtained.

Example 78

A gel formulation containing 10% muscle relaxant was prepared from 12 g of crushed carisoprodol, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) so that a total volume of 120 ml was obtained.

Example 79

A gel formulation containing 10% methocarbamol was prepared from 12 g of crushed methocarbamol, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) to give a total volume of 120 ml.

Example 80

A gel formulation containing 10% muscle relaxant is prepared from 12 g of crushed dantrolene sodium, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) so that a total volume of 120 ml is obtained.

Example 81

A gel formulation containing 7% antidepressant and 10% muscle relaxant was prepared from 8.4 g of crushed doxepin, 12 g of chlorzoxazone, 6 ml of ethoxy diglycol, 26.4 ml of soy lecithin and sufficient amount of Pluronica F127 NF (33%) so that gets a total volume of 120 ml.

Example 82

A series of experiments were conducted with people using different combinations of drugs. These results are shown in Figure 2.

Pain relief values, as ranked by the patients, are given for each part of the body to which the drug was applied. The scale used in Figure 2 is as follows:

0 = nothing, no improvement or doubtful

1 = mild, pain reduction less than 15%;

1.5 = mild-moderate, pain reduction by 15-20%;

2.0 = moderate, pain reduction by 25-33%;

2.5 = moderate-great, pain reduction by 33-45%;

3.0 = major, pain reduction by 45-60%;

3.5 = major-total, pain reduction by 60-60%;

4.0 = overall, pain reduction of more than 80%;

For each part of the body and for each percentage of the composition of each compound in the drug, individual ratings are given as well as an average, which is a statistical average of the values given according to the scale below. For example, 3 patients received doxepin 5% on their backs, and the average level was 2.333. In contrast, 13 patients received a combination of 5%/10% doxepin and guaifenesin and their average pain relief score was 2.885. The results for the 7/10 and 10/10 preparations of doxepin and guaifenesin are also given and the average for the total dox-guai sample in all combinations at the end of the experiment is given, namely 2.722.

Abbreviations used in Figure 2 are as follows:

Abbreviations of generic pharmaceutical names

c-dox-gu carbamazepine doxepin guaifenesin

c-gab-do carbamazepine gabapentin doxepin

carb carbamazepine

carb-ami carbamazepine amitriptyline

carb-gab carbamazepine gabapentin

dox doxepin

dox-chi doxepin chlorzoxazone

dox-guai doxepin guaifenesin

g-dox-gu gabapentin doxepin guaifenesin

gab-dox gabapentin doxepin

k-ca-dox ketoprofen carbamazepine doxepin

k-car-pi ketoprofen carbamazepine piroxicam

k-dox-ch ketoprofen doxepin chlorzoxazone

k-dox-gu ketoprofen doxepin guaifenesin

k-dox-pi ketoprofen doxepin piroxicam

k-g-do-g ketoprofen gabapemin doxepin guaifenesin

k-gab ketoprofen gabapentin

k-gab-ami ketoprofen gabapentin amitriptyline

k-gab-do ketoprofen gabapemin doxepin

k-gab-gu ketoprofen gabapentin guaifenesin

k-gab-pi ketoprofen gabapentin piroxicam

k-pi ketoprofen piroxicam

la-li-eu lamotrigine lidocaine guaifenesin

lam-chi lamotrigine chlorzoxazone

n-dox-ch naproxen doxepin chlorzoxazone

tri-chi trimipramine chlorzoxazone

naproxen naproxen

tri-chi trimipramine chlorzoxazone

Based on the results described herein, doxepin appears to be effective in relieving pain when administered transdermally and appears to be largely free of side effects when administered transdermally as described herein.

Doxepin appears to give a positive reaction of approx. three times faster compared to at least some of the other pharmaceutical agents described herein, whether that other pharmaceutical agent is administered alone or in combination. Doxepin, when applied transdermally, appears to be generally more effective against pain, eg neuropathic pain, than amitriptyline. This occurs regardless of whether doxepin is administered as a single agent or in combination with other drugs, as described herein.

Carbamazepine appears to have positive effects as an agent against, for example, neuropathic pain, at least in properly selected patients. Carbamazepine appears to cause a rash in at least some patients, and its use must therefore be discontinued.

These side effects appear to be similar to those seen with oral carbamazepine. Gabapentin does not appear to cause side effects when administered transdermally. Although the combination of transdermally applied ketoprofen, gabapentin, and prioxicam has been beneficial in some patients, it appears relatively weak compared to the effect obtained with doxepin.

Guaifenesin appears to be good for adjunctive treatment of painful spasticity. For the patient population described here, amitriptyline appears to offer limited pain relief when administered transdermally. It appears that combining gabapentin with doxepin may offer some additional benefits. The addition of guaitenesin to doxepin may be particularly beneficial if painful spasticity is present.

In light of the above, the invention provides for the treatment of patients for whom oral administration is not optimal, such as patients who suffer from gastrointestinal or other side effects, patients who show poor absorption of orally delivered drugs and/or patients who benefit from long-term drug administration period or a relatively fast release of the drug or a high rate of increase in plasma levels. The proposed invention achieves the release of a therapeutic amount of drug, at least in some patient populations, largely without skin irritation, gastrointestinal or other side effects, which are associated with orally delivered drugs, especially psychopharmaceuticals, and provides clinical improvements that are comparable or greater than those achieved by patients with appropriate medications when they are given orally. For the above reasons, particularly effective pain management is described in Examples 65, 67, 69 and 70.

Numerous changes and modifications of the invention can also be applied. It is believed that blood plasma levels can be increased by performing two or more transdermal applications per day and/or by applying the transdermal preparation to two or more sites.

In at least one case, application of the Prozac gel formulation appears to approximately double the plasma level. An approach such as twice-daily administration of the Prozac gel formulation is believed to provide a mid-range therapeutic level of approx. 140-250 ng/ml. At least in part, based on the fluoxetine results described here, olanzapine (sold under the trade name Zyprexa) or a mixture of fluoxetine and olanzapine in a lecithin organogel is believed to be of proven benefit.

Other types of psychotropic or psychopharmaceutical drugs for which transdermal release has been described can also be used, including psychostimulant drugs. One example of a psychostimulant drug is methylphenidate (sold under the trade name Ritalin), which is used to treat attention deficit hyperactivity disorder (ADHD). Methylphenidate has a typical duration of action of 2-4 hours, which is why the patient has to dose it frequently, which is especially difficult to implement in school children. It is believed that with transdermal application it will be possible to achieve more effective dosing during the day and eliminate the need for frequent oral administration of the drug.

It is also believed that transdermal application will eliminate both peak and trough levels in the blood plasma and that the drug will be clinically much more effective. It is also believed that similar results will be obtained with other drugs, for example with dextroamphetamine (sold under the commercial name Dexedrine), although the need is believed to be less acute, as a "spansula" time release from the drug is possible and typically has duration of action of 5-6 hours. Another group of psychotropic drugs believed to be useful to administer transdermally include antipsychotic drugs such as those used to treat schizophrenia.

Embodiments of the invention include, but are not necessarily limited to, use in patients with enteric absorption deficits.

Equivalents

Through routine experimentation, one skilled in the art will recognize or be able to determine the application of many equivalents to the specific embodiments of the invention described herein. Such equivalents are considered covered by the following claims.

Claims (53)

1. Transdermal preparation for the treatment of the subject's pain, characterized in that it contains: (a) an amine-containing compound having biphasic solubility in an amount effective to treat pain in a subject; and (b) a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine-containing compound. 2. Transdermal preparation according to claim 1, characterized in that it further contains an agent that enhances the action of the amine-containing compound and has biphasic solubility. 3. Transdermal preparation according to claim 2, characterized in that the agent that enhances the action of the compound, which contains an amine and has a biphasic solubility, is a muscle relaxant. 4. Transdermal preparation according to claim 1, characterized in that the compound containing the amine is an antidepressant compound. 5. Transdermal preparation according to claim 4, characterized in that the antidepressant compound is a tricyclic antidepressant compound. 6. Transdermal preparation according to claim 1, characterized in that the amine-containing compound is doxepin. 7. Transdermal preparation according to claim 1, characterized in that the amine-containing compound is trimipramine. 8. Transdermal preparation according to claim 1, characterized in that the compound containing the amine is a sodium channel blocker. 9. Transdermal preparation according to claim 1, characterized in that the pharmaceutically acceptable carrier is a lecithin organogel. 10. Transdermal preparation according to claim 3, characterized in that the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and their combinations. 11. Transdermal preparation according to claim 10, characterized in that the muscle relaxant is guaifenesin. 12. Transdermal preparation according to claim 3, characterized in that the muscle relaxant is a benzodiazepine. 13. Transdermal preparation according to claim 12, characterized in that the benzodiazepine is clozapine. 14. Transdermal preparation according to claim 12, characterized in that the benzodiazepine is diazopam. 15. Transdermal preparation according to claim 1, characterized in that it further contains an anti-inflammatory compound. 16. Transdermal preparation according to claim 15, characterized in that the anti-inflammatory compound is a non-steroidal anti-inflammatory compound. 17. Transdermal preparation according to claim 16, characterized in that the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx®, and their combinations. 18. Transdermal preparation for the treatment of the subject's pain, characterized in that it contains: (a) an amine-containing compound having biphasic solubility in an amount effective in treating the subject's pain; (b) a muscle relaxant in an amount effective to enhance the action of the amine-containing compound having biphasic solubility; and (c) a pharmaceutically acceptable carrier suitable for transdermal delivery of a compound comprising an amine and a muscle relaxant. 19. Transdermal preparation according to claim 18, characterized in that the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and their combinations. 20. Transdermal preparation according to claim 18, characterized in that the muscle relaxant is guaifenesin. 21. Transdermal preparation according to claim 18, characterized in that the muscle relaxant has two-phase solubility. 22. Transdermal preparation according to claim 18, characterized in that the compound containing the amine is an antidepressant compound. 23. Transdermal preparation according to claim 22, characterized in that the antidepressant compound is a tricyclic antidepressant compound. 24. Transdermal preparation according to claim 22, characterized in that the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and their combinations. 25. Transdermal preparation according to claim 18, characterized in that the amine-containing compound is doxepin. 26. Transdermal preparation according to claim 18, characterized in that the amine-containing compound is a sodium channel blocker. 27. Transdermal preparation according to claim 18, characterized in that the pharmaceutically acceptable carrier is a lecithin organogel. 28. Transdermal preparation according to claim 18, characterized in that it further contains an anti-inflammatory compound. 29. Transdermal preparation according to claim 28, characterized in that the anti-inflammatory compound is a non-steroidal anti-inflammatory compound. 30. Transdermal preparation according to claim 29, characterized in that the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx®, and their combinations. 31. Transdermal preparation for the treatment of pain in a subject, characterized in that it includes: (a) doxepin in an amount effective to treat pain in the subject; (b) guaifenesin in an amount effective in enhancing the action of doxepin; and (c) a pharmaceutically acceptable carrier suitable for transdermal delivery of doxepin and guaifenesin. 32. Transdermal preparation according to claim 31, characterized in that the pharmaceutically acceptable carrier is a lecithin organogel. 33. Transdermal preparation according to claim 31, characterized in that it further contains an anti-inflammatory compound. 34. A method of treating pain in a subject, indicated by the fact that it includes contact of the subject with a transdermal preparation containing: (a) an amine-containing compound having biphasic solubility in an amount effective in treating the subject's pain; and (b) a pharmaceutically acceptable carrier suitable for transdermal delivery of the amine-containing compound. 35. The method according to claim 34, characterized in that the transdermal preparation further contains an agent that enhances the action of the amine-containing compound and has biphasic solubility. 36. The method according to claim 35, characterized in that the agent that enhances the action of the compound, which contains an amine and has biphasic solubility, is a muscle relaxant. 37. The method according to claim 34, characterized in that the amine-containing compound is an antidepressant compound. 38. The method according to claim 37, characterized in that the antidepressant compound is a tricyclic antidepressant compound. 39. The method according to claim 37, characterized in that the antidepressant compound is selected from the group consisting of doxepin, trimipramine, and their combinations. 40. The method according to claim 37, characterized in that the antidepressant compound is doxepin. 41. The method according to claim 34, characterized in that the amine-containing compound is a sodium channel blocker. 42. The method according to claim 34, characterized in that the pharmaceutically acceptable carrier is a lecithin organogel. 43. The method according to claim 36, characterized in that the muscle relaxant is selected from the group consisting of guaifenesin, chlorzoxazone, dantrolene sodium, metaxalone, carisoprodol, and their combinations. 44. The method according to claim 43, characterized in that the muscle relaxant is guaifenesin. 45. The method according to claim 36, characterized in that the muscle relaxant is a benzodiazepine. 46. The method according to claim 45, characterized in that the benzodiazepine is clozapine. 47. The method according to claim 45, characterized in that the benzodiazepine is diazopam. 48. The method according to claim 34, characterized in that the transdermal preparation further contains an anti-inflammatory compound. 49. The method according to claim 48, characterized in that the anti-inflammatory compound is a non-steroidal anti-inflammatory compound. 50. The method according to claim 49, characterized in that the non-steroidal anti-inflammatory compound is selected from the group consisting of celecoxib, etodolac, mefanamic acid, nabumetone, salsalate, naproxen, Vioxx®, and combinations thereof. 51. A method for selecting a compound suitable for treating pain in a subject, comprising: (a) transdermal application of a compound containing an amine and having biphasic solubility to a subject: i (b) determining whether the subject's pain has been cured, thereby selecting a compound suitable for treating the subject's pain. 52. Transdermal preparation for the treatment of pain in a subject, characterized in that it contains: (a) a compound capable of blocking afferent neuron transmission in an amount effective to block afferent neuron transmission in a subject; and (b) a pharmaceutically acceptable carrier suitable for transdermal delivery of the compound. 53. Transdermal preparation according to claim 52, characterized in that it further contains an agent that enhances the action of a compound suitable for blocking afferent neuronal transmission.