WO2015134695A1

WO2015134695A1 - Method of mitigating the side effects of a phosphodiesterase type v inhibitor in a subject

Info

Publication number: WO2015134695A1
Application number: PCT/US2015/018855
Authority: WO
Inventors: David Bar-Or; Raphael Bar-Or
Original assignee: Vyrix Pharmaceuticals, Inc.
Priority date: 2014-03-07
Filing date: 2015-03-05
Publication date: 2015-09-11

Abstract

The invention relates to a method of mitigating the side effects of a phosphodiesterase type V (PDE5) inhibitor in a subject that experiences side effects when administered a PDE5 inhibitor. The method comprises simultaneously administering to the subject active ingredients comprising an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor. The invention also relates to a method of administering a PDE5 inhibitor to a subject who is otherwise unable or unwilling to be administered the PDE5 inhibitor due to intolerable side effects.

Description

METHOD OF MITIGATING THE SIDE EFFECTS OF A

PHOSPHODIESTERASE TYPE V INHIBITOR IN A SUBJECT

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/949,882, filed 7 March 2014, the entirety of which is hereby incorporated by reference.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Erectile dysfunction is a common form of male sexual dysfunction, with an estimated 5-15% of males suffering from it. The prevalence of erectile dysfunction increases with age and certain medical conditions, such as heart disease, hypertension and diabetes.

One common treatment for erectile dysfunction, alone or in combination with treatments for premature ejaculation, is the administration of phosphodiesterase type V (PDE5) inhibitors, such as, by way of non-limiting example, sildenafil (Viagra®), tadalafil (Cialis®), and vardenafil (Levitra®). PDE5 inhibitors block the degradation of cyclic guanosine monophosphate (cGMP) by cGMP-specific PDE5 in the smooth muscle cells lining the blood vessels that supply the corpus cavernosum of the penis. The increased levels of cGMP cause the smooth muscle to relax, resulting in increased blood flow to the corpus cavernosum and an erection. However, PDE5 inhibitors can cause a number of side effects, or adverse drug reactions (ADRs). These ADRs include, but are not limited to, headache, dizziness, flushing, dyspepsia, nasal congestion, rhinitis, sudden hearing loss, anterior optic neuropathy, photophobia, blurred vision, cyanopsia, loss of peripheral vision, priapism, hypotension, myocardial infarction, ventricular arrhythmia, stroke, increased intraocular pressure, discomfort or pain in the stomach or abdomen, burping, acid reflux, back pain, pain or aches in the muscles or joints, nausea, photosensitivity, eye pain, facial edema, palpitation, tachycardia, rash, and itch. These ADRs of PDE5 inhibitors can discourage men from seeking treatment for erectile dysfunction, or from continuing treatment once it has begun.

Thus, there is a need for a method of mitigating the side effects of a PDE5 inhibitor in a subject.

SUMMARY OF THE INVENTION

The invention provides a method of mitigating the side effects of a phosphodiesterase type V (PDE5) inhibitor in a subject that experiences side effects when administered a PDE5 inhibitor, comprising simultaneously administering to the subject active ingredients comprising an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor.

The invention also provides a method of administering a PDE5 inhibitor to a subject in need thereof, comprising simultaneously administering to the subject an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor, wherein a half life (Ti/₂) of the PDE5 inhibitor in plasma of the subject is shorter than when the PDE5 inhibitor is administered alone, and wherein the subject is unable or unwilling to be administered the PDE5 inhibitor alone due to intolerable side effects.

The invention further provides a method of mitigating the side effects of a PDE5 inhibitor in a subject that experiences side effects when administered a PDE5 inhibitor, comprising administering to the subject a single dosage form comprising between about 25 milligrams and about 150 milligrams of a tramadol material, between about 25 milligrams and about 150 milligrams of a PDE5 inhibitor, and a pharmaceutically acceptable carrier or binder; wherein the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol, (¾)czs-tramadol, a pharmaceutically acceptable salt of (¾)cz^'s-tramadol, and ( )cz^'s-tramadol hydrochloride; wherein the PDE5 inhibitor is one or more of sildenafil, a pharmaceutically acceptable salt of sildenafil, vardenafil, a pharmaceutically acceptable salt of vardenafil, tadalafil, a pharmaceutically acceptable salt of tadalafil, sildenafil citrate, and vardenafil hydrochloride; and wherein a half-life of the PDE5 inhibitor in the subject is shorter than when the PDE5 inhibitor is administered alone.

In embodiments, the active ingredients are present in a single dosage form. In an embodiment, the single dosage form further comprises at least one pharmaceutically acceptable carrier or binder. In another embodiment, the administering step comprises simultaneously administering ingredients consisting of one or more pharmaceutically- acceptable carriers and/or binders, an effective amount of a tramadol material and an effective amount of one or more PDE5 inhibitors, all in a single dosage form.

In embodiments, the subject engages in sexual activity within about 280 minutes after the administering step. Within this time period, the PDE5 inhibitor that has been administered to the subject is therapeutically effective against erectile dysfunction.

In embodiments, the effective amount of the tramadol material is between about 25 milligrams and about 150 milligrams.

In embodiments, the effective amount of the one or more PDE5 inhibitors is between about 25 milligrams and about 150 milligrams.

In embodiments, the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol, (+)cis -tramadol, a pharmaceutically acceptable salt of

and (+)cis-tramadol hydrochloride.

In embodiments, the PDE5 inhibitor is selected from the group consisting of sildenafil, a pharmaceutically acceptable salt of sildenafil, vardenafil, a pharmaceutically acceptable salt of vardenafil, tadalafil, a pharmaceutically acceptable salt of tadalafil, sildenafil citrate, and vardenafil hydrochloride.

In embodiments, a half-life of the PDE5 inhibitor in the subject is shorter than when the PDE5 inhibitor is administered alone.

In embodiments, the subject does not have a medical need for the tramadol material.

These and other advantages will be apparent from the disclosure contained herein.

As used herein, "at least one," "one or more," and "and/or" are open-ended expressions that are both conjunctive and disjunctive in operation. For example, each of the expressions "at least one of A, B and C," "at least one of A, B, or C," "one or more of A, B, and C," "one or more of A, B, or C" and "A, B, and/or C" means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B and C together.

It is to be noted that the term "a" or "an" entity refers to one or more of that entity. As such, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising," "including," and "having" can be used interchangeably.

The embodiments and configurations described herein are neither complete nor exhaustive. As will be appreciated, other embodiments of the invention are possible utilizing, alone or in combination, one or more of the features set forth above or described in detail below. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates stereoisomers of tramadol.

Fig. 2 illustrates a calibration curve for tramadol.

Fig. 3 illustrates a calibration curve for Viagra®.

Fig. 4 illustrates a chromatogram of both tramadol and Viagra®.

Fig. 5 illustrates the concentration of both tramadol and Viagra® in the blood plasma of a human male versus time, from data generated in Example 1.

Fig. 6 illustrates a calibration curve for tramadol.

Fig. 7 illustrates a calibration curve for Viagra®.

. 8 illustrates a chromatogram of both tramadol and Viagra®.

Fig. 9 illustrates the concentration of both tramadol and Viagra® in the blood plasma of a human male versus time, from data generated in Example 2.

Fig. 10 illustrates the concentration of both tramadol and Viagra® in the blood plasma of a human male versus time, from data generated in Example 2.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those provided in the Summary prevail unless stated otherwise.

As used herein, the term "erectile dysfunction" means the consistent or recurrent inability to achieve and/or maintain a penile erection sufficient to permit satisfactory sexual intercourse or activity. "Erectile dysfunction" is also used herein to mean the partial, temporary or episodic absence of a penile erection.

The erectile function (EF) domain of the International Index of Erectile Function

(IIEF) has been developed and validated as a patient-based questionnaire that is now widely use for the diagnosis of erectile dysfunction. The EF domain of the IIEF has demonstrated test reliability and validity with a high degree of sensitivity and specificity. In particular, men scoring 25 or less are classified as having ED and those scoring above 25 are classified as not having ED (sensitivity = 0.97; specificity = 0.88). Further, responses to IIEF erectile function questions can classify erectile dysfunction into five diagnostic categories: no erectile dysfunction (score 26-30); 'mild' erectile dysfunction (score 22-25); 'mild-to-moderate' erectile dysfunction (score 17-21); 'moderate' erectile dysfunction (score 11-16); and 'severe' erectile dysfunction (score 6-10). See Rosen, et al, Int. J. Impot. Res., 14(4):226-244 (August 2002) and Rosen, et al, Urology, 49:822- 830 (1997) (includes a copy of the IIEF questionnaire and an identification of the EF questions). Another subset of the IIEF called the Sexual Health Inventory for Men (SHIM) was also developed and validated as a diagnostic tool that is now widely use for the diagnosis of erectile dysfunction. Men scoring 21 or less are classified as having ED and those scoring above 21 are classified as not having ED (sensitivity = 0.98; specificity = 0.88). Further, responses to SHIM questions can classify erectile dysfunction into five diagnostic categories: no erectile dysfunction (score 22-25); 'mild' erectile dysfunction (score 17-21); 'mild-to-moderate' erectile dysfunction (score 12-16); 'moderate' erectile dysfunction (score 8-11); and 'severe' erectile dysfunction (score 5-7). See Rosen, et al, Int. J. Impot. Res., 14(4):226-244 (August 2002) (identifies the SHIM questions) and Rosen, et al., Urology, 49:822-830 (1997) (includes a copy of the IIEF questionnaire). Accordingly, erectile dysfunction can be diagnosed using the EF score and/or the SHIM score, and the severity of erectile dysfunction can also be assessed using these scores.

The term "tramadol material" is used herein to refer to 2-[(dimethylamino)methyl]- l-(3-methoxyphenyl)-cyclohexanol ("tramadol") and all pharmaceutically-acceptable forms and derivatives of tramadol. In particular, the term includes the N-oxide derivative ("tramadol N-oxide") and the O-desmethyl derivative ("O-desmethyl tramadol"). The term also includes the solvates, polymorphs, and pharmaceutically-acceptable acid addition salts of tramadol and its derivatives. The term further includes all of the stereoisomers of any of the foregoing, including individual stereoisomers (including individual enantiomers) and mixtures of stereoisomers (including the racemates).

The stereoisomers of tramadol are shown in Fig. 1. There appears to be some discrepancy in the literature regarding the nomenclature of the individual stereoisomers of tramadol. For the purposes of the present application, the designations of "cis" and "trans" stereoisomers of tramadol are made in reference to the relative positions of the dimethylamino and the hydroxy substituents on the cyclohexane ring within the tramadol molecule. As shown in Fig. 1, the R,R and S,S enantiomers will be referred to herein as the "cis" isomers while the R,S and S,R isomers will be referred to herein as the "trans" isomers. As also shown in Fig. 1, the R,R isomer of tramadol will be referred to herein as the "+" cis isomer and the S,S isomer will be referred to as the "-" cis isomer. It is presently understood that R,S and S,R isomers are not optically active. Presently preferred is tramadol and the acid addition salts thereof, particularly the hydrochloride. Even more preferred is (+)cis-tramadol, the acid addition salts, particularly the hydrochloride, and the individual enantiomers.

Methods of making tramadol, tramadol N-oxide, and O-desmethyl tramadol are well known. See, e.g., U.S. Patents Nos. 3,652,589, 3,830,934, 5,223,541, 5,336,691, 5,723,668, 5,728,885, and 5,874,620, the complete disclosures of which are incorporated herein by reference. Tramadol is also commercially available from several sources, including Gruenenthal GmbH, Aschen, Germany.

The pharmaceutically-acceptable acid addition salts are prepared by conventional methods well known in the art using pharmaceutically-acceptable, substantially non-toxic, organic and inorganic acids. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, benzoic acid, salicylic acid, phthalic acid, nicotinic acid, etc. Preferred is hydrochloric acid, and tramadol hydrochloride is the most preferred compound for practicing the invention.

Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the metabolism of the second messenger nucleotides cAMP and cGMP. The PDEs have now been classified into eleven major families, Types I-XI. The members of the families vary in their tissue, cellular and subcellular distribution, as well as their links to the cAMP and cGMP pathways. For example, PDE type III (PDE3), PDE type IV (PDE4) and PDE type V (PDE5) are found in the corpus cavernosum, with PDE5 being the most abundant.

A "phosphodiesterase inhibitor" is an agent that is capable of inhibiting or reducing, selectively or nonselectively, the activity of a PDE. Suitable PDE inhibitors for use in the present invention include those described in U.S. Patents Nos. 5,250,534, 5,859,006, 6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975, 6,943,166 and 6,943,171, the complete disclosures of which are incorporated herein by reference. Methods of making PDE inhibitors are known. See, e.g., U.S. Patents Nos. 5,250,534, 5,859,006, 6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975, 6,943,166 and 6,943,171. The PDE inhibitor used in the present invention is preferably an inhibitor of PDE3, PDE4 and/or PDE5. More preferably, the PDE inhibitor is a selective inhibitor of PDE5. Even more preferably, the inhibitor is sildenafil, vardenafil and/or tadalafil, and pharmaceutically-acceptable forms (e.g., salts, solvates, stereoisomers (individual isomers and mixtures of isomers), etc.) of them. Most preferably, the inhibitor is sildenafil citrate (e.g., Viagra® sildenafil citrate; Pfizer), vardenafil hydrochloride (e.g., Levitra® vardenafil HC1; Schering-Plough) and/or tadalafil (e.g., Cialis®; Lilly ICOS).

A "side effect" or "adverse drug reaction" (ADR) is an adverse effect of administering a pharmaceutical compound to a subject. Side effects of PDE5 inhibitors include, but are not limited to, headache, dizziness, flushing, dyspepsia, nasal congestion, rhinitis, sudden hearing loss, anterior optic neuropathy, photophobia, blurred vision, cyanopsia, loss of peripheral vision, priapism, hypotension, myocardial infarction, ventricular arrhythmia, stroke, increased intraocular pressure, discomfort or pain in the stomach or abdomen, burping, acid reflux, back pain, pain or aches in the muscles or joints, nausea, photosensitivity, eye pain, facial edema, palpitation, tachycardia, rash, and itch. These side effects of PDE5 inhibitors can discourage men from seeking treatment for erectile dysfunction, or from continuing treatment once it has begun.

To treat erectile dysfunction while mitigating the side effects of PDE5 inhibitors, an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor are administered to a male an effective time prior to sexual activity. The two drugs may be administered simultaneously or substantially simultaneously in any order. By substantially simultaneously, it is meant that the tramadol material and the PDE5 inhibitor are administered within about 2 hours, within about 1.5 hours, within about 60 minutes, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 20 minutes, within about 10 minutes, or within about 5 minutes of each other. They may be administered separately, by the same or different modes of administration, but preferably they may be administered in combination in a single dosage form by a single route of administration. Preferred is a single dose of each drug taken orally prior to sexual activity. By an "effective amount" of the PDE5 inhibitor is meant a nontoxic, but sufficient, amount of the PDE5 inhibitor to reduce the incidence or severity of erectile dysfunction. By an "effective amount" of the tramadol material is meant a nontoxic, but sufficient, amount of the tramadol material to mitigate the side effects of the effective amount of the PDE5 inhibitor. By an "effective time" is meant the range of time prior to sexual activity during which each of the two drugs must be administered so that they will be effective to reduce the incidence of erectile dysfunction and mitigate the side effects of the PDE5 inhibitor. An effective amount of (±)cis -tramadol HC1 can be from about 1 mg to about 250 mg, preferably from about 10 mg to about 200 mg, more preferably from about 25 mg to about 150 mg. An effective amount of the tramadol material can also be about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 89 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. The tramadol material can be given orally from about 30 minutes to about 24 hours before sexual activity, or can be given less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, less than about 1.5 hours, less than about 1 hour, or less than about 30 minutes before sexual activity. In these embodiments, the tramadol material is given far enough prior to sexual activity to be effective, such as a minimum time of about 15 minutes, a minimum time of about 30 minutes, a minimum time of about 45 minutes, a minimum time of about 1 hour, a minimum time of about 1.5 hours, or a minimum time of about 2 hours. An effective amount of Viagra® sildenafil citrate can be from about 5 mg to about 500 mg, preferably from about 25 mg to about 100 mg, given orally from about 30 minutes to about 4 hours before sexual activity. An effective amount of Levitra® vardenafil hydrochloride can be from about 1 mg to about 100 mg, preferably from about 5 mg to about 20 mg, given orally from about 30 minutes to about 2 hours before sexual activity. An effective amount of Cialis® tadalafil can be from about 1 mg to about 100 mg, preferably from about 5 mg to about 20 mg, given orally from about 30 minutes to about 36 hours before sexual activity. An effective amount of the PDE5 inhibitor can also be about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 89 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, or about 150 mg. The PDE5 inhibitor can be given less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2.5 hours, less than about 2 hours, less than about 1.5 hours, less than about 1 hour, or less than about 30 minutes before sexual activity. In these embodiments, the PDE5 inhibitor is given far enough prior to sexual activity to be effective, such as a minimum time of about 15 minutes, a minimum time of about 30 minutes, a minimum time of about 45 minutes, a minimum time of about 1 hour, a minimum time of about 1.5 hours, or a minimum time of about 2 hours. However, it is understood by those skilled in the art that the dosage amount will vary with the particular form of tramadol employed and the particular PDE5 inhibitor employed, the route(s) of administration, the timing of the administration, the identity of any other drugs being administered, the severity of the premature ejaculation and erectile dysfunction conditions, the age, size and condition of the patient, and like factors known in the medical art. In general, a suitable dose will be that amount of the compound which is the lowest dose effective to reduce the incidence or severity of erectile dysfunction and/or mitigate the side effects of the PDE5 inhibitor without toxicity. However, the dosage, route of administration, etc., will be determined by an attending physician within the scope of sound medical judgment. Effective dosage forms, modes and times of administration, and dosage amounts can be determined empirically. As a result of the present invention, it has surprisingly and unexpectedly been discovered that when a tramadol material and one or more PDE5 inhibitors are administered to a male, the side effects of the PDE5 inhibitor are mitigated.

The invention also provides a method of administering a PDE5 inhibitor to a subject in need thereof, comprising simultaneously administering to the subject an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor, wherein a half life (Ti_/2) of the PDE5 inhibitor in plasma of the subject is shorter than when the PDE5 inhibitor is administered alone, and wherein the subject is unable or unwilling to be administered the PDE5 inhibitor alone due to intolerable side effects.

The present invention is based on the surprising effect that administration of a tramadol material has on the pharmacokinetic properties of PDE5 inhibitors. As shown below in Examples 1 and 2, a PDE5 inhibitor has a shorter half-life in the plasma of a subject when administered simultaneously with a tramadol material than when administered alone. Therefore, any side effects experienced by the subject as a result of administration of the PDE5 inhibitor will be less severe and/or shortened in duration when the PDE5 inhibitor is administered simultaneously with a tramadol material.

In embodiments, the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol, (+)cis -tramadol, a pharmaceutically acceptable salt of (±)cis-tramadol; and (±)cis-tramadol hydrochloride.

In embodiments, the subject does not have a medical need for the tramadol material. As used herein, "reduce the incidence of erectile dysfunction" means that erectile dysfunction will be prevented in a male receiving treatment according to the invention or that the number of incidences of erectile dysfunction will be reduced. As used herein, "reduce the severity of erectile dysfunction" means that the severity of erectile dysfunction as measured by the EF and/or SHIM score is reduced (i.e., the EF or SHIM score increases).

The tramadol material and phosphodiesterase inhibitor may be administered by any suitable route of administration, including orally, nasally, rectally, parenterally (e.g., intravenously, subcutaneously, or intramuscularly), topically (i.e., delivery to the skin or mucosa), transdermally (i.e., delivery by passage of a drug through the skin into the bloodstream), transmucosally (i.e., delivery by passage of a drug through the mucosal tissue into the bloodstream), intracavernosally (i.e., injection into one or both corpora of the corpora cavernosal tissues of the penis), and intarurethrally (i.e., delivery into the urethra). Highly preferred is oral administration.

While it is possible for the tramadol material and phosphodiesterase inhibitor to be administered alone, it is preferable to administer them (individually or in combination) as a pharmaceutical formulation (composition). The pharmaceutical compositions will comprise a tramadol material, a phosphodiesterase inhibitor or both as the active ingredient(s) in admixture with one or more pharmaceutically-acceptable carriers and, optionally, with one or more other compounds, drugs, or other materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the male who will take the composition. Pharmaceutically-acceptable carriers are well known in the art. Regardless of the route of administration selected, the active ingredient(s) are formulated into pharmaceutically- acceptable dosage forms by conventional methods known to those of skill in the art. See, e.g., Remington =s Pharmaceutical Sciences.

Pharmaceutical compositions containing a tramadol material and methods of making the pharmaceutical compositions have been described. See, e.g., U.S. Patents Nos. 3,652,589, 3,830,934, 5,223,541, 5,591,452, 5,601,842, 5,728,885, 6,017,963, 6,090,856, and 6,156,342, the complete disclosures of which are incorporated herein by reference. Moreover, pharmaceutical compositions containing tramadol and pharmaceutically-acceptable salts thereof are manufactured and sold worldwide. In the United States, (±)cis-2- [(dimethylamino)methyl] - 1 -(3 -methoxyphenyl)-cyclohexanol hydrochloride for oral administration is available from Ortho-McNeil Pharmaceutical, Inc., Raritan, New Jersey 08869, as ULTRAM tablets. Each ULTRAM tablet contains 50 milligrams (j+^c5-2-[(dimethylamino)methyl]- 1 -(3-methoxyphenyl)-cyclohexanol hydrochloride and a number of inactive ingredients (corn starch, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, titanium dioxide and wax). It is understood that the commercial preparation of tramadol marketed under the brand name ULTRAM 7 consists of a mixture of the R,R and S,S isomers of tramadol hydrochloride.

Pharmaceutical compositions containing a phosphodiesterase inhibitor and methods of making the pharmaceutical compositions have also been described. See, e.g., U.S. Patents Nos. 5,250,534, 5,859,006, 6,140,329, 6,362,178, 6,403,597, 6,469,012, 6,821,975, 6,943,166 and 6,943,171, the complete disclosures of which are incorporated herein by reference. Suitable phosphosdiesterase inhibitors are also available commercially from, e.g, Pfizer (Viagra® sildenafil citrate), Schering-Plough (Levitra® vardenafil HC1) and Lilly ICOS (Cialis® tadalafil).

Formulations for use with the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsions, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), and the like, each containing a predetermined amount of the active ingredient(s). Preferred oral administration forms are tablets and capsules.

In solid dosage forms for use with the invention in the context of oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient(s) are mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monosterate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions for use with the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient(s) therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. These compositions may also be of a composition so that they release the active ingredient(s) only, or preferentially, in a certain sequence (e.g., one before the other, one immediately and the other over time, both over time but with different release profiles, etc.). Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient(s) can also be in microencapsulated form.

Liquid dosage forms for oral administration of the compounds used in the invention include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient(s), the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, thickening, and preservative agents.

Suspensions, in addition to the active ingredient(s), may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallme cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions for use with the invention in the context of rectal administration may be presented as a suppository, which may be prepared by mixing the active ingredient(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum and release the active ingredient(s).

Dosage forms for the topical, transdermal or transmucosal administration of the active ingredient(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops and inhalants. The active ingredient(s) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to the active ingredient(s), excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the active ingredient(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The active ingredient(s) may also be delivered through the skin using conventional transdermal drug delivery systems, i.e., transdermal patches, wherein the active ingredient(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin. In such a structure, the active ingredient(s) are typically contained in a layer, or "reservoir," underlying an upper backing layer. The laminated device may contain a single reservoir, or it may contain multiple reservoirs. In one embodiment, the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.

The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing material should be selected so that it is substantially impermeable to the active ingredient and any other materials that are present. The backing layer may be either occlusive or nonocclusive, depending on whether it is desired that the skin become hydrated during drug delivery. The backing is preferably made of a sheet or film of a preferably flexible elastomeric material. Examples of polymers that are suitable for the backing layer include polyethylene, polypropylene, polyesters, and the like.

During storage and prior to use, the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device to expose the basal surface thereof, either the drug reservoir or a separate contact adhesive layer, so that the system may be affixed to the skin. The release liner should be made from a drug/vehicle impermeable material.

Transdermal drug delivery devices may be fabricated using conventional techniques, known in the art, for example by casting a fluid admixture of adhesive, drug and vehicle onto the backing layer, followed by lamination of the release liner. Similarly, the adhesive mixture may be cast onto the release liner, followed by lamination of the backing layer. Alternatively, the drug reservoir may be prepared in the absence of drug or excipient, and then loaded by "soaking" in a drug/vehicle mixture.

The laminated transdermal drug delivery systems may in addition contain a skin permeation enhancer. That is, because the inherent permeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of unbroken skin, it is necessary to coadminister a skin permeation enhancer with such drugs. Suitable enhancers are well known in the art. The pharmaceutical compositions adapted to be used with the invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.

Preferred formulations for topical drug delivery are ointments and creams. Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent(s), are, as known in the art, viscous liquid or semisolid emulsions, either oil-in- water or water-in-oil. Cream bases are water- washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. The specific ointment or cream base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

Formulations for buccal administration include tablets, lozenges, gels and the like.

Alternatively, buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.

Pharmaceutical compositions suitable for parenteral administrations comprise the active ingredient(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders or other solid forms which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents which delay absorption such as aluminum monosterate and gelatin.

In some cases, in order to prolong the effect of the active ingredient(s), it is desirable to slow the absorption of the active ingredient(s) from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient(s) then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered active ingredient(s) is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the active ingredient(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of active ingredient(s) to polymer, and the nature of the particular polymer employed, the rate of release of the active ingredient(s) can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the active ingredient(s) in liposomes or microemulsions which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through a bacterial-retaining filter.

Intracavernosal injection can be carried out by use of a syringe or any other suitable device. An example of a hypodermic syringe useful herein, that can be used for simultaneous injection into both corpora, is described in U.S. Pat. No. 4,127,118. The injection is made on the dorsum of the penis by placement of the needle to the side of each dorsal vein and inserting it deep into the corpora.

The active ingredient(s) can be administered in a pharmaceutical formulation suitable for transurethral drug delivery. The formulation contains one or more selected carriers or excipients, such as water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and/or a variety of other materials, with polyethylene glycol and derivatives thereof particularly preferred. It may be desirable to incorporate a transurethral permeation enhancer in the urethral dosage form. Examples of suitable transurethral permeation enhancers include dimethylsulfoxide, dimethyl formaminde, Ν,Ν-dimethylacetamide, decylmethylsulfoxide, polyethylene glycol monolaurate, glycerol monolaurate, lecithin, the 1 -substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone7 from Nelson Research & Development Co., Irvine, Calif), SEPA7 (available from Macrochem Co., Lexington, Mass.), alcohols (e.g., ethanol), detergents (such as Tergitol7, Nonoxynol-97 and TWEEN-807) and the like. Transurethral formulations may additionally include one or more enzyme inhibitors effective to inhibit drug-degrading enzymes which may be present in the urethra. Additional optional components include excipients, preservatives (e.g., antioxidants), chelating agents, solubilizing agents (e.g., surfactants), and the like, as will be appreciated by those skilled in the art of drug formulation preparation and delivery.

Transurethral drug administration, as explained in PCT application WO 91/16021, can be carried out in a number of different ways using a variety of urethral dosage forms. For example, the drug can be introduced into the urethra from a flexible tube, squeeze bottle, pump or aerosol spray. The drug may also be contained in coatings, pellets or suppositories which are absorbed, melted or bioeroded in the urethra. In certain embodiments, the drug is included in a coating on the exterior surface of a penile insert. Drug delivery devices for administering a drug transurethrally are described in U.S. Patent No. 6,037,360 and PCT application WO 91/16021.

Urethral suppository formulations containing polyethylene glycol or a polyethylene glycol derivative can be used as the urethral dosage form, and may be conveniently formulated using conventional techniques, e.g., compression molding, heat molding or the like, as will be appreciated by those skilled in the art and as described in the pertinent literature and pharmaceutical texts. See, for example, Remington: The Science and Practice of Pharmacy, 19th Ed. (Easton, PA: Mack Publishing Co., 1995), which discloses typical methods of preparing pharmaceutical compositions in the form of urethral suppositories. It is also preferred that urethral suppositories contain one or more solubilizing agents (e.g., a nonionic, anionic, cationic or amphoteric surfactant) effective to increase the solubility of the active ingredient(s) in the polyethylene glycol or other transurethral vehicle.

It may be desirable to deliver the active ingredient(s) in a urethral dosage form which provides for controlled or sustained release of the agent(s). In such a case, the dosage form typically comprises a biocompatible, biodegradable material, typically a biodegradable polymer. Examples of such polymers include polyester, polyalkylcyanoacrylate, polyorthoester, polyanhydride, albumin, gelatin and starch. As explained, for example, in PCT application WO 96/40054, these and other polymers can be used to provide biodegradable microparticles which enable controlled and sustained drug release, in turn minimizing the required dosing frequency.

The method of intraurethral administration may involve an "active" delivery mechanism such as iontophoresis, electroporation or phonophoresis. Devices and methods for delivering drugs in this way are well known in the art. Iontophoretically assisted drug delivery is, for example, described in PCT application WO 96/40054. Briefly, the active agent(s) are driven through the urethral wall by means of an electric current passed from an external electrode to a second electrode contained within or affixed to a urethral probe.

The pharmaceutical formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampules, vials and blister packs, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.

Co-pending US Patent Application Publication Numbers 2008/0262094 entitled "Treatment Of Comorbid Premature Ejaculation and Erectile Dysfunction" and 2008/0261991 entitled "Reducing Side Effects Of Tramadol" are incorporated herein by reference in their entirety.

It is to be noted that "a" or "an" entity refers to one or more of that entity. For example, "a container" refers to one or more containers.

The following examples are intended to illustrate and explain exemplary embodiments. Embodiments of the disclosure, therefore, should not be limited to any of the details in these examples.

EXAMPLES

Literature has indicated that a single oral dose of 100 mg sildenafil citrate (Viagra®) yields a maximum plasma concentration (C_max) of about 560 ng/ml, at a time (T_max) of about 0.95 hours and with a half life (Ti/₂) of about 4 hours (Nichols, D. J., Muirhead, G. J., & Harness, J. A. (2002). Pharmacokinetics of sildenafil citrate after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. J Clin Pharmacol , 53, 5s-12s.). Literature has indicated that 100 mg of oral tramadol has a C_max of about 340 ng/ml, T_max of about 1.5 hours and T ₂ of about 7 hours (Ardakani, Y. H., & Rouini, M.-R. (2007). Pharmacokinetics of Tramadol and its Three Main Metabolites in Healthy Male and Female Volunteers. Biopharm. Drug Dispos., 28, 526-533.). While the pharmacokinetics of both drugs individually has been reported, the pharmacokinetics of a single dose of both Viagra® and tramadol taken together have not previously been characterized.

EXAMPLE 1

The objective of this example is to measure the plasma concentration time course of tramadol and Viagra® in a healthy volunteer that was administered an oral combination tablet of tramadol (89 mg) and Viagra® (100 mg). The T_max, C_max and Ti_/2 were calculated for tramadol and Viagra®.

Methods

A healthy 38 year old male volunteer was given a single combination tablet of 89 mg tramadol and 100 mg Viagra® (sildenafil citrate). Venous blood was collected in heparinized tubes at time zero (pre-dose), 1 hour, 2 hours, 3 hours, 6 hours and 8 hours. Plasma was obtained from the whole blood following standard centrifugation protocols and the plasma was stored at -80 C prior to analysis.

Analyte plasma samples were prepared by combining 400ul of each plasma sample with 1 ml of hexane and thoroughly mixing (vortex, followed by overnight shaker). 800ul of the organic phase was removed and dried to completion in a rotovap for 10 min. 150ul of 30% acetonitrile (ACN)/70% water/0.1% trifluoroacetic acid (TFA) was added to each sample and the solutions were vortexed and sonicated to re-dissolve the analytes. A standard curve was prepared by spiking plasma with 2500 ng/ml, 500 ng/ml, 100 ng/ml, and 20 ng/ml of both Viagra® and tramadol. The standards were processed identically to the analyte plasmas.

Both tramadol and Viagra® were analyzed on a Waters 2975 liquid chromatograph coupled to a Micromass LCT mass spectrometer. The HPLC column was a Waters XTerra C-18 2.1 x 100 mm at a flow rate of 0.4 ml/min. The mobile phases were water with 0.1% TFA (A) and acetonitrile with 0.1%TFA (B). A gradient from 5% B to 95% B over 15 min was used. Tramadol elutes at 4.3 min and Viagra® elutes at 6.2 min. The mass spectrometer was set in positive electrospray ionization mode with a capillary voltage of 3200, cone voltage of 30, desolvation temperature of 300 C, and desolvation gas flow of 680 L/hr. Tramadol appears at an m/z of 264.2 while Viagra® appears at an m/z of 475.2 in positive mode both representing the M+H ion. These masses were monitored in time and integrated by area. 20 ul of each sample including the standards were injected. A cubic polynomial log-transformed calibration curve was derived from the standards.

Results

Calibration curves for tramadol and Viagra® are shown in Figs. 2 and 3 respectively.

The resulting quantitation in the plasma samples of the volunteer are tabulated results in Table 1.

Table 1

Fig. 4 shows a typical chromatogram of both tramadol and Viagra®.

To calculate the pharmacokinetic parameters T_max, C_max and Ti/₂, a model of absorption and elimination was fitted to the data in Matlab and the parameters were estimated from the model. The model took the form:

Ak_a (e ^~ket - e ^{~k t})

C(t) where C(t) is concentration as a function of time, A is a scale constant, k_e is the elimination rate constant and k_a is the absorption rate constant. Fig. 5 shows both the raw data (circles) and the fitted data (lines).

Tmax for tramadol and Viagra® were calculated as 1.85 hours and 0.98 hours respectively. C_max for tramadol and Viagra® were calculated as 707 ng/ml and 1121 ng/ml respectively. Half- lives (T_½) were estimated using k_e only as 3.1 hours for tramadol and 1.1 hours for Viagra®.

Conclusions

The plasma concentrations of both tramadol and Viagra® were successfully measured in a healthy volunteer who was administered a combination tablet of 100 mg Viagra® and 89 mg tramadol. The plasma concentration time courses of both analytes fit well to a theoretical absorption / elimination model. The dosing profiles for each drug seem to overlap most in the 1-2 hour regime (both drugs appear to peak at about the same time), as illustrated in Fig. 5. The C_max of both drugs were approximately twice as high as previously reported for the individual drugs (340 vs. 707 ng/ml for tramadol and 560 vs. 1121 ng/ml for Viagra®) implying better absorption when used in combination in a single dose tablet, which is a surprising and unexpected advantage of simultaneous administration. The tramadol and Viagra® are in the plasma of the human male for less time, the half-life for both the tramadol and Viagra® are significantly shorter than previously reported for the individual drugs; and the 2 drugs exhibit a synchronized onset of action, as well as a coordinated therapeutic window. These advantageous properties of the drugs when administered together were surprising and unexpected, as well as beneficial.

EXAMPLE 2

The objective of this example is to measure the plasma concentration time course of tramadol and Viagra® in two healthy volunteers who were each administered an oral combination tablet of tramadol (89 mg) and Viagra® (100 mg). The T_max, C_max, and T ₂ were calculated for tramadol and Viagra®.

Methods

A healthy 42-year-old male volunteer and a healthy 39-year-old male volunteer were each given a single combination tablet of 89 mg tramadol and 100 mg Viagra® (sildenafil citrate). Venous blood was collected in heparinized tubes at time zero (pre- dose), 1 hour, 2 hours, 3 hours, 6 hours, and 8 hours. Plasmas were obtained from the whole blood following standard centrifugation protocols and the plasmas were stored at - 80 °C prior to analysis.

Analyte plasma samples were prepared by combining 400 of each plasma sample with 1 mL of hexane and thoroughly mixing (vortex, followed by overnight shaker). 800 of the organic phase was removed and dried to completion in a rotovap for 10 min. 150 μΕ of 30% acetonitrile (CAN)/70% water/0.1% trifluoroacetic acid (TFA) was added to each sample and the solutions were vortexed and sonicated to re-dissolve the analytes. A standard curve as prepared by spiking plasma with 2500 ng/mL, 500 ng/mL, 100 ng/mL, and 20 ng/mL of each of Viagra® and tramadol. The standards were processed identically to the analyte plasmas. Both tramadol and Viagra® were analyzed on a Waters 2975 liquid chromatograph coupled to a Micromass LCT mass spectrometer. The HPLC column was a Waters XTerra C-18 2.1 x 100 mm at a flow rate of 0.4 mL/min. The mobile phases were water with 0.1% TFA (A) and acetonitrile with 0.1% TFA (B). A gradient from 5% B to 95% B over 15 min was used. Tramadol elutes at 4.3 min and Viagra® elutes at 6.2 min. The mass spectrometer was set in positive electrospray ionization mode with a capillary voltage of 3200 V, cone voltage of 30 V, desolvation temperature of 300 °C, and desolvation gas flow of 680 L/hr. Tramadol appears at an m/z of 264.2 while Viagra® appears at an m z of 475.2 in positive mode, both representing the M+H ion. These masses were monitored in time and integrated by area. 20 μΐ, of each sample, including the standards, were injected. A cubic polynomial log-transformed calibration curve was derived from the standards. Results

Calibration curves for tramadol and Viagra® are shown in Figures 6 and 7, respectively.

The resulting quantitations in the plasma samples of the two volunteers are tabulated in Table 2.

Table 2

Time Subject 1 Subject 1 Subject 2 Subject 2 (hr) Viagra® (ng/mL) Tramadol (ng/m Viagra® (ng/mL) Tramadol (ng/mL)

0.0 0.0 0.0 0.0 0.4

1.0 175.9 215.1 415.8 342.1 2.0 103.7 256.2 275.6 419.1 3.0 64.8 239.0 19.5 224.9 6.0 12.2 148.1 123.2 98.7

8.0 0.0 93.8 7.8 75.8

Figure 8 shows a typical chromatogram of both tramadol and Viagra®.

To calculate the pharmacokinetic parameters T_max, C_max, and Ty₂, a model of absorption and elimination was fitted to the data in Matlab and the parameters were estimated from the model. The model took the form:

Ak_a (e

C(t) where C(t) is concentration as a function of time, A is a scale constant, k_e is the elimination rate constant, and k_a is the absorption rate constant. Figures 9 and 10 show both the raw data (circles) and the fitted data (lines) for Subjects 1 and 2, respectively.

For Subject 1, T_max for tramadol and Viagra® were calculated as 2.04 hours and 0.83 hours, respectively. C_max for tramadol and Viagra® were calculated as 257 ng/mL and 179 ng/mL, respectively. Half-lives ( ) were estimated using k_e only as 3.4 hours for tramadol and 1.1 hours for Viagra®.

For Subject 2, T_max for tramadol and Viagra® were calculated as 1.40 hours and 0.75 hours, respectively. C_max for tramadol and Viagra® were calculated as 381 ng/mL and 445 ng/mL, respectively. Half-lives ( ) were estimated using k_e only as 1.9 hours for tramadol and 0.6 hours for Viagra®.

Conclusions

The plasma concentrations of both tramadol and Viagra® were successfully measured in two healthy volunteers who were each administered a combination tablet of 100 mg Viagra® and 89 mg tramadol. The plasma concentration time courses of both analytes fit well to a theoretical absorption/elimination model. The dosing profiles for each drug seem to overlap most in the 1-2 hour regime (both drugs appear to peak within about an hour of each other), as illustrated in Figures 9 and 10. For Subject 1 the C_max of tramadol was similar to that which was previously reported for the individual drugs, while the C_max of Viagra was somewhat lower (340 vs. 257 ng/mL for tramadol and 560 vs. 179 ng/mL for Viagra®). For Subject 2 the C_max of both drugs was similar to that which was previously reported for the individual drugs (340 vs. 381 ng/mL for tramadol and 560 vs. 445 ng/mL for Viagra®). There appears to be some variability in the pharmacokinetic properties of the two drugs between individuals, but in general tramadol and Viagra® are in the plasma of the human male for less time; the half-life for both tramadol and Viagra® are significantly shorter than previously reported for the individual drugs; and the two drugs exhibit a synchronized onset of action, as well as a coordinated therapeutic window. These advantageous properties of the drugs were administered together were surprising and unexpected, as well as beneficial.

The invention illustratively disclosed herein suitably may be practiced in the absence of any element, which is not specifically disclosed herein. It is apparent to those skilled in the art, however, that many changes, variations, modifications, other uses, and applications to the method are possible, and also changes, variations, modifications, other uses, and applications which do not depart from the spirit and scope of the invention are deemed to be covered by the invention, which is limited only by the claims which follow.

The foregoing discussion of the invention has been presented for purposes of illustration and description. The foregoing is not intended to limit the invention to the form or forms disclosed herein. In the foregoing Detailed Description for example, various features of the invention are grouped together in one or more embodiments for the purpose of streamlining the disclosure. The features of the embodiments of the invention may be combined in alternate embodiments other than those discussed above. This method of disclosure is not to be interpreted as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the invention.

Moreover, though the description of the invention has included description of one or more embodiments and certain variations and modifications, other variations, combinations, and modifications are within the scope of the invention, e.g., as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative embodiments to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter.

Claims

What is Claimed is:

1. A method of mitigating the side effects of a phosphodiesterase type V (PDE5) inhibitor in a subject that experiences side effects when administered a PDE5 inhibitor, comprising simultaneously administering to the subject active ingredients comprising an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor.

2. The method of claim 1, wherein the active ingredients are present in a single dosage form.

3. The method of claim 2, wherein the single dosage form further comprises at least one pharmaceutically acceptable carrier or binder.

4. The method of claim 1, wherein the effective amount of the tramadol material is between about 25 milligrams and about 150 milligrams.

5. The method of claim 1, wherein the effective amount of the PDE5 inhibitor is between about 25 milligrams and about 150 milligrams.

6. The method of claim 1, wherein the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol, (±)cis -tramadol, a pharmaceutically acceptable salt of (±)cis -tramadol, and (+)cis -tramadol hydrochloride.

7. The method of claim 1, wherein the PDE5 inhibitor is one or more of sildenafil, a pharmaceutically acceptable salt of sildenafil, vardenafil, a pharmaceutically acceptable salt of vardenafil, tadalafil, a pharmaceutically acceptable salt of tadalafil, sildenafil citrate, and vardenafil hydrochloride.

8. The method of claim 1, wherein a half- life of the PDE5 inhibitor in the subject is shorter than when the PDE5 inhibitor is administered alone.

9. The method of claim 1, wherein the subject does not have a medical need for the tramadol material.

10. A method of administering a PDE5 inhibitor to a subject in need thereof, comprising:

simultaneously administering to the subject an effective amount of a tramadol material and an effective amount of a PDE5 inhibitor;

wherein a half life (Ti_/2) of the PDE5 inhibitor in plasma of the subject is shorter than when the PDE5 inhibitor is administered alone; and

wherein the subject is unable or unwilling to be administered the PDE5 inhibitor alone due to intolerable side effects.

11. The method of claim 10, wherein the effective amount of the tramadol material and the effective amount of the PDE5 inhibitor are present in a single dosage form.

12. The method of claim 11, wherein the single dosage form further comprises at least one pharmaceutically acceptable carrier or binder.

13. The method of claim 10, wherein the subject engages in sexual activity within about 280 minutes after the administering step.

14. The method of claim 10, wherein the effective amount of the tramadol material is between about 25 milligrams and about 150 milligrams.

15. The method of claim 10, wherein the effective amount of the PDE5 inhibitor is between about 25 milligrams and about 150 milligrams.

16. The method of claim 10, wherein the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol, (±)cis -tramadol, a pharmaceutically acceptable salt of (±)cis -tramadol, and (+)cis -tramadol hydrochloride.

17. The method of claim 10, wherein the PDE5 inhibitor is one or more of sildenafil, a pharmaceutically acceptable salt of sildenafil, vardenafil, a pharmaceutically acceptable salt of vardenafil, tadalafil, a pharmaceutically acceptable salt of tadalafil, sildenafil citrate, and vardenafil hydrochloride.

18. The method of claim 10, wherein the subject does not have a medical need for the tramadol material.

19. A method of mitigating the side effects of a PDE5 inhibitor in a subject that experiences side effects when administered a PDE5 inhibitor, comprising:

administering to the subject a single dosage form comprising between about 25 milligrams and about 150 milligrams of a tramadol material, between about 25 milligrams and about 150 milligrams of a PDE5 inhibitor, and a pharmaceutically acceptable carrier or binder;

wherein the tramadol material is one or more of tramadol, a pharmaceutically acceptable salt of tramadol,

a pharmaceutically acceptable salt of (±)cis- tramadol, and (±)cis-tramadol hydrochloride;

wherein the PDE5 inhibitor is one or more of sildenafil, a pharmaceutically acceptable salt of sildenafil, vardenafil, a pharmaceutically acceptable salt of vardenafil, tadalafil, a pharmaceutically acceptable salt of tadalafil, sildenafil citrate, and vardenafil hydrochloride; and wherein a half-life of the PDE5 inhibitor in the subject is shorter than when the PDE5 inhibitor is administered alone.

20. The method of claim 19, wherein the subject does not have a medical need for the tramadol material.