United States Patent [19]
`El-Rashidy
`
`US006087362A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,087,362
`Jul. 11,2000
`
`[54] APOMORPHINE AND SILDENAFIL
`COMPOSITION
`
`[75] Inventor: Ragab El-Rashidy, Deer?eld, Ill.
`
`[73] Assignee: Pentech Pharmaceuticals, Inc., Buffalo
`Grove, Ill.
`
`[21] Appl. No.: 09/270,035
`[22]
`Filed:
`Mar. 16, 1999
`
`[51] Int. Cl.7 ....................... .. A61K 31/495; A61K 31/44
`[52] US. Cl. ........................................... .. 514/253; 514/284
`[58] Field of Search .................................... .. 514/284, 253
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,256,652 10/1993 El-Rashidy .............................. .. 514/58
`5,770,606
`6/1998 El-Rashidy et a1. .................. .. 514/284
`
`OTHER PUBLICATIONS
`
`Leland, J., “A Pill for Impotence?,” Newsweek, pp. 62—68,
`(Nov. 17, 1997).
`Goldstein et al., “Oral Sildena?l in the Treatment of Erectile
`Dysfunction”, The New England Journal of Medicine,
`338(20), pp. 1397—1404 (1998).
`Handy B., “The ViagraTM Craze,” Time, pp. 50—57 (May 4,
`1998).
`Valdes—Rodriguez A., “Viagra for her,” Chicago Tribune,
`WomaneWs Section 13, p. 7 (Dec. 20, 1998).
`
`Wilson E., “Impotence Drugs: More than Viagra,” C&EN,
`pp. 29—33 (Jun. 29, 1998).
`Japsen B., “Impotency drug trials promising for Abbott,”
`Chicago T ribuen, Business Section, pp. 1—2 (Sep. 4, 1998).
`Kaplan S. et al., “Combination Therapy Using Oral
`Alpha—Blockers and Intracavernosal Injection in Men With
`Erectile Dysfunction,” Urology 52(5), pp. 739—743 (1998).
`Utiger R., “A Pill for Impotence,” The New Englana'Journal
`ofMedicine, 338(20), pp. 1458—1459 (May 14, 1998).
`VIAGRATM, Prescription Information published by PRO—
`MARK® Pharmacies, http://WWW.pro—mark—pharmaci
`es.com/viagra.html (May 8, 1998).
`
`Primary Examiner—Raymond Henley, III
`Attorney, Agent, or Firm—Olson & Hierl, Ltd.
`
`[57]
`
`ABSTRACT
`
`The treatment of sexual dysfunction in human patients by an
`oral therapy regimen of administration of apomorphine and
`sildena?l is disclosed. This treatment optimizes the ef?cacy
`of each drug and substantially minimizes the undesirable
`side effects associated individually therewith. Apomorphine
`and sildena?l can be co-administered With a combination
`dosage unit or administered sequentially in separate dosage
`units, substantially prior to sexual activity. Other erectogenic
`agents can be administered along With apomorphine and
`sildena?l.
`
`20 Claims, N0 Drawings
`
`MonoSol 1004-0001
`
`MonoSol v. ICOS
`IPR2017-00412
`
`

`
`1
`APOMORPHINE AND SILDENAFIL
`COMPOSITION
`
`FIELD OF THE INVENTION
`
`This invention relates to compositions, dosage forms and
`methods for treating sexual dysfunction in humans. More
`particularly, this invention relates to the use of compositions
`containing apomorphine and sildena?l.
`
`BACKGROUND OF THE INVENTION
`
`A normal erection occurs as a result of a coordinated
`vascular event in the penis. This is usually triggered neurally
`and consists of vasodilation and smooth muscle relaxation in
`the penis and its supplying arterial vessels. Arterial in?oW
`causes enlargement of the substance of the corpora cavern
`osa. Venous out?oW is trapped by this enlargement, permit
`ting sustained high blood pressures in the penis suf?cient to
`cause and maintain rigidity. Muscles in the perineum also
`assist in creating and maintaining penile rigidity. Erections
`are induced centrally in the nervous system by sexual
`thoughts, fantasy, and/or stimulation and can be reinforced
`locally by re?ex mechanisms (e.g., tactile stimulation).
`Impotence or male erectile dysfunction is de?ned as an
`inability to achieve and sustain an erection sufficient for
`satisfactory sexual performance and intercourse. Impotence
`in any given case can result from psychological disturbances
`(psychogenic), from physiological abnormalities in general
`(organic), from neurological disturbances (neurogenic), hor
`monal de?ciencies (endocrine) or from a combination of the
`foregoing.
`As used herein, psychogenic impotence is de?ned as
`functional impotence With no apparent overWhelming
`organic basis. It may be characteriZed by an ability to have
`an erection in response to some stimuli (e.g., masturbation,
`spontaneous nocturnal, spontaneous early morning, video
`erotica, etc.) but not others (e.g., partner or spousal
`attention).
`Current diagnosis of and professional thinking on the
`etiology of male erectile dysfunction has focused on the
`severity of the condition, i.e., mild, moderate and severe.
`One method of diagnosis employs oral medication as a
`means to distinguish dysfunctional patients Who can respond
`to oral medications from those Who require more direct
`intervention, i.e., such as intracavernosal injection or sur
`gery.
`Oral medicines, are particularly desirable and sought after
`discreet forms of treatment. See, for example, Leland J ., “A
`Pill for Impotence?”, Newsweek, pp. 62—68 (Nov. 17, 1997).
`Apomorphine, a selective dopamine receptor agonist, has
`been Widely utiliZed as an emetic agent, sedative, antipar
`kinsonian agent and a behavior altering agent and previously
`Was shoWn to have very poor oral bioavailability. See, for
`example, Baldessarini et al., in Gessa et al., eds., Apomor
`phine and Other Dopaminomimetics, Basic Pharmacology,
`1, pp. 219—228, Raven Press, NY. (1981). HoWever, recent
`research and clinical studies of the effect of orally admin
`istered apomorphine on penile tumescence in male patients
`afflicted with psychogenic impotence shoW that oral admin
`istration of apomorphine can indeed induce an erection in a
`psychogenic male patient in response to physical sexual
`stimulation. The speci?c mechanisms by Which apomor
`phine acts to produce an erectile response in a human male
`are not yet completely understood, but are believed to be
`centrally acting through dopamine receptor stimulation in
`the medial preoptic area of the brain.
`
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`While apomorphine can be orally administered in an
`effective dose, the dose required to achieve a signi?cant
`erectile response must not be accompanied by substantial
`nausea and vomiting, or other undesirable side effects, such
`as arterial hypotension, ?ushing and diaphoresis (sWeating).
`At dosages of more than 6 milligrams, for example, in some
`instances the level of accompanying nausea and vomiting
`interferes With the bene?t in treating male erectile dysfunc
`tion With apomorphine.
`During normal penile erections, When the in?oW of blood
`to the corpora cavernosa engages the sinusoidal spaces, the
`trabecular tissue compresses small cavernosal veins against
`the thick ?brous tissue surrounding the corpora to maintain
`the erection. To mediate these changes in blood ?oW, nitric
`oxide is released from postsynaptic parasympathetic neu
`rons and, to a lesser extent, endothelial cells and
`ot-adrenergic neurons are inhibited in the arterial and trabe
`cular smooth muscle. Nitric oxide, Which is readily
`diffusible, stimulates the formation of increased cyclic gua
`nosine monophosphate (GMP) in the corpus cavernosum by
`guanylate cyclase to relax the smooth muscle cells.
`Recently, the oral use of the citrate salt of sildena?l has
`been approved by the US. Food and Drug Administration
`(FDA) for the treatment of male erectile dysfunction.
`Sildena?l is reported to be a selective inhibitor of cyclic
`GMP-speci?c phosphodiesterase type 5 (PDE5), the pre
`dominant isoZyme metaboliZing cyclic GMP formed in the
`corpus cavernosum. Since sildena?l is a potent inhibitor of
`PDE5 in the corpus cavernosum, it is believed to enhance
`the effect of nitric oxide, thereby increasing cavernosal
`blood How in the penis, especially With sexual stimulation.
`Inasmuch as sildena?l at the currently recommended doses
`of 25—100 mg has little effect in the absence of sexual
`stimulation, sildena?l is believed to restore the natural
`erectile response to sexual stimulation but not cause erec
`tions in the absence of such stimulation. See, for example,
`Goldstein et al., “Oral Sildena?l in the Treatment of Erectile
`Dysfunction,” The New England Journal of Medicine, 338,
`pp 1397—1404 (1998). The localiZed mechanism by Which
`cyclic GMP stimulates relaxation of the smooth muscles has
`not been elucidated.
`In dose-response studies, increasing doses of sildena?l
`(25 to 100 mg) reportedly increased the erectogenic ef?cacy
`of sildena?l. HoWever, the oral administration of sildena?l
`is also accompanied by dose-responsive undesirable side
`effects. Consequently, at dosages higher than 50 milligrams,
`the incidence of such side effects as abnormal vision prob
`lems ranging from blue or green halo effects to blurring,
`dyspepsia, nasal congestion, blinding headaches, ?ushing
`redness, diarrhea, diZZiness, rash, and urinary tract infection
`increases.
`Other more serious side effects have been reported, such
`as syncope (loss of consciousness), priapism (erection last
`ing 4 hours or more) and increased cardiac risk (coital
`coronaries), can be brought on in some cases by physiologi
`cal predisposition, adverse drug interaction or potentiation,
`or by drug abuse. In particular, hypotension crisis can result
`from the combination of sildena?l citrate and organic
`nitrates, causing, in some cases death, so its administration
`to patients Who are concurrently using organic nitrates (such
`as nitroglycerin) in any form is contraindicated. Moreover,
`the long-term effects of large doses of sildena?l containing
`drugs is not knoWn. See, for example, Handy B., “The
`ViagraTM Craze,” Time, pp 50—57 (May 4, 1998).
`Some attempts have been made to treat sexual dysfunc
`tion in females caused by hysterectomy, menopause and
`
`MonoSol 1004-0002
`
`

`
`6,087,362
`
`3
`vascular disorders, like diabetes, by employing topical gels
`containing ViagraTM. See, for example, Valdes-RodrigueZ,
`A, “Viagra for her,” Chicago Tribune, WomaneWs Section
`13, p 7 (Dec. 20, 1998).
`Thus there is an ongoing need and desire for a discreet,
`convenient treatment of sexual dysfunction in humans,
`suitable for men or Women, and preferably for oral delivery
`systems Without the incidence or likelihood of undesirable
`attendant side effects.
`
`SUMMARY OF THE INVENTION
`The present invention provides a therapy regimen of oral
`administration of apomorphine and sildena?l compositions.
`Apomorphine and sildena?l can be either co-administered or
`administered sequentially, prior to sexual activity. A practi
`cal therapeutic delivery system is provided employing apo
`morphine and sildena?l Which system sustains satisfaction
`during sexual activity; i.e., it optimiZes the erectile penile
`response in human males and clitoral response in females to
`sexual stimuli While minimizing the undesirable side effects
`associated individually thereWith. The oral compositions are
`preferably administered in sublingual dosage forms.
`In one composition embodiment suitable for oral therapy,
`apomorphine and sildena?l can be concurrently
`co-administered as a combination sublingual dosage unit.
`Sublingual combination dosage units preferably contain
`apomorphine in the range of about 1 to about 6 milligrams
`(mg) and sildena?l in the range of about 10 to about 75 mg,
`so long as the ?nal dosage combination received by the
`patient is accompanied by minimal or substantially no
`undesirable side effects. Apreferred sublingual combination
`dosage unit contains about 2 mg apomorphine and about 15
`to about 50 mg sildena?l.
`For sequential administration therapy, apomorphine and
`sildena?l are administered in separate dosage units each of
`Which employs a lesser dosage amount of the respective
`drug than is required for achieving the same level of erectile
`response When it is used as the sole active medicament.
`Composition embodiments suitable for sequential adminis
`tration of sildena?l and apomorphine, preferably each in
`sublingual dosage form, preferably contain sildena?l in a
`range of about 10 to about 75 mg, more preferably in the
`range of about 15 to about 50 mg, and apomorphine in a
`range of about 1 to not more than 6 mg, more preferably in
`the range of about 2 to about 5 mg so long as the total dose
`combination received by the patient is accompanied by
`minimal or substantially no undesirable side effects.
`The administration of apomorphine and sildena?l, either
`co-administered or administered sequentially, bene?cially
`provides a discreet, convenient therapy regimen for effec
`tively achieving and maintaining erections sufficient for
`vaginal penetration in response to physical sexual stimuli
`Within a practical therapy period.
`For co-administration of sildena?l and apomorphine, the
`combination dosage unit preferably is taken by a male
`patient suffering from erectile dysfunction about 20—45
`minutes before sexual activity to achieve and maintain an
`erection of suf?cient rigidity for vaginal penetration With
`substantially no attendant adverse side effects, most notably,
`substantially no nausea and vomiting.
`For sequential administration, the male patient preferably
`takes one dosage unit of sildena?l containing the appropriate
`sildena?l dosage and one dosage unit of apomorphine con
`taining the appropriate apomorphine dosage substantially
`Within 30—60 minutes of one another and Within 15—30
`minutes prior to sexual activity.
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`It has noW been found that an oral therapy regimen
`employing apomorphine and sildena?l in combination With
`one another can effectively optimiZe the initiation and
`maintenance of penile erection in response to sexual stimuli
`and minimiZe the side effects associated With each respec
`tive medicament. Moreover optimiZation is achieved at
`dosage levels beloW the efficacy levels required in oral
`therapies employing each drug as the sole medicament.
`Further, apomorphine and sildena?l can also be
`combined, for concurrent or sequential administration
`therapies, With lesser amounts of erectogenic agents selected
`from adrenal steroids, such as testosterone, dehydroepi
`androsterone (DHEA), and the like; alpha receptor blockers,
`such as phentolamine, yohimbine, praZosin, doxaZosin,
`teraZosin, trimaZosin, and the like; or peripheral
`vasodilators, such as prostaglandin E1 (alprostadil), and like
`smooth muscle relaxants. Preferably, the erectogenic agents
`are added in an amount in the range of about 50 to about 100
`percent by Weight of the Weight of apomorphine adminis
`tered.
`Advantageously, practicing the method of this invention,
`avoids or minimiZes the possibility of abusive use of
`sildena?l because the emetic effect of increased apomor
`phine ingestion makes the combination substantially self
`limiting.
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`Apomorphine is a dopamine receptor agonist that has a
`recogniZed use as an emetic When administered subcutane
`ously in about a 5-milligram dose. For the purposes of the
`present invention, apomorphine or a similarly acting dopam
`ine receptor agonist, is administered in an amount su?icient
`to excite cells in the mid-brain region of the patient but With
`minimal side effects. This cell excitation is believed to be
`part of a cascade of stimulation that is likely to include
`neurotransmission With serotonin and oxytocin and Which
`initiates erection upon physical sexual stimulation.
`The dopamine receptors in the mid-brain region of a
`patient can be stimulated to a degree suf?cient to cause an
`erection by the sublingual administration of apomorphine.
`Apomorphine, also knoWn by the chemical name (R)-5,6,
`6a,7-tetrahydro-6-methyl-4H-dibenZo- [de,g] quinoline-10,
`11-diol, has the folloWing chemical structure:
`
`OH
`
`HO
`
`N
`H l
`CH3
`
`Apomorphine exists in a free base form or as an acid
`addition salt. For the purposes of the present invention
`apomorphine hydrochloride is preferred; hoWever, other
`pharmacologically acceptable moieties thereof can be uti
`liZed as Well. The term “apomorphine” as used herein
`includes the free base form of this compound as Well as the
`pharmacologically acceptable acid addition salts thereof. In
`addition to the hydrochloride salt, other acceptable acid
`addition salts are the hydrobromide, the hydroiodide, the
`bisulfate, the phosphate, the acid phosphate, the lactate, the
`citrate, the tartarate, the salicylate, the succinate, the
`maleate, the gluconate, and the like.
`
`MonoSol 1004-0003
`
`

`
`5
`Sublingual administration of apomorphine preferably
`takes place over a time period in the range of about 2 to
`about 10 minutes, or longer. When apomorphine is the sole
`therapeutic agent, the amount of apomorphine administered
`sublingually over this time period preferably is in the range
`of about 5 to about 74 micrograms per kilogram (ug/kg) of
`the patient’s body Weight, and most preferably Within the
`range of about 50 to about 74 pig/kg of body Weight.
`A maximum plasma concentration (Cmax) of the apomor
`phine drug at Which the onset of adverse effects, such as
`nausea, occur in human male subjects is at a threshold Cmwc
`of about 2.5 nanograms/milliliter (ng/ml). Plasma concen
`tration is preferably maintained at no more than 5.5 ng/ml
`during sexual activity, When apomorphine is the sole active
`agent.
`Sildena?l is designated chemically as 1-[[3-(6,7-dihydro
`1-methyl-7-oxo-3-propyl-1H-pyraZolo[4,3-d] pyrimidin-5
`yl)-4-ethoxyphenyl]sulfonyl]-4-methyl piperaZine and has
`the folloWing structural formula:
`
`The term “sildena?l” as used herein includes the free base
`form of this compound as Well as pharmacologically accept
`able acid addition salts thereof formed With organo
`carboxylic acids, organo-sulphonic acids or inorganic acids.
`For purposes of the present invention, the organo-carboxylic
`acid salt, sildena?l citrate, having a solubility in Water of 3.5
`mg/ml is particularly preferred. Reference to “sildena?l”
`includes sildena?l citrate.
`Sildena?l citrate is presently the active ingredient of a
`commercial medication for impotence sold under the des
`ignation ViagraTM (P?zer Labs, N.Y.) formulated in tablets
`equivalent to 25 mg, 50 mg and 100 mg sildena?l for oral
`administration. According to the manufacturer, in addition to
`the active ingredient, sildena?l citrate, each tablet contains
`the folloWing inactive ingredients: microcrystalline
`cellulose, anhydrous dibasic calcium phosphate, croscarmel
`lose sodium, magnesium stearate, hydroxypropyl
`methylcellulose, titanium dioxide, lactose, triacetin, and
`FD&C Blue #2 aluminum lake.
`It is knoWn from in vitro studies that sildena?l is approxi
`mately 4,000 fold more selective for inhibiting phosphodi
`esterase type 5 (PDE5) than on other knoWn
`phosphodiesterases, such as PDE3, Which is involved in
`control of cardiac contractility. Sildena?l is reportedly only
`about 10-fold as potent for PDE5 compared to PDE6, an
`enZyme found in the retina and it is this loWer selectivity
`Which is thought to be the basis for abnormalities related to
`color vision observed With higher doses or plasma levels.
`Sildena?l, administered as the commercially available
`ViagraTM formulation, is reported to be rapidly absorbed
`after oral administration, With absolute bioavailability of
`about 40%. Its pharmacokinetics are dose-proportional over
`
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`6
`the recommended dose range. Based on the ViagraTM manu
`facturer’s product literature, maximum observed plasma
`concentrations are reached Within 30 to 120 minutes
`(median 60 minutes) of oral dosing in the fasted state. When
`the ViagraTM formulation is taken With a high fat meal, the
`rate of absorption is reduced, With a mean delay in Tmax of
`60 minutes and mean reduction in Cmax of 29%. The mean
`steady state volume of distribution (Vss) for sildena?l is
`reportedly 105 L, indicating distribution into the tissues.
`Based upon reported measurements of sildena?l in the
`semen of healthy volunteers 90 minutes after dosing, less
`than 0.001% of the administered dose appeared in the semen
`of the patients.
`Ordinarily When higher doses of apomorphine alone are
`administered sublingually, apomorphine is administered
`preferably about 15 to about 20 minutes prior to sexual
`activity to affect that part of the brain that initiates erection
`and When higher doses of sildena?l alone are administered,
`sildena?l is taken about 1 hour or more before sexual
`stimulation to induces smooth muscle cell relaxation for
`maintaining an erection. Surprisingly, a therapeutically
`effective dosage combination of apomorphine and sildena?l
`employed With the compositions of this invention maxi
`miZes the bene?cial erectogenic efficacy of both apomor
`phine and sildena?l at dosages of each drug substantially
`loWer than required respectively and substantially mini
`miZes nausea or undesirable side effects associated With
`such dosages.
`Illustrative preferred sublingual dosage forms for
`co-administration of apomorphine are set forth in Table I,
`beloW.
`Sublingual combination dosage units preferably contain
`apomorphine in the range of about 1 to not more than 6
`milligrams (mg), preferably in the range of about 2 and
`about 5 mg and of sildena?l in the range of about 10 to about
`75 mg, preferably in the range of about 15 to about 50 mg,
`so long as the combined dose received by the patient is
`accompanied by minimal or substantially no undesirable
`side effects. Aparticularly preferred sublingual combination
`dosage unit contains about 2 mg apomorphine and not more
`than 50 mg sildena?l, more preferably about 2 mg apomor
`phine and not more than about 25 mg sildena?l.
`Alternatively, the apomorphine and sildena?l may be
`formulated separately in the foregoing compositions as the
`sole active ingredient for practicing sequential administra
`tion of each respective drug.
`For sequential administration therapy, sildena?l and apo
`morphine each is administered in a separate dosage unit
`containing a lesser dosage amount of respective drug than is
`required for achieving the same level of erectile response
`When the drug is the sole medicament. For sequential
`administration of sildena?l, the dosage unit preferably con
`tains sildena?l in a range of about 10 to about 75 mg, more
`preferably in the range of about 15 to about 50 mg, and for
`administration of apomorphine the dosage unit preferably
`contains apomorphine in a range of about 1 to not more than
`6 mg, more preferably in the range of about 2 to about 5 mg
`so long as the total combined dose received by the patient is
`accompanied by minimal or substantially no undesirable
`side effects.
`A particularly preferred sequential administration dosage
`unit of sildena?l contains sildena?l in the range of about 15
`to about 35 mg and of apomorphine contains apomorphine
`in the range of about 2 to about 4 mg. Preferably, each drug
`is administered sublingually. Alternatively, each drug can be
`administered by different oral routes; i.e., one can be
`ingested and the other administered sublingually or by
`buccal patch.
`
`MonoSol 1004-0004
`
`

`
`6,087,362
`
`7
`Preferably, sublingual dosage forms dissolve Within a
`time period of at least about 2 minutes but less than about 10
`minutes. The dissolution time can be longer, hoWever, if
`desired as long as the necessary plasma concentration of
`apomorphine and sildena?l can be maintained. More
`preferably, the dissolution time in Water for the presently
`contemplated dosage forms is about 3 minutes to about 5
`minutes.
`If desired, to facilitate absorption and thus bioavailability,
`absorption enhancing agents, such as cyclodeXtrins, particu
`larly [3-cyclodeXtrin, or a derivative thereof, such as
`hydroXypropyl-[3-cyclodeXtrin (HPBCD) and the like may
`be included. CyclodeXtrins are a group of cyclic, nonreduc
`ing oligosaccharides built up from siX, seven or eight
`glucopyranose rings, respectively knoWn as alpha, beta and
`gamma cyclodeXtrins. The cyclodeXtrins are a class of
`cavity-containing cyclic compounds possessing the property
`of forming a molecular inclusion compleXes, Which anchor
`or entrap another chemical compounds Without the forma
`tion of covalent bonds. HPBCD is a cyclic polymer having
`a doughnut-shaped molecular structure including an inner
`cavity, as shoWn beloW:
`
`5
`
`15
`
`8
`preferably in the range of about 1 to about 10 Weight percent
`of the total composition.
`Particularly in the case of sildena?l, it has been found that
`HPBCD enhances bioavailability. Thus, the desired thera
`peutic effect can be achieved With a relatively loWer dose of
`sildena?l, thereby minimiZing the likelihood of adverse
`affects.
`For effective sequential administration of sildena?l and
`apomorphine, the release of each drug is preferably stag
`gered to maXimiZe the bene?cial inducement of erection by
`apomorphine and maintenance of erection by sildena?l upon
`seXual stimulation.
`To augment the bene?cial effect of apomorphine and
`sildena?l therapy, lesser amounts of erectogenic agents can
`be included. The term “erectogenic agents” as used herein
`refers to adrenal steroids, such as testosterone, dehydroepi
`androsterone (DHEA) and the like; alpha receptor blockers,
`such as phentolamine, yohimbine, praZosin, doXaZosin,
`teraZosin, trimaZosin and the like; or peripheral vasodilators,
`such as prostaglandin E1 (alprostadil) and like smooth
`muscle relaXants that are knoW to improve the blood How in
`the vascular system. Preferably, the erectogenic agents are
`
`OH
`
`o
`
`HO
`OH
`
`H
`
`O
`
`HOHZC
`
`0
`
`OH
`
`O
`
`CH2O—CH2—(|IH—CH3
`0
`OH
`
`HO
`
`HO
`
`0
`
`HO
`
`HO
`
`0
`
`0
`
`CH2O-—CH2—CH-—CH3
`|
`OH
`
`HO
`
`OH OH HO
`
`0
`
`o
`
`O CHZOH
`
`HydroXypropyl-[3-cyclodeXtrins are commercially avail
`able compounds that are derived from [3-cyclodeXtrins by
`condensation With a propylene oXide to provide the corre
`sponding hydroXypropyl derivatives having a degree of
`substitution (D.S.) of up to about 15 or higher. For the
`purposes of the present invention a D.S. value of about 5 to
`7 is preferred.
`The preparation of such suitable hydroXypropyl-[3
`cyclodeXtrins is described, inter alia, in the International
`Journal of Pharmaceutics, 29, 73—82 (1986) and in the
`Journal of Pharmaceutical Sciences, 75 (6), 571—572
`(1986). Also knoWn and suitable for the present invention
`are the hydroXypropyl-[3-cyclodeXtrins that are polyethers of
`cyclodeXtrins and are obtained by the condensation of an
`eXcess of hydroXypropylene oXide With [3-cyclodeXtrin as
`described in Us. Pat. No. 3,459,731. to Gramera et al.
`HydroXypropyl-[3-cyclodeXtrin (HPBCD) is particularly
`preferred cyclodeXtrin constituent, but is not limited thereto.
`The Weight percent of the HPBCD in the composition is
`
`50
`
`55
`
`65
`
`added in an amount in the range of about 50 to about 100
`percent by Weight, more preferably in the range of about 60
`to about 80 percent by Weight of the Weight of apomorphine
`administered.
`While nausea from the use of the inventive combination
`of apomorphine and sildena?l is unlikely, the onset of
`nausea, should it occur, can also be substantially obviated or
`delayed by including an antiemetic agent. Antiemetic agents
`are antinauseant drugs that prevent or substantially reduce
`nausea and vomiting. As used herein, the terms “antiemetic
`agent” and “antinausea agent” are interchangeable and mean
`a pharmaceutically acceptable compound that substantially
`reduces nausea symptoms.
`Antiemetic agents that can be used in conjunction With
`apomorphine in the present compositions are antidopamin
`ergic agents, such as the benZamides, e.g., metoclopramide,
`trimethobenZamide, benZquinamid, and the like; the
`phenothiaZines, e.g., chlorpromaZine, prochlorperaZine,
`pipamaZine, thiethylperaZine, oXypendyl hydrochloride,
`
`MonoSol 1004-0005
`
`

`
`6,087,362
`
`10
`
`-continued
`
`promaZine, tri?upromaZine, propiomaZine, acepromaZine,
`acetophenaZine, butaperaZine, carphenaZine, ?uphenaZine,
`perphenaZine, thiopropaZate, tri?uoperaZine, mesoridaZine,
`piperacetaZine, thioridaZine, pipotiaZine, pipotiaZine
`palmitate, chlorprothixine, thiothixine, doxepin, loxapin,
`tri?upromaZine, methdilaZine, trimepraZine,
`methotrimepraZine, and the like; serotonin
`(5-hydroxytryptamine or 5-HT) antagonists such as
`domperidone, odansetron (commercially available as the
`hydrochloride salt under the designation Zofran®), and the
`like; the histamine antagonists such as bucliZine
`hydrochloride, cycliZine hydrochloride, dimenhydrinate
`(Dramamine), and the like; the parasympathetic depressants
`such as scopolamine, and the like; other antiemetics such as
`metopimaZine, trimethobenZamide, benZquinamine
`hydrochloride, diphenidol hydrochloride, and the like; and
`piperaZines, such as mecliZine, chlorcycliZine and the like.
`Antiemetic containing apomorphine compositions are
`described in co-pending US. patent application Ser. No.
`09/138,982, ?led on Aug. 24, 1998, the description thereof
`is incorporated herein by reference to the extent pertinent.
`
`The likelihood of the onset of nausea can also be sub
`stantially obviated or delayed by including in the formula
`tion a ganglionic agent (inhibitor of ganglionic response), or
`certain ganglionic stimulating alkaloids, such as nicotine or
`lobeline, preferably as lobeline sulfate, Which can serve as
`antiemetic agents.
`The present invention may be illustrated by studies With
`participating male patients selected on the basis of their
`response to a Baseline Sexual History Questionnaire shoWn
`beloW as initially presenting With a complaint of impotence
`or erectile dysfunction. Instructions are given regarding the
`protocol to be folloWed by the volunteer patients in a home
`use trial employing sublingual tablets and informed consent
`is obtained. Patients are advised that they are free to With
`draW from the trial at any time Without penalty or prejudice.
`During the home use trial, the volunteer male patients are
`asked to ?ll out a Sexual Function Study Home Question
`naire shoWn beloW in Example 2.
`
`BASELINE SEXUAL HISTORY QUESTIONNAIRE
`Male
`
`Initials:
`
`Subject#:
`
`Time:
`Today’s Date:
`Time:
`Date Tablet Taken:
`Each line beloW represent the full range of feeling or response.
`Please mark each line clearly With a vertical (straight up and doWn) stroke
`at the point Which represents your response.
`(There are no right or Wrong answers. Do not Write in boxes on right.)
`1.
`Rate your overall (on the average) level of satisfaction
`With your sexual performance Within the past tWo months.
`Extremely
`Extremely
`]
`Unsatis?ed
`Satis?ed [
`2. What Was your level of satisfaction With your most recent attempt
`at sexual intercourse With your Wife/partner?
`Extremely
`Extremely
`]
`Satis?ed [
`Unsatis?ed
`3. What Were the results of your erection during your most recent
`attempt at sexual intercourse With your Wife/partner?
`Rigid Erection
`Suitable for
`No
`]
`Penetration [
`Erection
`4. What are your overall (on the average) erection results When you
`attempt sexual intercourse?
`
`No
`Erection
`5. Were your successful in completing sexual
`intercourse during your most recent attempt?
`6. On the average, hoW frequently do you attempt sexual intercourse?
`
`]
`] No
`
`Rigid Erections
`Suitable for
`Penetration [
`[ ]Yes [
`
`BASELINE SEXUAL HISTORY QUESTIONNAIRE
`Male
`
`(Pease circle one answer)
`1) rarely or never
`2) 2 to 6 times a years
`3) once a month
`4) 2 to 3 times a month
`
`5) 4 to 5 times a month
`6) 6 to 8 times a month
`7) more than 8 times a month
`
`The present invention is illustrated further by the folloW
`ing Examples.
`
`EXAMPLE 1
`
`Sublingual Tablets
`This example illustrates the preparation of sublingual
`(SL) tablets dosage forms tablets suitable for oral
`co-administration of apomorphine and sildena?l.
`A series of SL tablets Were prepared as combination
`dosage units to contain apomorphine in a range of 2 to 6 mg
`and sildena?l in a range of 15 to 35 mg as shoWn beloW. For
`purposes of illustration and not as limitation, the SL tablets
`Were prepared by grinding tablets of the ViagraTM formula
`tion (50 mg) to a poWder, blending the ViagraTM poWder
`With apomorphine and conventional excipients, and com
`pressing the mixture to tablet form.
`
`Apomorphine HCl (mg)
`
`Sildena?l (mg)
`
`# of Tablets
`
`2
`2
`2
`4
`6
`
`15
`25
`35
`35
`35
`
`10
`10
`10
`5
`5
`
`EXAMPLE 2
`
`Home-Use Trial
`This example illustrates the oral co-administration of
`apomorphine and sildena?l by sublingual (SL) tablet dosage
`forms by four healthy male volunteer patients, ranging in
`age from 36 to 54 years, in an informal home-use trial.
`The folloWing Tablet nos. 1—6 Were prepared containing
`the amounts of drug indicated to be taken sublingually (SL)
`or conventi