WO1999066916A1 - Apomorphine-containing dosage forms for ameliorating male erectile dysfunction - Google Patents

Apomorphine-containing dosage forms for ameliorating male erectile dysfunction Download PDF

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Publication number
WO1999066916A1
WO1999066916A1 PCT/US1999/014053 US9914053W WO9966916A1 WO 1999066916 A1 WO1999066916 A1 WO 1999066916A1 US 9914053 W US9914053 W US 9914053W WO 9966916 A1 WO9966916 A1 WO 9966916A1
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WO
WIPO (PCT)
Prior art keywords
antiemetic agent
åhine
apomo
accordance
patient
Prior art date
Application number
PCT/US1999/014053
Other languages
French (fr)
Inventor
Ragab El-Rashidy
Bruce Ronsen
Original Assignee
Pentech Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP99930538A priority Critical patent/EP1094799B1/en
Application filed by Pentech Pharmaceuticals, Inc. filed Critical Pentech Pharmaceuticals, Inc.
Priority to NZ509438A priority patent/NZ509438A/en
Priority to DE69932823T priority patent/DE69932823T2/en
Priority to PL99345401A priority patent/PL195119B1/en
Priority to JP2000555602A priority patent/JP2002518439A/en
Priority to IL140272A priority patent/IL140272A/en
Priority to CA002336095A priority patent/CA2336095A1/en
Priority to AU47058/99A priority patent/AU776686B2/en
Priority to BR9911408-9A priority patent/BR9911408A/en
Priority to MXPA00012620A priority patent/MXPA00012620A/en
Publication of WO1999066916A1 publication Critical patent/WO1999066916A1/en
Priority to NO20006560A priority patent/NO20006560L/en
Priority to HK01109138A priority patent/HK1040179A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • This invention in one aspect, relates to dosage forms and methods for ameliorating erectile dysfunction in psychogenic male patients. In another aspect this invention relates to diagnosis of erectile dysfunction. More particularly, this invention relates to the use of apomorphine-containing compositions for amelioration of erectile dysfunction in psychogenic male patients and for diagnostic purposes.
  • 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 inflow causes enlargement of the substance of the corpora cavernosa. Venous outflow is trapped by this enlargement, permitting sustained high blood pressures in the penis sufficient to cause rigidity. Muscles in the perineum also assist in creating and maintaining penile rigidity. Erection may be induced centrally in the nervous system by sexual thoughts or fantasy, and is usually reinforced locally by reflex mechanisms. Erectile mechanics are substantially similar in the female for the clitoris.
  • Impotence or male erectile dysfunction is defined as the inability to achieve and sustain an erection sufficient for intercourse. Impotence in any given case can result from psychological disturbances (psychogenic), from physiological abnormalities in general (organic), from neurological disturbances (neurogenic), hormonal deficiencies (endocrine) or from a combination of the foregoing.
  • psychogenic impotence is defined 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).
  • stimuli e.g. , masturbation, spontaneous nocturnal, spontaneous early morning, video erotica, etc.
  • others e.g. , partner or spousal attention
  • the ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin.
  • U.S. Patent No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-( ⁇ -cyclodextrin.
  • apomorphine has been shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al.. eds. , Apomorphine and Other Dopaminomimetics. Basic Pharmacology. Vol. 1, Raven Press, N.Y. (1981), pp. 219-228.
  • Sublingual apomorphine dosage forms usually containing about 2.5 to about 10 milligrams of apomorphine, have been found to be effective in male patients suffering from psychogenic erectile dysfunction for the induction and maintenance of an erection sufficient for intercourse (i.e. , vaginal penetration) without nausea or other undesirable side effects.
  • the apomorphine is administered sublingually, preferably about 15 to about 20 minutes prior to sexual activity, and so as to maintain a predetermined circulating serum levels and mid-brain tissue levels of apomorphine during the period of sexual activity sufficient to induce an erection adequate for vaginal penetration but less than the amount that induces nausea.
  • the plasma concentration of apomorphine should be maintained at no more than about 5.5 nanograms per milliliter, preferably about 0.3 to about 4 nanograms per milliliter, and more preferably about 1 to about 2 nanograms per milliliter.
  • the foregoing sublingual apomorphine dosage forms are also suitable for screening patients complaining of erectile dysfunction so as to identify patients of psychogenic etiology.
  • a method suitable for treating erectile dysfunction in a male patient comprises administering to the patient prior to sexual activity, an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomorphine, and apomorphine in an amount sufficient to induce and maintain an erection adequate for vaginal penetration.
  • the antiemetic agent is preferably co-administered with the apomorphine in a single sublingual dosage unit.
  • Separate dosage units with differing delivery routes are also suitable for practicing the present invention, however.
  • the antiemetic agent and apomorphine may be administered to the patient sequentially by first administering a composition comprising an antiemetic agent and thereafter a composition comprising apomorphine.
  • a dosage unit for administering the antiemetic-apomorphine combination comprises an antiemetic agent as a relatively faster release component and apomorphine as a component released after release of the antiemetic agent has begun.
  • This staggered release dosage unit is preferably a layered tablet having a core portion containing the apomorphine and an outer layer portion containing the antiemetic agent.
  • a sublingual tablet for administering the antiemetic-apomorphine combination comprises apomorphine, an antiemetic agent, an osmotic agent and a swellable hydrophilic carrier.
  • the preferred osmotic agent is mannitol, while the preferred swellable hydrophilic carrier is microcrystalline cellulose.
  • apomorphine and an antiemetic agent also can be applied to the treatment of severe motor fluctuations in Parkinson's disease.
  • FIG. 1 is a graphical representation of mean erectile function, expressed as RIGISCANTM monitor value, as a function of apomorphine dose
  • FIG. 2 is a bar graph depicting the percent successful erectile function for placebo, 3 -milligram apomorphine dose, and 4-milligram apomo ⁇ hine dose under erotic and neutral conditions;
  • FIG. 3 is a bar graph presenting yet another comparison of erectile function noted in Pilot Study #4 in terms of RIGISCANTM monitor score versus placebo, 3 milligrams of apomorphine and 4 milligrams of apomorphine under erotic and neutral conditions;
  • FIG. 5 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent nicotine for the tablets of Example 1 ;
  • FIG. 6 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent nicotine for the tablets of Example 2;
  • FIG. 7 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent nicotine for the layered tablets of Example 3 ;
  • FIG. 8 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent prochlo ⁇ erazine for the tablets of Example 4;
  • FIG. 9 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent prochlo ⁇ erazine for the layered tablets of Example 5 ;
  • FIG. 10 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent prochlo ⁇ erazine for the layered tablets of Example 6;
  • FIG. 11 is a graph of the dissolution pattern of apomo ⁇ hine and the antiemetic agent prochlo ⁇ erazine for the layered tablets of Example 7;
  • FIG. 12 is a graph of the dissolution of apomo ⁇ hine for a sublingual apomo ⁇ hine tablet as discussed in Example 8; and FIG. 13 is a graph comparing the dissolution pattern for the layered tablets of
  • Example 7 with the dissolution of apomo ⁇ hine for a commercially available soluble apomo ⁇ hine tablet.
  • Apomo ⁇ hine is a dopamine receptor agonist that has a recognized use as an emetic when administered subcutaneously in about a 5-milligram dose.
  • apomo ⁇ hine or a similarly acting dopamine receptor agonist is administered in an amount sufficient 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.
  • the dopamine receptors in the mid-brain region of a patient can be stimulated to a degree sufficient to cause an erection by the sublingual administration of apomo ⁇ hine so as to maintain a plasma concentration of apomo ⁇ hine of no more than about 5.5 nanograms per milliliter (5.5 ng/ml).
  • the sublingual administration usually takes place over a time period in the range of about 2 to about 10 minutes, or longer.
  • the amount of apomo ⁇ hine administered sublingually over this time period preferably is in the range of about 25 micrograms per kilogram ( ⁇ g/kg) of body weight to about 60 ⁇ g/kg of body weight.
  • the apomo ⁇ hine is administered preferably about 15 to about 20 minutes prior to sexual activity.
  • Apomo ⁇ hine can be represented by the formula:
  • apomo ⁇ hine hydrochloride is preferred; however, other pharmacologically acceptable moieties thereof can be utilized as well.
  • the term "apomo ⁇ hine” as used herein includes the free base form of this compound as well as the pharmacologically acceptable acid addition salts thereof.
  • 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.
  • Illustrative preferred sublingual dosage forms are set forth in Table I, below.
  • the presently contemplated dosage forms can also contain, in addition to tabletting excipients, ⁇ -cyclodextrin or a -cyclodextrin derivative such as hydroxypropyl-/3- cyclodextrin (HPBCD).
  • HPBCD hydroxypropyl-/3- cyclodextrin
  • the onset of nausea can be obviated or delayed by delivering apomo ⁇ hine at a controlled dissolution rate so as to provide circulating serum levels and mid- brain tissue levels of apomo ⁇ hine sufficient for an erection without inducing nausea.
  • apomo ⁇ hine is administered at or near the relatively higher amounts of the aforementioned dosage range, the likelihood of nausea onset can be reduced by concurrent administration of a ganglionic agent (inhibitor of ganglionic response) such as nicotine or lobeline sulfate.
  • a ganglionic agent inhibitor of ganglionic response
  • the weight ratio of apomo ⁇ hine to ganglionic agent is in the range of about 300: 1 to about 5: 1.
  • sublingual dosage units for co-administration of nicotine and apomo ⁇ hine preferably contain apomo ⁇ hine in the range of about 1 to about 8 milligrams (mg) and nicotine in the range of about 0.25 to about 3 mg.
  • a particularly preferred sublingual combination dosage unit contains apomo ⁇ hine in the range of about 4 mg to about 8 mg, and nicotine in the range from about 0.75 mg to about 1.25 mg. Nicotine and lobeline sulfate have been classified as ganglionic stimulating alkaloids.
  • ganglionic stimulating alkaloids such as nicotine and lobeline sulfate serve as antiemetic agents.
  • Antiemetic agents are drugs that prevent or substantially reduce nausea and vomiting.
  • antiemetic agent and “antinausea agent” are interchangeable and mean a pharmaceutically acceptable compound that substantially reduces nausea symptoms.
  • antiemetics may be classified according to their structure or their mechanism of operation.
  • antiemetic agents that can be used in conjunction with apomo ⁇ hine are antidopaminergic agents such as metoclopramide, and the phenothiazines, e.g.
  • chlo ⁇ romazine prochlo ⁇ erazine, pipamazine, thiethylperazine, oxypendyl hydrochloride, promazine, triflupromazine, propiomazine, acepromazine, acetophenazine, butaperazine, ca ⁇ henazine, fluphenazine, pe ⁇ henazine, thiopropazate, trifluoperazine, mesoridazine, piperacetazine, thioridazine, pipotiazine, pipotiazine palmitate, chlo ⁇ rothixine, thiothixine, doxepin, loxapin, triflupromazine, methdilazine, trimeprazine, methotrimeprazine, and the like.
  • Metoclopramide is a benzamide.
  • Benzamides are a recognized group of antiemetics that are suitable for the present invention and include in addition to metoclopramide, trimethobenzamide and benzquinamid, as well as others.
  • 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.
  • meclizines which include, for example, meclizine, chlorcyclizine, cyclizine, and buclizine.
  • a composition aspect of the present invention provides a combination of apomo ⁇ hine and an antiemetic agent which is a member of the group consisting of the phenothiazines, the benzamides, the meclizines, the serotonin antagonists, hydroxyzine, lobeline sulfate, dimenhydrinate, scopolamine, metopimazine. diphenidol hydrochloride, nicotine, and their acid addition salts.
  • Any pharmaceutically acceptable form of the antiemetic agents can be employed, i.e. , the free base or a pharmaceutically acceptable salt thereof (e.g. cyclizine hydrochloride, cyclizine acetate, diphenhydramine hydrochloride, meclizine hydrochloride, etc.)
  • a method suitable for treating erectile dysfunction in a male patient comprises administering to the patient (prior to sexual activity) an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomo ⁇ hine, and apomo ⁇ hine in an amount sufficient to induce and maintain an erection adequate for vaginal penetration.
  • an antiemetic agent may be co-administered with apomo ⁇ hine or may be administered concurrently or sequentially with apomo ⁇ hine to substantially reduce the symptoms of nausea associated with the use of apomo ⁇ hine.
  • co-administration is meant the administration of both apomo ⁇ hine and an antiemetic agent to the patient in a single unit dosage form as, for example, in a layered tablet.
  • Concurrent administration denotes the substantially simultaneous administration of the two drugs in separate unit dosage forms, while “sequential” administration is the administration of separate dosage forms of the two drugs with one being administered at some time interval after the other.
  • the co-administration of an antiemetic agent and apomo ⁇ hine is preferred and allows for a higher dose of apomo ⁇ hine with generally improved response and function.
  • the preferred weight ratio of apomo ⁇ hine hydrochloride to prochlo ⁇ erazine hydrochloride is in the range of about 5 to about 0.25.
  • the amount of prochlo ⁇ erazine hydrochloride administered sublingually preferably is in the range of about 5 ⁇ g/kg of body weight to about 200 ⁇ g/kg of body weight.
  • Apomo ⁇ hine with antiemetic-containing dosage forms including nicotine- containing dosage forms and domperidone-containing dosage forms are illustrated in Table IV, below.
  • Tablet core Apomo ⁇ hine Hydrochloride 4.0 Acesulfame-K 1.6 Microcrystalline Cellulose 21.6 Peppermint Flavor 1.0 Chocolate Flavor 0.8 Citric Acid 1.2
  • Tablet core Apomo ⁇ hine Hydrochloride 4.0 Acesulfame-K 1.6 Microcrystalline Cellulose 20.0 Peppermint Flavor 1.0 Chocolate Flavor 0.8 Citric Acid 1.2
  • Tablet outer layer Prochlo ⁇ erazine 5.0 Acesulfame-K 0.4 Microcrystalline Cellulose 35.6 Mannitol 46.0
  • the apomo ⁇ hine containing compositions of the present invention are preferably administered sublingually.
  • the preferred 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 apomo ⁇ hine can be maintained. More preferably, the dissolution time in water for the presently contemplated dosage forms is about 3 minutes to about 5 minutes.
  • Antiemetic agents of the present invention may be delivered to patients using other conventional drug delivery methods, such as orally, intravenous injection, subcutaneous injection, suppository, or patch (e.g. buccal patch).
  • patients may receive the antiemetic agent and the apomo ⁇ hine via different delivery mechanisms.
  • the apomo ⁇ hine may be delivered via sublingual tablet, while the antiemetic agent is delivered orally.
  • the antiemetic agent is preferably made available before the apomo ⁇ hine. This can be accomplished not only by administering the antiemetic agent before the apomo ⁇ hine but also by employing a staggered release dosage form as described below.
  • the present invention is also not limited to a particular sequence of administration or dosage form for the antiemetic agent and apomo ⁇ hine. If desired, the antiemetic agent may be administered substantially concurrently (i.e. , at the same time as) or even after the apomo ⁇ hine. For example, a separate dosage form of an antiemetic agent can be made available to patients for use after administration of the apomo ⁇ hine if nausea symptoms are encountered.
  • the antiemetic agent preferably is delivered to the patient with the apomo ⁇ hine via a single dosage unit.
  • a sublingual tablet comprises apomo ⁇ hine, an antiemetic agent, an osmotic agent, and a swellable hydrophilic carrier.
  • a preferred swellable hydrophilic carrier is microcrystalline cellulose.
  • Other suitable swellable hydrophilic carriers for the present pu ⁇ oses are ethyl cellulose, microcrystalline cellulose, cross-linked poly vinyl pyrrolidone, dicalcium phosphate, calcium carbonate and silica.
  • Suitable osmotic agents include monosaccharide and disaccharide sugars, such as glucose, fructose, mannitol, sorbitol, lactose, and sucrose. Glycerin or urea may also be used. Organic and inorganic salts, such as sodium chloride, potassium chloride and water soluble polyelectrolytes, are also suitable as osmotic agents.
  • a preferred osmotic agent is mannitol.
  • Preferred embodiments of a sublingual tablet according to the present invention also contain a lubricant such as magnesium stearate.
  • the present invention provides an apomo ⁇ hine/antiemetic combination formulated into a dosage unit that provides a staggered release of antiemetic agent and apomo ⁇ hine.
  • a dosage unit includes an antiemetic agent as a relatively faster release component and apomo ⁇ hine as a component released after release of the antiemetic agent has begun. Defined in terms of release rate, one preferred apomo ⁇ hine/antiemetic dosage unit obtains 50 percent release of the antiemetic agent at least 5 minutes before obtaining 50 percent release of the apomo ⁇ hine.
  • the present invention further provides a layered tablet that comprises a core layer containing apomo ⁇ hine and an outer layer containing an antiemetic agent.
  • Table IV above as well as the Examples below contain illustrative compositions for layered tablets.
  • Illustrative preferred sublingual dosage forms for apomo ⁇ hine/antiemetic combinations are set forth in the Examples 1-7.
  • the present invention is illustrated further by the following studies which were focused on two specific objectives.
  • the first was to determine whether, relative to placebo response, patients who presented with "psychogenic" impotence (i.e. , patients who were still capable of achieving erections) demonstrated improved erectile function and/or enhanced sexual desire post-dosing with sublingual apomo ⁇ hine (APO).
  • the second objective was to determine what dose(s) of various forms of sublingual APO are effective in this group of patients for inducing an erection that is sufficient for vaginal penetration. Participating patients were selected from among those that initially presented with the complaint of impotence. These patients underwent a thorough urological assessment by a urologist as well as an assessment by a psychiatrist.
  • a RIGISCANTM ambulatory tumescence monitor (Dacomed Co ⁇ . , Minneapolis, Minnesota) was placed on the patient and the computer was set in the real time monitoring mode. Blood pressure and heart rate were recorded pre-dosing with APO or placebo and at the end of the testing session. Visual analogue scales (VAS) were completed by the patient pre-dosing as well as post-dosing (at the end of the testing session). These scales reflected the patient's sense of well being, level of sedation, tranquilization, anxiousness, arousal and any changes in yawning behavior. In a single-blind fashion, apomo ⁇ hine or placebo was administered to the patient sublingually.
  • VAS Visual analogue scales
  • Symptoms as they were volunteered were recorded by the research clinician. If the patient complained of nausea or felt unwell in any way he was asked if he wanted to abort the trial. If the trial was aborted, the patient was given Gravol 50 mg p.o. at that time. The patient was monitored by the research clinician until these side-effects had subsided. He was asked to return the following week for retesting at the same dose and was instructed to begin treatment with Domperidone 10 m.g. p.o. TID the day before and morning of his next session. Patients not experiencing nausea or any other significant adverse effects within fifteen minutes post-dosing with APO or placebo viewed segments of standardized erotic videos to provide sexual stimulation.
  • Visual analogue scales (See Table IX) were compared both pre- and post- dosing, and examined for changes in feeling of well being, levels of arousal, anxiousness, sedation/ tranquilization and yawning behavior. Blood pressure and heart rate were also compared pre- and post-dosing.
  • Pilot Study #1 Each pilot study was reviewed under the categories mentioned above. Pilot Study #1
  • the initial formulation evaluated was liquid apomo ⁇ hine administered via sublingual route.
  • APO was prepared by a clinic pharmacist and dissolved in a solution of sodium metabisulfite and ethylenediamine tetraacetic acid (EDTA).
  • EDTA ethylenediamine tetraacetic acid
  • the final concentration was 100 mg/ml.
  • Patients were tested on three separate occasions at three separate doses (placebo; 10 mg; 20 mg) Twelve patients entered into this trial. All patients had reported erectile dysfunction greater than 1 year in duration. The age range in this group was from 38 to 60 years. One patient withdrew after placebo and another withdrew after adverse effects at the 20 mg dose. That left a total evaluable group of ten. All ten patients had previously received yohimbine HC1 for erectile dysfunction.
  • Apomo ⁇ hine is effective in inducing erectile episodes without increasing libido in the "psychogenically" impotent male.
  • the first sublingual tablet formulations evaluated were 2.5 and 5 mg. Patients were tested on three separate occasions at three separate doses (placebo; 2.5 mg, 5 mg).
  • the 5 mg dose can produce adverse effects (i.e. , nausea, diaphoresis, etc.) that may be unacceptable to patients and their partners. These effects can be counteracted with the administration of Domperidone or nicotine (e.g. , by smoking).
  • the sublingual tablets were easy to administer and dissolved within five minutes.
  • Apomo ⁇ hine was evaluated as an aqueous intranasal spray (1.25 mg per puff). The first patient was an anxious, 53 year old male who had been experiencing erectile dysfunction for two years. This patient had previously failed a trial of yohimbine.
  • Patient No. 2 was twenty-one year old male with erectile problems of a duration of three years. He had failed a previous course of yohimbine HC1. Ten minutes post-dosing with apomo ⁇ hine at 2.5 mg he experienced yawing for a total of five yawns, and then experienced immediately major hemodynamic adverse effects. These included pale and ashen coloring, diaphoresis, nausea and vomiting, blurred vision, hypotension with a blood pressure of 70/50. Twenty minutes post adverse effect, vital signs were stable. The patient was feeling well, and coloring was good. This patient was then dropped from further testing.
  • Pilot Study #4 The data of Pilot Study #4 were analyzed in two ways. First, mean erectile function was compared across placebo, 3 mg and 4 mg doses under two stimulus backgrounds, erotic and neutral. Next erectile function scores were dichotomized, with values less than sixteen considered to reflect erectile insufficiency.
  • Table VIII A shows means and standard errors for all three treatments under both backgrounds, erotic and neutral. Means were compared using a restricted maximum likelihood generalized linear model containing two main effects, treatment and stimulus, and the treatment by stimulus interaction. An appropriate variance-covariance structure was established for the underlying statistical model using Akaike's criterion. Table VIII B presents the statistical results for the main effects of treatment and of stimulus, for the treatment by stimulus interaction, and for orthogonal contrasts within the erotic and neutral conditions. It can be seen that the treatment main effect (i.e. , general difference across treatment conditions without regard to stimulus background) is statistically significant; that the main effect of stimulus (i.e.
  • FIG. 2 and Table VIII C show that the statistically significant superiority of active over placebo treatment, regardless of stimulus background, is maintained when the erectile function scores are classified to reflect success (score at least 16) or failure (score less than 16).
  • Clinical response to sublingual administration of apomorphine was evaluated utilizing a group of 60 non-vasculogenic impotent patients. Each patient had a history of erectile dysfunction for at least 3 months, normal biothesiometry response, and normal cavernosometry results.
  • the patients were divided into seven groups. Each group received a predetermined dosage of apomorphine for 20 days in the form of apomorphine hydrochloride tablets 20 minutes prior to intercourse. Seven different dosages were evaluated — 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg and 10 mg The tablet constituents were those shown in Table I, above. Assessment of response was made on the basis of the patient's report of his experience. A response was deemed positive when the patient experienced an erection sufficiently rigid to effect penetration. Side effects such as nausea and/or vomiting, if present, were noted as well.
  • the aforesaid apomorphine dosage forms are also well suited for diagnosing male human patients suffering from male erectile dysfunction.
  • at least about 3 milligrams of apomorphine are administered sublingually to the patient and the patient is exposed to a visual erotic stimulus, e.g. , an erotic videotape, while the patient's response thereto is monitored. If deemed desirable for diagnostic purposes, up to about 10 milligrams of apomorphine can be administered to the patient.
  • the patient's maximum increase in penile circumference is determined and the patient's maximum penile rigidity (preferably tip as well as basal) is determined.
  • the determined circumferential increase and rigidity values are then compared against a predetermined base value. Equivalent methods of determining tumescence and rigidity can also be utilized. Pilot Study #5
  • the study population was seven healthy, Caucasian male volunteers between 18 and 35 years of age.
  • Three doses (one intravenous; 2 sublingual) were administered to each subject in random order 4 days apart.
  • Plasma apomorphine concentration was described for sublingual tablet administration by equations (2) and (3):
  • C t is the apomorphine plasma concentration at time t
  • F is the relative bioavailability, which is assumed to be one for intravenous administration
  • K ⁇ is the first order rate constant for sublingual absorption
  • K g is the first order rate constant for elimination
  • V d is the volume of distribution
  • D is the apomorphine dose
  • t is time
  • t lag is the lag time before onset of sublingual absorption
  • A, B, C are the intercepts of the distribution, elimination, and absorption phases, respectively
  • ⁇ is the distribution rate constant
  • ⁇ is the elimination rate constant
  • K a is the absorption rate constant.
  • ANOVA analysis of variance
  • Vd volume of distribution @ ⁇ stage
  • Vd (SS) volume of distribution steady state
  • a clinical study of patient tolerance of escalating doses in sublingual tablet administration of APO for the treatment of psychogenic male erectile dysfunction was performed.
  • the pilot study compared the effects of sublingual tablet administration of placebo, and 4, 6 and 8 mg apomorphine hydrochloride (APO) on male erectile dysfunction as measured by RIGISCANTM monitoring and self- reported satisfaction with the treatment results.
  • APO apomorphine hydrochloride
  • VAS visual analogue scale questionnaire
  • hypotension was reported as an adverse event in some subjects in this study, along with bradycardia, dizziness, syncope, and pallor. Only single cases of hypotension and pallor were judged severe in this study. Increased sweating and fatigue were also reported. One of the cases of increased sweating was considered severe. The other severe adverse events (mouth edema, dysphagia, upper respiratory tract infection) were judged unrelated to treatment. Changes in the serum chemistry values and vital signs paralleled the adverse event reports. There were no clinically significant changes except for one subject judged to have abnormal liver function of unknown origin. There were no clinically significant changes in the blood or urinalysis values due to drug.
  • APO efficacy of APO was evaluated during the first two phases of the study in which subjects were attached to the RIGISCANTM monitor. Subjects were initially treated with placebo in the first phase. In the second phase, patients received 4, 6 and 8 mg APO tablets with a placebo tablet randomly interspersed in the treatment.
  • the highest success rate was 73% in both males and females at a tablet strength of 6 mg (TABLE XX) .
  • a dosage range of 50-74 ⁇ g/kg gave the highest success rate(: 82%) in females and (80%) in males (Table XXI).
  • the dosage range of 35-50 ⁇ g/kg gave the highest success rate.
  • Placebo #1 11 9 73 2 854 9 73 2 931 4mg vs Placebo #2 0 1504
  • Placebo #2 10 9 00 3 300 9 21 2 996 6mg vs Placebo #2 0 0166 *
  • EXAMPLE 1 Apomorphine/Nicotine Combination By Wet Granulation Technique - Composition A
  • composition A Tablets were prepared from the ingredients listed in Table
  • a solution containing the apomorphine HCL, the citric acid, half the acesulfame-K, half the peppermint flavor and half the chocolate flavor was prepared by dissolving the ingredients into a mixture of equal volumes of purified water and ethanol,
  • the solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302).
  • the resulting wet mass which will be labelled "Part A, " was mixed in a porcelain dish at room temperature (20 ° C)for 30 minutes, and then partially dried to obtain a solid mass.
  • the mass was next granulated by screening through a #50 mesh (ASTM)(sieve opening of about 0.297 mm) stainless steel screen.
  • the wet granules were dried at about 60 ' C to 70 ° C for about 1 to 1.5 hours.
  • the resulting dried granules were then passed through a #35 mesh screen (sieve opening of about 0.51 mm).
  • nicotine was added to and blended with all the remaining ingredients except for the magnesium stearate. Specifically, the nicotine was added to the second half of the acesulfame-K, half the peppermint flavor, half the chocolate flavor, the hydroxypropylmethylcellulose (methocel E4M, premium), and the mannitol. The resulting blend will be labelled "Part B. " Parts A and B were then combined and mixed for about 5 minutes in a V-shaped blender. Next, magnesium stearate was added to the blender and blending continued for about 2 minutes. The final mix was removed from the blender and fed into a Stoke 's single punch tablet press fitted with biconvex 5/16" diameter tooling for tablet preparation.
  • Tablets were prepared at various compressional forces, yielding tablets of different hardness. In general, the harder the tablet the slower the release of the active ingredients therefrom.
  • U.S. Patent No. 5,624,677 to El-Rashidy et al. which is incorporated here by reference to the extent that it is not inconsistent.
  • the dissolution of apomorphine and nicotine for Composition A Tablets was measured using a USP Type II apparatus (USP XXIII) stirred at 40 rpm.
  • the dissolution medium was 500 ml of 10 millimolar ammonium phosphate buffer at a pH of 3.0 ⁇ 0.5 at about 37 °C.
  • the amount of apomorphine and nicotine released into the medium was detected by measuring absorbance at two different wavelengths, 259 nm and 272 nm, and resolving the following two equations:
  • a T259 ( ⁇ 25 0 )(C apo )(l) + ( ⁇ n ⁇ c )(C n ⁇ c )(l) (5)
  • a T272 ( ⁇ 272 apo )(C apo )(l) + ( ⁇ 272 mc )(C mc )(l) (6)
  • a ⁇ 259 is the total absorbance at 259 nanometers (nm);
  • a T272 is the total absorbance at 272 nm; ⁇ 259 apo is the molar absorptivity of apomorphine at 259 nm; ⁇ 259 mc is the molar absorptivity of nicotine at 259 nm; ⁇ 272 apo is the molar absorptivity of apomorphine at 272 nm; ⁇ 272 n ⁇ c is the molar absorptivity of nicotine at 272 nm; C apo is the molar concentration of apomorphine; C n ⁇ c is the molar concentration of nicotine; and 1 is the cell path length.
  • the molar concentration of apomorphine (C apo ) and nicotine (C mc ) can be calculated from total absorbance data (A ⁇ and A T272 ) as follows:
  • Dissolution kinetic constants (K dlss ) for apomorphine and nicotine were calculated assuming zero-order release kinetics.
  • the tablets prepared were compared against a commercially available soluble apomorphine HCl tablet for dissolution characterization.
  • the results are presented in Table XXVI (below) and in FIG. 5. Specifically, the time to 50 percent drug release (T 50 ) and 90 percent drug release (T ⁇ ) for both apomorphine and nicotine are reported together with dissolution constants.
  • tablet hardness was measured using a Computest Tablet Hardness
  • composition A Tablets released apomo ⁇ hine relatively slower as compared to the release of the antiemetic agent, nicotine.
  • Composition B Tablets were prepared from the ingredients listed in Table XXII (above). Each ingredient was weighed as indicated and passed through a
  • #35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation.
  • Apomo ⁇ hine HCL, the hydroxypropylmethyl cellulose, the citric acid, the acesulfame-K, the peppermint flavor, and the chocolate flavor were blended together with the indicated amount of microcrystalline cellulose using 25 percent ethanol in deionized water.
  • the solution was mixed until clear, and then absorbed into half the listed amount of microcrystalline cellulose (Avicel 302).
  • the resulting wet mass (Part A) was mixed in a porcelain mortar at room temperature
  • the mass was granulated using a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • the wet granules were dried at about 60 * C to 70 ° C for about 1 to 1.5 hours, and periodically mixed during the drying stage.
  • the resulting dried granules were then passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • the final mix was removed from the blender and compressed into tablets using a Stoke's single punch tablet press fitted with 5/16" diameter biconvex tooling.
  • Tablets were prepared at various compressional forces, yielding tablets of different hardness. Dissolution of apomo ⁇ hine and nicotine for Composition B Tablets was measured and reported as described in Example 1. The results are presented in
  • the core portion was prepared by dry mixing apomo ⁇ hine HCL, citric acid, peppermint flavor, chocolate flavor and acesulfame-K. The resulting mixture was blended in a V-shaped blender for about 5 minutes. Hydroxypropylmethylcellulose was than added and the blending continued for an additional 5 minutes. The microcrystalline cellulose was then added to the blender and mixing was continued for yet another 5 minutes. Next mannitol was added to the blender, followed by another 5 minute stage of blending. Finally, magnesium stearate was added and blended in for about 2 minutes. The resulting mixture was transferred to a Stoke 's tablet press fitted with
  • the outer antiemetic layer was prepared by mixing nicotine with the listed amount of microcrystalline cellulose in a porcelain mortar until the mixture became homogeneous. The homogeneous mixture was then transferred to a V- shaped blender, where the listed amounts of mannitol, hydroxypropylmethylcellulose, and acesulfame-K were blended in for about 5 minutes. Magnesium stearate was then added followed by an additional 2 minutes of blending.
  • a portion of the nicotine mixture was then transferred to the die of the Stoke' s tablet press fitted with 5/16" biconvex tooling.
  • an apomo ⁇ hine tablet core discussed above was placed in the die and then covered with another portion of the nicotine mixture.
  • the nicotine mixture and core portion were finally compressed together to form layered tablets.
  • Composition C Tablets released nicotine from their outer layer relatively sooner and faster than the apomo ⁇ hine from the core portion.
  • Composition D Tablets were prepared from the ingredients listed in Table
  • #35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation.
  • a solution containing the apomo ⁇ hine HCL, acesulfame-K, peppermint flavor, chocolate flavor, and citric acid was prepared by dissolving these ingredients into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302) by further mixing over a stainless steel pan at room temperature (20 ° C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen (sieve opening of about 0.25 mm).
  • the resulting granules were dried at about 60 ° C to 70 °C for about 2 hours.
  • the dried granules were then mixed in a porcelain mortar and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • Composition D Tablets were evaluated as described for Example 1 , except that absorbance was measured at 254 nm rather than 259 nm. The results are presented in Table XXVI (below) and in FIG. 8. Composition D Tablets released apomo ⁇ hine relatively slower as compared to the release of prochlo ⁇ erazine.
  • Composition E Tablets were prepared from the ingredients listed in Table
  • XXIV (above). Each ingredient was weighed as indicated and passed through a #35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation. Apomo ⁇ hine HCL, the hydroxypropylmethyl cellulose, the sodium alginate, the citric acid, the acesulfame-K, the peppermint flavor, and the chocolate flavor were blended using 25 percent ethanol in deionized water. The resulting wet mass (Part A) was mixed in a porcelain mortar at room temperature (20 ° C) for about 30 minutes, and then partially dried to obtain a single piece. The resulting mass was granulated using a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • the wet granules were dried at about 60 °C to 70 ° C for about 1 to 1.5 hours, and periodically mixed during the drying stage.
  • the resulting dried granules were then passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • prochlo ⁇ erazine was added to and blended with the mannitol (Part B). Parts A and B were then combined and mixed for about 5 minutes in a V- shaped blender. Next, magnesium stearate was added to the blender, followed by continued blending for about 2 minutes.
  • the final mix was removed from the blender and compressed into tablets using a Stoke's single punch tablet press fitted with 5/16" diameter biconvex tooling. Tablets were prepared at various compressional forces, yielding tablets of different hardness.
  • Composition F Tablets were prepared according to the instructions presented in Example 3, except that the ingredients of Table XXV (below) were used.
  • Composition F Tablets were evaluated as described for Example 1. The results are presented in Table XXVI (below) and in FIG. 10. Composition F
  • the core portion was prepared by dissolving the apomo ⁇ hine HCL, acesulfame-K, peppermint flavor, chocolate flavor, and citric acid into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302) by further mixing over a stainless steel pan at room temperature (20 ° C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen.
  • the resulting granules were dried at about 60 ° C to 70 ° C for about 2 hours.
  • the dried granules were then mixed in a porcelain mortar and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • the outer antiemetic layer was prepared by dissolving the prochlo ⁇ erazine and acesulfame-K into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose by mixing over a stainless steel pan at room temperature (20 °C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen.
  • the resulting granules were dried at about 60 ° C to 70 ° C for about 2 hours, mixed in a porcelain mortar, and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
  • the mannitol and the hydroxypropylmethyl cellulose were blended with the dry outer-layer granules for about 5 minutes using a V- shaped blender. After 5 minutes of blending, magnesium stearate was added and the blending repeated for an additional 2 minutes.
  • Table XXVI Also reported in Table XXVI are the time to 50 percent drug release (T 50 ), the time to 90 percent drug release (Too), an d tne calculated dissolution constants of both the apomo ⁇ hine and antiemetic agent (nicotine or prochlo ⁇ erazine) for each example composition.
  • FIGs. 5 through 13 are graphs generated from the data presented in TABLE XXVI. Significantly, and well represented in graphical form, compositions according to the present invention also release apomo ⁇ hine at an advantageously slower rate than that of the commercial sublingual table.
  • FIG. 13 is a composite graph of the dissolution profiles for a commercially available apomo ⁇ hine soluble tablet and a Composition G Tablet (Example 7). This graph well demonstrates the advantage of a layered, staggered-release tablet according to the present invention.

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Abstract

Psychogenic impotence can be ameliorated without substantial undesirable side effects by administration of apomorphine and an antiemetic agent in an amount sufficient to substantially reduce nausea symptoms associated with the use of apomorphine.

Description

APOMORPHINE-CONTAINING DOSAGE FORMS FOR AMELIORATING MALE ERECTILE DYSFUNCTION
Cross-Reference to Related Applications
This application is a continuation in part of our co-pending application, U.S. Serial No. 08/546,498 filed on October 20, 1995 and now U.S. Patent No.
5,770,606, which in turn is a continuation-in-part of U.S. Serial No. 08/231,250, filed on April 22, 1994. Field of the Invention
This invention, in one aspect, relates to dosage forms and methods for ameliorating erectile dysfunction in psychogenic male patients. In another aspect this invention relates to diagnosis of erectile dysfunction. More particularly, this invention relates to the use of apomorphine-containing compositions for amelioration of erectile dysfunction in psychogenic male patients and for diagnostic purposes. 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 inflow causes enlargement of the substance of the corpora cavernosa. Venous outflow is trapped by this enlargement, permitting sustained high blood pressures in the penis sufficient to cause rigidity. Muscles in the perineum also assist in creating and maintaining penile rigidity. Erection may be induced centrally in the nervous system by sexual thoughts or fantasy, and is usually reinforced locally by reflex mechanisms. Erectile mechanics are substantially similar in the female for the clitoris.
Impotence or male erectile dysfunction is defined as the inability to achieve and sustain an erection sufficient for intercourse. Impotence in any given case can result from psychological disturbances (psychogenic), from physiological abnormalities in general (organic), from neurological disturbances (neurogenic), hormonal deficiencies (endocrine) or from a combination of the foregoing.
These descriptions are not exact, however. There is currently no standardized method of diagnosis or treatment. As used herein, psychogenic impotence is defined 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).
Various methods for the treatment of impotence have been suggested, including external devices, for example, tourniquets (see U.S. Patent No.
2,818,855). In addition, penile implants, such as hinged or solid rods and inflatable, spring driven or hydraulic models, have been used for some time. The administration of erection effecting and enhancing drugs is taught in U.S. Patent No. 4,127, 118 to LaTorre. That patent teaches a method of treating male impotence by injecting into the penis an appropriate vasodilator, in particular, an adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an erection. More recently, U.S. Patent No. 4,801 ,587 to Voss et al. teaches the application of an ointment to relieve impotence. The ointment consists of the vasodilators papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or phentolamine and a carrier to assist absorption of the primary agent through the skin. U.S. Patent No. 5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a vasodilator such as papaverine together with hydroxypropyl-(β-cyclodextrin.
Recently the effect of apomorphine on penile tumescence in male patients afflicted with psychogenic impotence has been studied. These studies show that while apomorphine can indeed induce an erection in a psychogenic male patient, the apomorphine dose required to achieve a significant erectile response is usually accompanied by nausea or other serious undesirable side effects such as hypertension, flushing and diaphoresis. The specific mechanisms by which apomorphine acts to produce an erectile response in a human patient are not yet completely understood, however.
Moreover, apomorphine has been shown to have very poor oral bioavailability. See, for example, Baldessarini et al., in Gessa et al.. eds. , Apomorphine and Other Dopaminomimetics. Basic Pharmacology. Vol. 1, Raven Press, N.Y. (1981), pp. 219-228.
Thus the search is continuing for an effective treatment of psychogenic impotence in male patients as well as for diagnostic methods that can identify such patients. It has now been found that certain delivery systems for apomorphine can provide a practical therapeutic and/or diagnostic "window" while reducing the likelihood of undesirable side effects. It has also been found that nausea side effects associated with the use of apomorphine can be substantially reduced by the pre-administration or co-administration of an antiemetic agent. Summary of the Invention
It has now been found that, for an optimal erectile response, steady state circulating serum and mid-brain tissue levels of apomorphine are to be maintained within a relatively closely defined range.
Sublingual apomorphine dosage forms, usually containing about 2.5 to about 10 milligrams of apomorphine, have been found to be effective in male patients suffering from psychogenic erectile dysfunction for the induction and maintenance of an erection sufficient for intercourse (i.e. , vaginal penetration) without nausea or other undesirable side effects. The apomorphine is administered sublingually, preferably about 15 to about 20 minutes prior to sexual activity, and so as to maintain a predetermined circulating serum levels and mid-brain tissue levels of apomorphine during the period of sexual activity sufficient to induce an erection adequate for vaginal penetration but less than the amount that induces nausea. The plasma concentration of apomorphine should be maintained at no more than about 5.5 nanograms per milliliter, preferably about 0.3 to about 4 nanograms per milliliter, and more preferably about 1 to about 2 nanograms per milliliter.
The foregoing sublingual apomorphine dosage forms are also suitable for screening patients complaining of erectile dysfunction so as to identify patients of psychogenic etiology.
The nausea side effect associated with the use of apomorphine can be substantially reduced by administration of an antiemetic agent. Specifically, a method suitable for treating erectile dysfunction in a male patient comprises administering to the patient prior to sexual activity, an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomorphine, and apomorphine in an amount sufficient to induce and maintain an erection adequate for vaginal penetration.
The antiemetic agent is preferably co-administered with the apomorphine in a single sublingual dosage unit. Separate dosage units with differing delivery routes are also suitable for practicing the present invention, however. For example, the antiemetic agent and apomorphine may be administered to the patient sequentially by first administering a composition comprising an antiemetic agent and thereafter a composition comprising apomorphine.
A dosage unit for administering the antiemetic-apomorphine combination comprises an antiemetic agent as a relatively faster release component and apomorphine as a component released after release of the antiemetic agent has begun. This staggered release dosage unit is preferably a layered tablet having a core portion containing the apomorphine and an outer layer portion containing the antiemetic agent. A sublingual tablet for administering the antiemetic-apomorphine combination comprises apomorphine, an antiemetic agent, an osmotic agent and a swellable hydrophilic carrier. The preferred osmotic agent is mannitol, while the preferred swellable hydrophilic carrier is microcrystalline cellulose.
The practice of this invention using apomorphine and an antiemetic agent also can be applied to the treatment of severe motor fluctuations in Parkinson's disease.
Brief Description of the Drawings
In the drawings,
FIG. 1 is a graphical representation of mean erectile function, expressed as RIGISCAN™ monitor value, as a function of apomorphine dose; FIG. 2 is a bar graph depicting the percent successful erectile function for placebo, 3 -milligram apomorphine dose, and 4-milligram apomoφhine dose under erotic and neutral conditions;
FIG. 3 is a bar graph presenting yet another comparison of erectile function noted in Pilot Study #4 in terms of RIGISCAN™ monitor score versus placebo, 3 milligrams of apomorphine and 4 milligrams of apomorphine under erotic and neutral conditions;
FIG. 4 is a graphical representation of a comparison of the plasma concentration time profiles of apomoφhine after intravenous administration at a dose of 1 mg (open circles, n=7), sublingual administration at a dose of 4 mg (open squares, n=4) and sublingual administration at a dose of 8 mg (half-filled squares, n=4);
FIG. 5 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent nicotine for the tablets of Example 1 ; FIG. 6 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent nicotine for the tablets of Example 2;
FIG. 7 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent nicotine for the layered tablets of Example 3 ; FIG. 8 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent prochloφerazine for the tablets of Example 4;
FIG. 9 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent prochloφerazine for the layered tablets of Example 5 ;
FIG. 10 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent prochloφerazine for the layered tablets of Example 6;
FIG. 11 is a graph of the dissolution pattern of apomoφhine and the antiemetic agent prochloφerazine for the layered tablets of Example 7;
FIG. 12 is a graph of the dissolution of apomoφhine for a sublingual apomoφhine tablet as discussed in Example 8; and FIG. 13 is a graph comparing the dissolution pattern for the layered tablets of
Example 7 with the dissolution of apomoφhine for a commercially available soluble apomoφhine tablet. Detailed Description of Preferred Embodiments
Apomoφhine is a dopamine receptor agonist that has a recognized use as an emetic when administered subcutaneously in about a 5-milligram dose. For the puφoses of the present invention, apomoφhine or a similarly acting dopamine receptor agonist is administered in an amount sufficient 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.
The dopamine receptors in the mid-brain region of a patient can be stimulated to a degree sufficient to cause an erection by the sublingual administration of apomoφhine so as to maintain a plasma concentration of apomoφhine of no more than about 5.5 nanograms per milliliter (5.5 ng/ml). The sublingual administration usually takes place over a time period in the range of about 2 to about 10 minutes, or longer. The amount of apomoφhine administered sublingually over this time period preferably is in the range of about 25 micrograms per kilogram (μg/kg) of body weight to about 60 μg/kg of body weight. The apomoφhine is administered preferably about 15 to about 20 minutes prior to sexual activity.
Apomoφhine can be represented by the formula:
Figure imgf000008_0001
and exists in a free base form or as an acid addition salt. For the puφoses of the present invention apomoφhine hydrochloride is preferred; however, other pharmacologically acceptable moieties thereof can be utilized as well. The term "apomoφhine" 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.
Illustrative preferred sublingual dosage forms are set forth in Table I, below.
TABLE I 150-Milligram Apomorphine Hydrochloride Sublingual Tablets
3-mg Tablet
Apomoφhine Hydrochloride 2.00 wt-%
Mannitol 66.67 wt-%
Ascorbic Acid 3.33 wt-%
Citric Acid 2.00 wt-%
Avicel PH102 15.00 wt-%
Methocel E4M 10.00 wt-%
Aspartame 0.67 wt-%
Magnesium Stearate 0.33 wt-%
4-mg Tablet
Apomoφhine Hydrochloride 2.66 wt-%
Mannitol 66.00 wt-%
Ascorbic Acid 3.33 wt-%
Citric Acid 2.00 wt-%
Avicel PH102 15.00 wt-%
Methocel E4M 10.00 wt-%
Aspartame 0.67 wt-%
Magnesium Stearate 0.33 wt-%
5-mg Tablet
Apomoφhine Hydrochloride 3.33 wt-%
Mannitol 65.34 wt-%
Ascorbic Acid 3.33 wt-%
Citric Acid 2.00 wt-%
Avicel PH102 15.00 wt-%
Methocel E4M 10.00 wt-%
Aspartame 0.67 wt-%
Magnesium Stearate 0.33 wt-%
If desired, and in order to facilitate absoφtion and thus bioavailability, the presently contemplated dosage forms can also contain, in addition to tabletting excipients, β -cyclodextrin or a -cyclodextrin derivative such as hydroxypropyl-/3- cyclodextrin (HPBCD). Illustrative dosage forms containing HPBCD are shown in Tables II and III, below. TABLE II
Apomorphine Hydrochloride Sublingual Tablets With Hydroxypropyl-j5-Cyclodextrin
mg/Tab
Apomoφhine Hydrochloride 4.0
HPBCD 5.0
Ascorbic Acid 10.0
PEG8000 39.5
Mannitol 39.5
Aspartame 2.0
TOTAL 100.0
TABLE HI
Apomorphine Hydrochloride Sublingual Tablets With j8-Cyclodextrin mg/Tab
Apomoφhine Hydrochloride 5.0
/5-Cyclodextrin 20.0
Ascorbic Acid 5.0
Mannitol 68.9
Magnesium Stearate 1.0
D&C Yellow 10 Aluminum Lake 0.1
TOTAL 100.0
The onset of nausea can be obviated or delayed by delivering apomoφhine at a controlled dissolution rate so as to provide circulating serum levels and mid- brain tissue levels of apomoφhine sufficient for an erection without inducing nausea. When apomoφhine is administered at or near the relatively higher amounts of the aforementioned dosage range, the likelihood of nausea onset can be reduced by concurrent administration of a ganglionic agent (inhibitor of ganglionic response) such as nicotine or lobeline sulfate. For this puφose, the weight ratio of apomoφhine to ganglionic agent is in the range of about 300: 1 to about 5: 1.
The preferred weight ratio necessarily varies according to the potency of the agent employed, however. When nicotine is used, the preferred weight ratio of apomoφhine to nicotine is in the range of about 10 to about 1. With regard to specific drug loadings, sublingual dosage units for co-administration of nicotine and apomoφhine preferably contain apomoφhine in the range of about 1 to about 8 milligrams (mg) and nicotine in the range of about 0.25 to about 3 mg. A particularly preferred sublingual combination dosage unit contains apomoφhine in the range of about 4 mg to about 8 mg, and nicotine in the range from about 0.75 mg to about 1.25 mg. Nicotine and lobeline sulfate have been classified as ganglionic stimulating alkaloids. See, for example, Goodman, Louis S. and Alfred Gilman, eds. , The Pharmacological Basis of Therapeutics , 5th Ed. , MacMillan Publishing Co. , New York, N.Y. (1975), pp. 567-569. For the puφoses of the present invention, ganglionic stimulating alkaloids such as nicotine and lobeline sulfate serve as antiemetic agents.
Antiemetic agents are 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. As described below, antiemetics may be classified according to their structure or their mechanism of operation.
In addition to the ganglionic stimulating alkaloids discussed above, other antiemetic agents that can be used in conjunction with apomoφhine are antidopaminergic agents such as metoclopramide, and the phenothiazines, e.g. , chloφromazine, prochloφerazine, pipamazine, thiethylperazine, oxypendyl hydrochloride, promazine, triflupromazine, propiomazine, acepromazine, acetophenazine, butaperazine, caφhenazine, fluphenazine, peφhenazine, thiopropazate, trifluoperazine, mesoridazine, piperacetazine, thioridazine, pipotiazine, pipotiazine palmitate, chloφrothixine, thiothixine, doxepin, loxapin, triflupromazine, methdilazine, trimeprazine, methotrimeprazine, and the like. Metoclopramide is a benzamide. Benzamides are a recognized group of antiemetics that are suitable for the present invention and include in addition to metoclopramide, trimethobenzamide and benzquinamid, as well as others. Also suitable are the 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, as well as other antiemetics such as metopimazine, trimethobenzamide, benzquinamine hydrochloride, diphenidol hydrochloride, and the like. Another suitable group of antiemetics are the meclizines which include, for example, meclizine, chlorcyclizine, cyclizine, and buclizine.
Accordingly, a composition aspect of the present invention provides a combination of apomoφhine and an antiemetic agent which is a member of the group consisting of the phenothiazines, the benzamides, the meclizines, the serotonin antagonists, hydroxyzine, lobeline sulfate, dimenhydrinate, scopolamine, metopimazine. diphenidol hydrochloride, nicotine, and their acid addition salts. Any pharmaceutically acceptable form of the antiemetic agents can be employed, i.e. , the free base or a pharmaceutically acceptable salt thereof (e.g. cyclizine hydrochloride, cyclizine acetate, diphenhydramine hydrochloride, meclizine hydrochloride, etc.)
The nausea side effect associated with the use of apomoφhine can be substantially reduced by administration of an antiemetic agent. Specifically, a method suitable for treating erectile dysfunction in a male patient comprises administering to the patient (prior to sexual activity) an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomoφhine, and apomoφhine in an amount sufficient to induce and maintain an erection adequate for vaginal penetration. For treatments according to the present invention, an antiemetic agent may be co-administered with apomoφhine or may be administered concurrently or sequentially with apomoφhine to substantially reduce the symptoms of nausea associated with the use of apomoφhine. By the term "co-administration" is meant the administration of both apomoφhine and an antiemetic agent to the patient in a single unit dosage form as, for example, in a layered tablet. "Concurrent" administration denotes the substantially simultaneous administration of the two drugs in separate unit dosage forms, while "sequential" administration is the administration of separate dosage forms of the two drugs with one being administered at some time interval after the other. The co-administration of an antiemetic agent and apomoφhine is preferred and allows for a higher dose of apomoφhine with generally improved response and function.
When the antiemetic agent prochloφerazine hydrochloride is used, the preferred weight ratio of apomoφhine hydrochloride to prochloφerazine hydrochloride is in the range of about 5 to about 0.25. The amount of prochloφerazine hydrochloride administered sublingually preferably is in the range of about 5 μg/kg of body weight to about 200 μg/kg of body weight.
Apomoφhine with antiemetic-containing dosage forms including nicotine- containing dosage forms and domperidone-containing dosage forms are illustrated in Table IV, below.
TABLE IV
Apomorphine Hydrochloride Sublingual Tablets Containing an Antiemetic Agent mg/Tab
Apomoφhine Hydrochloride 5.0
Ascorbic Acid 5.0
Mannitol 67.9
Magnesium Stearate 1.0
Nicotine 1.0 β-Cyclodextrin 20.0
D&C Yellow 10 Aluminum Lake 0.1
TOTAL 100.0
mg/Tab
Apomoφhine Hydrochloride 5.0
Ascorbic Acid 5.0
Mannitol 58.9
Magnesium Stearate 1.0
Domperidone 10.0 -Cyclodextrin 20.0
D&C Yellow 10 Aluminum Lake 0.1
TOTAL 100.0
mg/Tab
Apomoφhine Hydrochloride 4.0
Nicotine Base 1.0
Acesulfame-K 4.0
Microcrystalline Cellulose 37.5
Peppermint Flavor 2.5
Chocolate Flavor 2.0
Citric Acid 3.0
Hydroxypropylmethylcellulose 13.0
Mannitol 80.0
Magnesium Stearate 3.0
TOTAL 150.0 mg/Tab
Tablet core: Apomoφhine Hydrochloride 4.0 Acesulfame-K 1.6 Microcrystalline Cellulose 21.6 Peppermint Flavor 1.0 Chocolate Flavor 0.8 Citric Acid 1.2
Hydroxypropylmethylcellulose 4.0 Mannitol 24.6 Magnesium Stearate 1.2
Tablet outer layer: Nicotine Base 1.0 Acesulfame-K 0.4 Microcrystalline Cellulose 36.6 Mannitol 47.0
Hydroxypropylmethylcellulose 4.0 Magnesium Stearate 1.0
TOTAL 150
mg/Tab
Apomoφhine Hydrochloride 4.0
Prochloφerazine Hydrochloride 5.0
Acesulfame-K 4.0
Microcrystalline Cellulose 37.5
Peppermint Flavor 2.5
Chocolate Flavor 2.0
Citric Acid 3.0
Hydroxypropylmethylcellulose 10.0
Mannitol 68.0
Sodium Alginate 10.0
Magnesium Stearate 3.0
TOTAL 150.0
mg/Tab
Tablet core: Apomoφhine Hydrochloride 4.0 Acesulfame-K 1.6 Microcrystalline Cellulose 20.0 Peppermint Flavor 1.0 Chocolate Flavor 0.8 Citric Acid 1.2
Hydroxypropylmethylcellulose 5.0 Mannitol 20.2 Sodium Alginate 5.0 Magnesium Stearate 1.2
Tablet outer layer: Prochloφerazine 5.0 Acesulfame-K 0.4 Microcrystalline Cellulose 35.6 Mannitol 46.0
Hydroxypropylmethylcellulose 2.0 Magnesium Stearate L0
TOTAL 100.0
For improved bioavailability. controlled release, and reliable dosage control, the apomoφhine containing compositions of the present invention are preferably administered sublingually. The preferred 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 apomoφhine can be maintained. More preferably, the dissolution time in water for the presently contemplated dosage forms is about 3 minutes to about 5 minutes.
The methods and compositions of the present invention are not limited to sublingual drug delivery, however. Antiemetic agents of the present invention may be delivered to patients using other conventional drug delivery methods, such as orally, intravenous injection, subcutaneous injection, suppository, or patch (e.g. buccal patch). In addition, patients may receive the antiemetic agent and the apomoφhine via different delivery mechanisms. For example, the apomoφhine may be delivered via sublingual tablet, while the antiemetic agent is delivered orally.
When an antiemetic agent is used, the antiemetic agent is preferably made available before the apomoφhine. This can be accomplished not only by administering the antiemetic agent before the apomoφhine but also by employing a staggered release dosage form as described below. The present invention is also not limited to a particular sequence of administration or dosage form for the antiemetic agent and apomoφhine. If desired, the antiemetic agent may be administered substantially concurrently (i.e. , at the same time as) or even after the apomoφhine. For example, a separate dosage form of an antiemetic agent can be made available to patients for use after administration of the apomoφhine if nausea symptoms are encountered.
The antiemetic agent preferably is delivered to the patient with the apomoφhine via a single dosage unit. Provided for this p pose, a sublingual tablet comprises apomoφhine, an antiemetic agent, an osmotic agent, and a swellable hydrophilic carrier. A preferred swellable hydrophilic carrier is microcrystalline cellulose. Other suitable swellable hydrophilic carriers for the present puφoses are ethyl cellulose, microcrystalline cellulose, cross-linked poly vinyl pyrrolidone, dicalcium phosphate, calcium carbonate and silica.
Suitable osmotic agents include monosaccharide and disaccharide sugars, such as glucose, fructose, mannitol, sorbitol, lactose, and sucrose. Glycerin or urea may also be used. Organic and inorganic salts, such as sodium chloride, potassium chloride and water soluble polyelectrolytes, are also suitable as osmotic agents. A preferred osmotic agent is mannitol. Preferred embodiments of a sublingual tablet according to the present invention also contain a lubricant such as magnesium stearate.
The present invention provides an apomoφhine/antiemetic combination formulated into a dosage unit that provides a staggered release of antiemetic agent and apomoφhine. Specifically, a dosage unit includes an antiemetic agent as a relatively faster release component and apomoφhine as a component released after release of the antiemetic agent has begun. Defined in terms of release rate, one preferred apomoφhine/antiemetic dosage unit obtains 50 percent release of the antiemetic agent at least 5 minutes before obtaining 50 percent release of the apomoφhine.
For this staggered release puφose, the present invention further provides a layered tablet that comprises a core layer containing apomoφhine and an outer layer containing an antiemetic agent. Table IV (above) as well as the Examples below contain illustrative compositions for layered tablets. Illustrative preferred sublingual dosage forms for apomoφhine/antiemetic combinations are set forth in the Examples 1-7.
The present invention is illustrated further by the following studies which were focused on two specific objectives. The first was to determine whether, relative to placebo response, patients who presented with "psychogenic" impotence (i.e. , patients who were still capable of achieving erections) demonstrated improved erectile function and/or enhanced sexual desire post-dosing with sublingual apomoφhine (APO). The second objective was to determine what dose(s) of various forms of sublingual APO are effective in this group of patients for inducing an erection that is sufficient for vaginal penetration. Participating patients were selected from among those that initially presented with the complaint of impotence. These patients underwent a thorough urological assessment by a urologist as well as an assessment by a psychiatrist. Diagnostic testing for erectile difficulties was extensive and included the following: biochemical profile, nocturnal penile tumescence (NPT) monitoring, doppler flow studies, biothesiometry, coφoral calibration testing with an intracoφoral injection of triple therapy and dynamic cavernosometry . These tests were used to rule out any arterial, venous or peripheral neural causality of impotence. Any patients with abnormalities in any of these three areas were excluded from entry to the trials. The inclusion/exclusion criteria for all four pilot studies are set forth in Table V, below. Patients who met all criteria were diagnosed as having impotence primarily of a psychogenic origin. If there were no known medical contraindications to the use of a dopaminergic medication they were offered entry into an APO trial.
Instructions were given regarding the protocol by the research clinician, and an informed consent was obtained. Patients were advised that they were free to withdraw from the trial at any time without penalty or prejudice. They were tested on at least three separate days at three separate doses (placebo and two active medication doses) with an interval of no less than three days between. The experimental scheme described below was used in all four pilot studies.
Patients were seated in a comfortable chair and a RIGISCAN™ ambulatory tumescence monitor (Dacomed Coφ. , Minneapolis, Minnesota) was placed on the patient and the computer was set in the real time monitoring mode. Blood pressure and heart rate were recorded pre-dosing with APO or placebo and at the end of the testing session. Visual analogue scales (VAS) were completed by the patient pre-dosing as well as post-dosing (at the end of the testing session). These scales reflected the patient's sense of well being, level of sedation, tranquilization, anxiousness, arousal and any changes in yawning behavior. In a single-blind fashion, apomoφhine or placebo was administered to the patient sublingually.
Doses of active medication varied on the formulation of the apomoφhine administered (liquid or tablet). Because of the possibility of nausea and the tolerance to this effect that prior dosing conveys, the patient was given increasing doses at each testing. However, the patient was unaware of the dose that he was receiving (single-blind). Patients were instructed not to swallow the medication, but to keep it under their tongue and allow it to be absorbed there.
Symptoms as they were volunteered were recorded by the research clinician. If the patient complained of nausea or felt unwell in any way he was asked if he wanted to abort the trial. If the trial was aborted, the patient was given Gravol 50 mg p.o. at that time. The patient was monitored by the research clinician until these side-effects had subsided. He was asked to return the following week for retesting at the same dose and was instructed to begin treatment with Domperidone 10 m.g. p.o. TID the day before and morning of his next session. Patients not experiencing nausea or any other significant adverse effects within fifteen minutes post-dosing with APO or placebo viewed segments of standardized erotic videos to provide sexual stimulation. The following sequence of videos was viewed: a ten minute erotic video, a neutral video lasting between five and ten minutes in duration and finally another ten minute erotic video. The duration of the testing session for each dose level lasted between 45 and 60 minutes. After determining the most effective dose of apomoφhine for the patient, he was then offered APO for domestic trial at that dose. Results of Pilot Studies 1 to 4 The frequency and the magnitude of erectile responses were documented with each dose of apomoφhine or placebo. Data obtained from the RIGISCAN™ monitor was downloaded and each session was scanned. Erection responses were then scored for rigidity (%) and tumescence (cm.) at both the tip and base of the penis and an overall score was given that corresponded to these parameters during the viewing of both erotic and neutral video segments (see Table VI, below). A score of less than 16 indicated erectile dysfunction and a poor response to apomorphine at that dose.
Visual analogue scales (See Table IX) were compared both pre- and post- dosing, and examined for changes in feeling of well being, levels of arousal, anxiousness, sedation/ tranquilization and yawning behavior. Blood pressure and heart rate were also compared pre- and post-dosing.
Effects of apomoφhine that were both reported to and observed by the research clinician were grouped into two categories: Adverse Effects (i.e. , flushing, diaphoresis, nausea, vomiting, changes in blood pressure or heart rate) or Primary Effects (i.e. , yawning and erections).
Each pilot study was reviewed under the categories mentioned above. Pilot Study #1
The initial formulation evaluated was liquid apomoφhine administered via sublingual route. APO was prepared by a clinic pharmacist and dissolved in a solution of sodium metabisulfite and ethylenediamine tetraacetic acid (EDTA).
The final concentration was 100 mg/ml. Patients were tested on three separate occasions at three separate doses (placebo; 10 mg; 20 mg) Twelve patients entered into this trial. All patients had reported erectile dysfunction greater than 1 year in duration. The age range in this group was from 38 to 60 years. One patient withdrew after placebo and another withdrew after adverse effects at the 20 mg dose. That left a total evaluable group of ten. All ten patients had previously received yohimbine HC1 for erectile dysfunction.
Eight had failed a trial of yohimbine HC1. Of this group of eight, 6 were successful with apomoφhine.
Seven (70%) were successes (score of no less than 16 on both neutral and erotic video segments; Table VI) and three (30%) were categorized as failures with apomoφhine. Six out of the seven successful patients continued on with a domestic trial of apomoφhine at the dose that gave them the best response during testing. Three required treatment with Domperidone the day before and morning of apomoφhine usage. The range of domestic use varied from two to seven months. Analysis of visual analogue scales pre- and post-dosing with apomoφhine indicated the following. At the end of the session patients were relaxed but not sedated. There was no evidence of arousal or anxiousness. Yawning behavior changes were evident on these scales with the incidence of yawning increasing between 15 and fifty minutes post-dosing and with each increase in dosing. Each patient experienced between two to five yawns per session. These changes were not evident with placebo.
The primary effect of yawning was both reported by patients and observed at both 10 mg and 20 mg doses. No yawning was reported with placebo. Adverse effects were reported at both dose levels. Two patients who did not experience nausea or diaphoresis were researched for similarities in their patient profiles but none were found. Anywhere from ten to fifteen minutes post-dosing the other eight patients developed sudden onset of various levels of nausea (and in one instance vomiting), diaphoresis, dizziness, double or blurred vision, decrease in both blood pressure and heart rate and pale or ashen coloring. Side effects varied from being transient and brief to lasting as long as from 30 to 40 minutes. One patient reported a stuffy nose starting approximately 30 minutes post-dosing and lasting for approximately 10 minutes. No adverse effects were reported post placebo dosing. The foregoing Pilot Study leads to the following conclusions:
1. Apomoφhine is effective in inducing erectile episodes without increasing libido in the "psychogenically" impotent male.
2. Both 10 mg and 20 mg doses produce erectile responses. 3. Both doses produced adverse effects (nausea, vomiting, diaphoresis, etc.) that would be unacceptable to patients and their partners, however. These effects can be counteracted with the use of Domperidone. Pilot Study #2
The first sublingual tablet formulations evaluated were 2.5 and 5 mg. Patients were tested on three separate occasions at three separate doses (placebo; 2.5 mg, 5 mg).
A total of eight patients entered into this trial . All patients reported erectile difficulties for more that two years. The age range was from 38 to 62 years. All had failed a trial of yohimbine HC1. One patient withdrew from the trial after experiencing adverse effects at the 5 mg dose. That left a total of seven evaluable patients.
Two (29%) were successes (score of no less than 16; Table VI) and five (71 %) were failures during lab testing. The two successful patients went onto a domestic trial of apomoφhine at the 2.5 mg dose which was the most effective and did not produce adverse effects. Both patients used apomoφhine at home for no less than two months with satisfactory results.
Analysis of visual analogue scales pre- and post-dosing with apomoφhine indicated the same trends as with the liquid apomoφhine preparation. Patients were relaxed but not sedated. No evidence of arousal or anxiousness was noted. The primary effect of yawning was both reported by patients and observed at both 2.5 mg and 5 mg doses. The incidence of yawning increased between fifteen and forty minutes post-dosing. At the 2.5 mg dose all patients who failed testing had only one or two yawns per session. The 5 mg dose not only produced adverse effects (nausea, diaphoresis, dizziness, blurred vision, facial flushing, drop in both heart rate and blood pressure) but also increased yawning responses to three to five times per session. The two successful patients experienced three to five yawns at both the 2.5 mg and 5 mg doses. These changes were not evident with placebo. At the end of Pilot Study #2 the following conclusions were made:
1. There appears to be a correlation between the effectiveness of the dose and yawning response (poor responders experience less yawning).
2. Both 2.5 and 5 mg doses produced erectile responses in some patients. The apparent 28 % success rate was because of lab use only (failures were not given drug to take home) and lack of available intermediate doses.
3. In some instances the 5 mg dose can produce adverse effects (i.e. , nausea, diaphoresis, etc.) that may be unacceptable to patients and their partners. These effects can be counteracted with the administration of Domperidone or nicotine (e.g. , by smoking).
4. The sublingual tablets were easy to administer and dissolved within five minutes.
Pilot Study #3
Apomoφhine was evaluated as an aqueous intranasal spray (1.25 mg per puff). The first patient was an anxious, 53 year old male who had been experiencing erectile dysfunction for two years. This patient had previously failed a trial of yohimbine.
He was tested on three separate occasions at three separate doses (placebo, 2.5 mg; 3.75 mg) and was categorized as a failure with the score of less than sixteen on both erotic and neutral video segments. He experienced yawning with both 2.5 mg and the 3.75 mg and was successful with this trial for two months until he inadvertently increased the dose. Adverse effects occurred within five minutes post-dosing (nausea and vomiting, dizziness, double and blurred vision, diaphoresis, and ashen coloring). The patient refused to retry medication after this incident. He stated he did not like this formulation.
Patient No. 2 was twenty-one year old male with erectile problems of a duration of three years. He had failed a previous course of yohimbine HC1. Ten minutes post-dosing with apomoφhine at 2.5 mg he experienced yawing for a total of five yawns, and then experienced immediately major hemodynamic adverse effects. These included pale and ashen coloring, diaphoresis, nausea and vomiting, blurred vision, hypotension with a blood pressure of 70/50. Twenty minutes post adverse effect, vital signs were stable. The patient was feeling well, and coloring was good. This patient was then dropped from further testing. Although the intranasal administration was effective in eliciting an erection, further testing of this intranasal formulation of apomoφhine was discontinued because of possible overdose and increased side effects. The foregoing experience illustrates the need for reliable and relatively safer dosage forms. Pilot Study #4
New sublingual tablet formulations of apomoφhine at 3. 4 and 5 mg doses (Table I, above) were evaluated. Patients were tested on at least three separate occasions on at least three separate doses (placebo; 3 mg; and 4 mg). A 5 mg sublingual dose was also tested in some patients. The results of this study are summarized in Tables VII and VIII A-C, below.
To date, twelve patients have been completely evaluated on this formulation. All patients reported erectile dysfunction for more than two years. The patients' age range was thirty-nine to sixty-six years. Three patients had been successful with yohimbine HC1 in the past, and two had previously not tried this compound. Seven patients of this group of twelve had previously failed a trial of yohimbine
HC1. Of this latter group of seven, four were successfully treated with apomoφhine.
Eight (67%) have been successful with apomoφhine to date. Four (33%) were failures with apomoφhine. Both 3 mg and 4 mg doses produced erectile responses. Several patients went on to a trial of the 5 mg sublingual dose which did not appear to be more effective than the relatively lesser doses in terms of erectile response. All eight of the successful patients continued on with the domestic use for a time period of one to four months. All patients reported good erectile activity and no side effects. Analysis of visual analogue scales, both pre- and post-dosing with apomoφhine, again indicated that the patients were relaxed but not sedated, and did not have feelings of arousal or anxiousness post-dosing. The new formulations tested (3 mg; 4 mg; and 5 mg) were devoid of adverse effects. The patients felt well post testing, and did not report or demonstrate any adverse effects that had traditionally been seen with the administration of previous apomoφhine liquid and intranasal preparations (Pilot Studies No. 1 and No. 3). The primary effect of yawning was still reported and observed at all doses, but the number and frequency of yawns was small (one or two). The foregoing pilot study shows that 3-mg. 4-mg and 5-mg apomoφhine doses are effective m inducing penile erections, and also that there are no serious adverse effects with these preparations Domestic use of these preparations was well accepted by patients and their partners They were content with the convenience of dosmg approximately fifteen minutes prior to sexual activity All patients have stated that this was more acceptable than dealing with dosing on a routine basis
TABLE V Inclusion/Exclusion Criteria
INCLUSION CRITERIA
1 Age 18-66 years
2 NPT circumference increase of 1 5 cm or more on one night and > 70 % rigidity
3 ICI circumference increase of 1 5 cm or more and > 70 % rigidity EXCLUSION CRITERIA
1 Currently severe or life threatening systemic disease
2 Clinically significant ECG abnormalities
3 Personal or first degree family history of epilepsy
4 Abnormal Hepatic/renal function
Hematology
5 Low pre-trial testosterone Low or High LH
High Prolact
6 Hypertension requiring treatment
7 History of depression requiring treatment with antidepressants, ECT, or hospitalization
8 Symptomatic lschemic heart disease/or MI within the last three months
9 Diabetes
10 Failure to obtain informed consent
1 1 Legal cases
12 Unable or unwilling to comply with protocol
13 Drinks more than (on average) 45 units alcohol per week/or uses illicit drugs
14 History of syncope
15 Prohibited Drugs sympathetic or parasympathetic types drugs, Beta blockers, Vasodilators, psychotropic medications, tranquihzers, thiazides, Captopπl, Verapmil, Furosemide, Spironolactone, Metoclopramide, Cimetidme or other drugs which are likely to influence erectile function TABLE VI Response to Erotic Videotape
1. Maximum increase in penile circumference
Circumference (cms.) Score
0 - <0.5 cm. 0
0.5 - < 1.0 cm. 1
1.0 - <1.5 cm. 2
1.5 - <2.0cm. 3
2.0 - <2.5 cm. lasts < 1 min. 4
2.5 or more lasts < 1 min. 5
2.0 - <2.5 cm. lasts at least 1 min. 6
2.5 or more lasts at least 1 min. 7
3.0 or more lasts at least 5 min. 8
3.0 or more lasts at least 10 min. 9
Score
A. Maximum increase in penile tip circumference
B. Maximum increase in penile basal circumference 2. Maximum penile rigidity
Rigidity (%) Score
0- <10 0 10- <20 1 20 - < 30 2 30- <40 3 40- <50 4 50- <60 5 60 - <70 6 70- <80 7 80- <90 8 90 - 100 9
Score
C. Maximum penile tip rigidity
D. Maximum penile basal rigidity 3. Total score (A, B, C & D)
A score of less than 16 indicates erectile dysfunction TABLE VII Summary of Results from Pilot Study #4 in Psychogenic Patients
Figure imgf000026_0001
* Patients with score higher than 16 (see scoring table) are positive respondents.
Out of 12 patients who were treated in this study, 5 showed improvement at both 3 mg and 4 mg doses. Two (2) showed response only at one dose.
No improvement in clinical response was observed at 5 mg dose.
The data of Pilot Study #4 were analyzed in two ways. First, mean erectile function was compared across placebo, 3 mg and 4 mg doses under two stimulus backgrounds, erotic and neutral. Next erectile function scores were dichotomized, with values less than sixteen considered to reflect erectile insufficiency.
A. Mean Erectile Function
Table VIII A shows means and standard errors for all three treatments under both backgrounds, erotic and neutral. Means were compared using a restricted maximum likelihood generalized linear model containing two main effects, treatment and stimulus, and the treatment by stimulus interaction. An appropriate variance-covariance structure was established for the underlying statistical model using Akaike's criterion. Table VIII B presents the statistical results for the main effects of treatment and of stimulus, for the treatment by stimulus interaction, and for orthogonal contrasts within the erotic and neutral conditions. It can be seen that the treatment main effect (i.e. , general difference across treatment conditions without regard to stimulus background) is statistically significant; that the main effect of stimulus (i.e. , general difference across stimulus backgrounds without regard to treatment) is statistically significant; and that the treatment by stimulus interaction is not statistically significant. These findings imply that active treatment is more effective than placebo and that this finding, although stronger when using an erotic stimulus, is true regardless of stimulus background (see FIG. 1). The orthogonal (statistically independent) contrasts confirm that active treatment is superior at a statistically significant level under both erotic and neutral conditions, but also indicate that the difference between the 3 mg and 4 mg dose does not exceed that expected by chance for the number of patients (12) used in this study.
B. Percent Successful Erectile Function
FIG. 2 and Table VIII C show that the statistically significant superiority of active over placebo treatment, regardless of stimulus background, is maintained when the erectile function scores are classified to reflect success (score at least 16) or failure (score less than 16). TABLE VIII A
Mean and Percent Successful Erectile Function
Stimulus Treatment N Mean (SE) Percent (SE)
Erotic Placebo 12 14.08 (2.69) 33.33 (13.61)
3 mg 12 18.75 (2.51) 66.67 (13.61)
4 mg 12 19.83 (2.67) 66.67 (13.61)
Neutral Placebo 12 6.50 (2.45) 16.67 (10.76)
3 mg 12 11.83 (2.68) 50.00 (14.43)
4 mg 12 13.50 (2.61) 50.00 (14.43)
Note: Mean (SE) from SAS PROC UNIVARIATE. Percent (SE) from SAS PROC CATMOD.
TABLE VIII B Anova for Mean Erectile Function
EFFECT DF F P-value
Treatment 2.66 11.56 0.0000
Stimulus 1.66 37.14 0.0000
Treatment by Stimulus 2.66 0.10 0.9046
Contrasts
Erotic: Placebo vs. Treatment 1.66 9.30 0.0033
Erotic: 3 mg vs. 4 mg 1.66 0.30 0.5849
Neutral: Placebo vs. Treatment 1.66 13.03 0.0006
Neutral: 3 mg vs. 4 mg 1.66 0.71 0.4014
Note: Restπcted maximum likelihood analysis performed using SAS PROC MIXED.
TABLE VIII C
Logistic Regression for Percent Successful Erectile Function
EFFECT DF X2 P-value
Treatment 2 15.36 0.0005
Stimulus 1 5.14 0.0233
Treatment by Stimulus 2 0.00 1.0000
Contrasts
Erotic: Placebo vs. Treatment 1 9.60 0.0019
Erotic: 3 mg vs. 4 mg 1 0.00 1.0000
Neutral : Placebo vs. Treatment 1 9.60 0.0019
Neutral: 3 mg vs. 4 mg 1 0.00 1.0000
Note: Analysis performed using SAS PROC CATMOD. TABLE LX Visual Analogue Scale (VAS)
(to be completed by the patient)
Please mark each line clearly at the point which indicates how you are feeling right now. Each line represents the full range of each feeling. (There are no right or wrong answers)
Score (mm)
1 Alert Drowsy
2 Calm Excited
3 Yawning Not Yawning
4 Fuzzy Clear Headed
5 Well Coordinated Clumsy
6 Tired Energetic
7 Contented Disconnected
8 Troubled Tranquil
9 Mentally slow Quick Witted
10 Tense Relaxed
11 Attentive Dreamy
12. Stomach Upset Feeling Well
13 Anxious Carefree
(measure from left to right)
Dose Evaluation Study
Clinical response to sublingual administration of apomorphine was evaluated utilizing a group of 60 non-vasculogenic impotent patients. Each patient had a history of erectile dysfunction for at least 3 months, normal biothesiometry response, and normal cavernosometry results.
The patients were divided into seven groups. Each group received a predetermined dosage of apomorphine for 20 days in the form of apomorphine hydrochloride tablets 20 minutes prior to intercourse. Seven different dosages were evaluated — 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg and 10 mg The tablet constituents were those shown in Table I, above. Assessment of response was made on the basis of the patient's report of his experience. A response was deemed positive when the patient experienced an erection sufficiently rigid to effect penetration. Side effects such as nausea and/or vomiting, if present, were noted as well.
The results of this study are compiled in Table X, below. - 2 !
TABLE X
Results of Dose Evaluation Study
Figure imgf000030_0001
From the foregoing table it can be seen that at a 4-mg dosage 40 percent of patients had a positive response, at a 5-mg dosage 50 percent of patients had a positive response, at 6-mg, 7-mg, and 8-mg dosages 70 percent of patients had a positive response and at a 10-mg dosage 80 percent of patients had a positive response. However, the incidence of side effects increased as well as the dosage was increased.
The aforesaid apomorphine dosage forms are also well suited for diagnosing male human patients suffering from male erectile dysfunction. For diagnostic purposes, at least about 3 milligrams of apomorphine are administered sublingually to the patient and the patient is exposed to a visual erotic stimulus, e.g. , an erotic videotape, while the patient's response thereto is monitored. If deemed desirable for diagnostic purposes, up to about 10 milligrams of apomorphine can be administered to the patient.
In particular, the patient's maximum increase in penile circumference (preferably tip as well as basal) is determined and the patient's maximum penile rigidity (preferably tip as well as basal) is determined. The determined circumferential increase and rigidity values are then compared against a predetermined base value. Equivalent methods of determining tumescence and rigidity can also be utilized. Pilot Study #5
A clinical study, "Absorption and pharmacokinetic evaluation of apomorphine after sublingual and intravenous routes of administration" compared the absorption and pharmacokinetic profile of apomorphine administered intravenously and slowly at a 1 mg dose with apomorphine sublingual tablets at doses of 4 mg (Table I) and
8 mg administered on 3 occasions, 4 days apart, over a 12 day period in a crossover study design. The tolerance for apomorphine for each route and each dose administered was determined.
The study was conducted as an open-label, single center, 3-way crossover design. The study population was seven healthy, Caucasian male volunteers between 18 and 35 years of age. A 15-day pre-study evaluation period was followed by a 12-day active treatment phase. Three doses (one intravenous; 2 sublingual) were administered to each subject in random order 4 days apart. A total of 36 serum samples were obtained from each subject at the following time periods: 0, 2, 3, 5, 10, 20, 30 and 45 minutes; and 1, 2, 3, 4 and 6 hours post dose administration.
Safety was assessed within 15 days prior to study start and within one week after the last dose was administered. General physical examination was performed. Change from baseline in vital signs, height/ weight measurements, ECG, orthostatic arterial pressures, heart rate, serum chemistry profile, hematology profile and urinalysis were recorded. Adverse experiences were recorded at each visit and tabulated.
Data Analysis
1. Pharmacokinetic Analysis Pharmacokinetic analysis was performed by compartmental and noncompartmental methods described below. Nonlinear, iterative, least-squares regression analysis was performed with the computer program, PPHARM (Simed Co. , Philadelphia, PA). A. Compartmental Analysis The apomorphine plasma concentration data for each subject following intravenous administration was fitted to two-compartment open model with a first order input function as described by the following equations. Plasma apomorphine concentration was described for intravenous administration data by equation (1):
C<. = Ae - t + Be - t ( 1)
Plasma apomorphine concentration was described for sublingual tablet administration by equations (2) and (3):
F D k
( e e ( *- ^lag ) -ka ( t-tlαg )
(2 ) vd(ka - ke)
Figure imgf000032_0001
+ B e ~" < t ~ ti") + C e ~*« < t ~ ti") ( 3 )
In the above equations, Ct is the apomorphine plasma concentration at time t; F is the relative bioavailability, which is assumed to be one for intravenous administration; K^ is the first order rate constant for sublingual absorption; Kg is the first order rate constant for elimination; Vd is the volume of distribution; D is the apomorphine dose; t is time; tlag is the lag time before onset of sublingual absorption; A, B, C are the intercepts of the distribution, elimination, and absorption phases, respectively; α is the distribution rate constant; β is the elimination rate constant; and Ka is the absorption rate constant.
Initial estimates of the intravenous and sublingual pharmacokinetic parameters were obtained with the computer program PPHARM (Simed Co., Philadelphia, PA). These initial estimates were used to fit the data to equations (1), (2) and (3) by nonlinear iterative least squares regression analysis. The results are shown graphically in FIG. 4. The estimate of F (relative bioavailability) for sublingual administration was obtained from the noncompartmental analysis outlined below.
Visual inspection of the fitted curves, analysis of the residual plots, the Akaike information criterion, and correlation coefficients between observed and calculated values were used to select the appropriate pharmacokinetic model for each set of plasma concentration versus time data. A weighting factor was used to fit the data. The regression analysis provided the final estimates of the pharmacokinetic parameters: Vd, Ke, Ka, and tlag from equation (2), and A, B, C, , β, l ,, and tlag from equation (3). The maximum plasma concentration (C^J, time to maximum plasma concentration (T^), and Vd (volume of distribution) were calculated using standard compartmental pharmacokinetic equations (Gibaldi, M. & Perrier, D.
Pharmacokinetics. 2d edition, Marcel Dekker, Inc. New York, 1982).
The values for C^ and T^ obtained by visual inspection of the plasma concentration versus time curve were reported for comparative purposes. Model dependent and independent pharmacokinetic parameters (presented in Tables XI- XIV) were calculated for each patient using the best fit of Equation (3) to the data.
B. Noncompartmental Analysis:
The area under the curve, AllC^f, was determined by adding the AUC0.last to the AUCt.last, where AUCt.last = Ct / Re, Ct is the plasma concentration at time ', and Re is Ke, the first order rate constant for elimination. If the plasma concentration versus time data for a subject could not be adequately fit to equation (1), (2) or (3), the Ke was determined by linear regression analysis of the log plasma concentration versus time during the post- absorption phase. Estimates of noncompartmental parameters C,^ and T,^ were obtained from visual inspection of the plasma concentration time curves. The relative bioavailability (F) for a sublingual dose was calculated by the following equation:
F = AUC τ * D iτvv ( 4 )
AUCIV * DSL
2. Statistical Analysis:
An analysis of variance (ANOVA) for a three-way crossover study design was utilized to compare the pharmacokinetic parameters (AUC, C^, and tlag) determined as described above for the intravenous administration at 1 mg dose and those determined for the sublingual administration of apomorphine at the 4 mg and the 8 mg doses. The ANOVA was tested for the presence of any period or residual carryover effects in the data. Statistical significance was set at an alpha level equal to 0.05. The ability of the ANOVA to detect both a 20% difference and the observed difference between the sublingual and intravenous pharmacokinetic parameters was determined. In addition to the ANOVA, the 95 % confidence interval of the percent difference between the sublingual and SC parameters was calculated from the error variance and degrees of freedom of the ANOVA model.
The data were summarized as the mean + standard deviation in Tables XI- XIV below.
TABLE XI NONCOMPARTMENTAL PHARMACOLOGIC PARAMETERS
(MEAN + SD) AND RANGE
Figure imgf000035_0001
Cl = clearance
Vd = volume of distribution @ β stage
Vd (SS) = volume of distribution steady state
MRT = means residual time
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000037_0001
TABLE XIII
Noncompartmental Pharmacokinetic Parameters (Mean ± SD) for Sublingual Administration (4mg Dose) π=4
Figure imgf000037_0002
Figure imgf000038_0001
TABLE XIV
Noncompartmental Pharmacokinetic Parameters (Mean ± SD) for Sublingual Administration (8mg Dose) n=4
Figure imgf000038_0002
TABLE XV
Summary of Pharmacokinetic Parameters for Apomorphine HCl in Humans
Figure imgf000039_0001
Figure imgf000039_0002
n/d = not done n/a = not applicable
'Calculated
Clin. Neuropharm. 16:157-166 (1993)
The results, summarized in Tables XI-XIV above and shown graphically in FIG. 4, show that the plasma concentration of apomorphine drops quickly when the drug is administered intravenously. In contrast, the plasma concentration of apomorphine rises slowly to a lower level when administered sublingually. The importance of these findings is put into perspective when compared to information on the administration of apomorphine that is available in the literamre (Table XV). The sublingual administration of apomorphine by the present invention produced a lower plasma concentration than the administration and dosage regimes listed for previous reports. Pilot Study #6
A clinical study of patient tolerance of escalating doses in sublingual tablet administration of APO for the treatment of psychogenic male erectile dysfunction was performed. The pilot study compared the effects of sublingual tablet administration of placebo, and 4, 6 and 8 mg apomorphine hydrochloride (APO) on male erectile dysfunction as measured by RIGISCAN™ monitoring and self- reported satisfaction with the treatment results.
The study included 50 men with psychogenic male erectile dysfunction (MED). The study was conducted in three phases. In the first phase, the subject's penile erectile response (measured with the RIGISCAN™ ambulatory tumescence monitor) was evaluated. The subject received a placebo tablet for sublingual administration and then viewed a 30-minute video consisting of two 10- minute erotic sequences separated by a 10-minute neutral sequence. Subjects completed a visual analogue scale questionnaire (VAS, Table VI) about their feelings and well-being. In the second phase, subjects returned to the clinic for four visits, each visit one week apart. Subjects received one sublingual administration of either placebo, or 4, 6 and 8 mg APO at each visit. Doses of APO were administered in ascending order with the placebo being randomly assigned for use at one of the four visits. The procedures performed before and after drug administration were the same as those in the first phase. After completion of the fourth visit, the investigator determined for each subject the most effective and well-tolerated APO dose for home use in the third phase of the study. The third phase, a home-use phase, lasted 5 weeks. During this phase, subjects attempted coitus at least once each week after taking a single APO tablet. After each attempt the subject and his partner completed a Sexual Function questionnaire (Table XVI). Subjects had a final evaluation at the end of the 5- week, home-use phase.
Fifty males with psychogenic MED were enrolled in this three phase trial. The first aim of this study was to determine the safety and tolerance of APO in the treatment of MED. Several adverse events directly linked with administration of APO in humans were expected: yawning, nausea, vomiting, and cardiovascular effects. Indeed, nausea was the primary adverse event reported in this trial with an overall incidence of less than 13% of the subjects for all administered doses and only two cases were considered severe. The incidence of vomiting was less than 3 % for all administered doses.
Hypotension was reported as an adverse event in some subjects in this study, along with bradycardia, dizziness, syncope, and pallor. Only single cases of hypotension and pallor were judged severe in this study. Increased sweating and fatigue were also reported. One of the cases of increased sweating was considered severe. The other severe adverse events (mouth edema, dysphagia, upper respiratory tract infection) were judged unrelated to treatment. Changes in the serum chemistry values and vital signs paralleled the adverse event reports. There were no clinically significant changes except for one subject judged to have abnormal liver function of unknown origin. There were no clinically significant changes in the blood or urinalysis values due to drug.
The efficacy of APO was evaluated during the first two phases of the study in which subjects were attached to the RIGISCAN™ monitor. Subjects were initially treated with placebo in the first phase. In the second phase, patients received 4, 6 and 8 mg APO tablets with a placebo tablet randomly interspersed in the treatment.
There were highly significant effects of APO treatment compared to placebo. These observations indicate that APO has effects on penile function in both erotic and neutral environments (Tables XVII-XIX). All summed scores showed significant treatment effects at one or more of the three doses of APO. The overall RIGISCAN™ score results were significant to highly significant for a treatment effect of 4, 6 and 8 mg compared to the initial placebo. In addition, most of the treatment effects were significant to highly significant compared to the second placebo.
The effects in the erotic video sequences were larger than the effects in the neutral video sequence (TABLES XVII-XIX). Effects in erotic video sequence one were larger than the effects in erotic video sequence two (TABLE XVII). More significant treatment effects were seen in response to the neutral video sequence, but this reflects the larger number of subjects in this data subset, as one center did not show the erotic video sequences. All doses of APO were effective in causing erections (RIGISCAN™ reading _> 15 in the presence of erotic stimulation; TABLE XVII).
During the third phase, subjects had recorded at baseline, their satisfaction, erection, number of attempts, and successful intercourse on a VAS scale. Evaluable subjects first recorded a success rate, then completed VAS for erection results and satisfaction with intercourse following take-home treatment. Success rate was calculated for mg as well as μg/kg body weight doses (males) . Several evaluations of the data were made including the male and female responses to treatments. The overall average success rate is 69% with APO treatment which is much higher than the average baseline rate 28% (Tables XX, XXI). The success rate showed numerical increase at tablet strength from 4 mg to 6 mg, but a decrease at 8 mg (TABLE XX). The highest success rate was 73% in both males and females at a tablet strength of 6 mg (TABLE XX) . When the dosage is examined as a function of body weight, a dosage range of 50-74 μg/kg gave the highest success rate(: 82%) in females and (80%) in males (Table XXI). The dosage range of 35-50 μg/kg gave the highest success rate.
The optimal response was observed with 4 or 6 mg APO sublingual tablets which caused erections in the majority (72%) of men with male erectile dysfunction (MED) with few severe adverse effects. TABLE XVI
SEXUAL FUNCTION STUDY HOME QUESTIONNAIRE - Male
Please answer questions within 12-24 hours of taking sublingual tablet.
Initials: Subject^: Today's Date: Time:
Date Tablet Taken: Time:
The lines 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. What was your erection result after taking the sublingual tablet?
Rigid Erection No Suitable for Erection Penetration [ ]
2. Did you have intercourse with [ ]Yes [ ] No wife/partner after taking tablet?
IF NO. please circle 0 - No erection. all reasons that apply: 1 - Erection not sufficient for penetration.
2 - Felt sick after taking tablet. (Describe below in #4.)
3 - 1 decided not to participate in intercourse.
4 - Wife/partner decided not to participate.
5 - Unrelated interruption (example, telephone call).
6 - Wife/partner menstruating. 7 - Other, explain:
3. What was your level of satisfaction with this attempt at sexual intercourse?
Extremely Extremely
Unsatisfied Satisfied [ ]
4. Please describe any adverse reactions you experienced after taking the sublingual tablet. (Indicate when the reaction started and stopped, and any intervention taken i.e. "nosebleed on 5/1/94, used a cold compress".)
5. Other comments?
Figure imgf000044_0001
TABLE XVII Total RIGISCAN™ Scores by Phase
Mean ±SEM Phase II
Figure imgf000044_0002
* Significantly higher than placebo 1 ** Significantly higher than placebo 1 and placebo 2
TABLE XVIII Penile Measurements (Maximum Increases Measured by RIGISCAN™), Erotic Video Sequence #1
Figure imgf000045_0001
Repeated Measures Analysis of Variance
DESCRIPTIVE STATISTICS ADJUSTED (LS) MEAN ANALYSIS OF VARIANCE
Site Treatment N MEAN SEM LSMEAN SEM Source p-value
ALL SITES Placebo #1 36 11 44 1 770 12 22 1 666 Treatmenl 0 0001 *
Placebo #2 32 13 38 2 051 13 65 1 714 Site 0 0264 *
4 mg 35 15 31 1 761 15 80 1 674 Treatment by Site 0 0595
6 mg 34 17 09 1 841 17 20 1 695 4mg vs Placebo #1 0 0120 *
8 mg 31 19 84 1 610 19 11 1 745 6mg vs Placebo #1 0 0007 *
SITE #1 ALL TREATMENTS 11 10 76 2 372 11 04 2 498 8mg vs Placebo #1 0 0 0001
Placebo #1 11 9 73 2 854 9 73 2 931 4mg vs Placebo #2 0 1504
Placebo #2 10 9 00 3 300 9 21 2 996 6mg vs Placebo #2 0 0166 *
4 mg 11 8 09 2 410 8 09 2 931 8mg vs Placebo #2 0 0005 *
6 mg 11 10 82 3 065 10 82 2 931 Placebo #1 vs #2 0 3274
8 mg 9 17 89 2 988 17 36 3 070
SITE #2 ALL TREATMENTS 16 13 89 1 942 14 25 2 083
Placebo #1 16 8 94 2 233 8 94 2 430
Placebo #2 14 1 1 71 2 768 1 1 38 2 515
4 mg 15 15 27 2 379 15 10 2 476
6 mg 15 17 60 2 267 17 43 2 476
8 mg 15 18 60 2 265 18 43 2 476
SITE #4 ALL TREATMENTS 9 21 21 3 437 21 49 2 776
Placebo #1 9 18 00 4 304 18 00 3 240
Placebo #2 8 21 75 4 242 20 36 3 337
4 mg 9 24 22 2 837 24 22 3 240
6 mg 8 24 75 3 740 23 36 3 337
8 mg 7 25 00 3 259 21 52 3 444
TABLE XLX Penile Measurements (Maximum Increases Measured by RIGISCAN™), Neutral Video Sequence
Repeated Measures Analysis of Variance
Figure imgf000046_0001
DESCRIPTIVE STATISTICS ADJUSTED (LS) MEAN •ANALYSIS OF VARIANCE
Site Treatment N MEAN SEM LSMEAN SEM Source p-value
ALL SITES Placebo #1 48 7 98 1 236 8 34 1 220 Treatment 0 0002 *
Placebo #2 43 7 49 1 257 7 65 1 272 Site 0 1092
4 mg 47 11 11 1 295 11 47 1 226 Treatment by Site 0 7176
6 mg 45 12 76 1 116 13 10 1 268 4mg vs Placebo #1 0 0230 *
8 mg 41 11 98 1 366 12 40 1 331 6mg vs Placebo #1 0 0009 *
SITE #1 ALL TREATMENTS 11 10 56 1 987 10 70 1 789 8mg vs Placebo #1 0 0 0060 *
Placebo #1 11 8 91 2 470 8 91 2 494 4mg vs Placebo #2 0 0074 *
Placebo #2 10 5 60 2 574 5 68 2 587 6mg vs Placebo #2 0 0002 *
4 mg 11 10 45 1 965 10 45 2 494 8mg vs Placebo #2 0 0017 *
6 mg 11 12 73 2 832 12 73 2 494 Placebo #1 vs #2 0 6243
8 mg 9 16 22 3 099 15 73 2 692
SITE #2 ALL TREATMENTS 16 7 02 1 192 7 22 1 495
Placebo #1 16 4 44 1 554 4 44 2 068
Placebo #2 14 5 86 2 099 5 71 2 182
4 mg 15 8 73 2 610 8 70 2 126
6 mg 15 9 60 1 514 9 56 2 126
8 mg 15 7 73 1 694 7 70 2 126
SITE #3 ALL TREATMENTS 12 12 22 1 476 12 09 1 706
Placebo #1 12 11 33 2 244 11 33 2 388
Placebo #2 11 10 00 1 902 10 61 2 469
4 mg 12 11 83 2 564 11 83 2 388
6 mg 12 13 58 1 794 13 58 2 388
8 mg 11 12 45 2 458 13 07 2 469
SITE H ALL TREATMENTS 9 11 63 2 864 12 35 2 023
Placebo #1 9 8 67 4 052 8 67 2 758
Placebo #2 8 9 25 3 990 8 58 2 891
4 mg 9 14 89 3 071 14 89 2 758
6 mg 7 18 14 2 747 16 51 3 046
8 mg 6 15 33 4 462 13 1 1 3 236
TABLE XX
Reported Success by Tablet Strength
Figure imgf000047_0001
TABLE XXI
Reported Success by Apomorphine Dosage (μg/kg)
Figure imgf000047_0002
Subject Evaluability Rules for Take-home Part
1. Subjects who get one out of two successful intercourse is considered a success [based on subject's answers to the take-home questionnaires].
2. Subjects who tried the study medication at home, for at least two times.
3. Subjects who attempted to try a lower or higher does if the original take-home does did not produce optimum results in combination with anti-nausea agents.
4. Subjects [and partners] who filled out and returned take-home questionnaires.
The practice of the present invention is demonstrated in the following examples. These examples are meant to illustrate the invention rather than to limit its scope. Variations in the treating compositions which do not adversely affect the effectiveness of the apomorphine or the antiemetic agent will be evident to one skilled in the art, and are within the scope of this invention.
EXAMPLE 1: Apomorphine/Nicotine Combination By Wet Granulation Technique - Composition A
Composition A Tablets were prepared from the ingredients listed in Table
XXII (below). Each ingredient was weighed as indicated and passed through a
#35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation. A solution containing the apomorphine HCL, the citric acid, half the acesulfame-K, half the peppermint flavor and half the chocolate flavor was prepared by dissolving the ingredients into a mixture of equal volumes of purified water and ethanol,
USP. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302). The resulting wet mass, which will be labelled "Part A, " was mixed in a porcelain dish at room temperature (20°C)for 30 minutes, and then partially dried to obtain a solid mass. The mass was next granulated by screening through a #50 mesh (ASTM)(sieve opening of about 0.297 mm) stainless steel screen. The wet granules were dried at about 60 'C to 70 °C for about 1 to 1.5 hours. The resulting dried granules were then passed through a #35 mesh screen (sieve opening of about 0.51 mm).
TABLE XXII
Apomorphine/Nicotine Combination Tablet Composition
Ingredient mg/tablet
Apomorphine HCL 4.0
Nicotine Base 1.0
Acesulfame-K 4.0
Microcrystalline Cellulose 37.5
Peppermint flavor 2.5
Chocolate natural flavor 2.0
Citric acid 3.0
Hydroxypropylmethylcellulose 13.0
Mannitol 80.0
Magnesium stearate 3.0
TOTAL 150.0
Separately, nicotine was added to and blended with all the remaining ingredients except for the magnesium stearate. Specifically, the nicotine was added to the second half of the acesulfame-K, half the peppermint flavor, half the chocolate flavor, the hydroxypropylmethylcellulose (methocel E4M, premium), and the mannitol. The resulting blend will be labelled "Part B. " Parts A and B were then combined and mixed for about 5 minutes in a V-shaped blender. Next, magnesium stearate was added to the blender and blending continued for about 2 minutes. The final mix was removed from the blender and fed into a Stoke 's single punch tablet press fitted with biconvex 5/16" diameter tooling for tablet preparation. Tablets were prepared at various compressional forces, yielding tablets of different hardness. In general, the harder the tablet the slower the release of the active ingredients therefrom. For additional discussion on methods for preparing sublingual apomoφhine tablets see U.S. Patent No. 5,624,677 to El-Rashidy et al. , which is incorporated here by reference to the extent that it is not inconsistent.
The dissolution of apomorphine and nicotine for Composition A Tablets was measured using a USP Type II apparatus (USP XXIII) stirred at 40 rpm. The dissolution medium was 500 ml of 10 millimolar ammonium phosphate buffer at a pH of 3.0 ± 0.5 at about 37 °C. The amount of apomorphine and nicotine released into the medium was detected by measuring absorbance at two different wavelengths, 259 nm and 272 nm, and resolving the following two equations:
AT259 = (ε25 0)(Capo)(l) + (ε^nιc)(Cnιc)(l) (5)
AT272 = (ε272 apo)(Capo)(l) + (ε272 mc)(Cmc)(l) (6)
In the above equations, Aτ259 is the total absorbance at 259 nanometers (nm);
AT272 is the total absorbance at 272 nm; ε259 apo is the molar absorptivity of apomorphine at 259 nm; ε259 mc is the molar absorptivity of nicotine at 259 nm; ε272 apo is the molar absorptivity of apomorphine at 272 nm; ε272 nιc is the molar absorptivity of nicotine at 272 nm; Capo is the molar concentration of apomorphine; Cnιc is the molar concentration of nicotine; and 1 is the cell path length.
By solving equations (5) and (6), the molar concentration of apomorphine (Capo) and nicotine (Cmc) can be calculated from total absorbance data (A^^ and AT272) as follows:
Capo = (β^ s " ε259n,cA1 72)/(ε259 apoε272 mc - ε27 apoε^mc) (7)
Figure imgf000049_0001
Dissolution kinetic constants (Kdlss) for apomorphine and nicotine were calculated assuming zero-order release kinetics.
The tablets prepared were compared against a commercially available soluble apomorphine HCl tablet for dissolution characterization. The results are presented in Table XXVI (below) and in FIG. 5. Specifically, the time to 50 percent drug release (T50) and 90 percent drug release (T^) for both apomorphine and nicotine are reported together with dissolution constants.
In addition, tablet hardness was measured using a Computest Tablet Hardness
Tester. These results are also reported in Table XXVI. Composition A Tablets released apomoφhine relatively slower as compared to the release of the antiemetic agent, nicotine.
EXAMPLE 2: Apomorphine/Nicotine Combination By Wet Granulation Technique - Composition B
Composition B Tablets were prepared from the ingredients listed in Table XXII (above). Each ingredient was weighed as indicated and passed through a
#35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation.
Apomoφhine HCL, the hydroxypropylmethyl cellulose, the citric acid, the acesulfame-K, the peppermint flavor, and the chocolate flavor were blended together with the indicated amount of microcrystalline cellulose using 25 percent ethanol in deionized water. The solution was mixed until clear, and then absorbed into half the listed amount of microcrystalline cellulose (Avicel 302). The resulting wet mass (Part A) was mixed in a porcelain mortar at room temperature
(20 °C) for about 30 minutes, and then partially dried to obtain a single piece.
The mass was granulated using a #35 mesh hand screen (sieve opening of about 0.51 mm). The wet granules were dried at about 60 *C to 70 °C for about 1 to 1.5 hours, and periodically mixed during the drying stage. The resulting dried granules were then passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
Separately, nicotine was added to and blended with the second half of the microcrystalline cellulose and the mannitol (Part B). Parts A and B were then combined and mixed for about 5 minutes in a V-shaped blender. Next, magnesium stearate was added to the blender, followed by continued blending for about 2 minutes.
The final mix was removed from the blender and compressed into tablets using a Stoke's single punch tablet press fitted with 5/16" diameter biconvex tooling.
Tablets were prepared at various compressional forces, yielding tablets of different hardness. Dissolution of apomoφhine and nicotine for Composition B Tablets was measured and reported as described in Example 1. The results are presented in
Table XXVI (below) and in FIG. 6. Composition B Tablets released apomoφhine relatively slower as compared to the release of nicotine. EXAMPLE 3: Apomorphine/Nicotine Layered Tablet Combination -
Composition C
The ingredients listed in TABLE XXIII (below) were used to prepare a layered tablet having a core portion containing apomoφhine HCL and an outer layer containing the antiemetic agent nicotine. All ingredients were first passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
TABLE XXIII Apomorphine/nicotine Layered Tablet Composition
Ingredient mg/tablet
Tablet core:
Apomorphine HCL 4.0
Acesulfame-K 1.6
Microcrystalline Cellulose 21.6
Peppermint flavor 1.0
Chocolate flavor 0.8
Citric acid 1.2
Hydroxypropylmethylcellulose 4.0
Mannitol 24.6
Magnesium stearate 1.2
Tablet outer layer:
Nicotine base 1.0
Acesulfame-K 0.4
Microcrystalline Cellulose 36.6
Mannitol 47.0
Magnesium stearate 1.0
Hydroxypropylmethylcellulose 4.0
TOTAL 150.0
The core portion was prepared by dry mixing apomoφhine HCL, citric acid, peppermint flavor, chocolate flavor and acesulfame-K. The resulting mixture was blended in a V-shaped blender for about 5 minutes. Hydroxypropylmethylcellulose was than added and the blending continued for an additional 5 minutes. The microcrystalline cellulose was then added to the blender and mixing was continued for yet another 5 minutes. Next mannitol was added to the blender, followed by another 5 minute stage of blending. Finally, magnesium stearate was added and blended in for about 2 minutes. The resulting mixture was transferred to a Stoke 's tablet press fitted with
7/32" diameter biconvex tooling to generate tablet cores with a hardness of about 3 kilopascals (Kp).
The outer antiemetic layer was prepared by mixing nicotine with the listed amount of microcrystalline cellulose in a porcelain mortar until the mixture became homogeneous. The homogeneous mixture was then transferred to a V- shaped blender, where the listed amounts of mannitol, hydroxypropylmethylcellulose, and acesulfame-K were blended in for about 5 minutes. Magnesium stearate was then added followed by an additional 2 minutes of blending.
A portion of the nicotine mixture was then transferred to the die of the Stoke' s tablet press fitted with 5/16" biconvex tooling. Next an apomoφhine tablet core discussed above was placed in the die and then covered with another portion of the nicotine mixture. The nicotine mixture and core portion were finally compressed together to form layered tablets.
Dissolution of apomoφhine and nicotine for Composition C Tablets was measured and reported as described in Example 1. The results are presented in
Table XXVI (below) and in FIG. 7. As expected, Composition C Tablets released nicotine from their outer layer relatively sooner and faster than the apomoφhine from the core portion.
EXAMPLE 4: Apomorphine/Prochlorperazine Combination By Wet Granulation Technique - Composition D
Composition D Tablets were prepared from the ingredients listed in Table
XXIV (below). Each ingredient was weighed as indicated and passed through a
#35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation. A solution containing the apomoφhine HCL, acesulfame-K, peppermint flavor, chocolate flavor, and citric acid was prepared by dissolving these ingredients into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302) by further mixing over a stainless steel pan at room temperature (20 °C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen (sieve opening of about 0.25 mm).
TABLE XXrV Apomorphine/Prochlorperazine Combination Tablet Composition
Ingredient mg/tablet
Apomorphine HCL 4.0
Prochlorperazine HCL 5.0
Acesulfame-K 4.0
Microcrystalline Cellulose 37.5
Peppermint flavor 2.5
Chocolate flavor 2.0
Citric acid 3.0
Hydroxypropylmethylcellulose 10.0
Mannitol 68.0
Sodium alginate 10.0
Magnesium stearate 3.0
TOTAL 150.0
The resulting granules were dried at about 60 °C to 70 °C for about 2 hours.
The dried granules were then mixed in a porcelain mortar and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
All remaining ingredients listed in Table XXIV, except the magnesium stearate, were blended with the dry granules for about 5 minutes using a V-shaped blender. After 5 minutes of blending, magnesium stearate was added and the blending repeated for an additional 5 minutes. The resulting blend was compressed into tablets using the Stoke 's tablet press fitted with 5/16" biconvex tooling.
Composition D Tablets were evaluated as described for Example 1 , except that absorbance was measured at 254 nm rather than 259 nm. The results are presented in Table XXVI (below) and in FIG. 8. Composition D Tablets released apomoφhine relatively slower as compared to the release of prochloφerazine.
EXAMPLE 5: Apomorphine/Prochlorperazine Combination By Wet Granulation Technique - Composition E
Composition E Tablets were prepared from the ingredients listed in Table
XXIV (above). Each ingredient was weighed as indicated and passed through a #35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation. Apomoφhine HCL, the hydroxypropylmethyl cellulose, the sodium alginate, the citric acid, the acesulfame-K, the peppermint flavor, and the chocolate flavor were blended using 25 percent ethanol in deionized water. The resulting wet mass (Part A) was mixed in a porcelain mortar at room temperature (20 ° C) for about 30 minutes, and then partially dried to obtain a single piece. The resulting mass was granulated using a #35 mesh hand screen (sieve opening of about 0.51 mm). The wet granules were dried at about 60 °C to 70 °C for about 1 to 1.5 hours, and periodically mixed during the drying stage. The resulting dried granules were then passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
Separately, prochloφerazine was added to and blended with the mannitol (Part B). Parts A and B were then combined and mixed for about 5 minutes in a V- shaped blender. Next, magnesium stearate was added to the blender, followed by continued blending for about 2 minutes.
The final mix was removed from the blender and compressed into tablets using a Stoke's single punch tablet press fitted with 5/16" diameter biconvex tooling. Tablets were prepared at various compressional forces, yielding tablets of different hardness.
Dissolution of apomoφhine and prochloφerazine for Composition E Tablets was measured and reported as described in Example 1. The results are presented in Table XXVI (below) and in FIG. 9. Composition E Tablets released apomoφhine relatively slower as compared to the release of prochloφerazine. EXAMPLE 6: Apomorphine/Prochlorperazine Layered Tablet Combination
- Composition F
Composition F Tablets were prepared according to the instructions presented in Example 3, except that the ingredients of Table XXV (below) were used.
Prochloφerazine was substimted for nicotine and the sodium alginate was added in the same step as the hydroxypropylmethylcellulose. TABLE XXV
Apomorphine/Prochlorperazine Layered Tablet Composition
Ingredient mg/tablet
Tablet core:
Apomorphine HCL 4.0
Acesulfame-K 1.6
Microcrystalline Cellulose 20.0
Peppermint flavor 1.0
Chocolate flavor 0.8
Citric acid 1.2
Hydroxypropylmethylcellulose 5.0
Mannitol 20.2
Sodium alginate 5.0
Magnesium stearate 1.2
Tablet outer layer:
Prochlorperazine 5.0
Acesulfame-K 0.4
Microcrystalline Cellulose 35.6
Mannitol 46.0
Magnesium stearate 1.0
Hydroxypropylmethylcellulose 2.0
TOTAL 150.0
Composition F Tablets were evaluated as described for Example 1. The results are presented in Table XXVI (below) and in FIG. 10. Composition F
Tablets released the antiemetic prochloφerazine relatively faster than the apomoφhine, as expected. EXAMPLE 7: Apomorphine/Prochlorperazine Layered Tablet Combination
- Composition G
The ingredients listed in Table XXV (above) were used to prepare a layered tablet having a core portion containing apomoφhine HCL and an outer layer containing the antiemetic agent prochloφerazine. Each ingredient was weighed as indicated and passed through a #35 mesh screen (sieve opening of about 0.51 mm) to ensure granulation.
The core portion was prepared by dissolving the apomoφhine HCL, acesulfame-K, peppermint flavor, chocolate flavor, and citric acid into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose (Avicel 302) by further mixing over a stainless steel pan at room temperature (20 ° C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen.
The resulting granules were dried at about 60 °C to 70 °C for about 2 hours. The dried granules were then mixed in a porcelain mortar and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm).
All remaining core ingredients listed in Table XXV, except the magnesium stearate, were blended with the dry granules for about 5 minutes using a V-shaped blender. After 5 minutes of blending, magnesium stearate was added and the blending repeated for an additional 2 minutes. The resulting blend was compressed into 60 mg tablet cores using the Stake's tablet press fitted with 7/32" biconvex tooling. The outer antiemetic layer was prepared by dissolving the prochloφerazine and acesulfame-K into a mixture of equal volumes of distilled water and ethanol. The solution was mixed until clear, and then absorbed into the listed amount of microcrystalline cellulose by mixing over a stainless steel pan at room temperature (20 °C) for about 30 minutes. The mixture was partially dried before granulating with a #60 mesh hand screen.
The resulting granules were dried at about 60 °C to 70 °C for about 2 hours, mixed in a porcelain mortar, and passed through a #35 mesh hand screen (sieve opening of about 0.51 mm). The mannitol and the hydroxypropylmethyl cellulose were blended with the dry outer-layer granules for about 5 minutes using a V- shaped blender. After 5 minutes of blending, magnesium stearate was added and the blending repeated for an additional 2 minutes.
Layered tablets were then prepared by compressing the outer-coating granules around tablet cores as described in Example 3.
Dissolution of apomoφhine and prochloφerazine for Composition G Tablets was measured and reported as described in Example 1. The results are presented in Table XXVI (below) and in FIG. 11. As expected, Composition G Tablets released prochloφerazine from their outer layer relatively sooner and faster than the apomoφhine, which escapes from the core portion. EXAMPLE 8: Comparison Of Drug Release Profiles
The dissolution profile of a commercially available soluble apomoφhine HCl tablet (Apomoφhine HCl. 6 mg of Apomoφhine HCL in a 60 mg tablet) was analyzed as described for Example 1. The results of this test are shown graphically in FIG. 12. and listed in Table XXVI (below).
Also reported in Table XXVI are the time to 50 percent drug release (T50), the time to 90 percent drug release (Too), and tne calculated dissolution constants of both the apomoφhine and antiemetic agent (nicotine or prochloφerazine) for each example composition.
Table XXVI Comparison Of Release Profiles And Tablet Hardness
Apomorphine HCL Antiemetic Ag ent
Comp τ» K ta τ» *<x> Kdiss r2 Hardness, kp
A 60 60 1.44 10 25 3.34 0.908 4.5
B 12 40 3.92 5 12 6.51 0.912 4.7
C 13 45 4.29 8 20 5.66 0.899 2.5/4.9
D > 90 > 90 0.54 90 > 90 0.54 0.945 6.5
E 22 40 2.76 16 27 3.16 0.944 4.2
F 15 60 3.42 7 30 5.29 0.956 2.5/4.8
G 80 > 120 0.67 < 10 40 2.68 0.932 3.5/5.5
Soluable
Apo Tablet 13 30 3.82 — — — 0.909 4.2
These data demonstrate the ability of the present invention to release antiemetic agent relatively sooner and faster than the apomoφhine. FIGs. 5 through 13 are graphs generated from the data presented in TABLE XXVI. Significantly, and well represented in graphical form, compositions according to the present invention also release apomoφhine at an advantageously slower rate than that of the commercial sublingual table.
FIG. 13 is a composite graph of the dissolution profiles for a commercially available apomoφhine soluble tablet and a Composition G Tablet (Example 7). This graph well demonstrates the advantage of a layered, staggered-release tablet according to the present invention. The foregoing discussion, examples, and the reported studies are intended as illustrative of the present invention and are not to be taken as limiting. Still other variants within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.

Claims

WE CLAIM:
1. A method suitable for treating erectile dysfunction in a male patient which comprises administering to the patient prior to sexual activity: an antiemetic agent in an amount sufficient to substantially reduce nausea associated with use of apomoφhine; and apomoφhine or a pharmaceutically acceptable acid addition salt thereof in an amount sufficient to induce and maintain an erection adequate for vaginal penetration.
2. The method in accordance with claim 1 wherein the antiemetic agent is a phenothiazine.
3. The method in accordance with claim 2 wherein the antiemetic agent is prochloφerazine.
4. The method in accordance with claim 1 wherein the antiemetic agent is a benzamide.
5. The method in accordance with claim 1 wherein the antiemetic agent is a meclizine.
6. The method in accordance with claim 1 wherein the antiemetic agent is a serotonin antagonist.
7. The method in accordance with claim 1 wherein the antiemetic agent is a member of the group consisting of hydroxyzine, dimenhydrinate, scopolamine, metopimazine, and diphenidol hydrochloride.
8. The method in accordance with claim 1 wherein the antiemetic agent is a ganglionic stimulating alkaloid and the apomoφhine is administered to the patient as the hydrochloride salt.
9. The method in accordance with claim 8 wherein the antiemetic agent is nicotine sulfate and the weight ratio of apomoφhine hydrochloride to nicotine sulfate administered to the patient is in the range of about 10 to about 1.
10. The method in accordance with claim 8 wherein the apomoφhine and the antiemetic agent are co-administered to the patient in a single dosage unit comprising about 1 to about 10 milligrams apomoφhine and about 0.5 to about 2 milligrams nicotine sulfate.
11. The method in accordance with claim 1 wherein the antiemetic agent is prochloφerazine hydrochloride.
12. The method in accordance with claim 11 wherein the weight ratio of apomoφhine hydrochloride to prochloφerazine hydrochloride administered to the patient is in the range of about 5 to about 0.25.
13. The method in accordance with claim 11 wherein the amount of prochloφerazine hydrochloride administered to the patient is in the range of about 5 to about 150 micrograms per kilogram of patient's body weight.
14. The method in accordance with claim 1 wherein the apomoφhine and the antiemetic agent are administered to the patient substantially concurrently.
15. The method in accordance with claim 1 wherein the apomoφhine and the antiemetic agent are administered to the patient sequentially by first administering a composition comprising an antiemetic agent and thereafter a composition comprising apomoφhine.
16. The method in accordance with claim 1 wherein the apomoφhine and the antiemetic agent are co-administered to the patient as a sublingual tablet.
17. The method in accordance with claim 1 wherein the apomoφhine is administered as a sublingual tablet and the antiemetic agent is administered as a buccal patch.
18. The method in accordance with claim 1 wherein the apomoφhine and the antiemetic agent are administered to the patient by intravenous injection.
19. The method in accordance with claim 1 wherein the apomoφhine is administered to the patient as a subcutaneous injection.
20. The method in accordance with claim 1 wherein the apomoφhine is administered to the patient as a suppository.
21. The method in accordance with claim 1 wherein apomoφhine is administered to the patient as the hydrochloride salt.
22. A combination of apomoφhine and an antiemetic agent which is a member of the group consisting of the phenothiazines, the benzamides, the meclizines, the serotonin antagonists, hydroxyzine, lobeline sulfate, dimenhydrinate, scopolamine, metopimazine, diphenidol hydrochloride, nicotine, and the acid addition salts thereof.
23. A dosage unit comprising an antiemetic agent as a relatively faster release component and apomoφhine as a component released after release of the antiemetic agent has begun.
24. The dosage unit of claim 23 in the form of a layered tablet.
25. The dosage unit of claim 23 wherein the antiemetic agent is a member of the group consisting of the phenothiazines, the benzamides, the meclizines, the serotonin antagonists, hydroxyzine, lobeline sulfate, dimenhydrinate, scopolamine, metopimazine, diphenidol hydrochloride, nicotine, and the acid addition salts thereof.
26. The dosage unit of claim 23 wherein the antiemetic agent is a prochloφerazine.
27. The dosage unit of claim 23 wherein the antiemetic agent is metoclopramide hydrochloride.
28. The dosage unit of claim 23 in the form of a tablet having a core portion containing the apomoφhine and an outer layer portion containing the antiemetic agent.
29. The dosage unit of claim 23 having a time to 90 percent release of apomoφhine in the range of about 25 minutes to about 300 minutes.
PCT/US1999/014053 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction WO1999066916A1 (en)

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IL140272A IL140272A (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction
NZ509438A NZ509438A (en) 1998-06-22 1999-06-22 A dosage form containing apomorphine and antiemetic agent for ameliorating male erectile dysfunction
DE69932823T DE69932823T2 (en) 1998-06-22 1999-06-22 APOMORPHINE CONTAINING PHARMACEUTICAL FORMS FOR IMPROVING MALE EFFECTS DYSFUNCTION
PL99345401A PL195119B1 (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction
JP2000555602A JP2002518439A (en) 1998-06-22 1999-06-22 Apomorphine containing dosage form for improving male erectile dysfunction
EP99930538A EP1094799B1 (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction
CA002336095A CA2336095A1 (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction
MXPA00012620A MXPA00012620A (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction.
BR9911408-9A BR9911408A (en) 1998-06-22 1999-06-22 Dosage forms containing apomorphine for improvement of male erectile dysfunction
AU47058/99A AU776686B2 (en) 1998-06-22 1999-06-22 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction
NO20006560A NO20006560L (en) 1998-06-22 2000-12-21 Apomorphine-containing dosage forms to improve erectile dysfunction in men
HK01109138A HK1040179A1 (en) 1998-06-22 2002-03-25 Apomorphine-containing dosage forms for ameliorating male erectile dysfunction

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AU4705899A (en) 2000-01-10
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JP2002518439A (en) 2002-06-25
CA2336095A1 (en) 1999-12-29
PL195119B1 (en) 2007-08-31
ATE336234T1 (en) 2006-09-15
NO20006560L (en) 2001-02-22
CN1313762A (en) 2001-09-19
IL140272A (en) 2007-07-04
DE69932823T2 (en) 2007-03-15
EP1094799A1 (en) 2001-05-02
HUP0102834A3 (en) 2002-10-28
US6306437B1 (en) 2001-10-23
EP1094799A4 (en) 2002-05-08
BR9911408A (en) 2001-12-04
HK1040179A1 (en) 2002-05-31
MXPA00012620A (en) 2005-11-08
CN1201738C (en) 2005-05-18
AU776686B2 (en) 2004-09-16
DE69932823D1 (en) 2006-09-28
HUP0102834A2 (en) 2002-07-29
PL345401A1 (en) 2001-12-17
US6121276A (en) 2000-09-19
IL140272A0 (en) 2002-02-10
NO20006560D0 (en) 2000-12-21

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