CZ20004653A3 - Apomorphine and antiemetic intended for use in therapy, apomorphine mixture, antiemetics, and medicamentous form - Google Patents

Abstract

Psychogenic impotence can be eliminated essentially without adverse side effects with apomorphine and antiemetics in a quantity that substantially suppresses undesirable symptoms of nausea associated with ingestion of apomorphine.

Description

TECHNICAL FIELD

The present invention describes dosage forms and methods for eliminating erectivity disorders in male psychogenic patients. Further, the present invention provides a diagnosis of erectile function disorders. In particular, the present invention describes the use of compositions comprising apomorphine for the eradication of erectivity disorders in psychogenic patients and for diagnostic purposes. BACKGROUND OF THE INVENTION

Common erection is the result of coordinated vascular processes taking place in the penis. These processes are usually triggered by a nerve stimulus, and in particular, vascular enlargement, relaxation of the penis smooth muscle and blood vessels supplying the penis. Increased blood supply results in enlargement of the part referred to as "corpora cavernosa". Blood flow through the veins is hampered by this increase, thereby achieving the increased blood pressure in the penis that is necessary to achieve the required strength. The muscles in the perineum also contribute to maintaining penile strength. The erection can be achieved through the central nervous system through sexual thoughts and fantasies and manifests locally through reflexive mechanisms. These erective mechanisms are basically the same as those that make the clitoris erect in women.

Male impotence or erectivity disorders are defined as the inability to achieve sufficient erection required for sexual intercourse. Impotence can be caused by psychological problems (psychogenic), physiological abnormalities in general (organ), neurological disorders (neurogenic), hormonal disorders (endocrine), or a combination thereof.

However, this description is not sufficiently precise. To date, there is no standard procedure for diagnosis or treatment. As used herein, the term "psychogenic impotence" is defined as functional impotence without obvious organ failure. It may be characterized by the ability to achieve an erection in response to some stimuli (eg masturbation, spontaneous night erections, videoerotics, etc.) but not to others (eg partner or marital sex).

Various techniques have previously been used to treat impotence using various devices, e.g., turnstiles (see U.S. Patent 2,818,855). In some cases, penis implants such as bending or rigid stiffeners and inflatable, spring-loaded or hydraulic models have been used. Administration of drugs affecting erection is mentioned in U.S. Pat

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LaTorre. This patent describes a method of treating male impotence by injecting a vasodilator into the penis, usually adrenaline blockers or smooth muscle relaxants and thereby enhancing erection. The use of an ointment for the treatment of impotence is even described today (U.S. Pat. No. 4,801,587). This ointment consists of vasodilators of papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine or phentolamine and a carrier which ensures the absorption of these substances into the skin. In U.S. Pat. No. 5,256,652, El-Rashidy discloses the use of a topical aqueous composition comprising a vasodilator such as papaverine and hydroxypropyl-β-cyclodextrin.

Recent studies have investigated the possibility of using apomorphine to treat psychogenic impotence in men. These studies show that although apomorphine is capable of inducing erection in psychogenic patients, the doses of apomorphine necessary to achieve the desired result produce nausea or even side effects such as high blood pressure, redness and severe sweating. Unfortunately, the specific mechanisms by which apomorphine affects erectivity in human patients are not yet fully understood.

In addition, apomorphine has been shown to exhibit very low activity after oral administration. See, e.g., Baldessarini et al., Apomorphin and Other Dopaminomimetics, Basic Pharmacology, Vol. 1, Raven Press, N.Y. (1981) pp. 219-228.

There is therefore a need to seek further effective treatments for psychogenic impotence in men, as well as diagnostic techniques that could identify potential patients. It has now been found that some targeting systems for apomorphine can help its therapeutic use by eliminating its side effects. It has also been found that nausea induced by the use of apomorphine can be substantially suppressed by premedication or concomitant administration of an antiemetic.

SUMMARY OF THE INVENTION

It has been found that stable levels of apomorphine circulating in serum and middle brain tissue, in a very narrow range, are required for optimal erective response.

Apomorphine dosage forms applicable in sublingual capsules, which usually contain from

2.5 to about 10 mg of apomorphine are effective for patients suffering from a psychogenic erectile dysfunction to the extent that it provides an erection sufficient to effect sexual intercourse (i.e., vaginal penetration) without inducing nausea or other adverse side effects. Apomorphine is administered in sublingual capsules about 15 to 20 minutes before sexual intercourse to achieve the desired serum and middle brain tissue levels throughout the duration of sexual activity sufficient to induce an erection required to penetrate into the vagina, but less than · · 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

999 99 9999 99 994 amount causing nausea. The plasma apomorphine concentration should be maintained at a level of less than 5.5 ng / ml, preferably from about 0.3 to 4 ng / ml, and most preferably from 1 to 2 ng / ml.

The aforementioned dosage forms of apomorphine administered in sublingual capsules are also suitable for testing patients suffering from erectile dysfunction to identify those who have a proven psychogenic etiology.

Nausea, manifested as a side effect of apomorphine administration, can be substantially suppressed by administration of antiemetics. The proposed method of treating patients with erectile dysfunction then, prior to sexual activity, comprises administering an anti-emetic agent in an amount sufficient to suppress apomorphine nausea, which is also administered in an amount that causes and is able to maintain the erection for a period of time to possible sexual intercourse.

The anti-emetic is usually administered concurrently with apomorphine in a single dose of the sublingual dosage form. Various, independent modes of application can be used to achieve the same effect described by the present invention. E.g. the antiemetic and apomorphine are administered sequentially by first administering to the patient in a single dose a composition comprising an antiemetic and then a composition comprising apomorphine.

Dosage forms intended for simultaneous administration of an anti-emetic-apomorphine combination should contain such anti-emetic drugs that are released relatively rapidly from the dosage form and only after the anti-emetic has been released does apomorphine begin to be released gradually. These sustained release dosage forms are generally tablets with an apomorphine-containing core and an antiemetic outer layer.

Tablets for sublingual administration include apomorphine, an anti-emetic, an osmotic agent, and a swallowable hydrophilic carrier. The most suitable osmotically active ingredient is mannitol, and the most suitable swallowable carrier is microcrystalline cellulose.

The use of a combination of apomorphine and an anti-emetic may also be used in practice to treat certain motor disorders in Parkinson's disease.

Detailed description of the most suitable variants

Apomorphine is a dopamine receptor agonist known to have strong emetic effects when administered subcutaneously at a dose of about 5 mg. For the purposes of the present invention, apomorphine and the like-acting dopamine receptor agonist is administered in amounts sufficient to activate cells in the intermediate patient, but with minimized side effects. Activation of intermediate cells is likely to be part of a cascade of stimulation, which probably also includes activation with serotonin and oxytocin.

The dopamine receptors in the intermediate patients can be stimulated to a degree sufficient to induce an erection by sublingual apomorphine administration such that the apomorphine plasma concentration is less than about 5.5 ng / ml. Sublingual administration usually lasts about 2 to 10 minutes or longer. The total amount of sublingual apomorphine administered during this time is in the range of about 25 pg / kg body weight to 60 pg body weight.

Apomorphine should be administered about 15 to 20 minutes before sexual activity.

Apomorphine can be represented by the following formula:

and may exist in the form of the free base or as an acid salt. For the purposes of the present invention, apomorphine chloride is most suitable, but a variety of other pharmaceutically active forms can be used. The term "apomorphine" as used herein describes the free base of the compound as well as its pharmacologically acceptable acids and salts. In addition to the chloride salts, other salts such as bromides, iodides, bisulfates, phosphates, acid phosphates, lactates, citrates, tartrates, salicillates, succinates, maleate gluconates and the like are acceptable.

An illustrative example of a sublingual dosage form is shown in Table 1.

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Table 1: Sublingual tablets containing 150 mg apomorphine chloride mg tablets apomorphine hydrochloride 2.00% mannitol 66.67% ascorbic acid 3.33% citric acid 2.00%

AvicelPH102 15,00%

Methocel E4M 10.00%

Aspartame 0.67% magnesium stearate 0.33% mg tablets apomorphine hydrochloride mannitol ascorbic acid citric acid Avicel PH102 Methocel E4M Aspartame magnesium stearate mg tablets apomorphine hydrochloride mannitol ascorbic acid citric acid Avicel PH102 Methocel E4M · · · ··· · · ···· · ·

2,660%

66.00%

3.33%

2,00%

15,00%

10,00%

0.67%

0.33%

3.33% 65.34% 3.33% 2.00% 15.00% 10.00% 0.67% 0.33%

If desired, and in order to achieve better absorption and hence bioavailability, the above dosage forms may also contain β-cyclodextrin or β-cyclodextrin derivatives such as hydroxypropyl β-cyclodextrin (HPBCD) in addition to carriers. Illustrative examples of HPBCD containing dosage forms are shown in Tables 2 and 3 below.

Table 2: Sublingual tablets containing apomorphine hydrochloride and hydroxypropyl-β-cyclodextrin mg / tablet apomorphine hydrochloride 4.0

HPBCD 5.0 ascorbic acid 10.0

PEG8000 39.5 mannitol 39.5

Aspartame 2.0

Total

100.0 • · φ «« φ φ φ φ

ΦΦΦ φ φ φ · · φφ φφφφ φφφφ

Table 3: Sublingual tablets containing apomorphine hydrochloride and β-cyclodextrin mg / tablet apomorphine hydrochloride 5.0 β-cyclodextrin 20.0 ascorbic acid _t 5.0 mannitol 68.9 magnesium stearate 1.0

D&C Yellow Aluminum Lake 0.1

Total 100.0

The onset of nausea may be delayed or suppressed by administration of apomorphine under controlled conditions such that serum circulating and intermediate levels are sufficient to induce an erection without developing nausea. When apomorphine is administered at doses close to the relatively high levels listed above, the likelihood of onset of nausea may be reduced by concomitant administration of an anti-emetic such as nicotine or lobelin sulfate. For this purpose, the weight ratio between apomorphine and antiemetic is in the range of 300: 1 to 5: 1.

Of course, the appropriate weight ratio depends on the effectiveness of the antiemetic used. When nicotine is used, a suitable apomorphine to nicotine weight ratio is from 10 to 1. Due to the specific absorption of substances, the sublingual doses intended for concomitant administration of nicotine and apomorphine should contain apomorphine in the range of 1 to about 8 mg and nicotine in the range of 0 25 to about 3 mg.

The most suitable combination for sublingual administration comprises apomorphine in the range of 4 to 8 mg and nicotine in the range of 0.75 to about 1.25 mg.

Nicotine and lobelin sulfate are referred to as ganglion stimulating alkaloids. See, e.g., Goodman, Louis S. and Alfred Gilman eds., The Pharmacologic Basis of Therapeutics, 5th Edition, MacMillan Publishing Co., New York, N.Y. (1975), pp. 567-569. For the purpose of . of the present invention, ganglion stimulating alkaloids such as nicotine and lobelin sulfate can serve as antiemetics.

Anti-emetics are substances that are able to prevent or substantially suppress nausea and vomiting. As used herein, the terms "antiemetics" and "nausea suppressants" are used interchangeably to refer to pharmaceutically acceptable substances that suppress the symptoms of nausea. As described below, antiemetics may be categorized according to their structure or principle of action. In addition to the ganglion stimulating alkaloids listed above, other anti-emetics such as antidopaminergic agents such as

In addition to the ganglion stimulant alkaloids listed above, other antiemetics such as, for example, antidopaminergic agents such as metoclopramide and phenothiazines such as chlorpromazine, prochlorperazine, pipamazine, thiethylperazine, oxypendil hydrochloride, promazine, propazine, triazolazine, triazepromazine can be used in combination with apomorphine. acetophenazine, butaperazine, carfenazine, flufenazine, perpenazine, thiopropazate, trifluoperazine, mesoridazine, piperactazine, thioridazine, pipothiazine, pipothiazine palmitate, chlorprothixin, thiothixin, doxepine, loxapine, trimhepromilazine, methepepilazine, methepepilazine, methepepilazine, methepepilazine, methepdeprazine

Methoclopramide is benzamide. Benzamides are a known class of antiemetics suitable for use in the present invention, and are especially metoclopramide, trimethobenzamide, benzquinamide and others. Also suitable are serotonin (5-hydroxytriptamine or 5-HT) antagonists such as domperidone, odnasterone (commercially available as hydrochloride under the designation Zofran ®) and the like, histamine antagonists such as buclizine hydrochloride, cyclizine hydrochloride, dimenhydrinate (Dramamine) and the like , parasympathetic suppressants such as scopolamine and the like, as well as other antiemetics such as metopimazine, trimethobenzamide, benzquinamine hydrochloride, diphenidol hydrochloride and the like. Another suitable class of antiemetics are meclozins, such as meclozin, chlorocyclizine, cyclizine, and bucclizine. Thus, the composition of the present invention consists of a combination of apomorphine and an antiemetic, which may be any phenothiazine, benzamide, meclozin, serotonin antagonist, hydroxyzine, lobelin sulfate, dimenhydrinate, scopolamine metopimazine, diphenidol hydrochloride, nicotine and salts thereof. Any pharmaceutically acceptable form of antiemetic can be used, eg, a free base or a pharmaceutically acceptable salt (eg, cyclizine hydrochloride, cyclizine acetate, diphenhydramine hydrochloride, meclozin hydrochloride, etc.)

The nausea caused by the side effect of the use of apomorphine can be substantially suppressed by the administration of an antiemetic. In particular, in the treatment of erectile dysfunction in men, it comprises (just prior to sexual activity) the administration of an anti-emetic in an amount so as to suppress the symptoms of nausea associated with the use of apomorphine, and

For the treatment of the present invention, the antiemetics may be administered in combination with apomorphine, or may be administered concurrently with or subsequent to apomorphine, so as to suppress the symptoms of nausea associated with apomorphine administration. By &quot; in combination &quot; is meant the administration of apomorphine and an anti-emetic in a single dose of the dosage form, such as a layered tablet. By &quot; co-administration &quot; is meant administration of the two drugs at once, in independent dosage forms, and &quot; sequential administration &quot; is intended to mean a period of time between apomorphine and antiemetics. The best application is 9 9 9 99 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 ············ 99 99 9 apomorphine and antiemetics in combination, allowing maximum apomorphine doses to be administered with the best achievable results.

When prochlorperazine hydrochloride is used as an antiemetic, the most suitable weight ratio of apomorphine to prochlorperazine hydrochloride is in the range of from about 5 to about 0.25. The amount of prochlorperazine hydrochloride administered sublingually is preferably in the range of from 5 pg / kg body weight to about 200 pg / kg body weight.

Apomorphine and an antiemetic containing the nicotine and domperidone dosage forms are listed in Table 4.

Table 4: sublingual tablets containing apomorphine hydrochloride and an anti-emetic mg / tablet

apomorphine hydrochloride 5.0 β-cyclodextrin 20.0 ascorbic acid 5.0 mannitol 67.9 magnesium stearate 1.0 nicotine 1.0 D&C Yellow Lake 0A

Total 100.0 mg / tablet

apomorphine hydrochloride 5.0 β-cyclodextrin 20.0 ascorbic acid 5.0 mannitol 58.9 magnesium stearate 1.0 domperidone 10.0 D&C Yellow Lake QA

100.0

Total • 0 • · 0 0 0 0 0 0 0 0 0 • 00 0 0 0 ··· * · ··· 0000 00 00 0 mg / tablet

apomorphine 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 / tablet Tablet core: apomorphine hydrochloride 4.0 Acesulfame-K 1.6 microcrystalline cellulose 37.5 peppermint flavor 2.5 chocolate flavor 2,0 citric acid 1,2 hydroxypropylmethylcellulose 4.0 mannitol 24.6 magnesium stearate 1,2 Tablet outer shell: nicotine base 1.0 Acesulfame-K 0.4 microcrystalline cellulose 36.6 hydroxypropylmethylcellulose 4.0 mannitol 47.0 magnesium stearate ± o

150.0

Total:

9 9 9 9 9 9 9 9 9 99 9999 99 9 mg / tablet

apomorphine hydrochloride 4.0 Prochloperazine 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 Tablet core: mg / tablet apomorphine 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 shell: Prochloperazine Hydrochloride 5.0 Acesulfame-K 0.4 microcrystalline cellulose 35.6 hydroxypropylmethylcellulose 2,0 mannitol 46.0 magnesium stearate L0

100.0

Total:

· 99 99 99 99 99 · · · · 99 99 99 99 99 · · · · · ·

To improve body availability, controlled release, and reliable drug delivery, the compositions of the present invention are preferably administered in a sublingual form. Preferably, the sublingual dosage form dissolves within about 2 minutes, more preferably within about 10 minutes. The dissolution time may be longer and may be as long as necessary to maintain the necessary plasma apomorphine concentration. Specifically, the dissolution time in water for the above dosage forms is about 3 to 5 minutes.

The methods and compositions of the present invention are not limited to sublingual administration. The antiemetics of the present invention may be administered to patients using other conventional techniques such as oral administration, intravenous injection, subcutaneous injection, suppository or patches. In addition, patients may receive apomorphine and an anti-emetic by means of separate mechanisms. E.g. apomorphine can be administered as a sublingual tablet while the antiemetic is administered orally.

If an anti-emetic is used, it is usually necessary to administer it before apomorphine administration. This can be achieved not only by administering an antiemetic prior to apomorphine, but also by using multi-stage dosage forms as described below. The present invention is not limited to the particular sequence of application of the amtiemetic and apomorphine dosage forms. If desired, the antiemetic may be administered substantially simultaneously (i.e. at the same time) or even later than apomorphine. E.g. a separate dosage form of the antiemetic may be administered to the patient only after apomorphine administration if there is reason to expect nausea.

It is recommended that the anti-emetic be given to patients at the same time as apomorphine. For this reason, the sublingual tablet comprises apomorphine, an anti-emetic, an osmotically active ingredient, and a swallowable hydrophilic carrier. The most suitable swallowable hydrophilic carrier is microcrystalline cellulose. Other suitable swallowable hydrophilic carriers suitable for use in the present invention are ethyl cellulose, microcrystalline cellulose, polymerized polyvinyl pyrrolidone, calcium phosphate, calcium carbonate, and silica.

Suitable osmotically active ingredients are monosaccharides and disaccharides such as glucose, fructose, mannitol, sorbitol, lactose and sucrose. Glycerin or urea may also be used. Other suitable osmotically active ingredients are sodium hydrochloride, potassium hydrochloride and water-soluble polyelectrolytes. The most suitable osmotically active ingredient is mannitol. Preferred particular variations of the present invention also include a lubricant, such as magnesium stearate.

The present invention describes an apomorphine / antiemetic combination administered in a single dosage form that provides a sustained release of the antiemetic and apomorphine. The form contains an anti-emetic as a relatively fast-releasing drug. a component and apomorphine as a component whose release begins only after the release of the antiemetic. Specifically, in terms of release rates, in one particular variation where the apomorphine / antiemetic combination is present in the dosage form, 50% of the antiemetic is released at least 5 minutes before 50% of the apomorphine is released.

For such sustained release, the present invention describes layered tablets comprising apomorphine in the core and an antiemetic in the outer layer. Table 4, (supra) provides illustrative examples of such tablets. The most suitable illustrative examples of sublingual dosage forms comprising are the apomorphine / antiemetic combinations are shown in Examples 1 to 7. The present invention is further complemented by the following studies, which mainly deal with two aspects. Firstly, because of the placebo effect, patients showing 'psychogenic' impotence (ie patients who are still able to achieve an erection) exhibit improved erectile function and increased sexual desire following sublingual apomorphine (APO) administration. The second aspect is whether the doses of the different dosage forms of sublingual administered APO are effective for this group of patients to achieve an erection sufficient to effect intercourse.

The patients involved were selected from the group of patients suffering from impotence. These patients underwent a detailed urological examination as well as a psychiatric examination. Diagnostic tests for erectile dysfunction are extensive and include the following tests: biochemical profile, biotheziometry, corporate calibration with intracorporeal triple therapy injection, and dynamic cavernosometry. These tests were performed to exclude any arterial, venous or nerve causes of impotence. All patients with any abnormality in these parameters were excluded from this testing. All necessary patient selection criteria for these pilot studies are listed in Table 5 below. Patients who met all necessary criteria were further diagnosed as having impotence caused primarily by psychogenic factors. If no contraindications for dopaminergic medications were known, these patients were admitted to the APO tests.

Patients were informed and consented as required by clinical trials. Patients were informed that they could withdraw from the tests at any time, without any penalties or penalties. They were then tested on at least three days with three independent doses (placebo and two dosage forms) with an interval between tests of at least three days. The following experimental scheme was used for all four pilot studies.

Patients were seated in a comfortable chair connected to an RIGISCAN ™ outpatient measuring system that was set to real-time monitoring mode. Blood pressure, heart rate was determined before APO or placebo and at the end of the test cycle. Before the drug was administered and at the end of each session, each patient completed a questionnaire on their feelings (“Visual”) · “··· ··············

Analogue Scales ”. This questionnaire describes the patient's feelings of well-being, degree of dulling, reassuring, or upsetting, arousal, the amount of yawning and any other changes in feelings and behavior. Patients were given a sublingual dose of placebo or apomorphine without knowing what they were given. The doses of active medication varied depending on the dosage form and mode of administration of apomorphine (liquid or tablet). Due to the possibility of nausea, patients were given ascending doses of apomorphine. However, patients did not know what dose they received. It was explained to all patients that they should not swallow the dosage form but let it dissolve under the tongue so that it could be absorbed. Reported symptoms were recorded by clinical researchers. If the patient felt sick or unwell, he was always asked if he wanted to stop the experiment. If he decided to quit, he was given Gravol 50 mg at that time. Thereafter, the patient was followed by clinics until these side effects were suppressed. He was then asked to appear a week later to receive the same dose, and was instructed to ingest 10 mg of Domperidone before the next test, the day before and the day of the test, in the morning.

Patients who did not feel nausea or any other adverse side effects within 15 minutes after APO or placebo were shown to have standardized erotic video sequences to achieve sexual stimulation. The following video sequences were used: 10 minutes of erotic video, another 5 to 10 minutes of neutral video, and finally 10 minutes of erotic video. The duration of the test session for each dose ranged from 45 to 60 minutes. After determining the most effective dose of apomorphine for individual patients, this dose of APO was given to them for home testing.

Results of pilot studies 1 to 4:

The frequency and potency of the erective reaction were documented separately for each single dose of apomorphine or placebo. The data obtained from the RIGISCAN ™ was stored separately from each session. The erectile response was evaluated by strength (%) and increase (cm) at the tip and at the root of the penis, and an overview of these values was related to the observation of both the erotic and the neutral part of the video (see Table 6 below). A value of less than 16 represents an erective disorder or a weak response to this dose of apomorphine.

In patient observation (VAS) (see Table 9), pre- and post-dosing data were compared and changes in feelings, level of arousal, desire, sedation, yawn rate and behavior were evaluated. Blood pressure and heart rate were also compared before and after administration.

The effects of apomorphine, both reported and observed by clinical researchers, have been divided into two categories: Adverse events (redness, sweating, nausea, vomiting, changes in blood pressure or heart rate) or desired effects (ie relaxation, yawning and erection).

Each study was evaluated according to the above categories.

Pilot study no

The starting dosage form is liquid apomorphine administered sublingually. APO was prepared by clinical pharmacologists and dissolved in a solution of sodium metabisulphate and ethylenediaminic acid (EDTA). The final concentration was 100 mg / ml. The patient was tested in three independent sessions and three independent doses (placebo, 10 mg, 20 mg)

Twelve patients entered the test. In all patients, erectivity disorders have been documented for more than a year. All patients were between 38 and 60 years of age. One patient dropped out of the trial after placebo-induced adverse effects and another dropped out after administration of 20 mg. 10 patients were evaluated. All 10 patients underwent treatment with yohimbine hydrochloride. Eight patients showed negative results in experiments with yohimbine hydrochloride. Six patients were successful in treatment with apomorphine.

Seven (70%) were successful (scores greater than 16 in both erotic and neutral video sequences, Table 6) and three were reported to have failed apomorphine treatment. Six of these seven patients continued testing at home, at doses that showed the highest effects during testing. Three of them needed Domperidone treatment one day before and the morning of use. Home testing ran from two to seven months.

Analysis of patient reports completed before and after ingestion of the apomorphine dose showed the following. At the end of the session, patients were relaxed but not sedated. There were no signs of nervousness or discomfort. There were changes in the number of yawns, with the yawn rate increasing 15 to 40 minutes after dosing and dose-dependent. All patients who were tested showed two to five yawns during the session. These changes were not evident with placebo.

The primary effect on yawning has been documented by patients and observed at both 10 mg and 20 mg doses. Yawning was not affected by placebo. Side effects were also documented at both doses. Two patients who showed no signs of nausea or sweating were compared their profiles, but no common signs were found. The other eight patients, each 10 to 15 minutes after administration, showed signs of varying degrees of nausea (even just vomiting), sweating, dizziness, double or blurred vision, drop in blood pressure and heart rate, and fading. However, these effects were only transient and lasted from 30 to 40 minutes. One patient complained about nasal congestion about 30 minutes after application, which took about 10 minutes. No adverse events were noticeable after placebo.

A preliminary pilot study showed that:

· «4 44 44 44

4 44 4 4 4 · 4 · 4 · 4 4 4 4 4 4

4 4 4 4 4 4 4 4 4

4 4 4 4 9 9 4

444 44 4944

1. Apomorphine is effective in inducing an erective response without increasing libido in patients suffering from psychogenic impotence

2. Both doses of 10 mg and 20 mg induce an erective reaction

3. both doses produce undesirable side effects (nausea, vomiting, sweating, etc.) that are unacceptable for patients and their partners. However, these adverse events can be suppressed using Domperidone.

Pilot studies

The first sublingual tablet form contained 2.5 mg of apomorphine. Patients were tested in three independent sessions and three independent doses (placebo, 2.5 mg, 5 mg).

Eight patients entered this test. Erectivity disorders for more than two years have been documented in all patients. All patients were 38-62 years old. All patients showed negative results in experiments with yohimbine hydrochloride. One patient dropped out of the trial following adverse effects due to the 5 mg dose. There were 7 patients evaluated.

Two (29%) were successful (scores higher than 16, Table 6) and five (71%) were unsuccessful in laboratory testing. Two successful patients entered the home phase of 2.5 mg apomorphine, which was most effective for them and did not cause any adverse effects. Both patients have successfully used apomorphine at home for at least two months.

Analysis of patient reports completed before and after ingestion of the apomorphine dose showed the same trends as after administration of the liquid dosage form. Patients were relaxed but not sedated. There were no signs of nervousness or discomfort. Yawning was increased in patients at both 2.5 mg and 5 mg doses. The number of yawns increased 15 to 40 minutes after dosing. At the dose

2.5 mg all patients who were tested and failed in the tests showed only two yawns during the session. The 5 mg dose did not show adverse effects (nausea, redness, nervousness, blurred vision, sweating, changes in blood pressure and heart rhythm), but increased the amount of yawning to 3 to 5 times per session. The two patients who were successful in the tests were yawning three to five times while sitting at both 2.5 ml and 5 mg. These changes were not evident with placebo.

At the end of pilot study 2, the following conclusions were drawn:

1) a dose-response relationship was found to the response measured as the amount of yawning (lower yawning rates were observed in a weak reaction).

2) Both doses of 2.5 and 5 mg induce an erective response in some patients. The observed 28% success rate was probably due to the use in the laboratory (patients in whom

0 0 0 0 0 0 0 0

0 0 0 0

0 0 0 0 0

000000 00 000 treatment failed, the drug was not passed on for home testing) and probably lack of testing for other possible doses.

3) In some cases, the 5 mg dose produced adverse reactions (ie nausea, redness, etc.) that are unacceptable for patients and their partners. These side effects can be avoided by administering Domperidone or nicotine (eg by smoking).

4) Tablets intended for sublingual administration are well administered and dissolve in approximately 5 minutes.

Pilot studies

Apomorphine was tested in aqueous solution as an intranasal spray (1.25 mg per dose). The first patient was a stressed 53 year old man who had suffered from erectivity disorders for 2 years. This patient underwent unsuccessful yohibine treatment. It was tested in three independent cases with three independent doses (placebo, 2.5 mg, 3.75 mg). The results of his test were evaluated according to the significance level 16 in both situations when watching erotic and neutral video sequences. He showed an increased yawning rate at both doses; 2.5 mg and 3.75 mg, and was successful throughout the duration of the experiment (2 months) until the dose was nonsensically increased. Within 5 minutes after dosing, undesirable effects (nausea and vomiting, confusion, blurred vision, redness, paleness) occurred. After this accident, the patient refused to continue taking the medicine. He said he did not like this pharmaceutical form. Patient # 2 was a 21-year-old man whose erectivity problems lasted for 3 years. He also underwent unsuccessful yohibin treatment. 10 minutes after the administration of the apomorphine dose (2.5 mg) he began to yawn and yawned a total of 5 times. Then he began to feel strong hemodynamic discomfort. These were paling, redness of some parts of the body, nausea and vomiting, blurred vision, lowering blood pressure to 70/50. 20 minutes after feeling these side effects, its parameters stabilized. The patient began to feel good and returned color. This patient was excluded from further testing.

Although intranasal administration was effective for inducing an erection, further testing of this intranasal dosage form was stopped due to the possibility of easy overdose and increased adverse effects. Previous experience suggests that apomorphine should be administered in a relatively safer dosage form.

Pilot studies

Another sublingual dosage form of apomorphine was tested at doses of 3, 4 and 5 mg (Table 1). Patients were tested in three independent sessions and three independent doses. The patients were tested in three independent sessions and three independent doses. (Placebo, 3 mg, 4 mg). A dose containing 5 mg of apomorphine was tested in some patients. The results of this study are shown in Tables 7 and 8 A to C, below.

A total of 12 patients with this formulation were tested. All patients have documented erectile dysfunction for more than 2 years. The patient's age ranged from 39 to 66 years. 3 patients were successful with yohibin and 2 patients had never tried this. Seven patients in this group did not respond to previous treatment with yohimbine. Of this last group of 7 patients, 4 were successfully treated with apomorphine.

Eight (67%) patients were successful with apomorphine treatment. Three (33%) failed apomorphine treatment. Both doses of 3 and 4 mg produced erective reactions. Several patients underwent testing with a sublingual formulation containing 5 mg of apomorphine, but did not prove significantly more effective due to the lower doses used in terms of erective response. All eight patients who were successful in this treatment continued to test the drug at home for one to four months. All patients report good results and do not complain of any side effects.

By analyzing the patient report from the pre and post apomorphine values, it was found that the patients were relaxed but not sedated and had no discomfort after confusion. This new dosage form tested (3, 4 and 5 mg) showed no side effects. Patients felt well after testing and did not describe adverse effects that have traditionally been reported by all patients receiving apomorphine in liquid form or intranasal formulation (Pilot Studies 1 and 3). The effect on the frequency of yawning was also noted at all doses, but the number of yawns was usually very small (1 or 2).

Previous pilot studies that doses of 3 mg, 4 mg, and 5 mg of apomorphine are effective for inducing an erection of the penis and there are no undesirable side effects after application. The home use of these preparations has been positively evaluated by patients and their partners. They were familiar with the fact that the dose should be given approximately 15 minutes before sexual activity. All patients reported that such a dosage is far more acceptable than the standard dosage used.

Table 5: Inclusion / exclusion conditions

Conditions for inclusion

1. ages 18 to 66

2. 1.5 cm increase in volume and 70% strength at night erection

3. ICI causes 1.5 cm volume increase and 70% strength · 4 4 4 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Conditions of disposal

1. ongoing serious or life-threatening illness

2. ECG abnormalities

3. occurrence of epilepsy in the patient or parents

4. abnormalities in liver function or blood counts

5. decreased testosterone, change in LH, increased prolactin

6. High pressure

7. recorded treatment with depression antidepressants, ECT or hospitalization

8. symptoms of cardiac ischemia or myocardial infarction in the last three months

9. diabetes

10. The patient did not give informed consent

11. legal reasons

12. opposition to the Protocol

13. alcohol consumption greater than 45 units per week (average) or drug use

14. Prone to fainting

15. unauthorized contraindications to: drugs affecting sympathetic or parasympathetic drugs, beta blockers, vasodilators, psychotropic substances, tranquillizers, thiazides, Captopril, Verpamil, Furosemide, Spironolactone, Metoclopramide, Cimetidine and other substances affecting erectivity.

Table 6: Reactions to erotic movies

1. Maximum penis circumference achieved circumference (cm) points

- <0.5 cm 0

0.5 - <1.0 cm 1

1.0 - <1.5 cm 2

1.5- <2.0 cm 3

2,0 - <2,5 cm, duration less than 1 minute 4

2,5 or more, duration less than 1 minute 5

2.0 - <2.5 cm, duration at least 1 minute 6

2.5 or more, duration of at least 1 minute 7

3,0 or more, duration of at least 5 minutes 8

3,0 or more, duration of at least 1 minute 9 points

A. maximum achieved penile circumference on the acorn __

B. maximum achieved penile circumference increase at the root __

2. Penis strength strength (%) _ points

0- <10 0

10- <20 1

20- <30 2

30- <40 3

- <50 4

- <60 5

- <70 6

- <80 7

- <90 8

90- <100 9 points

C. maximum achieved penis strength on the acorn _

D. maximum achieved penile strength at the root _

3. Overall points (A, B, C, D) _

A total value of less than 16 indicates ineffectiveness of treatment

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No improvement in the clinical response was seen at the 5 mg dose.

The results of pilot study 4 were analyzed in two ways. The first is to determine the effect on erective functions relative to the effects of placebo. Doses of 3 mg and 4 mg were evaluated in two stimulatory situations, ie. erotic and neutral video. Other values of erective functions were dichotomized with values lower than 16, indicating insufficient erective response.

A. Average erective reaction

Table 8A shows the means and standard deviations of all three assays in both pacing situations. The means were compared using the similarity of the limited linear maximum generalized by a linear model containing two main parameters, treatment and stimulus, and the interaction of treatment with the stimulus. The corresponding variance-covariance structure was determined for the relevant statistical model using the Akaike criterion. Table 8 B shows statistical results of treatment and stimulation effect, treatment-stimulation interaction and orthogonal contrast between erotic and neutral stimulation conditions. The main treatment effect (maximum treatment effect regardless of stimulation conditions) was found to be statistically significant. The main effect of stimulation (maximum effect of stimulation regardless of treatment) is statistically significant. The interaction of treatment and stimulation conditions is not statistically significant. These results show that active treatment is more effective than placebo and the level of effects, although it is statistically stronger when erotic stimulation occurs, does not really depend on stimulation conditions (see Figure 1). The orthogonal (statistically independent) contrast confirms that active treatment is far more effective at a statistically significant level under both erotic and neutral conditions, but also shows that the difference between the 3 and 4 mg dose did not affect the predicted efficacy of the treatment group (12).

B. Determination of Percent Effective Erective Reaction

Figure 2 and Table 8C show that active treatment is statistically significantly superior to placebo treatment, regardless of stimulation conditions, if the determined value of erective responses shows a value indicating treatment success (value of at least 16).

Table 8 A: Average and percent of successful erective response

Stimulation therapy N diameter (SO) percent (SO) Erotic Placebo 12 14.08 (2.69) 33.33 3 mg 12 18.75 (2.50) 66.67 (13.61) 4 mg 12 19.83 66.67 (13.61) Neutral Placebo 12 6.50 16.67 (10) 3 mg 12 11.83 50.00 4 mg 12 13.55 (2.61) 50.00

Table 8 B: ANOVA test for erective response averages

Effect DF F value P Therapy 2.66 11.56 0.0000 Stimulation 1.66 37.14 0.0000 Treatment of stimulation 2.66 0.10 0.9046 Comparison Erotic: Placebo vs. Therapy 1.66 9,30 0,0033 Erotic: 3 mg vs. 4 mg 1.66 0.30 0.5849 Neutral: Placebo vs. Therapy 1.66 13.03 0.0006 Neutral: 3 mg vs. 4 mg 1.66 0.71 0.4014

Table 8 C: Logistic regression of percent treatment success

Effect DF F value P Therapy 2 15.36 0.0005 Stimulation 1 5.14 0,0233 Treatment of stimulation 2 0.10 1.0000 Comparison Erotic: Placebo vs. Therapy 1 9.60 0.0019 Erotic: 3 mg vs. 4 mg 1 0.00 1.0000 Neutral: Placebo vs. Therapy 1 9.60 0.0019 Neutral: 3 mg vs. 4 mg 1 0.00 1.0000

Dose determination studies

The clinical response to sublingual apomorphine was tested in a group of 60 impotent patients without vascularization disorders. Each patient suffered from erectile dysfunction for at least three months, with biothesiometry and cavernosometry values showing normal values. Patients were divided into seven groups. Each group received a previously determined dose of apomorphine below both twenty days in the form of tablets containing apomorphine hydrochloride twenty minutes before intercourse. Seven different doses were evaluated - 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 10 mg. The composition of the tablets is shown in Table 1. Evaluation of the tests was based on patient reports. The response was determined to be positive when the patient stated that his erection was sufficient to successfully initiate intercourse. Side effects such as nausea and vomiting, if any, have also been evaluated. The results of this study are shown in Table 10.

Table 10: Results of the dosing study

Number of patients dose (mg) positive reaction nausea vomiting Number % Number % Number % 5 3 0 0 0 0 0 0 5 4 2 40 1 20 May 1 20 May 10 5 5 50 2 20 May 1 10 10 6 7 70 2 20 May 2 20 May 10 7 7 70 2 20 May 2 20 May 10 8 7 70 3 30 3 30 10 10 8 80 4 40 4 40

The table above shows that at 4 mg dose, 40% of patients showed positive reaction, at 5 mg dose, 50% showed positive reaction, at 6 mg, 7 mg and 8 mg dose, 70% showed positive reaction and at 10 mg dose 80% of patients showed a positive reaction. Unfortunately, the incidence of adverse reactions increased in proportion to the dose. The aforementioned dosage forms of apomorphine have also been studied in detail for use as a diagnostic agent in male patients suffering from erectivity disorders. For diagnostic purposes, at least a 3 mg dose of apomorphine was administered sublingually and the patient was subjected to erotic stimulation, e.g., erotic video film, and the patient response was closely monitored. If it seems • 000 000 0 0 0 0

0 0 0 · · · · · · · · · · · · · · ·

For diagnostic purposes, up to 10 mg of apomorphine can be administered to patients.

The maximum erection of the patient's penis (both length and width at the root) is determined at the maximum erection achieved. The increased values obtained are compared with the previously determined numbers.

Of course, other techniques for determining penile growth and strength may also be used.

Pilot studies

The clinical study, “Absorption and pharmacokinetic properties of apomorphine after sublingual or intravenous administration” compares the absorption and pharmacokinetic profile of the dose of apomorphine given intravenously as a 1 mg dose with sublingual tablets containing apomorphine 4 mg (Table 1) and 8 mg administered in three cases four days during the 12 day study period. As a result, apomorphine tolerance was evaluated in a dose-dependent manner.

The study was evaluated using a one-way three-way analysis. The study population was seven healthy male volunteers between 18 and 35 years of age. The 15 day period prior to testing was followed by a 12 day active treatment cycle. Three doses (one intravenous, two sublingual) were administered to each individual in random order every four days. A total of 36 serum samples were obtained from each individual within the following time-frame: 0, 2, 3, 5, 10, 20, 30 and 45 minutes, 1, 2, 3, 4 and 6 hours post-dose.

Individual health was tested 15 days prior to the start of the study and continued for a week after the last dose. Normal medical tests were performed. Changes in the level of common medically monitored signs such as weight, height, ECG, intravenous pressure, heart rate, serum protein profile, blood count and urine analysis have been carefully recorded. Patient feelings and experiences were recorded and tabulated.

Data analysis

1) Famakokinetic analysis:

Pharmacokinetic analysis was performed using the compartmental and compartmental analysis described below. Nonlinear interactive square regression analysis was performed using the PPHARM computer program (Simed Co., Philadelphia, PA).

A. Compartment analysis:

Plasma apomorphine concentrations in each subject after intravenous administration were placed in a two-compartment open model with an input function described by the following equation.

The plasma apomorphine concentration after intravenous administration is described in equation (1)

C _t = Ae ' ^at + Be' ^pt (2)

The concentration of apomorphine in plasma after administration of sublingual tablets described equation (2) and (3) ~ _ FDK, -kej-tlas) RFA _e) \ (2) ζ Ί _ ~ _e ~ f k (t TLOG) (β)

In the above equations, C _{t is the} plasma apomorphine concentration at time t, F is the relative bioavailability, which was determined to be 1 for intravenous administration, K _and is the first order constant for sublingual absorption, K _e is the first order constant for disappearance from the blood stream, Vj is the applied volume, D is the apomorphine dose, t is the time, t and _g is the delay before the onset of sublingual absorption, ABC is the distribution, disappearance and absorption phase constant, and is the distribution rate constant and β _and is the absorption rate constant. Initial testing of pharmacokinetics parameters after intravenous and sublingual administration was obtained using the PPHARM computer program (Simed Co., Philadelphia, PA). These original studies were used to insert data into equations 1, 2 and 3 using non-linear square regression analysis. The results are shown in Fig. 4. The F (relative bioavailability) value determined for the sublingual application was the result of the compartmental analysis described below.

Visual observation of the plots by analyzing residual data, testing the Akaike's information criterion, and comparing the coefficients between observed and calculated values, it was possible to select an appropriate pharmacokinetic model for each concentration-time pattern. Patient weight was also used as a factor to balance data.

Regression analysis represented the last testing of pharmacokinetic parameters: Vj, K _e , K _a , t | _{and g} from equation (2) and A, B, C, a, b, k, _and t _{and g} from equation (3). Peak plasma concentration (C _max ), peak plasma concentration time (T _max ), V <j (administered volume) were calculated using standard pharmacokinetic equations (Gibaldi, M. and Perrier, D. Pharmacokinetics, 2d edition, Marcel Dekker, Inc.) Nex Yourk (1982).

The C _max and T _max values obtained by visual testing of plasma concentration against the time curve are given for comparison only. Model dependent and independent famracokinetic parameters

equation 3.

B) Compartmental analysis;

The area under the curve AUC inf AUC was determined by adding ₀ to -iast AUC _t .i _part where AUC _t -i _and t = Ct / Re, C _t is the plasma concentration at time t, R _e K _e, constant first order for disappearance. If the plasma concentration versus time given to the subject does not match any equation (1), (2) or (3), K e is determined by linear regression analysis of the log concentration of plasma concentration versus time in the post-absorption phase. The observed parameters C _max and T _max were determined by visual observation.

The relative bioavailability (F) for sublingual application can be calculated from the following equation:

AUC, _y xD _SL

2. Statistical analysis:

Analysis of variance (YES VA) for a three-way cross-study was used to compare the pharmacokinetic parameters (AUC, C _max , t _agg ) as determined above for the 1 mg intravenous dose study and the sublingual apomorphine 4 dose study. mg and 8 mg ANOVA was used to detect other effects not previously apparent from the data obtained, the statistical significance was set to 0.05, the ability of the ANOVA to detect a 20% difference and the observed differences between sublingual and intravenous pharmacokinetics were tested. For the ANOVA assay, the interval between the sublingual and intravenous administration parameters, which were calculated from the variance variance and random grades of the ANOVA model, was determined with 95% probability, and the data were evaluated as the mean with standard deviation in Tables 11-14 below.

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The results summarized in Tables 11-14 and shown graphically in Figure 4 show that the plasma apomorphine concentration decreases very rapidly when administered intravenously. In contrast, the plasma concentration of apomorphine after sublingual administration decreases very slowly to zero.

The importance of these findings is evident, especially when compared to the information on apomorphine administration currently available in the prior art (Table 15). The sublingual administration of apomorphine according to the present invention provides greater plasma concentrations than the administration and dosages described in the previous reports.

Pilot studies

A clinical trial on patient tolerance to increasing doses of apomorphine in sublingual tablets for the treatment of patients with psychogenic erectile dysfunction was tested at this stage. This study compares the effects of sublingual tablets containing placebo, 4, 6, and 8 mg apomorphine on the patient's erectile function as measured by the RIGISCAN ™ device and the patient's own reports describing the results of this study.

50 men with psychogenic erectile dysfunction entered this study. The study was conducted in three phases. In the first phase, the erectile ability of the patient's penis (measured with a RIGISCAN ™ device) was tested. The objects received a placebo tablet and watched a 30 minute erotic video consisting of two 10 minute erotic sequences separated by one 10 minute neutral sequence. Patients then completed a prepared questionnaire (Table 6) about their feelings.

In the second phase, patients returned to the clinic for four independent sessions at one week intervals. Patients received either placebo or 4, 6 and 8 mg of apomorphine at these sessions. Apomorphine doses were administered in ascending order, with placebo being administered at random in only one session. The follow-up session was the same as after placebo in Phase 1. After all four Phase 2 sessions were completed, the most effective and best tolerated dose of apomorphine was determined for each individual patient who then entered Phase 3 - home testing.

The third phase, home testing, lasted five weeks. During this phase, patients achieved satisfaction at least once a week after a single dose of apomorphine. After each act, patients and their partners completed a form relating to sexual function (Table 16). At the end of the five-week trial, patients underwent final testing.

Fifty men suffering from psychogenic erectivity disorders entered this three-phase experiment. The first purpose of this study was to determine the safety and tolerance of apomorphine in the treatment of psychogenic erectile dysfunction. Some adverse events associated with apomorphine administration were

Expected: yawning, vomiting, nausea and cardiovascular disorders. Although nausea is the first undesirable effect that is usually reported, in this extensive trial, nausea occurred in only 13% of all patients at all doses and only in two cases it was a more serious disorder. Vomiting was less than 3%.

Low pressure has been reported as an adverse factor in several patients for inclusion in this study. It was also bradycardia, dizziness, transient unconsciousness and fading. Occasionally, only blood pressure reduction and fading have been reported in this study. Cases of increased sweating and fatigue have also been reported. In one case, increased sweating was observed repeatedly. Some other observed symptoms (such as swelling of the mouth, swallowing disorders of upper respiratory tract infection) have been evaluated as non-treatment-related symptoms.

Changes in serum protein composition and vital signs were consistent with adverse events. However, there were no serious problems or changes except in one case where one of the patients had abnormal liver function of unknown origin. There was no significant effect of the drug on blood and urine analysis.

The effects of apomorphine were determined during the first two phases of the study, when patients were connected to a RIGISCAN ™ monitor. In the first phase, patients received only placebo. In the second phase, patients received 4, 6 and 8 mg of apomorphine and randomly placebo. A significant effect of apomorphine treatment on placebo was found. These results demonstrate that apomorphine has a strong influence on penile functions under both erotic and neutral conditions (Tables 17-19). All summarized values show the therapeutic effect of one or more doses of apomorphine. The RIGISCAN ™ test results show a significant improvement in the treatment of 4, 6 and 8 mg compared to the original dose of placebo. Furthermore, all doses of apomorphine administered in the second phase showed far better results than the second dose of placebo.

The effects in erotic video sequences were stronger than in neutral video sequences (Tables 17-19). The effects in erotic video sequence 1 were better than those in video sequence 2 (Table 17). A strong therapeutic effect was also observed when watching a neutral video sequence. All doses of apomorphine were effective and caused erection (RIGISCAN ™ yielded values greater than 15 in erotic video viewing, Table 17).

During the third phase, patients were evaluated based on their erection satisfaction, the number of sexual acts and successful sexual intercourse from the questionnaire. Tested patients first recorded a number of successful trials and then completed the sections on erection and sexual intercourse at home testing. The success rate was evaluated relative to mg / kg body weight. Some data were evaluated independently from the responses of men and women. Overall

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

The number of successful trials after apomorphine treatment was 69%, which was a significant improvement over the original value of 28% (Tables 20, 21).

The number of successful trials was higher at 6 mg than after 4 mg, but decreased again at 8 mg (Table 20). The highest success rate, 73%, was at 6 mg and both men and women agreed (Table 20). Considering the dose as a function of body weight, it gave the highest successful ratio at a dose of 50 to 74 mg / kg (82% female, 80% male, Table 21). A dose in the range of 35 to 50 mg / kg showed the highest success rate.

The ideal response was observed after administration of 4 or 6 mg of apomorphine in a sublingual tablet, which caused erection in most men (72%) with erectile dysfunction with minimal side effects.

Table 16: Sexual function study home questionnaire - men

Please complete the questionnaire within 12 to 24 hours after applying the sublingual tablet

Initials: ............ No: ............. Date: .................. Time: ................

Tablet application date: .................. time: ................

The lines below provide space for filling our feelings or reactions. Please tick clearly the line that best matches your answer. (There are no bad or good answers. Do not write anything in the boxes on the right side)

1. What was the effect of the tablet on your erection?

No erection Fixed erection sufficient __for intercourse []

2. Have you had sex with your wife / partner [] Yes [] Not after applying the sublingual tablet?

If not, please circle all reasons that made it impossible:

- I didn't get an erection

- erection was insufficient to achieve sexual intercourse

- I feel bad after taking the tablet A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A ·· · ♦

- I decided not to have intercourse

- the wife / partner decided not to have contact

- unpredictable disturbance (eg telephone)

- the wife / partner had menstruation

- other reasons, explanation: ............................................ .................................................. ................

3. How were you satisfied with sexual intercourse?

Very Very dissatisfied_]

4. Please describe any adverse reactions you may have experienced after applying the sublingual tablet. (Please indicate when the reaction started and when did it disappear, and how did you eventually treat this reaction, eg "during nose bleeding on May 1, 1994, I used a cold compress")

5. Other comments? _ Co

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Table 20: Reported achievements in relation to dose

group 4 mg 6 mg 8 mg Total women 5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29 (69.0%) men 5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29 (69.0%)

Table 21: Reported achievements relative to apomorphine dose (pg / kg)

group 35-50 pg / kg 50-74 pg / kg &Gt; 74 pg / kg Total women 3/5 (61.0%) 9/11 (81.7%) 8/14 (61.5%) 20/29 (69.0%) men 4/5 (80.0%) 8/10 (72.7%) 8/14 (61.5%) 20/29 (69.0%)

Selection rules for home testing

1st individual who achieved one successful contact from two attempts was evaluated as successful (based on questionnaire responses)

2. the individual who tested the drug at home, at least twice

3. an individual who tested lower or higher doses if the dose given to him for home testing did not produce the desired effect in combination with an anti-emetic.

4. individuals who completed and returned questionnaires

The use of the present invention is demonstrated by the following examples. These examples are given by way of illustration only and are not to be construed as limiting the invention in any way. One of ordinary skill in the art can envision a number of other variations of the therapeutic composition of the present invention that do not affect the efficacy of apomorphine or antiemetics in any way, and all such variations are within the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Giant. 1 is a graphical representation of the average erective function plotted as the values obtained by the RIGISCAN ™ monitor and as a function of the apomorphine dose.

Giant. 2: Bar graph showing the percent of successful erective placebo function, 3 mg dose of apomorphine and 4 mg dose of apomorphine under erotic or neutral conditions.

Giant. 3 is a bar graph showing yet another comparison of the erective function reported in Pilot Study 4, comparing values obtained from a RIGISCAN ™ monitor after placebo administration, a 3 mg dose of apomorphine and a 4 mg dose of apomorphine under erotic or neutral conditions.

Giant. 4: Graphical comparison of apomorphine time concentration profiles in plasma following intravenous administration of 1 mg (open circles, n = 7), sublingual administration of 4 mg (open squares, n = 4) and sublingual administration of 8 mg (filled squares, n = 4) .

Giant. 5: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 1.

Giant. 6: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 2.

Giant. 7: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 3.

Giant. 8: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 4.

Giant. 9: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 5.

Giant. 10 is a graph showing the dissolution kinetics of apomorphine and antiemetic-nicotine for the tablets of Example 6.

Giant. 11 is a graph showing the dissolution kinetics of apomorphine and antiemetic-nicotine for the tablets of Example 7.

Giant. 12: is a graph showing the dissolution kinetics of apomorphine and antiemetic - nicotine for the tablets of Example 8.

Giant. 13 is a graph comparing the dissolution kinetics of the layered tablets of Example 7 and the dissolution kinetics of commercially available apomorphine containing tablets.

EXAMPLES OF EMBODIMENTS OF THE INVENTION

EXAMPLE 1. Combination of Apomorphine with Nicotine Using the Wet Granulation Technique Composition A.

Tablets containing composition A are prepared from the ingredients listed in Table 22 (hereinafter). Each of the ingredients is accurately weighed as described and passed through a No. 35 sieve (aperture about 0.51 mm) to provide granulation. A solution containing apomorphine hydrochloride, citric acid, half acesulfame K, half peppermint ingredient and half chocolate ingredient is prepared by dissolving these ingredients in a mixture of appropriate volumes of purified water and ethanol, USP. The mixture is stirred until clear and then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302). The resulting mass, referred to as Part A, is stirred in a porcelain bowl at room temperature (20 °) for 30 minutes and then partially dried to form a solid mass. This mass is then granulated by passing it through a No. 50 sieve (0.297 mm particles). The wet granules are dried at a temperature between 60 ° C to 70 ° C for 1 to 1.5 hours. The resulting dried granules are then passed through a No. 35 mesh screen (particles of about 0.51 mm in size).

Table 22: Composition of tablets containing the combination of apomorphine with nicotine

Folder_mg / tablet

Apomorphine hydrochloride Nicotine 1.0 Acesulfem-K 4.0 microcrystalline cellulose 37.5 peppermint ingredients 2.5 chocolate ingredients 2,0 citric acid 3.0 hydroxyproopylmethylcellulose 13.0 mannitol 80.0 magnesium stearate 3.0 TOTAL 150.0

To the rest of the ingredients, in addition to magnesium stearate, said amount of nicotine was added, namely, nicotine was added to the rest of acesulfame K, half of the peppermint ingredient, half of the chocolate ingredient, hydroxypropylmethylcellulose, (methocel E4M, premium), and mannitol. The resulting mixture was designated Part B. Parts A and B were then mixed and mixed for about five minutes in a V-shaped container. Magnesium stearate was then added to the mixture and stirring was continued for about two minutes.

The resulting mixture was removed from the container and transferred to a boulder press with biconvex 5/16 ”tablets. Tablets were prepared using different strengths to produce tablets of different strengths. In general, the stronger the tablet, the slower the release of the active ingredients. For further discussion of methods of preparing sublingual tablets containing apomorphine, see p. U.S. Patent No. 5,624,677 to L-Rashida et. Al., Which is incorporated herein by reference.

The dissolution of apomorphine and nicotine from tablets containing composition A was measured using a USP type II apparatus (USP XXIII) with stirring at 40 rpm. The dissolution medium was 500 mL of 10 mM ammonium phosphate buffer at pH 3.0 ± 0.5 at about 37 ° C. Quantity released • · • 9 • · ·

Apomorphine and nicotine in the medium were measured by determining the absorbance at two different wavelengths, 250 nm and 272 nm, and calculated according to the following two equations:

At259 = (B ²⁵⁹ apo) (Capo) (l) + (with ²⁵⁹ nothing) (C _nothing ) (l)

At272 = (e apo ²⁷²⁾ (Capo) (L) + ⁽²⁷² nothing e) (C _nic) (I) (5) (5)

In the above equations, At259 is the total absorbance at 259 nanometers (nm), At ₂ 72 is the total absorbance at 272 nm, with ²⁵⁹ apo is the molar absorption coefficient of apomorphine at 259 nm, ε nothing is the molar absorption coefficient at 259 nm, ε _apo is apomorphine molar absorption coefficient at 272 nm, e ²⁷² nJ _C is the molar absorption coefficient at 272 nm, C _ap0 is the molar concentration of apomorphine, C _n i _c is the molar concentration of nicotine and 1 is the thickness of the cuvette.

By calculating equations (5) and (6), molar concentrations of apomorphine (C _apo ) and nicotine (C _n j _c ) can be obtained from the total absorbance values (A _T 259 and AT272) according to the following formulas:

ZD '~ \ Λ \ // "ZDV" 2 / z "z / z" Z37 λ

Y-apo (θ nic / M’259 ~ E nic 2 ^ 272) / (- apon nic ~ θ apon), 259

259 "272" 272 "259,259

272 "259" 259 "272 r ¹ - / -272 *" zoy λ \ // z / z " ^{z? Y} " zoy "z / z λ '—apo (£ _apo Λ. 259 ε _ap o ΛΤ272)' \ ε apot nothing “ε apcU nothing) (7) (8)

The dissolution constant (Ki) for apomorphine and nicotine was calculated according to zero order kinetics.

The prepared tablets were compared to commercially available tablets containing soluble apomorphine, due to their dissolution characteristics. The results are shown in Table 26 and Figure 5. Specifically, the time period necessary to release 50% of the drug (T50) and 90% of the drug (T90) for both apomorphine and nicotine was determined and is shown along with the dissolution constant .

Further, the strength of the tablets was tested using a Computest device. These results are shown in Table 26.

Tablets containing composition A release apomorphine relatively slowly compared to the release of the antiemetic, nicotine.

EXAMPLE 2: Combination of Apomorphine with Nicotine Using the Wet Granulation Technique Composition B.

Tablets of Formulation B are prepared from the ingredients listed in Table 22 (above). Each of the ingredients is accurately weighed as described and passed through a No. 35 sieve (aperture about 0.51 mm) to provide granulation. Apomorphine hydrochloride, hydroxypropyl methylcellulose, citric acid, acesulfame K, peppermint ingredient and chocolate ingredient were mixed with the indicated amount of microcrystalline cellulose and dissolved in 25% ethanol in deionized water. The mixture is stirred until clear and then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302). The resulting mass, referred to as Part A, is stirred in a porcelain bowl at room temperature (20 ° C) for 30 minutes and then partially dried to form a solid mass. This mass is then granulated by passing it through a No. 35 sieve (0.51 mm particle size). The wet granules are dried at a temperature between 60 ° C to 70 ° C for a period of from 1 to 1.5 hours and are continuously stirred during drying. The resulting dried granules are then passed through a No. 35 mesh screen (particles of about 0.51 mm in size).

The amount of nicotine was added to the remainder of the ingredients, in particular, nicotine was added to the microcrystalline cellulose and mannitol. The resulting mixture was designated Part B. Parts A and B were then mixed and mixed for about five minutes in a V-shaped container. Magnesium stearate was then added to the mixture and stirring was continued for about two minutes.

The resulting mixture was removed from the container and transferred to a boulder tablet with biconvex 5/16 tablets. Tablets were prepared using different strengths to produce tablets of different strengths. The dissolution of apomorphine and nicotine from tablets containing formulation B was measured and evaluated as in Example 1. The results are shown in Table 26 and Figure 6. Tablets containing formulation B release apomorphine relatively slowly compared to nicotine.

EXAMPLE 3: Layered Tablets Combining Apomorphine with Nicotine - Composition C. The ingredients listed in Table 23 were used to prepare layered tablets with a core comprising apomorphine hydrochloride and an outer layer containing an anti-emetic component - nicotine. All components were first sieved through a No. 35 mesh screen (aperture about 0.51 mm)

Table 23: components of a layered tablet containing apomorphine and nicotine

Folder_mg / tablet

Tablet core:

Apomorphine hydrochloride

4.0

0 0 ·· 00 • 000 0 0 0 0 000

000 000 0 «0 000 000 0000« 0

Acesulfem-K 1.6 microcrystalline cellulose 21.6 peppermint ingredients 1.0 chocolate ingredients 0.8 citric acid 1,2 hydroxyproopylmethylcellulose 4.0 mannitol 24.6 magnesium stearate 1,2 coating tablets Nicotine 1.0 Acesulfame-K 0.4 microcrystalline cellulose 36.6 hydroxyproopylmethylcellulose 4.0 mannitol 47.0 magnesium stearate 1.0 TOTAL 150.0

The tablet core was prepared by mixing apomorphine hydrochloride, citric acid, peppermint ingredient, chocolate ingredient and acesulfame K in a dry state. The resulting mixture was stirred in a V-shaped vessel for 5 minutes.

Hydroxypropylmethylcellulose was then added to the mixture and stirring was continued for another five minutes. Microcrystalline cellulose was then added to the mixture and stirring was continued for another five minutes. Mannitol was then added to the mixture and stirring was continued for another five minutes. Magnesium stearate was then added to the mixture and stirring was continued for two minutes.

The resulting mixture was transferred to a 7/32 ”diameter biconvex tablet press to form tablet cores with a hardness of about 3 kilopascals (Kp).

The outer coating of the tablet containing the antiemetic was prepared by mixing nicotine with the indicated amount of microcrystalline cellulose in a porcelain container. The mixture was stirred until homogeneous. The homogeneous mixture was transferred to a V-shaped vessel, where the indicated amounts of mannitol, hydroxypropyl methylcellulose and acesulfame K were added over 5 minutes with stirring. Finally, magnesium stearate was added and stirring was continued for two minutes. A portion of the nicotine-containing mixture was transferred to a 5/16 ”biconvex tablet press. Next, an already compressed tablet core was inserted into the mold and overlaid with another portion of the nicotine-containing mixture. The nicotine-containing mixture and the already compressed core were finally pressed together to form layered tablets.

The dissolution of apomorphine and nicotine from tablets containing formulation C was measured and evaluated as described in Example 1. The results are shown in Table 26 and Fig. 7. As expected, tablets containing formulation C release nicotine from the outer layer substantially earlier and faster than apomorphine from the tablet core.

EXAMPLE 4: Combination of Apomorphine with Prochlorperazine Using a Wet Granulation Technique, Composition D.

Tablets of Formulation D are prepared from the ingredients listed in Table 24. Each ingredient is accurately weighed as indicated and screened through a No. 35 sieve (aperture about 0.51mm) to ensure granulation. A solution containing apomorphine hydrochloride, citric acid, acesulfame K, peppermint ingredient and chocolate ingredient is prepared by dissolving these ingredients in a mixture of appropriate volumes of purified water and ethanol. The mixture is stirred until bright, then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302) and stirred in a stainless steel vessel at room temperature (20 °) for 30 minutes and then partially dried to form a solid mass. This mass is then granulated by passing it through a No. 60 sieve (0.25 mm particles).

Table 24: Composition of tablets containing the combination of apomorphine with prochlorperazine

Ingredient mg / tablet

Apomorphine hydrochloride Prochlorperazine Hydrochloride 5.0 Acesulfem-K 4.0 microcrystalline cellulose 37.5 peppermint ingredients 2.5 chocolate ingredients 2,0 citric acid 3.0 hydroxyproopylmethylcellulose 10.0 mannitol 68.0 sodium alginate 10.0 magnesium stearate 3.0 TOTAL 150, '

The wet granules are dried at a temperature between 60 ° C to 70 ° C for about 2 hours. The resulting dried granules are then passed through a No. 35 mesh screen (particles of about 0.51 mm in size).

All remaining ingredients of Table 24, except magnesium stearate, were mixed with the dry granules in a V-shaped container. Magnesium stearate was then added to the mixture and stirring was continued for about five minutes.

The resulting mixture was removed from the container and transferred to a boulder press with biconvex 5/16 ”tablets.

Tablets containing composition D were tested as described in Example 1, only the absorbance was measured at 254 nm instead of 259 nm. The results are shown in Table 26 and Figure 8. Tablets containing composition D release apomorphine relatively slower compared to the release of prochlorperazine.

EXAMPLE 5: Combination of Apomorphine with Prochlorperazine by Wet Granulation, Formulation E.

Tablets of Formulation E are prepared from the ingredients listed in Table 24. Each ingredient is accurately weighed as indicated and screened through a sieve with holes. 35 (aperture about 0.51 mm) so as to ensure granulation. Apomorphine hydrochloride, hydroxypropyl methylcellulose, sodium alginate, citric acid, acesulfame K, peppermint ingredient and chocolate ingredient were mixed with the indicated amount of microcrystalline cellulose and dissolved in 25% ethanol in deionized water. The mixture is stirred until clear and then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302). The resulting mass, referred to as Part A, is stirred in a porcelain bowl at room temperature (20 ° C) for 30 minutes and then partially dried to form a solid mass. This mass is then granulated by passing it through a No. 35 sieve (0.51 mm particle size). The wet granules are dried at a temperature between 60 ° C to 70 ° C for a period of from 1 to 1.5 hours and are continuously stirred during drying. The resulting dried granules are then passed through a No. 35 mesh screen (particles of about 0.51 mm in size).

To the remainder of the additives was added the indicated amount of prochlorperazine, in particular, prochlorperazine was added to mannitol. The resulting mixture was designated Part B. Parts A and B were then mixed and mixed for about five minutes in a V-shaped container. Magnesium stearate was then added to the mixture and stirring was continued for about two minutes. The resulting mixture was removed from the container and transferred to a boulder press with biconvex 5/16 ”tablets. Tablets were prepared using different compression forces to produce tablets of different strengths.

φ φ φ • • • · · · φ φ φ φ φ φ φ φ φ · · · φ φ

The dissolution of apomorphine and prochlorperazine from tablets containing formulation E was measured and evaluated as in Example 1. The results are shown in Table 26 and Figure 9. Tablets containing formulation E release apomorphine relatively slowly compared to prochlorperazine.

EXAMPLE 6: Layered Tablets Combining Apomorphine with Prochloreperazine Formulation F.

Tablets containing formulation F were prepared according to the procedure described in Example 3 and using the ingredients listed in Table 25. Prochlorperazine replaced nicotine and sodium alginate was added at the same time as hydroxypropylmethylcellulose.

Table 25: Components of a layered tablet containing apomorphine and nicotine

Component mg / tablet Tablets: Apomorphine hydrochloride 4.0 Acesulfem-K 1.6 microcrystalline cellulose 20.0 peppermint ingredients 1.0 chocolate ingredients 0.8 citric acid 1,2 hydroxypropylmethylcellulose 5.0 mannitol 20.2 sodium alginate 5.0 magnesium stearate 1,2 the coating of the tablet prochlorperazine 1.0 Acesulfame-K 0.4 microcrystalline cellulose 35.6 hydroxyproopylmethylcellulose 2,0 mannitol 46.0 magnesium stearate 1.0 TOTAL 150.0

9 99 9 9 9 9 9 9 9 9 9 9 9 99 9

The dissolution of apomorphine and prochlorperazine from tablets containing formulation F was measured and evaluated as in Example 1. The results are shown in Table 26 and Figure 10. Tablets containing formulation F release apomorphine relatively slowly compared to prochlorperazine.

Example 7: Layered tablets containing a combination of apomorphine with prochloreperazine - composition G.

The ingredients listed in Table 25 were used to prepare layered tablets with a core containing apomorphine hydrochloride and an outer layer containing the anti-emetic component - prochlorperazine. All components were first weighed as indicated and sieved through a No. 35 mesh screen (aperture about 0.51 mm).

The tablet core was prepared by dissolving apomorphine hydrochloride, citric acid, peppermint ingredient, chocolate ingredient and acesulfame K in the corresponding dimensions of acesulfame K and ethanol. The mixture is stirred until clear, then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302) and stirred in a stainless steel vessel at room temperature (20 ° C) for 30 minutes and then partially dried to form solid matter. This mass is then granulated by passing it through a No. 60 sieve (0.25 mm particles).

The wet granules are dried at a temperature between 60 ° C to 70 ° C for about 2 hours. The resulting dried granules are then passed through a No. 35 mesh screen (particles of about 0.51 mm in size).

All remaining ingredients of Table 25, with the exception of magnesium stearate, were mixed with the dry granules in a V-shaped container. Magnesium stearate was then added to the mixture and stirring was continued for about two minutes.

The resulting mixture was compressed into a 60 mg tablet core using a bead tablet press using a 7/32 ”biconvex.

The outer coating of the tablet containing the antiemetic was prepared by dissolving prochlorperazine with acelufam K in a mixture of appropriate volumes of distilled water and ethanol. The mixture is stirred until clear, then absorbed with the indicated amount of microcrystalline cellulose (Avicel 302) and stirred in a stainless steel vessel at room temperature (20 ° C) for 30 minutes and then partially dried to form a solid. mass. This mass is then granulated by passing it through a No. 60 sieve (0.25 mm particles).

The wet granules are dried at a temperature between 60 ° C to 70 ° C for about 2 hours. The resulting dried granules are then passed through a sieve with mesh size. 35 (particles of about 0.51 mm in size).

Mannitol and hydroxypropylmethylcellulose were mixed with granules to be used for the outer coating of tablets in a V-shaped container for 5 minutes. Magnesium stearate was then added to the mixture and stirring was continued for about two minutes.

The layered tablets were prepared by compressing the outer coating around the prepared cores as described in Example 3.

The dissolution of apomorphine and prochlorperazine from tablets containing formulation G was measured and evaluated as described in Example 1. The results are shown in Table 26 and Fig. 11. As expected, tablets containing formulation G release prochlorperazine from the outer layer substantially earlier and faster than apomorphine from the tablet core.

EXAMPLE 8: Comparison of drug release profiles.

The drug release profile of the commercially available soluble tablets containing apomorphine hydrochloride (apomorphine hydrochloride, 6 mg apomorphine hydrochloride in a 60 mg tablet) was evaluated as described in Example 1. The results of this test are graphically shown in Figure 12 and shown in Table 26. Table 26 the time to release 50% of the drug (T50), the time to release 90% of the drug (T90), and the calculated apomorphine dissolution constant and antiemetic (nicotine or prochlorperazine) for each individual example are also shown.

Table 26: Comparison of release profiles and tablet hardness with apomorphine antiemetic

Means T ₅₀ T90 Kdiss T ₅₀ T90 Kdiss r ² hardness, k. AND 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 May 5.66 0.899 2.5 / 4.9 D > 90 > 90 0.54 90 > 90 0.54 0,945 6.5 E 22nd 40 2.76 16 27 Mar: 3.16 0,944 4.2 F 15 Dec 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 Soluble apomorphine tablet 13 30 3.82 0.909 4.2

0 0 · * · · · 0 0 0 · 00000000 000 00

000 00 0000 0 ·

These data show the ability of the compositions of the present invention to release the anemetic earlier and faster than apomorphine. Figures 5 to 13 are graphs based on the values given in Table 26. It is clear and clearly visible also in graphical form that the compositions of the present invention release apomorphine at a much slower rate than commercially available sublingual tablets.

Figure 13 is a summary graph comparing dissolution profiles of commercially available tablets containing apomorphine and tablets containing formulation G (Example 7). This graph very well shows the advantages of a layered tablet capable of releasing drugs sequentially as described in the present invention.

The above examples, discussions, and studies described herein are given by way of illustration only and are not to be construed as limiting. One of ordinary skill in the art will appreciate that there are a number of variations of the present invention which do not depart from the described scope.

Claims (1)

PATENT CLAIMS • · · e · ··· Use of an antiemetic in an amount sufficient to suppress nausea induced by the use of apomorphine, and apomorphine, or a pharmaceutically acceptable salt thereof, in an amount sufficient to induce and maintain an erection to an extent sufficient to effect sexual intercourse to prepare a pharmaceutical composition suitable for treating the disorder. erectivity in men. Use according to claim 1, wherein the anti-emetic is selected from the group consisting of phenothiazines, benzamides, meclizines, serotonin antagonists or pharmaceutically acceptable salts thereof. Use according to claim 2, wherein the antiemetic is prochlorperazine or a pharmaceutically acceptable salt thereof. Use according to claim 1, wherein the antiemetic is selected from the group consisting of hydroxyzine, dimenhydrinate, scopolamine, metopimazine and / or diphenidol hydrochloride. The use according to claim 1, wherein the antiemetic is a node-stimulating alkaloid and apomorphine is administered to the patient in the form of the hydrochloride. The use of claim 5, wherein the antiemetic is nicotine sulfate and the weight ratio of apomorphine hydrochloride to nicotine sulfate administered to the patient ranges from 10 to about 1. The use of claim 5, wherein the apomorphine and the antiemetic are administered simultaneously in a single dose containing from 1 to about 10 mg of apomorphine and about 0.5 to about 2 mg of nicotine sulfate. The use of claim 3, wherein the weight ratio of apomorphine hydrochloride to prochlorperazine hydrochloride administered to the patient is in the range of from about 5 to about 0.25. The use of claim 3, wherein the amount of prochlorperazine hydrochloride is in the range of 5 to about 150 pg per kilogram of patient's body weight. Use according to claim 1, wherein the apomorphine and the antiemetic are administered simultaneously as a sublingual tablet. The use of claim 1, wherein the apomorphine is administered in a sublingual tablet and the antiemetic is administered buccally. • · · · · · · · · · · · · · · · · · · The use of claim 1, wherein the apomorphine-containing pharmaceutical composition is administered by intravenous injection. The use of claim 1, wherein the apomorphine-containing pharmaceutical composition is administered by subcutaneous injection. The use of claim 1, wherein the apomorphine-containing pharmaceutical composition is in the form of a suppository. The use of claim 1, wherein the apomorphine is in the form of the hydrochloride salt. 16. A mixture of apomorphine and an antiemetic, wherein the antiemetic is selected from the group consisting of phenothiazines, benzamides, meclizines, serotonin antagonists, hydroxyzines, lobelinesulfate, dimenhydrinate, scopolamine, metopimazine, diphenidol hydrochloride, nicotine, and acid addition salts thereof. 17. A dosage form comprising an antiemetic as a relatively more rapidly releasing component and apomorphine as a component which only begins to release after the release of the antiemetic. A dosage form according to claim 17, characterized in that it is a layered tablet. The dosage form of claim 17, wherein the antiemetic is selected from the group consisting of phenothiazine, benzamide, meclizine, serotonin antagonist, hydroxyzine, lobelin sulfate, dimenhydrinate, scopolamine, metopimazine, diphenidol hydrochloride, nicotine, and acid addition salts thereof. The dosage form of claim 17, wherein the antiemetic is prochlorperazine. The dosage form of claim 17, wherein the antiemetic is metoclopramide hydrochloride. 22. The dosage form of claim 17, wherein the dosage form is a layered tablet having a core comprising apomorphine and an outer coating comprising an anti-emetic. 23. A dosage form according to claim 17 wherein the time required to release 90% apomorphine is in the range of 25 minutes to 300 minutes. The use of claim 1, wherein the antiemetic is domperodine. 000 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 00000 5J, The use of claim 24, wherein the apomorphine and the antiemetic are administered simultaneously in a single dose containing from 1 to about 10 mg of apomorphine and about 5 to about 20 mg of domperodine.