U.S. patent application number 10/440760 was filed with the patent office on 2004-05-13 for method for ameliorating male erectile dysfunction.
Invention is credited to Adams, Michael A., El-Rashidy, Ragab, Heaton, Jeremy P.W., Morales, Alvaro.
Application Number | 20040092493 10/440760 |
Document ID | / |
Family ID | 21933190 |
Filed Date | 2004-05-13 |
United States Patent
Application |
20040092493 |
Kind Code |
A1 |
El-Rashidy, Ragab ; et
al. |
May 13, 2004 |
Method for ameliorating male erectile dysfunction
Abstract
Impotence can be ameliorated without substantial undesirable
side effects by nasal administration of apomorphine, optionally
with an antiemetic agent present in an amount sufficient to
substantially reduce nausea symptoms that may be associated with
the use of apomorphine.
Inventors: |
El-Rashidy, Ragab;
(Deerfield, IL) ; Heaton, Jeremy P.W.; (Gananoque,
CA) ; Morales, Alvaro; (Kingston, CA) ; Adams,
Michael A.; (Kingston, CA) |
Correspondence
Address: |
OLSON & HIERL, LTD.
36th Floor
20 North Wacker Drive
Chicago
IL
60606
US
|
Family ID: |
21933190 |
Appl. No.: |
10/440760 |
Filed: |
May 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10440760 |
May 19, 2003 |
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10044588 |
Oct 23, 2001 |
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6566368 |
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10044588 |
Oct 23, 2001 |
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09606919 |
Jun 29, 2000 |
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6306437 |
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09606919 |
Jun 29, 2000 |
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09102406 |
Jun 22, 1998 |
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6121276 |
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09102406 |
Jun 22, 1998 |
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08546498 |
Oct 20, 1995 |
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5770606 |
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08546498 |
Oct 20, 1995 |
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08231250 |
Apr 22, 1994 |
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Current U.S.
Class: |
514/171 ;
514/289 |
Current CPC
Class: |
A61K 9/0056 20130101;
A61K 31/4045 20130101; A61K 31/485 20130101; A61K 31/506 20130101;
A61K 31/472 20130101; A61K 31/00 20130101; A61P 43/00 20180101;
A61P 1/08 20180101; A61K 49/0004 20130101; A61P 9/02 20180101; A61P
15/10 20180101; A61K 31/44 20130101; A61K 31/473 20130101 |
Class at
Publication: |
514/171 ;
514/289 |
International
Class: |
A61K 031/56; A61K
031/4745 |
Claims
We claim:
1. A method of ameliorating erectile dysfunction in a male patient
which comprises administering to said patient apomorphine or a
pharmaceutically acceptable acid addition salt thereof prior to
sexual activity, in an amount sufficient to induce an erection
adequate for vaginal penetration but less than an amount that
induces nausea and to maintain a plasma concentration of
apomorphine at a level of no more than about 5.5 ng/ml.
2. The method in accordance with claim 1 wherein the plasma
concentration of apomorphine is maintained at a level of about 0.3
to about 4 ng/ml.
3. The method in accordance with claim 1 wherein the plasma
concentration of apomorphine is maintained at a level of about 1 to
about 2 ng/ml.
4. The method in accordance with claim 1 wherein the amount of
apomorphine administered is in the range of about 2.5 milligrams to
about 10 milligrams.
5. The method in accordance with claim 1 wherein the amount of
apomorphine administered is in the range of about 25 to about 75
micrograms per kilogram of body weight.
6. The method in accordance with claim 1 wherein apomorphine is
administered as the hydrochloride salt.
7. The method in accordance with claim 1 wherein the apomorphine is
administered together with an anti-emetic agent.
8. The method in accordance with claim 7 wherein the antiemetic
agent is domperidone.
9. A method of inducing an erection by stimulating dopamine
receptors in the mid-brain region of a patient to cause an erection
without inducing nausea which comprises administering to the
patient apomorphine in a dose containing about 25 to about 60
micrograms of apomorphine per kilogram of body weight and at a rate
so as to maintain a patient's plasma concentration of apomorphine
at a value of no more than about 5.5 nanograms per milliliter
during sexual activity.
10. The method in accordance with claim 9 wherein the patient's
plasma concentration of apomorphine is maintained in the range of
about 0.3 to about 4 nanograms per milliliter during sexual
activity.
11. The method in accordance with claim 9 wherein the patient's
plasma concentration of apomorphine is maintained in the range of
about 1 to about 2 nanograms per milliliter during sexual activity.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of co-pending application
U.S. Ser. No. 10/044,588, filed on Oct. 23, 2001 and now U.S. Pat.
No. 6,566,368, which is a continuation-in-part of U.S. Ser. No.
09/606,919, filed on Jun. 29, 2000 and now U.S. Pat. No. 6,306,437,
which is a continuation of U.S. Ser. No. 09/102,406, filed on Jun.
22, 1998 and now U.S. Pat. No. 6,121,276, which is a
continuation-in-part of U.S. Ser. No. 08/546,498 filed on Oct. 20,
1995 and now U.S. Pat. No. 5,770,606, which in turn is a
continuation-in-part of U.S. Ser. No. 08/231,250, filed on Apr. 22,
1994, abandoned.
FIELD OF THE INVENTION
[0002] 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 male patients and for diagnostic
purposes.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] 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.
[0005] 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).
[0006] Various methods for the treatment of impotence have been
suggested, including external devices, for example, tourniquets
(see U.S. Pat. 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. Pat. 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.
Pat. 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. Pat. No.
5,256,652 to El-Rashidy teaches the use of an aqueous topical
composition of a vasodilator such as papaverine together with
hydroxypropyl-.beta.-cyclodextrin.
[0007] 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.
[0008] 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.
[0009] 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
[0010] 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.
[0011] Nasal spray apomorphine dosage forms, usually containing
about 1 to about 3 milligrams of apomorphine, are effective in male
patients suffering from 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 intranasally, 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.
[0012] The foregoing intranasal apomorphine dosage forms are also
suitable for screening patients complaining of erectile
dysfunction.
[0013] The nausea side effect associated with the use of
apomorphine can be substantially reduced by administration of an
antiemetic agent together with the apomorphine. 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.
[0014] The antiemetic agent is preferably co-administered with the
apomorphine in a single nasal spray 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 by any desired route of administration and
thereafter a nasal spray composition comprising apomorphine.
[0015] A nasal spray dosage form for administering the
antiemetic-apomorphine combination comprises apomorphine, an
antioxidant, and optionally an antiemetic agent, in an aqueous
pharmacologically acceptable liquid vehicle. The preferred
anti-emetic agent is domperidone.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] In the drawings,
[0017] FIG. 1 is a graphical representation of mean erectile
function, expressed as RIGISCAN.TM. monitor value, as a function of
apomorphine dose;
[0018] FIG. 2 is a bar graph depicting the percent successful
erectile function for placebo, 3-milligram apomorphine dose, and
4-milligram apomorphine dose under erotic and neutral
conditions;
[0019] FIG. 3 is a bar graph presenting yet another comparison of
erectile function noted in Pilot Study #4 in terms of RIGISCAN.TM.
monitor score versus placebo, 3 milligrams of apomorphine and 4
milligrams of apomorphine under erotic and neutral conditions;
[0020] FIG. 4 is a graphical representation of a comparison of the
plasma concentration time profiles of apomorphine 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);
[0021] FIG. 5 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent nicotine for the tablets of Example 1;
[0022] FIG. 6 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent nicotine for the tablets of Example 2;
[0023] FIG. 7 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent nicotine for the layered tablets of
Example 3;
[0024] FIG. 8 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent prochlorperazine for the tablets of
Example 4;
[0025] FIG. 9 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent prochlorperazine for the layered tablets
of Example 5;
[0026] FIG. 10 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent prochlorperazine for the layered tablets
of Example 6;
[0027] FIG. 11 is a graph of the dissolution pattern of apomorphine
and the antiemetic agent prochlorperazine for the layered tablets
of Example 7;
[0028] FIG. 12 is a graph of the dissolution of apomorphine for a
sublingual apomorphine tablet as discussed in Example 8; and
[0029] FIG. 13 is a graph comparing the dissolution pattern for the
layered tablets of Example 7 with the dissolution of apomorphine
for a commercially available soluble apomorphine tablet.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0030] Apomorphine is a dopamine receptor agonist that has a
recognized use as an emetic when administered subcutaneously in
about a 5-milligram dose. For the purposes of the present
invention, apomorphine 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.
[0031] 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 apomorphine so as to maintain a
plasma concentration of apomorphine 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 apomorphine administered
sublingually over this time period preferably is in the range of
about 25 micrograms per kilogram (.mu.g/kg) of body weight to about
60 .mu.g/kg of body weight.
[0032] The apomorphine is administered preferably about 15 to about
20 minutes prior to anticipated sexual activity.
[0033] Apomorphine can be represented by the formula 1
[0034] and exists in a free base form or as an acid addition salt.
For the purposes of the present invention apomorphine hydrochloride
is preferred; however, other pharmacologically acceptable moieties
thereof can be utilized as well. The term "apomorphine" as used
herein includes the free base form of this compound as well as the
pharmacologically acceptable acid addition salts thereof. In
addition to the hydrochloride salt, other acceptable acid addition
salts are the hydrobromide, the hydroiodide, the bisulfate, the
phosphate, the acid phosphate, the lactate, the citrate, the
tartarate, the salicylate, the succinate, the maleate, the
gluconate, and the like.
[0035] Illustrative preferred sublingual dosage forms are set forth
in Table I, below.
1TABLE I 150-Milligram Apomorphine Hydrochloride Sublingual Tablets
3-mg Tablet Apomorphine 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 Apomorphine 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 Apomorphine 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-%
[0036] If desired, and in order to facilitate absorption and thus
bioavailability, the presently contemplated dosage forms can also
contain, in addition to tabletting excipients, .beta.-cyclodextrin
or a .beta.-cyclodextrin derivative such as
hydroxypropyl-.beta.-cyclodextrin (HPBCD). Illustrative dosage
forms containing HPBCD are shown in Tables II and III, below.
2TABLE II Apomorphine Hydrochloride Sublingual Tablets With
Hydroxypropyl-.beta.-Cyclodextrin mg/Tab Apomorphine Hydrochloride
4.0 HPBCD 5.0 Ascorbic Acid 10.0 PEG8000 39.5 Mannitol 39.5
Aspartame 2.0 TOTAL 100.0
[0037] Apomorphine may be included in a nasal spray composition
comprising apomorphine and a physiologically tolerable diluent. The
present invention includes apomorphine and salts thereof formulated
into sprayable compositions together with one or more non-toxic,
physiologically tolerable or acceptable diluent, carrier, adjuvant
or vehicle collectively referred to herein as a diluent for
intranasal delivery.
[0038] Nasal spray dosage forms preferably comprise an aqueous
apomorphine solution packaged in a nasal spray device, e.g., a pump
driven spray device or the like, capable of delivering a spray
aliquot that contains apomorphine in an amount sufficient to induce
an erection adequate for vaginal penetration but less than an
amount that induces substantial nausea. The dosage form preferably
is acidic, usually in the pH range of about 3 to 4. Antioxidants
and preservatives can be included in the spray dosage form if
desired.
[0039] These nasal spray compositions can also contain adjuvants
such as preservatives and/or wetting, emulsifying, and dispensing
agents. Inhibition of microorganisms can be achieved by various
antibacterial and antifungal agents, for example, the parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars and sodium
chloride, among others.
[0040] Preferred compositions for intranasal delivery contain a
stabilizer and a surfactant. Among the pharmaceutically acceptable
surfactants are polyoxyethylene castor oil derivatives, such as
polyoxyethylene-glycerol-- triricinoleate, also known as polyoxoyl
35 castor oil (CREMOPHOR EL), or poloxyl 40 hydrogenated castor oil
(CREMOPHOR RH40) both available from BASF Corp.; mono-fatty acid
esters of polyoxyethylene (20) sorbitan, such as polyoxyethylene
(20) sorbitan monolaurate (TWEEN 80), polyoxyethylene monostearate
(TWEEN 60), polyoxyethylene (20) sorbitan monopalmitate (TWEEN 40),
or polyoxyethylene 20 sorbitan monolaurate (TWEEN 20) all available
from ICI Surfactants of Wilmington, Del.); polyglyceryl esters,
such as polyglyceryl oleate; and polyoxyethylated kernel oil
(LABRAFIL, available from Gattefosse Corp.) Preferably, the
surfactant will be between about 0.01% and 10% by weight of the
pharmaceutical composition.
[0041] Among the pharmaceutically acceptable stabilizers are
antioxidants such as sodium sulfite, sodium metabisulfite, sodium
thiosulfate, sodium formaldehyde sulfoxylate, sulfur dioxide,
ascorbic acid, isoascorbic acid, thioglycerol, thioglycolic acid,
cysteine hydrochloride, acetyl cysteine, ascorbyl palmitate,
hydroquinone, propyl gallate, nordihydroguaiaretic acid, butylated
hydroxytoluene, butylated hydroxyanisole, alpha-tocopherol and
lecithin. Preferably, the stabilizer is present in an amount in the
range of about 0.01% and 5% by weight of the composition.
[0042] Chelating agents such as ethylene diamine tetraacetic acid,
its derivatives and salts thereof, e.g, edetate disodium, as well
as dihydroxyethyl glycine, citric acid, tartaric acid, and the like
may also be utilized.
[0043] Illustrative nasal spray compositions are presented in Table
IV, below.
3TABLE IV Nasal Spray Compositions A B C D E Apomorphine.HCl 0.6 g
0.5 g 0.05 g 0.005 g 1 g Ascorbic acid 1 g -- -- 1 g -- Edetate
disodium -- 0.01 g 0.01 g -- -- Sodium bisulfite 0.05 g 0.1 g 0.1 g
0.05 g 0.1 g Sodium chloride 0.75 g 0.75 g -- 0.75 g --
Hydrochloric acid (0.1 N) 0.9 g 0.9 g 0.3 g q.s. q.s. Distilled
water, q.s. 1000 ml 1000 ml 1000 ml 1000 ml 1000 ml pH about 3-4
about 3.3 about 3.8 about 3-4 about 3-4
[0044] Optionally, the nasal spray compositions shown in Table IV
can include an effective amount of an anti-emetic agent such as
domperidone, nicotine, lobeline sulfate, and the like as discussed
in greater detail hereinbelow.
[0045] The onset of nausea can be obviated or delayed by delivering
apomorphine at a controlled rate so as to provide circulating serum
levels and mid-brain tissue levels of apomorphine sufficient for an
erection without inducing substantial nausea. When apomorphine 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 purpose, the weight ratio of apomorphine to
ganglionic agent is in the range of about 300:1 to about 5:1.
[0046] The preferred weight ratio necessarily varies according to
the potency of the agent employed, however. When nicotine is used,
the preferred weight ratio of apomorphine 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 apomorphine preferably contain apomorphine 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 apomorphine 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.
[0047] 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 purposes of the present invention,
ganglionic stimulating alkaloids such as nicotine and lobeline
sulfate serve as antiemetic agents.
[0048] 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.
[0049] In addition to the ganglionic stimulating alkaloids
discussed above, other antiemetic agents that can be used in
conjunction with apomorphine are antidopaminergic agents such as
metoclopramide, and the phenothiazines, e.g., chlorpromazine,
prochlorperazine, pipamazine, thiethylperazine, oxypendyl
hydrochloride, promazine, triflupromazine, propiomazine,
acepromazine, acetophenazine, butaperazine, carphenazine,
fluphenazine, perphenazine, thiopropazate, trifluoperazine,
mesoridazine, piperacetazine, thioridazine, pipotiazine,
pipotiazine palmitate, chlorprothixine, 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.RTM.), 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.
[0050] Accordingly, a composition aspect of the present invention
provides a combination of apomorphine 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.
[0051] 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.)
[0052] 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.
[0053] For treatments according to the present invention, an
antiemetic agent may be co-administered with apomorphine or may be
administered concurrently or sequentially with apomorphine to
substantially reduce the symptoms of nausea associated with the use
of apomorphine. By the term "co-administration" is meant the
administration of both apomorphine and an antiemetic agent to the
patient in a single unit dosage form as, for example, in an aqueous
spray. "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 apomorphine is
preferred and allows for a higher dose of apomorphine with
generally improved response and function.
[0054] When the antiemetic agent prochlorperazine hydrochloride is
used, the preferred weight ratio of apomorphine hydrochloride to
prochlorperazine hydrochloride is in the range of about 5 to about
0.25. The amount of prochlorperazine hydrochloride administered
sublingually preferably is in the range of about 5 .mu.g/kg of body
weight to about 200 .mu.g/kg of body weight.
[0055] Apomorphine with antiemetic-containing dosage forms
including nicotine-containing dosage forms and
domperidone-containing dosage forms are illustrated in Table V,
below.
4TABLE V Apomorphine Hydrochloride Sublingual Tablets Containing an
Antiemetic Agent mg/Tab Apomorphine Hydrochloride 5.0 Ascorbic Acid
5.0 Mannitol 67.9 Magnesium Stearate 1.0 Nicotine 1.0
.beta.-Cyclodextrin 20.0 D&C Yellow 10 Aluminum Lake 0.1 TOTAL
100.0 Apomorphine Hydrochloride 5.0 Ascorbic Acid 5.0 Mannitol 58.9
Magnesium Stearate 1.0 Domperidone 10.0 .beta.-Cyclodextrin 20.0
D&C Yellow 10 Aluminum Lake 0.1 TOTAL 100.0 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 Tablet core:
Apomorphine 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
Apomorphine Hydrochloride 4.0 Prochlorperazine 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: 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 layer: Prochlorperazine 5.0
Acesulfame-K 0.4 Microcrystalline Cellulose 35.6 Mannitol 46.0
Hydroxypropylmethylcellulose 2.0 Magnesium Stearate 1.0 TOTAL
100.0
[0056] For improved bioavailability, controlled release, and
reliable dosage control, the apomorphine containing compositions of
the present invention are preferably administered intranasally. The
preferred nasal spray dosage forms contain about 1 to about 3.75
milligrams of apomorphine preferably about 1.25 to about 2.5
milligrams of apomorphine.
[0057] Antiemetic agents may also 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
apomorphine and the antiemetic agent via different delivery
mechanisms. For example, the apomorphine may be delivered via a
nasal spray, while the antiemetic agent is delivered orally.
[0058] When an antiemetic agent is used, the antiemetic agent is
preferably made available before the apomorphine. This can be
accomplished not only by administering the antiemetic agent before
the apomorphine 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 apomorphine. If desired, the antiemetic agent
may be administered substantially concurrently (i.e., at the same
time as) or even after the apomorphine. For example, a separate
dosage form of an antiemetic agent can be made available to
patients for use after administration of the apomorphine if nausea
symptoms are encountered.
[0059] The antiemetic agent preferably is delivered to the patient
with the apomorphine via a single dosage unit. Provided for this
purpose, a sublingual tablet comprises apomorphine, 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 purposes are ethyl cellulose, microcrystalline cellulose,
cross-linked polyvinyl pyrrolidone, dicalcium phosphate, calcium
carbonate and silica.
[0060] 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.
[0061] One aspect of the present invention provides an
apomorphine/antiemetic combination formulated into a dosage unit
that provides a staggered release of antiemetic agent and
apomorphine. Specifically, a dosage unit includes an antiemetic
agent as a relatively faster release component and apomorphine as a
component released after release of the antiemetic agent has begun.
Defined in terms of release rate, one preferred
apomorphine/antiemetic dosage unit obtains 50 percent release of
the antiemetic agent at least 5 minutes before obtaining 50 percent
release of the apomorphine.
[0062] For this staggered release purpose, the present invention
further provides a layered tablet that comprises a core layer
containing apomorphine and an outer layer containing an antiemetic
agent. Table V (above) as well as the Examples below contain
illustrative compositions for layered tablets.
[0063] Illustrative preferred sublingual dosage forms for
apomorphine/antiemetic combinations are set forth in the Examples
1-7.
[0064] 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 apomorphine (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.
[0065] 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, corporal calibration testing with an
intracorporal 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 VI, 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.
[0066] 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.
[0067] Patients were seated in a comfortable chair and a
RIGISCAN.TM. ambulatory tumescence monitor (Dacomed Corp.,
Minneapolis, Minn.) 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, apomorphine or placebo was administered to the patient
sublingually. Doses of active medication varied on the formulation
of the apomorphine 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.
[0068] 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.
[0069] 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 apomorphine for the patient, he was then offered
APO for domestic trial at that dose.
[0070] Results of Pilot Studies 1 to 4
[0071] The frequency and the magnitude of erectile responses were
documented with each dose of apomorphine or placebo. Data obtained
from the RIGISCAN.TM. 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 VII, below). A score of less than 16 indicated erectile
dysfunction and a poor response to apomorphine at that dose.
[0072] Visual analogue scales (See Table X) 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.
[0073] Effects of apomorphine 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).
[0074] Each pilot study was reviewed under the categories mentioned
above.
[0075] Pilot Study #1
[0076] The initial formulation evaluated was liquid apomorphine
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)
[0077] 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 HCl for erectile
dysfunction. Eight had failed a trial of yohimbine HCl. Of this
group of eight, 6 were successful with apomorphine.
[0078] Seven (70%) were successes (score of no less than 16 on both
neutral and erotic video segments; Table VII) and three (30%) were
categorized as failures with apomorphine. Six out of the seven
successful patients continued on with a domestic trial of
apomorphine at the dose that gave them the best response during
testing. Three required treatment with Domperidone the day before
and morning of apomorphine usage. The range of domestic use varied
from two to seven months.
[0079] Analysis of visual analogue scales pre- and post-dosing with
apomorphine 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.
[0080] 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.
[0081] The foregoing Pilot Study leads to the following
conclusions:
[0082] 1. Apomorphine is effective in inducing erectile episodes
without increasing libido in the "psychogenically" impotent
male.
[0083] 2. Both 10 mg and 20 mg doses produce erectile
responses.
[0084] 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.
[0085] Pilot Study #2
[0086] 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).
[0087] 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 HCl. One patient withdrew from the trial after
experiencing adverse effects at the 5 mg dose. That left a total of
seven evaluable patients.
[0088] Two (29%) were successes (score of no less than 16; Table
VII) and five (71%) were failures during lab testing. The two
successful patients went onto a domestic trial of apomorphine at
the 2.5 mg dose which was the most effective and did not produce
adverse effects. Both patients used apomorphine at home for no less
than two months with satisfactory results.
[0089] Analysis of visual analogue scales pre- and post-dosing with
apomorphine indicated the same trends as with the liquid
apomorphine preparation. Patients were relaxed but not sedated. No
evidence of arousal or anxiousness was noted.
[0090] 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.
[0091] At the end of Pilot Study #2 the following conclusions were
made:
[0092] 1. There appears to be a correlation between the
effectiveness of the dose and yawning response (poor responders
experience less yawning).
[0093] 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.
[0094] 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).
[0095] 4. The sublingual tablets were easy to administer and
dissolved within five minutes.
[0096] Pilot Study #3
[0097] Apomorphine 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.
[0098] 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.
[0099] 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 HCl. Ten minutes post-dosing with apomorphine
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.
[0100] Although the intranasal administration was effective in
eliciting an erection, further testing of this intranasal
formulation of apomorphine was discontinued because of possible
overdose and increased side effects. The foregoing experience
illustrates the need for reliable and relatively safer dosage
forms.
[0101] Pilot Study #4
[0102] New sublingual tablet formulations of apomorphine 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 VIII and IX A-C, below.
[0103] 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
HCl 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 HCl. Of this latter group of seven, four were
successfully treated with apomorphine.
[0104] Eight (67%) have been successful with apomorphine to date.
Four (33%) were failures with apomorphine. 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.
[0105] Analysis of visual analogue scales, both pre- and
post-dosing with apomorphine, 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 apomorphine 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).
[0106] The foregoing pilot study shows that 3-mg, 4-mg and 5-mg
apomorphine doses are effective in 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 dosing approximately fifteen minutes prior to sexual
activity. All patients have stated that this was more acceptable
than dealing with dosing on a routine basis.
5TABLE VI 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: Prolactin 6.
Hypertension requiring treatment. 7. History of depression
requiring treatment with antidepressants, ECT, or hospitalization.
8. Symptomatic ischemic heart disease/or MI within the last three
months. 9. Diabetes. 10. Failure to obtain informed consent. 11.
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, tranquilizers, thiazides,
Captopril, Verapamil, Furosemide, Spironolactone, Metoclopramide,
Cimetidine or other drugs which are likely to influence erectile
function.
[0107]
6TABLE VII 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-<1.5cm. 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
[0108]
7TABLE VIII Summary of Results from Pilot Study #4 in Psychogenic
Patients Apomorphine.HCl Sublingual Tablet PLACEBO 3 Mg Dose
(.mu.g/kg) 4 Mg Dose(.mu.g/kg) 5 Mg Dose (.mu.g/kg) Patient # (Wt.,
kg) Erotic #1 Neutral #1 Erotic #2 Neutral #2 Erotic #3 Neutral #3
Erotic #4 Neutral #4 401 (68.5) 31 28 29 (44) 27 (44) 33 (58) 27
(58) 402 (70.3) 12 4 12 (43) 4 (43) 17 (57) 6 (57) 403 (118) 16 4
22* (25) 5 (25) 22* (34) 25 (34) 404 (83.5) 24 10 26* (36) 17 (36)
25* (48) 17 (48) 405 (78) 11 1 18* (38) 6 (38) 12 (51) 8 (51) 10
(64) 5 (64) 406 (80) 14 5 18* (38) 17 (38) 17* (50) 2 (50) 407
(100) 8 0 18* (30) 4 (30) 10 (40) 3 (40) 408 (86.2) 28 18 32 (35)
21 (35) 34 (46) 22 (46) 409 (93) 2 0 4 (32) 1 (32) 8 (43) 6 (43) 5
(54) 4 (54) 410 (80) 3 0 13 (38) 16 (38) 8 (50) 7 (50) 411 (98) 13
5 26* (31) 23* (31) 24* (42) 20 (42) 412 (73) 7 3 7 (41) 1 (41) 28*
(55) 19* (55) *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.
[0109] 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.
[0110] A. Mean Erectile Function
[0111] Table IX 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 IX 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.
[0112] B. Percent Successful Erectile Function
[0113] FIG. 2 and Table IX 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).
8TABLE IXA 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.
[0114]
9TABLE IXB 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: Restricted maximum likelihood analysis performed
using SAS PROC MIXED.
[0115]
10TABLE IXC Logistic Regression for Percent Successful Erectile
Function EFFECT DF X.sup.2 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.
[0116]
11TABLE X 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)
[0117] Dose Evaluation Study
[0118] 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.
[0119] 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.
[0120] The results of this study are compiled in Table XI,
below.
12TABLE XI Results of Dose Evaluation Study Positive No. of Dosage,
Responses Nausea Vomiting Patients mg No. % No. % No. % 5 3 0 0 0 0
0 0 5 4 2 40 1 20 1 20 10 5 5 50 2 20 1 10 10 6 7 70 2 20 2 20 10 7
7 70 2 20 2 20 10 8 7 70 3 30 3 30 10 10 8 80 4 40 4 40
[0121] 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.
[0122] 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.
[0123] 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.
[0124] Pilot Study #5
[0125] 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 cross-over study design. The tolerance for apomorphine
for each route and each dose administered was determined.
[0126] 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.
[0127] 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.
[0128] Data Analysis
[0129] 1. Pharmacokinetic Analysis
[0130] 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.).
[0131] A. Compartmental Analysis
[0132] 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.
[0133] Plasma apomorphine concentration was described for
intravenous administration data by equation (1):
C.sub.t=Ae.sup.-.alpha.t+Be.sup.-.beta.t (1)
[0134] Plasma apomorphine concentration was described for
sublingual tablet administration by equations (2) and (3): 1 C t =
FDk a V d ( k a - k e ) ( - k e ( t - t lag ) - - k a ( t - t lag )
) ( 2 )
C.sub.t=Ae.sup.-.alpha.(t-t.sup..sub.lag.sup.)+Be.sup.-.beta.(t-t.sup..su-
b.lag.sup.)+Ce.sup.-k.sup..sub.a.sup.(t-t.sup..sub.lag.sup.)
(3)
[0135] In the above equations, C.sub.t is the apomorphine plasma
concentration at time t; F is the relative bioavailability, which
is assumed to be one for intravenous administration; K.sub.a is the
first order rate constant for sublingual absorption; K.sub.e is the
first order rate constant for elimination; V.sub.d is the volume of
distribution; D is the apomorphine dose; t is time; t.sub.lag is
the lag time before onset of sublingual absorption; A, B, C are the
intercepts of the distribution, elimination, and absorption phases,
respectively; .alpha. is the distribution rate constant; .beta. is
the elimination rate constant; and K.sub.a is the absorption rate
constant.
[0136] 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.
[0137] 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.
[0138] The regression analysis provided the final estimates of the
pharmacokinetic parameters: V.sub.d, K.sub.e, K.sub.a, and
t.sub.lag from equation (2), and A, B, C, .alpha., .beta., k.sub.a,
and t.sub.lag from equation (3). The maximum plasma concentration
(C.sub.max), time to maximum plasma concentration (T.sub.max), and
V.sub.d (volume of distribution) were calculated using standard
compartmental pharmacokinetic equations (Gibaldi, M. & Perrier,
D. Pharmacokinetics, 2d edition, Marcel Dekker, Inc. New York,
1982).
[0139] The values for C.sub.max and T.sub.max 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 XII-XV) were
calculated for each patient using the best fit of Equation (3) to
the data.
[0140] B. Noncompartmental Analysis:
[0141] The area under the curve, AUC.sub.0-inf, was determined by
adding the AUC.sub.0-last to the AUC.sub.t-last, where
AUC.sub.t-last=C.sub.t/R.- sub.e, C.sub.t is the plasma
concentration at time.sup.t, and R.sub.e is K.sub.e, the first
order rate constant for elimination.
[0142] If the plasma concentration versus time data for a subject
could not be adequately fit to equation (1), (2) or (3), the
K.sub.e was determined by linear regression analysis of the log
plasma concentration versus time during the post-absorption phase.
Estimates of noncompartmental parameters C.sub.max and T.sub.max
were obtained from visual inspection of the plasma concentration
time curves.
[0143] The relative bioavailability (F) for a sublingual dose was
calculated by the following equation: 2 F = AUC SL * D IV AUC IV *
D SL ( 4 )
[0144] 2. Statistical Analysis:
[0145] An analysis of variance (ANOVA) for a three-way crossover
study design was utilized to compare the pharmacokinetic parameters
(AUC, C.sub.max, and t.sub.lag) 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.
[0146] The data were summarized as the mean.+-.standard deviation
in Tables XII-XV below.
13TABLE XII NONCOMPARTMENTAL PHARMACOLOGIC PARAMETERS (MEAN .+-.
SD) AND RANGE IV Administration 4 mg Dose 8 mg Dose Parameter Mean
.+-.SD Low High Mean .+-.SD Low High Mean .+-.SD Low High Ke
(min.sup.-1) 0.0237 0.0140 0.0091 0.0432 0.0156 0.0138 0.0038
0.0336 0.0056 0.0036 0.00222 0.0102 T.sub.1/2 (min) 39.44 0.219
16.04 76.49 89.18 75.43 20.62 183.60 176.30 112.30 68.09 314.6 Tmax
(min) 2.286 1.254 1.000 5.000 17.50 18.48 5.000 45.00 52.50 85.10
5.000 15.00 Cmax (min) 8.364 3.886 3.400 12.90 0.8375 0.6848 0.3000
0.8500 2.069 2.366 0.5750 1.150 AUC (0-inf) 206.9 45.47 140.8 260.1
31.64 18.62 10.13 55.55 339.9 459.2 15.00 316.6 (min * ng/ml) Cl
(ml/min) 0.0051 0.0012 0.0038 0.0071 0.0456 0.0361 0.0180 0.0988
0.2056 0.2460 0.0253 0.5333 Vd (beta) (ml) 0.2344 0.1532 0.0056
0.4982 4.076 2.053 1.017 5.277 69.09 115.80 7.932 64.27 Vd (SS)
(ml) 0.1942 0.0817 0.1357 0.3401 1.836 0.7112 0.999 2.475 46.30
74.46 6.523 12.42 MRT (min) 40.29 18.90 20.14 75.32 64.25 55.14
15.12 137.5 143.7 148.0 23.29 329.3 F' (% Relative -- -- 0.04
(4.0%) 0.21 (21%) Bioavailability) F' = (AUC.sub.SL *
DOSE.sub.IV)/(AUC.sub.IV * DOSE.sub.SL) Cl = clearance Vd = volume
of distribution @ cotage. Vd (SS) = volume of distribution steady
state MRT = means residual time
[0147]
14TABLE XIII Noncompartmental Pharmacokinetic Parameters (Mean .+-.
SD) for IV Administration (1 mg) n = 7 Subject Subject Range #1 #2
#3 #4 #5 #6 #7 Mean .+-.SD Low High Ke (/min) 0.0432 0.0129 0.0091
0.0419 0.0168 0.0150 0.0268 0.0237 0.0140 0.0091 0.0432 T.sub.1/2
(min) 16.04 53.79 76.49 16.56 41.22 46.18 25.84 39.44 21.92 16.04
76.49 Tmax (min) 2.000 2.000 2.000 2.000 2.000 5.000 1.000 2.286
1.254 1.000 5.000 Cmax (ng/ml) 8.400 11.200 4.150 12.250 12.900
3.400 6.250 8.364 3.886 3.400 12.900 AUC (0-inf) 140.8 255.4 221.5
177.1 224.6 169.0 260.1 206.9 45.47 140.8 260.1 (min * ng/ml) Cl
(ml/min) 0.0071 0.0039 0.0045 0.0056 0.0045 0.0059 0.0038 0.0051
0.0012 0.0038 0.0071 Vd (beta) (ml) 0.1643 0.3039 0.4982 0.0056
0.2648 0.2574 0.1466 0.2344 0.1532 0.0056 0.4982 Vd (SS) (ml)
0.1430 0.1512 0.3401 0.1147 0.2174 0.2574 0.1357 0.1942 0.0817
0.1357 0.3401 MRT (min) 20.14 38.62 75.32 20.32 48.82 43.50 35.31
40.29 18.90 20.14 75.32
[0148]
15TABLE XIV Noncompartmental Pharmacokinetic Parameters (Mean .+-.
SD) for Sublingual Administration (4 mg Dose) n = 4 Subjects Range
#1 #3 #6 #7 Mean .+-.SD Low High Ke (/min) 0.0188 0.0336 0.0060
0.0038 0.0156 0.0138 0.0038 0.0336 T.sub.1/2 (min) 36.78 20.62
115.7 183.6 89.18 75.43 20.62 183.6 Tmax (min) 10.00 10.00 5.000
45.00 17.50 18.48 5.000 45.00 Cmax (ng/ml) 0.8500 1.8000 0.3000
0.4000 0.8375 0.6848 0.3000 0.8500 AUC (0-inf) 10.13 29.25 31.64
55.55 31.64 18.62 10.13 55.55 (min * ng/ml) Cl (ml/min) 0.0988
0.0342 0.0316 0.0180 0.0456 0.0361 0.0180 0.0988 Vd (beta) (ml)
5.241 1.017 5.277 4.769 4.076 2.053 1.017 5.277 Vd (SS) (ml) 1.494
0.999 2.377 2.475 1.836 0.7112 0.999 2.475 MRT (min) 15.12 29.23
75.19 137.47 64.25 55.14 15.12 137.47
[0149]
16TABLE XV Noncompartmental Pharmacokinetic Parameters (Mean .+-.
SD) for Sublingual Administration (8 mg Dose) n = 4 Subjects Range
#2 #3 #4 #6 Mean .+-.SD Low High Ke (/min) 0.0067 0.0032 0.0120
0.0022 0.0056 0.0036 0.0022 0.0102 T.sub.1/2 (min) 104.0 218.4
68.09 314.6 176.3 112.3 68.09 314.6 Tmax (min) 180.0 10.00 15.00
5.000 52.50 85.10 5.000 180.0 Cmax (ng/ml) 5.600 1.150 0.9500
0.5750 2.069 2.366 0.5750 5.600 AUC (0-inf) 996.6 316.6 31.25 15.00
339.9 459.2 15.00 996.6 (min * ng/ml) Cl (ml/min) 0.008 0.0253
0.2560 0.5333 0.2056 0.2460 0.008 0.5333 Vd (beta) (ml) 1.204 7.932
25.15 242.1 69.09 115.8 1.204 242.1 Vd (SS) (ml) 157.9 8.320 6.523
12.42 46.30 74.46 6.523 157.9 MRT (min) 196.7 329.3 25.48 23.29
143.7 148.0 23.29 329.3
[0150]
17TABLE XVI Summary of Pharmacokinetic Parameters for Apomorphine
HCl in Humans PUBLISHED DATA Durif, F. et al., Clin. Neuropharm.
Gancher, S. T., et al. Montastruc, J. L., et al. 16: 157-166
Movement Disorders Clin. Neuropharmacol. THIS STUDY (1933) 6:
212-216 (1991). 14: 432-437 (1991). ROUTE i.v. s.l. s.l. s.l. s.l.
s.l. s.c. i.v. s.l. s.c. # Subjects 7 7 7 7 7 5 5 5 9 9 # Tablets x
n/d 1 .times. 4 1 .times. 8 7 .times. 3 14 .times. 3 3 .times. 6
n/a n/a 10 .times. 3 n/a Strength (mg) Dose (mg/kg) 0.01 0.06 0.114
0.3 0.6 0.25 0.02 0.038 0.42 0.04 Cmax (ng/ml) 8.3 0.83 2.07 7.5
22.7 14.3 19.36 31.2 28 26 T.sub.max (min) 2.2 17.5 52.5 31.5 38.3
45 6.5 6.7 41 18 AUC 207 31.6 340 929 2,277 1,057 592.7 881.1 1,882
837 (min * ng/ml) Cl (l/hr/kg) 4.37 n/d n/d 2.1 1.8 n/d n/d n/d n/d
n/d Vd (l/kg) 3.35 2.33 2.07 3.4 2.8 n/d n/d 0.043 n/d n/d MRT
(min) 40.3 64.2 143.7 128 125 n/d n/d n/d n/d n/d T.sub.1/2 (min)
39.4 89.2 176.3 72 70 n/d n/d n/d n/d n/d Bioavailability (F) n/a
4% 21% 10% 10% 17% n/a n/a n/d n/a n/d = not done n/a = not
applicable *Calculated Clin. Neuropharm. 16: 157-166 (1993)
[0151] The results, summarized in Tables XII-XV 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.
[0152] The importance of these findings is put into perspective
when compared to information on the administration of apomorphine
that is available in the literature (Table XVI). The sublingual
administration of apomorphine by the present invention produced a
lower plasma concentration than the administration and dosage
regimes listed for previous reports.
[0153] Pilot Study #6
[0154] 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.TM. monitoring and
self-reported satisfaction with the treatment results.
[0155] 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.TM. 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 VII)
about their feelings and well-being.
[0156] 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.
[0157] 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 XVII).
Subjects had a final evaluation at the end of the 5-week, home-use
phase.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] The efficacy of APO was evaluated during the first two
phases of the study in which subjects were attached to the
RIGISCAN.TM. 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.
[0162] 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 XVIII-XX). All summed scores showed significant treatment
effects at one or more of the three doses of APO. The overall
RIGISCAN.TM. 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.
[0163] The effects in the erotic video sequences were larger than
the effects in the neutral video sequence (TABLES XVIII-XX).
Effects in erotic video sequence one were larger than the effects
in erotic video sequence two (TABLE XVIII). 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.TM.
reading .gtoreq.15 in the presence of erotic stimulation; TABLE
XVIII).
[0164] 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 .mu.g/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 XXI, XXII).
[0165] The success rate showed numerical increase at tablet
strength from 4 mg to 6 mg, but a decrease at 8 mg (TABLE XXI). The
highest success rate was 73% in both males and females at a tablet
strength of 6 mg (TABLE XXI). When the dosage is examined as a
function of body weight, a dosage range of 50-74 .mu.g/kg gave the
highest success rate (:82%) in females and (80%) in males (Table
XXII). The dosage range of 35-50 .mu.g/kg gave the highest success
rate.
[0166] 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.
18TABLE XVIII Total RIGISCAN .TM. Scores by Phase Mean .+-. SEM
Phase II Phase I Phase II Video Placebo 1 Placebo 2 4 mg 6 mg 8 mg
Erotic 1 11.44 .+-. 1.77 13.38 .+-. 2.05 15.31 .+-. 1.76* 17.09
.+-. 1.64** 19.84 .+-. 1.61** N = 31 - 36 Erotic 2 11.39 .+-. 1.70
13.31 .+-. 1.88 15.26 .+-. 1.72* 16.44 .+-. 1.98* 17.79 .+-. 1.96**
N = 29 - 36 Neutral 7.98 .+-. 1.24 7.49 .+-. 1.26 11.11 .+-. 1.30**
12.76 .+-. 1.12** 11.98 .+-. 1.37** N = 41 - 48 Corresponding
p-values (placebl 1/placebo 2) Erotic 1 -- 0.3274 0.0120 0.0007
0.0001 -- -- 0.1405 0.0166 0.0005 Erotic 2 -- 0.4013 0.0276 0.0196
0.0007 -- -- 0.1907 0.1365 0.0091 Neutral -- 0.6243 0.0230 0.0009
0.0060 -- -- 0.0074 0.0002 0.0017 *Significantly higher than
placebo 1 **Significantly higher than placebo 1 and placebo 2
[0167]
19TABLE XIX Penile Measurements (Maximum Increases Measured by
RIGISCAN .TM.), Erotic Video Sequence #1 Repeated Measures Analysis
of Variance DESCRIPTIVE STATISTICS ADJUSTED Treatment MEAN (LS)
MEAN Site Source N p-value SEM LSMEAN SEM ANALYSIS OF VARIANCE ALL
SITES Placebo #1 36 11.44 1.770 12.22 1.666 Treatment 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 4 mg vs Placebo #1 0.0120 * 8 mg 31 19.84 1.610 19.11
1.745 6 mg vs Placebo #1 0.0007 * SITE #1 ALL TREATMENTS 11 10.76
2.372 11.04 2.498 8 mg vs Placebo #1 0.0001 * Placebo #1 11 9.73
2.854 9.73 2.931 4 mg vs Placebo #2 0.1504 Placebo #2 10 9.00 3.300
9.21 2.996 6 mg vs Placebo #2 0.0166 * 4 mg 11 8.09 2.410 8.09
2.931 8 mg 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 11.71 2.768 11.38 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
[0168]
20TABLE XX Penile Measurements (Maximum Increases Measured by
RIGISCAN .TM.), Neutral Video Sequence Repeated Measures Analysis
of Variance DESCRIPTIVE STATISTICS ADJUSTED (LS) Treatment MEAN
MEAN Site Source N p-value SEM LSMEAN SEM ANALYSIS OF VARIANCE 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 4 mg vs Placebo #1 0.0230 * 8 mg 41 11.98 1.366 12.40 1.331 6
mg vs Placebo #1 0.0009 * SITE #1 ALL TREATMENTS 11 10.56 1.987
10.70 1.789 8 mg vs Placebo #1 0.0060 * Placebo #1 11 8.91 2.470
8.91 2.494 4 mg vs Placebo #2 0.0074 * Placebo #2 10 5.60 2.574
5.68 2.587 6 mg vs Placebo #2 0.0002 * 4 mg 11 10.45 1.965 10.45
2.494 8 mg 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 #4 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 13.11 3.236
[0169]
21TABLE XXI Reported Success by Tablet Strength Group 4 mg 6 mg 8
mg Overall Female 5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29
(69.0%) Male 5/7 (71.4%) 11/15 (73.3%) 4/7 (57.1%) 20/29
(69.0%)
[0170]
22TABLE XXII Reported Success by Apomorphine Dosage (.mu.g/kg)
Group 35-50 .mu.g/kg 50-74 .mu.g/kg >74 .mu.g/kg Overall Female
3/5 (60.0%) 9/11 (81.8%) 8/13 (61.5%) 20/29 (69.0%) Male 4/5
(80.0%) 8/11 (72.7%) 8/13 (61.5%) 20/29 (69.0%) 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.
[0171] 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
[0172] Composition A Tablets were prepared from the ingredients
listed in Table XXIII, 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.degree. 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.degree. C. to 70.degree. 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).
23TABLE XXIII 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
[0173] 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 hydroxypropylmethylcell- ulose (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.
[0174] The final mix was removed from the blender and fed into a
Stoke's single punch tablet press fitted with biconvex {fraction
(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.
[0175] For additional discussion on methods for preparing
sublingual apomorphine tablets see U.S. Pat. No. 5,624,677 to
El-Rashidy et al., which is incorporated here by reference to the
extent that it is not inconsistent.
[0176] 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.degree. 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.sub.T259=(.epsilon..sup.259.sub.apo)(C.sub.apo)(l)+(.epsilon..sup.259.su-
b.nic)(C.sub.nic)(l) (5)
A.sub.T272=(.epsilon..sup.272.sub.apo)(C.sub.apo)(l)+(.epsilon..sup.272.su-
b.nic)(C.sub.nic)(l) (6)
[0177] In the above equations, A.sub.T259 is the total absorbance
at 259 nanometers (nm); A.sub.T272 is the total absorbance at 272
nm; .epsilon..sup.259.sub.apo is the molar absorptivity of
apomorphine at 259 nm; .epsilon..sup.259.sub.nic is the molar
absorptivity of nicotine at 259 nm; .epsilon..sup.272.sub.apo is
the molar absorptivity of apomorphine at 272 nm;
.epsilon..sup.272.sub.nic is the molar absorptivity of nicotine at
272 nm; C.sub.apo is the molar concentration of apomorphine;
C.sub.nic is the molar concentration of nicotine; and 1 is the cell
path length.
[0178] By solving equations (5) and (6), the molar concentration of
apomorphine (C.sub.apo) and nicotine (C.sub.nic) can be calculated
from total absorbance data (A.sub.T259 and A.sub.T272) as
follows.
C.sub.apo=(.epsilon..sup.272.sub.nicA.sub.T259-.epsilon..sup.259.sub.nicA.-
sub.T272)/(.epsilon..sup.259.sub.apo.epsilon..sup.272.sub.nic-.epsilon..su-
p.272.sub.apo.epsilon..sup.259.sub.nic) (7)
C.sub.nic=(.epsilon..sup.272.sub.apoA.sub.T259-.epsilon..sup.259.sub.apoA.-
sub.T272)/(.epsilon..sup.272.sub.apo.epsilon..sup.259.sub.nic-.epsilon..su-
p.259.sub.apo.epsilon..sup.272.sub.nic) (8)
[0179] Dissolution kinetic constants (K.sub.diss) for apomorphine
and nicotine were calculated assuming zero-order release
kinetics.
[0180] The tablets prepared were compared against a commercially
available soluble apomorphine HCl tablet for dissolution
characterization. The results are presented in Table XXVII (below)
and in FIG. 5. Specifically, the time to 50 percent drug release
(T.sub.50) and 90 percent drug release (T.sub.90) for both
apomorphine and nicotine are reported together with dissolution
constants.
[0181] In addition, tablet hardness was measured using a Computest
Tablet Hardness Tester. These results are also reported in Table
XXVII.
[0182] Composition A Tablets released apomorphine relatively slower
as compared to the release of the antiemetic agent, nicotine.
EXAMPLE 2
Apomorphine/Nicotine Combination By Wet Granulation
Technique--Composition B
[0183] Composition B Tablets were prepared from the ingredients
listed in Table XXIII (above). Each ingredient was weighed as
indicated and passed through a #35 mesh screen (sieve opening of
about 0.51 mm) to ensure granulation. Apomorphine 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.degree. 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.degree. C. to 70.degree. 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).
[0184] 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.
[0185] The final mix was removed from the blender and compressed
into tablets using a Stoke's single punch tablet press fitted with
{fraction (5/16)}" diameter biconvex tooling. Tablets were prepared
at various compressional forces, yielding tablets of different
hardness.
[0186] Dissolution of apomorphine and nicotine for Composition B
Tablets was measured and reported as described in Example 1. The
results are presented in Table XXVII (below) and in FIG. 6.
Composition B Tablets released apomorphine relatively slower as
compared to the release of nicotine.
EXAMPLE 3
Apomorphine/Nicotine Layered Tablet Combination--Composition C
[0187] The ingredients listed in TABLE XXIV (below) were used to
prepare a layered tablet having a core portion containing
apomorphine 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).
24TABLE XXIV 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
[0188] The core portion was prepared by dry mixing apomorphine 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.
[0189] The resulting mixture was transferred to a Stoke's tablet
press fitted with {fraction (7/32)}" diameter biconvex tooling to
generate tablet cores with a hardness of about 3 kilopascals
(Kp).
[0190] 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, hydroxypropylmethyl-cellulose, and
acesulfame-K were blended in for about 5 minutes. Magnesium
stearate was then added followed by an additional 2 minutes of
blending.
[0191] A portion of the nicotine mixture was then transferred to
the die of the Stoke's tablet press fitted with {fraction (5/16)}"
biconvex tooling. Next an apomorphine 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.
[0192] Dissolution of apomorphine and nicotine for Composition C
Tablets was measured and reported as described in Example 1. The
results are presented in Table XXVII (below) and in FIG. 7. As
expected, Composition C Tablets released nicotine from their outer
layer relatively sooner and faster than the apomorphine from the
core portion.
EXAMPLE 4
Apomorphine/Prochlorperazine Combination By Wet Granulation
Technique--Composition D
[0193] Composition D Tablets were prepared from the ingredients
listed in Table XXVII (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, 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.degree. 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).
25TABLE XXV 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
[0194] The resulting granules were dried at about 60.degree. C. to
70.degree. 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).
[0195] All remaining 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 5 minutes. The resulting blend was compressed into
tablets using the Stoke's tablet press fitted with {fraction
(5/16)}" biconvex tooling.
[0196] 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 XXVII (below) and
in FIG. 8. Composition D Tablets released apomorphine relatively
slower as compared to the release of prochlorperazine.
EXAMPLE 5
Apomorphine/Prochlorperazine Combination By Wet Granulation
Technique--Composition E
[0197] Composition E Tablets were prepared from the ingredients
listed in Table XXV (above). Each ingredient was weighed as
indicated and passed through a #35 mesh screen (sieve opening of
about 0.51 mm) to ensure granulation. Apomorphine 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.degree. 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.degree. C. to
70.degree. 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).
[0198] Separately, prochlorperazine 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.
[0199] The final mix was removed from the blender and compressed
into tablets using a Stoke's single punch tablet press fitted with
{fraction (5/16)}" diameter biconvex tooling. Tablets were prepared
at various compressional forces, yielding tablets of different
hardness.
[0200] Dissolution of apomorphine and prochlorperazine for
Composition E Tablets was measured and reported as described in
Example 1. The results are presented in Table XXVII (below) and in
FIG. 9. Composition E Tablets released apomorphine relatively
slower as compared to the release of prochlorperazine.
EXAMPLE 6
Apomorphine/Prochlorperazine Layered Tablet
Combination--Composition F
[0201] Composition F Tablets were prepared according to the
instructions presented in Example 3, except that the ingredients of
Table XXVI (below) were used. Prochlorperazine was substituted for
nicotine and the sodium alginate was added in the same step as the
hydroxypropylmethylcellulose.
26TABLE XXVI 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
[0202] Composition F Tablets were evaluated as described for
Example 1. The results are presented in Table XXVII (below) and in
FIG. 10. Composition F Tablets released the antiemetic
prochlorperazine relatively faster than the apomorphine, as
expected.
EXAMPLE 7
Apomorphine/Prochlorperazine Layered Tablet
Combination--Composition G
[0203] The ingredients listed in Table XXVI (above) were used to
prepare a layered tablet having a core portion containing
apomorphine HCL and an outer layer containing the antiemetic agent
prochlorperazine. Each ingredient was weighed as indicated and
passed through a #35 mesh screen (sieve opening of about 0.51 mm)
to ensure granulation.
[0204] The core portion was prepared by dissolving the apomorphine
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.degree. C.) for about 30 minutes. The mixture was partially
dried before granulating with a #60 mesh hand screen.
[0205] The resulting granules were dried at about 60.degree. C. to
70.degree. 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).
[0206] All remaining core ingredients listed in Table XXVI, 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 Stoke's tablet press fitted with
{fraction (7/32)}" biconvex tooling.
[0207] The outer antiemetic layer was prepared by dissolving the
prochlorperazine 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.degree. C.) for about 30 minutes. The mixture was partially
dried before granulating with a #60 mesh hand screen.
[0208] The resulting granules were dried at about 60.degree. C. to
70.degree. 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.
[0209] Layered tablets were then prepared by compressing the
outer-coating granules around tablet cores as described in Example
3.
[0210] Dissolution of apomorphine and prochlorperazine for
Composition G Tablets was measured and reported as described in
Example 1. The results are presented in Table XXVII (below) and in
FIG. 11. As expected, Composition G Tablets released
prochlorperazine from their outer layer relatively sooner and
faster than the apomorphine, which escapes from the core
portion.
EXAMPLE 8
Comparison Of Drug Release Profiles
[0211] The dissolution profile of a commercially available soluble
apomorphine HCl tablet (Apomorphine HCl, 6 mg of Apomorphine 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 XXVII (below).
[0212] Also reported in Table XXVII are the time to 50 percent drug
release (T.sub.50), the time to 90 percent drug release (T.sub.90),
and the calculated dissolution constants of both the apomorphine
and antiemetic agent (nicotine or prochlorperazine) for each
example composition.
27TABLE XXVII Comparison Of Release Profiles And Tablet Hardness
Apomorphine HCL Antiemetic Agent Hardness, Comp. T.sub.50 T.sub.90
K.sub.diss T.sub.50 T.sub.90 K.sub.diss r.sup.2 k.sub.p 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 0.13 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 13 30 3.82 -- -- -- 0.909 4.2 Apo Tablet
[0213] These data demonstrate the ability of the present invention
to release antiemetic agent relatively sooner and faster than the
apomorphine. FIGS. 5 through 13 are graphs generated from the data
presented in TABLE XXVII. Significantly, and well represented in
graphical form, compositions according to the present invention
also release apomorphine at an advantageously slower rate than that
of the commercial sublingual table.
[0214] FIG. 13 is a composite graph of the dissolution profiles for
a commercially available apomorphine 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.
[0215] 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.
* * * * *