U.S. patent application number 09/352515 was filed with the patent office on 2001-08-30 for dosage forms and method for ameliorating male erectile dysfunction.
Invention is credited to CLARKE, ANTHONY, GREEN, RICHARD DAVID, JOHNSON, EDWARD STEWART.
Application Number | 20010018069 09/352515 |
Document ID | / |
Family ID | 10806104 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018069 |
Kind Code |
A1 |
JOHNSON, EDWARD STEWART ; et
al. |
August 30, 2001 |
DOSAGE FORMS AND METHOD FOR AMELIORATING MALE ERECTILE
DYSFUNCTION
Abstract
The use of a pharmaceutical composition for oral administration
comprising a carrier and active ingredient selected from a dopamine
agonist, testosterone and mixtures thereof, the composition being
in the form of a fast-dispersing dosage form designed to release
the active ingredient rapidly in the oral cavity for the
manufacture of a medicament for treatment of male erectile
dysfunction.
Inventors: |
JOHNSON, EDWARD STEWART;
(BERKSHIRE, GB) ; CLARKE, ANTHONY; (OXFORDSHIRE,
GB) ; GREEN, RICHARD DAVID; (WILTSHIRE, GB) |
Correspondence
Address: |
DONALD O. NICKEY, ESQ.
CARDINAL HEALTH
7000 CARDINAL PLACE
DUBLIN
OH
43017
|
Family ID: |
10806104 |
Appl. No.: |
09/352515 |
Filed: |
July 12, 1999 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09352515 |
Jul 12, 1999 |
|
|
|
PCT/GB98/00143 |
Jan 16, 1998 |
|
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|
Current U.S.
Class: |
424/464 ;
424/465 |
Current CPC
Class: |
A61P 15/10 20180101;
A61K 45/06 20130101; A61K 31/568 20130101; A61K 31/48 20130101;
A61K 9/0056 20130101; A61K 31/4045 20130101; A61K 31/473 20130101;
A61K 31/485 20130101; A61K 31/485 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/464 ;
424/465 |
International
Class: |
A61K 009/20 |
Claims
1. The use of a pharmaceutical composition for oral administration
comprising a carrier and active ingredient selected from a dopamine
agonist, testosterone and mixtures thereof, the composition being
in the form of a fast-dispersing dosage form designed to release
the active ingredient rapidly in the oral cavity for the
manufacture of a medicament for treatment of male erectile
dysfunction.
2. The use to claim 1 in which the composition is in the form of a
solid fast-dispersing dosage form comprising a network of the
active ingredient and a water-soluble or water-dispersible carrier
which is inert towards the active ingredient, the network having
been obtained by subliming solvent from a composition in the solid
state, that composition comprising the active ingredient and a
solution of the carrier in a solvent.
3. The use according to claim 1 or claim 2 in which the composition
disintegrates within 1 to 60 seconds of being placed in the oral
cavity.
4. The use according to any one of the preceding claims in which
the dopamine agonist is apomorphine or a salt thereof.
5. The use according to any one of the preceding claims in which
the active ingredient is present in an amount of from 0.05 to 50
mg.
6. The use according to any one of the preceding claims which
further includes an anti-emetic.
7. The use according to claim 6 in which the anti-emetic is present
in an amount of from 1 to 120 mg.
8. The use according to any one of claims 4 to 7 which further
includes an opioid antagonist.
9. The use according to claim 8 in which the opioid antagonist is
present in an amount of from 0.5 to 100 mg.
10. The use as claimed in any preceding claim in which the active
ingredient comprises testosterone.
11. The use as claimed in claim 10 in which the testosterone is
present in an amount of 10 to 100 mg.
12. A method of treating male erectile dysfunction which comprises
administering to the oral cavity of a patient a dopamine agonist
and/or testosterone in a fast-dispersing dosage form designed to
release active ingredients rapidly in the oral cavity.
13. A method as claimed in claim 12 which comprises administering a
pharmaceutical composition as defined in any one of claims 2 to 10.
Description
[0001] This invention relates to dosage forms and methods for
ameliorating erectile dysfunction in male patients. More
particularly, this invention relates to the use of fast-dispersing
dosage forms of drugs for amelioration of erectile dysfunction in
male patients.
[0002] A normal erection occurs as a result of a coordinated
vascular event in the penis. This is usually triggered neurally and
consists of vasodilatation 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.
[0003] Male erectile dysfunction (MED) is defined as the inability
to achieve and sustain an erection sufficient for intercourse. In
any given case this 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.
[0004] The effect of apomorphine on penile tumescence in male
patients 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.
[0005] 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.
[0006] WO95/28930 discloses sublingual apomorphine dosage forms,
usually containing about 2.5 to about 10 milligrams of apomorphine,
and dissolving in water within a time period of at least about 2
minutes but less than about 10 minutes, preferably about 3 minutes
to about 5 minutes, have been found to be effective in male
patients suffering from psychogenic erectile dysfunction for the
induction and maintenance of an erection sufficient for intercourse
(i.e. vaginal penetration) without nausea or other undesirable side
effects. The apomorphine is administered sublingually, preferably
about 15 to 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.
[0007] The foregoing sublingual apomorphine dosage forms are also
suitable for screening patients complaining of erectile dysfunction
so as to identify patients of psychogenic etiology.
[0008] PCT/GB96/02020 discloses a pharmaceutical composition for
oral administration comprising a carrier and, as active ingredient,
a dopamine agonist, in which the composition is in the form of a
fast-dispersing dosage form designed to release the active
ingredient rapidly in the oral cavity.
[0009] It was found that such fast-dispersing dosage forms promote
pre-gastric absorption of the active ingredient, that is,
absorption of the active ingredient from that part of the
alimentary canal prior to the stomach. The term "pre-gastric
absorption" thus includes buccal, sublingual, oropharyngeal and
oesophageal absorption. Dopamine agonists absorbed by such
pre-gastric absorption pass straight into the systemic circulatory
system thereby avoiding first pass metabolism in the liver.
Accordingly, bioavailability of dopamine agonists absorbed in this
way may also be increased. This means that the dose of such
dopamine agonists may be reduced whilst still producing the desired
beneficial effects and this decrease in dose will result in a
corresponding reduction of unwanted side effects.
[0010] The pharmaceutical compositions disclosed in PCT/GB96/02020
were developed for the treatment and/or evaluation of Parkinson's
disease.
[0011] It has now been found that fast-dispersing dosage forms
containing a dopamine agonist, such as apomorphine, may be used to
treat male erectile dysfunction.
[0012] According to the present invention there is provided a
pharmaceutical composition for oral administration for the
treatment of male erectile dysfunction comprising a carrier and
active ingredient comprising a dopamine agonist, testosterone or
mixtures thereof, the composition being in the form of a
fast-dispersing dosage form designed to release the active
ingredient rapidly in the oral cavity.
[0013] The use of a fast-dispersing dosage form has several
advantages over the use of conventional sublingual tablets.
[0014] The efficiency of the fast-dispersing dosage form allows low
doses to be employed thereby reducing undesirable side effects,
particularly nausea and vomiting.
[0015] The dosage form acts more quickly than sublingual tablets
which allows the dose to be taken when it is required rather than a
considerable time before sexual activity. This is both
psychologically and socially preferable to sucking a tablet for
several minutes in advance of sexual activity.
[0016] There is a faster offset of action since the active
ingredient is rapidly absorbed rather than absorbed over a
prolonged period of time. The faster offset avoids painful
persistent erection.
[0017] The rapid onset and offset of action is less likely to
induce tolerance to the dopamine agonist.
[0018] One example of a fast-dispersing dosage form is described in
U.S. Pat. No. 4,855,326 in which a melt spinnable carrier agent,
such as sugar, is combined with an active ingredient and the
resulting mixture spun into a "candy-floss" preparation. The spun
"candy-floss" product is then compressed into a rapidly dispersing,
highly porous solid dosage form.
[0019] U.S. Pat. No. 5,120,549 discloses a fast-dispersing matrix
system which is prepared by first solidifying a matrix-forming
system dispersed in a first solvent and subsequently contacting the
solidified matrix with a second solvent that is substantially
miscible with the first solvent at a temperature lower than the
solidification point of the first solvent, the matrix-forming
elements and active ingredient being substantially insoluble in the
second solvent, whereby the first solvent is substantially removed
resulting in a fast-dispersing matrix.
[0020] U.S. Pat. No. 5,079,018 discloses a fast-dispersing dosage
form which comprises a porous skeletal structure of a water
soluble, hydratable gel or foam forming material that has been
hydrated with water, rigidified in the hydrated state with a
rigidifying agent and dehydrated with a liquid organic solvent at a
temperature of about 0.degree. C. or below to leave spaces in place
of hydration liquid.
[0021] Published International Application No. WO 93/12769
(PCT/JP93/01631) describes fast-dispersing dosage forms of very low
density formed by gelling, with agar, aqueous systems containing
the matrix-forming elements and active ingredient, and then
removing water by forced air or vacuum drying.
[0022] U.S. Pat. No. 5,298,261 discloses fast-dispersing dosage
forms which comprise a partially collapsed matrix network that has
been vacuum-dried above the collapse temperature of the matrix.
However, the matrix is preferably at least partially dried below
the equilibrium freezing point of the matrix.
[0023] Published International Application No. WO 91/04757
(PCT/US90/05206) discloses fast-dispersing dosage forms which
contain an effervescent disintegration agent designed to effervesce
on contact with saliva to provide rapid disintegration of the
dosage form and dispersion of the active ingredient in the oral
cavity.
[0024] U.S. Pat. No. 5,595,761 discloses a particulate support
matrix for use in making a rapidly dissolving tablet,
comprising:
[0025] a first polypeptide component having a net charge when in
solution, e.g. non-hydrolysed gelatin;
[0026] a second polypeptide component having a net charge of the
same sign as the net charge of the first polypeptide component when
in solution e.g. hydrolysed gelatin; and
[0027] a bulking agent, and wherein the first polypeptide component
and the second polypeptide component together comprise about 2% to
20% by weight of the particulate support matrix and wherein the
bulking agent comprises about 60% to 96% by weight of the
particulate support matrix; and
[0028] wherein the second polypeptide component has a solubility in
aqueous solution greater than that of the first polypeptide
component and wherein the mass:mass ratio of the first polypeptide
component to the second polypeptide component is from about 1:1/2
to about 1:14; and
[0029] wherein when the support matrix is introduced into an
aqueous environment the support matrix is disintegrable within less
than about 20 seconds.
[0030] The term "fast-dispersing dosage form" therefore encompasses
all the types of dosage form described in the preceding paragraphs.
However, it is particularly preferred that the fast-dispersing
dosage form is of the type described in U.K. Patent No. 1548022,
that is, a solid fast-dispersing dosage form comprising a network
of the active ingredient and a water-soluble or water-dispersible
carrier which is inert towards the active ingredient, the network
having been obtained by subliming solvent from a composition in the
solid state, that composition comprising the active ingredient and
a solution of the carrier in a solvent.
[0031] It is preferred that the composition of the invention
disintegrates within 1 to 60 seconds, more preferably 1 to 30
seconds, especially 1 to 10 seconds and particularly 2 to 8
seconds, of being placed in the oral cavity.
[0032] In the case of the preferred type of fast-dispersing dosage
form described above, the composition will preferably contain, in
addition to the active ingredient, matrix forming agents and
secondary components. Matrix forming agents suitable for use in the
present invention include materials derived from animal or
vegetable proteins, such as the gelatins, dextrins and soy, wheat
and psyllium seed proteins; gums such as acacia, guar, agar, and
xanthan; polysaccharides; alginates; carboxymethylcelluloses;
carrageenans; dextrans; pectins; synthetic polymers such as
polyvinylpyrrolidone; and polypeptide/protein or polysaccharide
complexes such as gelatin-acacia complexes.
[0033] Other matrix forming agents suitable for use in the present
invention include sugars such as mannitol, dextrose, lactose,
galactose and trehalose; cyclic sugars such as cyclodextrin;
inorganic salts such as sodium phosphate, sodium chloride and
aluminium silicates; and amino acids having from 2 to 12 carbon
atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid,
L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
[0034] One or more matrix forming agents may be incorporated into
the solution or suspension prior to solidification. The matrix
forming agent may be present in addition to a surfactant or to the
exclusion of a surfactant. In addition to forming the matrix, the
matrix forming agent may aid in maintaining the dispersion of any
active ingredient within the solution or suspension. This is
especially helpful in the case of active agents that are not
sufficiently soluble in water and must, therefore, be suspended
rather than dissolved.
[0035] Secondary components such as preservatives, antioxidants,
surfactants, viscosity enhancers, colouring agents, flavouring
agents, pH modifiers, sweeteners or taste-masking agents may also
be incorporated into the composition. Suitable colouring agents
include red, black and yellow iron oxides and FD & C dyes such
as FD & C blue No. 2 and FD & C red No. 40 available from
Ellis & Everard. Suitable flavouring agents include mint,
raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla,
cherry and grape flavours and combinations of these. Suitable pH
modifiers include citric acid, tartaric acid, phosphoric acid,
hydrochloric acid and maleic acid. Suitable sweeteners include
aspartame, acesulfame K and thaumatin. Suitable taste-masking
agents include sodium bicarbonate, ion-exchange resins,
cyclodextrin inclusion compounds, adsorbates or microencapsulated
actives.
[0036] It is preferred that the dopamine agonist is selected from
5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[
de,g]quinoline-10,11-diol(apomor-
phine),5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol
(N-propylnoraporphine),
(5'.alpha.)-2-bromo-12'-hydroxy-2'-(1-methylethyl-
)-5'-(2-methylpropyl)ergotaman-3',6',18-trione(bromocriptine),
1-[(6-allylergolin-8.beta.-yl)
carbonyl]-1-[3-(dimethylamino)propyl]-3-et- hylurea (cabergoline),
N'-[(8.alpha.)-9,10-didehydro-6-methylergolin-8-yl]-
-N,N-diethylurea (lisuride), [[(8.beta.)-1,6-dimethylergolin-8-yl]
methyl]-carbamic acid phenylmethyl ester (metergoline),
(4aR)-trans-3,4,4a,5,6,10b-hexahydro-4-propyl-2H-naphth[1,2-b]-1,4-oxazin-
-9-ol(naxagolide),
8-[(methylthio)methyl]-6-propylergoline(pergolide),
2-[4-(1,3-benzodioxol-5-ylmethyl)-1-piperazinyl]pyrimidine
(piribedil), 4-[2-(dipropylamino)ethyl] indolin-2-one (ropinirole),
N,N-diethyl-N'-[ (8.alpha.)-6-methylergolin-8-yl]urea (terguride)
and
(.+-.)-N,N-diethyl-N'-[(3R,4aR*,10aS*)-1,2,3,4,4a,5,10,10a-octahydro-6-hy-
droxy-1-propylbenzo[ g]quinolin-3-yl]sulphamide (quinagolide) salts
thereof and mixtures thereof. More preferably, the dopamine agonist
is apomorphine or a salt, preferably an acid-addition salt,
thereof, especially the hydrochloride salt.
[0037] It is also preferred that the dopamine agonist is present in
the composition in an amount from 0.05 to 10 mg, preferably 0.05 to
5 mg.
[0038] The ability of dopamine receptor agonists to cause penile
erections in rodents has been reported in a review by Lal (Prog.
Neuro-Psychopharmacol. & Biol. Psychiat., 1988, vol 12, pp.
117-164). It has been said that dose, and presumably plasma
concentration, is critical with low doses of apomorphine or
bromocriptine more effective than higher doses. It has been
postulated that the physiological response is mediated through
activation of central D2 receptors, since it has been shown that
domperidone, a peripheral dopamine antagonist, does not interfere
with this response. It is thus believed that plasma levels of
apomorphine which induce dopamine receptor stimulation in
Parkinsonian patients should also be effective in the treatment of
male erectile dysfunction. However, the adverse side-effects, seen
with apomorphine, of nausea, hypotension and sedation should be
minimised by the use of as low a dose as possible.
[0039] Heaton et al, (1995), Urology, 45:200-206 reports patients
with MED were given apomorphine liquid sub-lingually (doses of 10
mg and 20 mg), a sub-lingual tablet (5 mg) or a slow-dissolving
sub-lingual tablet (3 mg and 4 mg). Plasma levels were not
recorded, but all doses and dosage forms were active, although side
effects were a problem in some groups.
[0040] Van Laar et al, 1996, Movement Disorders, 11: 634-638
reported peak plasma levels after administration of sub-lingual
apomorphine tablets (10 mg). The peak plasma levels (ng/ml) were
7.0.+-.0.8 in one experiment and 7.4.+-.1.0 in another. In a third
experiment, the sub-lingual tablets were acidified with ascorbic
acid--the plasma level reduced slightly to 4.3.+-.1.5.
[0041] Since efficacy in the Heaton et al paper was seen with doses
as low as 3 mg, the peak plasma level to achieve this (based on
dose-corrected data from the van Laar paper) would be around 1.3 to
2.2 ng/ml.
[0042] A study on the therapeutic window of apomorphine in 3 groups
of Parkinsonian patients, by the use of stepwise administration of
apomorphine by intravenous infusion, demonstrated that it is
possible to separate the onset of pharmacological activity and
side-effects. Clinical efficacy, in the treatment of symptoms of
Parkinson's disease, was seen at mean serum apomorphine levels
above 3.8-5.0 ng/ml whilst adverse effects were seen at mean serum
apomorphine levels above 12.2-18.5 ng/ml.
[0043] These reports would suggest that treatment of MED with
apomorphine should generally aim for plasma levels of at least 1 to
5 ng/ml and should not be allowed to exceed 10 ng/ml.
[0044] The precise quantity of active ingredient will depend on the
dopamine agonist chosen. Typical dose ranges for the dopamine
agonists mentioned above are as follows:
1 Apomorphine 1-20 mg, preferably 1-10 mg N-propylnoraporphine 1-20
mg, preferably 1-10 mg Bromocriptine 0.5-10 mg, preferably 0.5-5 mg
Cabergoline 0.05-2 mg, preferably 0.05-0.5 mg Lisuride 0.05-2 mg,
preferably 0.05-0.4 mg Metergoline 4-20 mg, preferably 4-8 mg
Naxagolide 0.1-10 mg, preferably 0.1-5 mg Pergolide 0.05-1 mg,
preferably 0.05-0.5 mg Piribedil 1-20 mg, preferably 1-10 mg
Ropinirole 0.25-20 mg, preferably 0.25-5 mg Terguride 1-10 mg,
preferably 1-5 mg Quinagolide 0.1-5 mg, preferably 0.1-1 mg
[0045] Dopamine agonists may produce side effects such as nausea
and vomiting. The composition used in the invention may be
administered in conjunction with an anti-emetic. The anti-emetic
may be conveniently administered in the same composition as the
dopamine agonist.
[0046] Alternatively, the anti-emetic may be administered
separately from the dopamine agonist by any of the usual oral or
parenteral routes of administration, for instance, by tablets,
capsules, suspensions, suppositories, infusions, injections, etc.,
at a suitable time which may be before, after or simultaneously
with administration of the dopamine agonist. It is particularly
preferred that the anti-emetic is formulated in a fast-dispersing
dosage form of the type described above as it is envisaged that
such a fast-dispersing dosage form of the anti-emetic would have
many of the advantages associated with such formulations, such as
increased bioavailability, dose reduction, ease of administration
etc. as described above, although the precise advantages observed
will depend on the nature of the anti-emetic chosen.
[0047] It is preferred that the anti-emetic is present in the
composition in an amount of from 1 to 60 mg. However, the precise
quantity of anti-emetic to be administered to the patient will
depend on the anti-emetic that is selected. Suitable anti-emetics
include anti-histamines, such as trimethobenzamide; peripheral
dopamine antagonists, such as
5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol--
1-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one(domperidone)
and salts thereof, and serotonin (5-HT.sub.3)receptor antagonists,
such as
endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-c-
arboxamide(granisetron),
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imida-
zol-1-yl)methyl]-4H-carbazol-4-one (ondansetron) and 1.alpha.H,
5.alpha.H-tropan-3.alpha.-yl indole-3-carboxylate (tropisetron) and
salts thereof. Of these, domperidone is especially preferred.
[0048] Typical dose ranges for the anti-emetics mentioned above are
as follows:
2 Dotuperidone 20-120 mg, preferably 30-60 mg Granisetron 1-10 mg,
preferably 1-3 mg Ondansetron 4-32 mg, preferably 4-8 mg
Tropisetron 1-10 mg, preferably 1-5 mg N-[p[2-(dimethylamino)-
750-1000 mg ethoxyl]benzyl]-3,4,5, trimethoxybenzamide
[0049] Apomorphine is an opium alkaloid. Thus, as mentioned above,
when apomorphine or another opium alkaloid or synthetic derivative
is selected as the dopamine agonist, further side-effects, such as
sedation, respiratory depression, hypotension, bradycardia,
sweating and yawning may be produced. However, it has been found
that all these side-effects can be treated by administration of an
opioid antagonist in conjunction with the opioid dopamine agonist.
The opioid antagonist may be conveniently administered in the same
composition as the dopamine agonist. Thus, such a composition may
also include an anti-emetic in addition to the dopamine agonist and
opioid antagonist although this is not essential since the opioid
antagonist also counteracts some of the emetic effects of the
dopamine agonist. Alternatively, the opioid antagonist may be
administered separately from the dopamine agonist by any of the
usual oral or parenteral routes of administration at a suitable
time which may be before, after or simultaneously with
administration of the dopamine agonist. It is particularly
preferred that the opioid antagonist is formulated in a
fast-dispersing dosage form of the type described above as it is
envisaged that such a fast-dispersing dosage form of the opioid
antagonist would exhibit many of the advantages associated with
such formulations, such as increased bioavailability, dose
reduction, ease of administration etc. as described above, although
the precise advantages observed will depend on the nature of the
opioid antagonist chosen.
[0050] It is preferred that the opioid antagonist is present in the
composition in an amount of from 0.5 to 100 mg, more preferably 0.5
to 50 mg. However, the precise quantity of opioid antagonist to be
administered to the patient will depend on the opioid antagonist
that is chosen. Suitable opioid antagonists include
4,5-epoxy-3,14-dihydroxy-17-(2-propen- yl)morphinan-6-one(naloxone)
and 17-(cyclopropylmethyl)-4,5-epoxy-3,14-dih-
ydroxymorphinan-6-one (naltrexone) and salts, particularly
acid-addition salts and, especially, the hydrochloride, thereof. A
typical dose range for naloxone is 0.25-10 mg, and for naltrexone
is 10-100 mg.
[0051] Alteration in endocrine function represents about one third
of the total organic causes of male erectile dysfunction as
reported in Aversa A et al, 1995, Mol Androl 7, 3-4. The
administration of testosterone in the fast-dispersing dosage form
assists in ameliorating this condition. A typical dosage range for
oral administration of testosterone is 10 to 100 mg, preferably 10
to 50 mg. The composition may contain testosterone alone or in
combination with a dopamine agonist.
[0052] The invention is further illustrated by the following
Examples.
EXAMPLE 1
Preparation of a Fast-Dispersing Dosage Form of Apomorphine
[0053] (a) Preparation of Apomorphine Hydrochloride 2.0%
Dispersion
[0054] Gelatin (792 g) and mannitol (594 g) were dispersed in a
portion of purified water (16 kg) by mixing thoroughly in the bowl
of a vacuum mixer. The mix was then heated to 40.degree.
C..+-.2.degree. C. and homogenised for ten minutes. The mix was
cooled down to room temperature (20-24.degree. C.). When cooled the
apomorphine hydrochloride (360 g) was added. The mix was
homogenised to ensure dissolution of the drug. Citric acid (166.32
g) was added gradually with stirring, to adjust the solution pH to
3.0. The remaining water (87.68 g) was added to the mixer and the
bulk mix homogenised to ensure dissolution was complete.
[0055] (b) Preparation of Apomorphine Hydrochloride 10 mg Units
[0056] 500mg of the apomorphine hydrochloride 2.0% dispersion
formed in (a) above was dosed into each one of a series of
pre-formed blister pockets having a pocket diameter of 16 mm. The
blister laminate comprised 200 .mu.m PVC coated with 40 g per
square meter PVdC. The product was frozen immediately in a liquid
nitrogen freeze tunnel. The frozen product was then stored below
-20.degree. C. for a minimum of 12 hours prior to freeze-drying in
a freeze drier using a drying temperature of +10.degree. C. and a
chamber pressure of 0.5 mbar. The freeze dried units were then
inspected for the presence of critical defects and the remainder of
the batch sealed with lidding foil consisting of a paper/foil
laminate (20 .mu.m aluminium). Each blister was then coded with a
batch number and overwrapped in a preformed sachet by placing the
blister in the sachet and sealing the open end of the sachet
completely. Each sachet was then labelled with the product name,
batch number, date of manufacture and suppliers name.
[0057] Each dosage unit had the following composition:
3 Parts by % by weight of Ingredient Weight composition Purified
water USP/EP* 446.880 89.4 Apomorphine HCl BP/EP 10.000 2.0 Gelatin
EP/USNF 22.000 4.4 Mannitol EP/USP 16.500 3.3 Citric Acid EP/USP
4.620 0.9 Total (pH = 3) 500.000 100.0 *Signifies removed during
the lyophilisation process.
EXAMPLE 2
[0058] The following formulation was prepared using the process
described in Example 1.
4 Parts by % by weight of Ingredient Weight composition Purified
water EP/USP* 433.000 86.60 Apomorphine HCl BP/EP 10.000 2.0
Gelatin EP/USNF 25.000 5.0 Mannitol EP/USP 20.000 4.0 Glycine USP
10.000 2.0 Citric Acid EP/USP 2.000 0.40 Total (pH = 4) 500.000
100.00 *signifies removed during lyophilisation process.
EXAMPLE 3
Comparative Pharmacokinetic Study
[0059] The objective of this study was to compare the
bioavailability of different fast dispersing formulations of
apomorphine hydrochloride, prepared by the method of Example 1,
following administration to six healthy volunteers.
[0060] Due to the emetic properties of apomorphine, subjects were
pre-treated with the anti-emetic domperidone. Following two days of
domperidone pre-treatment, subjects were randomised to receive the
following apomorphine treatments:
[0061] 10 mg Apomorphine HCl (one unit of Example 1)
[0062] 10 mg Apomorphine HCl (one unit of Example 2)
[0063] Blood samples for pharmacokinetic analysis were taken
pre-dose and at intervals for six hours after each dose of
apomorphine. The results are reported in FIG. 1 of the accompanying
drawings. It will be seen that apomorphine is rapidly absorbed from
both formulations of the fast-dispersing dosage form, reaching a
maximum concentration in plasma after about 30 minutes.
[0064] The following examples further exemplify formulations which
can be prepared using the process described in Example 1:
EXAMPLE 4
[0065]
5 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 438.500 87.70 Apomorphine HCl BP/EP 10.000 2.00
Gelatin EP/USNF 25.000 5.00 Mannitol EP/USP 20.000 4.00 Citric Acid
EP/USP 1.500 0.30 Aspartame EP/USNF 2.500 0.50 Peppermint Flavour
2.500 0.50 Total 500.000 100.00 *signifies removed during
lyophilisation process.
EXAMPLE 5
[0066]
6 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 215.000 86.00 Apomorphine HCl BP/EP 10.000 4.00
Gelatin EP/USNF 11.500 4.60 Mannitol EP/USP 10.000 4.00 Citric Acid
EP/USP 1.500 0.60 Aspartame EP/USNF 2.000 0.80 Total 250.000 100.00
*signifies removed during lyophilisation process.
EXAMPLE 6
[0067]
7 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 441.000 88.20 Apomorphine HCl BP/EP 10.000 2.00
Gelatin EP/USNF 25.000 5.00 Mannitol EP/USP 20.000 4.00 Citric Acid
EP/USP 1.500 0.30 Aspartame EP/USNF 2.500 0.50 Total 500.000 100.00
*signifies removed during lyophilisation process.
EXAMPLE 7
[0068]
8 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 425.000 85.00 Apomorphine HCl BP/EP 10.000 2.00
Domperidone 20.000 4.00 Gelatin EP/USNF 20.000 4.00 Mannitol EP/USP
15.000 3.00 Glycine USP 5.000 1.00 Aspartame EP/USNF 2.500 0.50
Peppermint Flavour 2.500 0.50 Total 500.000 100.00 *signifies
removed during lyophilisation process.
EXAMPLE 8
[0069]
9 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 138.2500 92.1667 Lisuride Maleate 0.2000 0.1333
Gelatin EP/USNF 6.0000 4.0000 Mannitol EP/USNF 4.5000 3.0000
Aspartame EP/USNF 0.3000 0.2000 Cherry Flavour 0.7500 0.5000 Total
150.000 100.0000 *signifies removed during lyophilisation
process.
EXAMPLE 9
[0070]
10 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 138.9500 92.6333 Pergolide Mesylate 0.2500 0.1667
Gelatin EP/USNF 6.0000 4.0000 Mannitol EP/USP 4.5000 3.0000
Aspartame EP/USNF 0.3000 0.2000 Total 150.0000 100.0000 *signifies
removed during lyophilisation process.
EXAMPLE 10
[0071]
11 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 226.250 90.50 Bromocriptine Mesylate 2.500 1.00
Gelatin EP/USNF 10.000 4.00 Mannitol EP/USP 7.500 3.00 Aspartame
EP/USNF 1.250 0.50 Cherry Flavour 1.250 0.50 Peppermint Flavour
1.250 0.50 Total 250.000 100.00 *signifies removed during
lyophilisation process.
EXAMPLE 11
[0072]
12 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 137.750 91.8333 Ropinirole 1.000 0.6667 Gelatin
EP/USNF 6.000 4.0000 Mannitol EP/USP 4.500 3.0000 Aspartame EP/USNF
0.750 0.5000 Total 150.000 100.0000 *signifies removed during
lyophilisation process.
EXAMPLE 12
[0073]
13 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 431.500 86.30 Apomorphine HCl BP/EP 10.000 2.00
Naloxone HCl BP/EP 10.000 2.00 Gelatin EP/USNF 20.500 4.10 Mannitol
EP/USP 15.000 3.00 Citric Acid EP/USP 1.500 0.30 Aspartame EP/USNF
3.000 0.60 Grapefruit Flavour 1.000 0.20 Glycine USP 7.500 1.50
Total 500.000 100.00 *signifies removed during lyophilisation
process.
EXAMPLE 13
[0074]
14 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 413.000 82.60 Apomorphine HCl BP/EP 10.000 2.00
Naltrexone HCl 25.000 5.00 Gelatin EP/USNF 22.500 4.50 Mannitol
EP/USP 15.000 3.00 Citric Acid EP/USP 2.500 0.50 Aspartame EP/USNF
5.000 1.00 Raspberry Flavour 2.000 0.40 Glycine USP 5.000 1.00
Total 500.000 100.00 *signifies removed during lyophilisation
process.
EXAMPLE 14
[0075]
15 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 397.250 79.45 Apomorphine HCl BP/EP 20.000 4.00
Naloxone HCl BP/EP 10.000 2.00 Domperidone 20.000 4.00 Gelatin
EP/USNF 22.500 4.50 Mannitol EP/USP 17.500 3.50 Citric Acid EP/USP
1.500 0.30 Lemon Lime Flavour 2.500 0.50 Glycine USP 5.000 1.00
Aspartame EP/USNF 3.750 0.75 Total 500.000 100.00 *signifies
removed during lyophilisation process.
EXAMPLE 15
[0076]
16 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 219.008 87.60 Apomorphine HCl BP/EP 5.000 2.00
Granisetron HCl 1.117 0.45 Gelatin EP/USNF 10.625 4.25 Mannitol
EP/USP 7.500 3.00 Citric Acid EP/USP 1.500 0.60 Mint Flavour 1.500
0.60 Glycine USP 1.250 0.50 Aspartame EP/USNF 2.500 1.00 Total
250.000 100.00 *signifies removed during lyophilisation
process.
EXAMPLE 16
[0077]
17 % by weight Parts by of Ingredient Weight composition Purified
Water EP/USP* 416.0 83.2 Gelatin 18.0 3.6 Mannitol 13.5 2.7
Testosterone undecanoate 50.0 10.0 Aspartame 2.5 0.5 500.00 100.0
*signifies removed during lyophilisation process.
* * * * *