U.S. patent application number 10/026492 was filed with the patent office on 2002-10-24 for oral fast-dissolving compositions for dopamine agonists.
Invention is credited to Clarke, Anthony, Green, Richard David, Johnson, Edward Stewart.
Application Number | 20020156056 10/026492 |
Document ID | / |
Family ID | 10806104 |
Filed Date | 2002-10-24 |
United States Patent
Application |
20020156056 |
Kind Code |
A1 |
Johnson, Edward Stewart ; et
al. |
October 24, 2002 |
Oral fast-dissolving compositions for dopamine agonists
Abstract
The present invention discloses 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;
(Ruscombe, GB) ; Clarke, Anthony;
(Henley-on-Thames, GB) ; Green, Richard David;
(Marlborough, GB) |
Correspondence
Address: |
Donald O. Nickey
Cardinal Health, Inc.
7000 Cardinal Place
Dublin
OH
43017
US
|
Family ID: |
10806104 |
Appl. No.: |
10/026492 |
Filed: |
December 24, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10026492 |
Dec 24, 2001 |
|
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09352515 |
Jul 12, 1999 |
|
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6342246 |
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Current U.S.
Class: |
514/171 ;
424/464 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/568 20130101; A61K 31/485 20130101; A61P 15/10 20180101;
A61K 31/48 20130101; A61K 9/0056 20130101; A61K 31/4045 20130101;
A61K 31/473 20130101; A61K 31/485 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/171 ;
424/464 |
International
Class: |
A61K 031/56 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 16, 1998 |
GB |
PCT/GB98/ 00143 |
Jan 17, 1997 |
GB |
9700878.3 |
Claims
What is claimed is:
1. A method for the treatment of male erectile dysfunction
comprising the step of oral administration of a pharmaceutical
composition comprising a carrier and an active ingredient selected
from the group consisting of 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 by disintegrating within 1 to
30 seconds of being placed in the oral cavity; and wherein said
composition is a solid fast-dispersing dosage form comprising a
network of the active ingredient and a carrier.
2. The method of claim 1 in which the dopamine agonist is
apomorphine or a salt thereof.
3. The method of claim 1 in which the active ingredient is present
in an amount of from 0.05 to 50 mg.
4. The method of claim 1 which further includes an anti-emetic.
5. The method of claim 1 in which the anti-emetic is present in an
amount from 1 to 120 mg.
6. The method of claim 1 which further includes an opioid
antagonist.
7. The method of claim 6 in which the opioid antagonist is present
in an amount of from 0.5 to 100 mg.
8. The method of claim 1 in which the active ingredient comprises
testosterone.
9. The method of claim 8 in which the testosterone is present in an
amount of 10 to 100 mg.
10. The method of claim 3 in which further includes an anti-emetic
present in an amount of from 1 to 120 mg.
11. The method of claim 6 in which the active ingredient comprises
testosterone.
12. The method of claim 7 in which the active ingredient comprises
testosterone.
13. The method of claim 11 in which the testosterone is present in
an amount of 10 to 100 mg.
14. The method of claim 1 wherein said matrix forming agent
comprises gelatin.
Description
[0001] This invention relates to pharmaceutical compositions, a
process for preparing such compositions, the use of such
compositions for the treatment and/or evaluation of Parkinson's
disease and products and kits for the administration of a dopamine
agonist and the co-administration of a dopamine agonist and an
anti-emetic and/or opioid antagonist.
[0002] Parkinson's disease is a progressive neurodegenerative
disorder caused by a loss of the cell bodies of dopaminergic
neurons from the substantia nigra and degeneration of nerve
terminals in the striatum resulting in low levels of dopamine in
the substantia nigra and corpus striatum. Parkinson's disease is
characterised by chronic, progressive motor dysfunction and its
main symptoms are tremor at rest, muscle rigidity and a decrease in
the frequency of voluntary movements (hypokinesia) with difficulty
in stopping, starting and turning when walking. A persistent tremor
is superimposed on hypertonicity of opposing muscle groups and
initiation of-movements becomes increasingly difficult and slow. In
advanced stages, patients' movements become virtually "frozen" and
patients are unable to care for themselves. Studies have shown that
the symptoms of Parkinson's disease appear when the striatal
dopamine content is reduced to 20-40% of normal.
[0003] As Parkinson's disease is associated with a loss of dopamine
from the striatum, it is commonly treated with drugs which replace
dopamine, the most commonly used of these being levodopa. Levodopa
is converted by dopa decarboxylase into dopamine in the brain and
it is this dopamine which exerts a therapeutic effect. However,
although levodopa is well absorbed from the small intestine, much
of it is inactivated by monoamine oxidase in the wall of the
intestine. Also, the plasma half-life of levodopa is short and
about 95% of the drug is converted to dopamine in peripheral
tissues, where dopa decarboxylase is widespread, with the result
that less than 1% enters the brain. Consequently levodopa has to be
administered in large and frequent doses. in addition, the
production of dopamine in peripheral tissues gives rise to unwanted
side effects. Accordingly, levodopa is normally given in
combination with other drugs to enhance the effects of levodopa in
the brain and minimise its peripheral effects. In particular,
levodopa is usually given in combination with a peripheral
dopa-decarboxylase inhibitor which cannot cross the blood-brain
barrier, such as carbidopa, which inhibits the breakdown of
levodopa to dopamine outside the brain, thereby reducing peripheral
unwanted effects. The inhibitor also ensures that a relatively
large amount of an oral dose of levodopa reaches the brain and thus
enables the dose of levodopa to be reduced which also reduces
peripheral side effects. In addition, a peripheral dopamine
antagonist which does not penetrate the blood-brain barrier, such
as domperidone, may also be administered to reduce the nausea and
vomiting side-effects of levodopa.
[0004] In addition to the side-effects mentioned above, further
undesirable effects are associated with the prolonged use of
levodopa. In particular, many patients develop involuntary
choreiform movements which are the result of excessive activation
of dopamine receptors. These movements usually affect the face and
limbs and can become very severe. Such movements disappear if the
dose of levodopa is reduced but this causes rigidity to return.
Moreover, the margin between the beneficial and the unwanted effect
appears to become progressively narrower as the period of levodopa
treatment increases. The traditional method of combating this
effect is to increase the frequency of administration of levodopa
whilst keeping the overall dose steady. This approach reduces
end-of-dose deterioration and diminishes the likelihood of the
patient developing the dyskinesias that occur with high peak
doses.
[0005] A further complication of long-term levodopa treatment is
the development of rapid fluctuations in clinical state where the
patient switches suddenly between mobility and immobility for
periods ranging from a few minutes to a few hours. This phenomenon
is known as the "on-off effect", the "on" state being the preferred
state during which nearly normal motor functioning can be attained
and the "off" state being characterised by dystonic postures during
periods of decreased mobility. Indeed, this effect can produce such
an abrupt loss of mobility that the patient may suddenly stop while
walking or be unable to rise from a chair in which he had sat down
normally a few moments earlier. This effect is commonly unaffected
by manipulation of the dose of levodopa and may require treatment
with alternative drugs.
[0006] In addition to the above long-term side-effects of levodopa
treatment, it has been found that the effectiveness of levodopa
gradually declines with time until it is no longer effective. Also,
an increased incidence of malignant melanoma has been observed in
patients undergoing treatment with levodopa and it has therefore
been suggested that treatment with levodopa may be linked with the
development of malignant melanoma. Accordingly, the use of levodopa
in the treatment of Parkinson's disease is far from ideal.
[0007] An alternative approach to the treatment of Parkinson's
disease is the use of drugs that mimic the action of dopamine. Such
drugs are collectively known as dopamine agonists because they
directly stimulate dopamine receptors within the dopamine-deficient
nigrostriatal pathway. Unlike levodopa, dopamine agonists do not
need to be converted in the brain to active compounds. Also,
dopamine agonists are effective in patients in the advanced stages
of Parkinson's disease when levodopa is no longer effective because
they act directly on the dopamine receptors and are therefore
unaffected by the lack of dopamine-producing nerve cells in such
patients. However, the action of such dopamine agonists on the
dopamine receptors also causes unwanted dopaminergic effects, such
as nausea, vomiting and extrapyramidal effects, which can be
debilitating and some dopamine agonists, such as apomorphine, are
associated with further undesirable side-effects, especially when
high doses are used, such as sedation, respiratory depression,
hypotension, bradycardia, sweating and yawning.
[0008] The severity and nature of such side-effects can be affected
by the mode of administration of the drug. For instance, studies
involving apomorphine have investigated a variety of routes for
administration of this drug. However, oral administration of
apomorphine tablets has required high doses to achieve the
necessary therapeutic effect because apomorphine administered by
this route undergoes extensive presystemic metabolism in the small
intestine and/or liver (the first pass effect). Also, long-term
studies involving such oral forms were stopped after 7-10 days due
to unexplained rises in blood urea nitrogen. Sub-lingual
administration of apomorphine tablets caused severe stomatitis on
prolonged use with buccal mucosal ulceration in half the patients
treated. Intranasal administration produced transient nasal
blockage, burning sensation and swollen nose and lips and, in some
of the patients tested, had to be withdrawn because of what was
considered to be chemical inflammation of the nasal mucosa.
Accordingly, the only satisfactory way of administering apomorphine
which avoids high first pass metabolism has been found to be
subcutaneous administration and, thus, the only commercially
available formulation of apomorphine is a liquid for subcutaneous
injection or subcutaneous infusion. Even so, subcutaneous
administration does not avoid the normal dopamine agonist
side-effects, such as nausea and vomiting and subcutaneous
administration, whether by injection or infusion, is not easy to
accomplish, particularly by patients whose motor functions are
already impaired, and therefore requires training of patients and
carers. Also, the injection site must be changed every 12 hours to
minimise risks of skin discolouration and nodules forming. In view
of these problems, it is not surprising that the use of dopamine
agonists, such as apomorphine, in the treatment of Parkinson's
disease has been largely confined to the treatment of "off" periods
caused by levodopa therapy despite the obvious clinical benefits of
such drugs over levodopa.
[0009] It is apparent from the above that it would be highly
desirable from a clinical point of view to find a way of
administering dopamine agonists, such as apomorphine, which is easy
for the patient to accomplish therefore reducing the need for
supervision of administration and which bypasses first pass
metabolism in the liver. According to the present invention there
is therefore provided a pharmaceutical composition for oral
administration comprising a carrier and, as active ingredient, a
dopamine agonist, characterised in that the composition is in the
form of a fast-dispersing dosage form designed to release the
active ingredient rapidly in the oral cavity.
[0010] It has been 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.
[0011] In addition, clinical studies have shown that 23-52% of
patients with Parkinson's disease have swallowing difficulties and
many such patients tend to dribble. Accordingly, such
fast-dispersing dosage forms have the further advantage that they
will disintegrate rapidly in the mouth thereby minimising the above
problems as large volumes of water will not be co-administered. It
is therefore anticipated that such fast-dispersing dosage forms
will be easier for patients to take and easier for carers to
administer.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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 a glycine, L-alanine, L-aspartic acid, L-glutamic
acid, L-hydroxyproline, L-isoleucine, L-leucine and
L-phenylalanine.
[0022] 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.
[0023] 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 thaumatic. Suitable taste-masking
agents include sodium bicarbonate, ion-exchange resins,
cyclodextrin inclusion compounds, adsorbates or microencapsulated
actives.
[0024] 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(apomorp-
hine),S,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-89-yl)
carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylur- ea (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,5,6,1-
0b-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-hyd-
roxy-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.
[0025] It is also preferred that the dopamine agonist is present in
the composition in an amount from 0.05 to 100 mg, preferably 0.05
to 20 mg.
[0026] The precise quantity of active ingredient will depend on the
dopamine agonist chosen. Preferred daily dose ranges for the
dopamine agonists mentioned above are as follows:
1 Apomorphine 1-150 mg, more preferably 10-60 mg
N-propylnoraporphine 1-150 mg more preferably 10-60 mg
Bromocriptine 0.5-100 mg, more preferably 0.5-10 mg Cabergoline
0.05-2 mg, more preferably 0.2-0.6 mg Lisuride 0.05-5 mg, more
preferably 0.05-1 mg Metergoline 4-20 mg, more preferably 4-8 mg
Naxagolide 0.1-10 mg, more preferably 0.1-5 mg Pergolide 0.05-10
mg, more preferably 0.05-1 mg Piribedil 1-20 mg, more preferably
3-20 mg Ropinirole 0.25-20 mg, more preferably 2-10 mg Terguride
1.0-10 mg, more preferably 3-6 mg Quinagolide 0.1-5 mg, more
preferably 0.1-1 mg
[0027] Where a high daily dose is required, this may be
administered in several units of smaller dose.
[0028] As mentioned above, dopamine agonists produce side effects
such as nausea and vomiting. It is therefore preferred that the
composition of the invention is administered in conjunction with an
anti-emetic. The anti-emetic may be conveniently administered in
the same composition as the dopamine agonist. in one preferred
aspect, the composition of the invention as defined above therefore
further includes an anti-emetic. 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.
[0029] It is preferred that the anti-emetic is present in the
composition in an amount of from 1 to 120 mg, more preferably 1-60
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 peripheral dopamine antagonists, such
as 5-chloro-l-[1-[3-(2,3-dihydro-2-- oxo-1H-benzimidazol-1-yl)
propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidaz- ol-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-carboxamide (granisetron),
1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carb-
azol-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.
[0030] Preferred daily dose ranges for the anti-emetics mentioned
above are as follows:
2 Domperidone 20-120 mg, more preferably 30-60 mg Granisetron 1-10
mg, more preferably 1-3 mg Ondansetron 4-32 mg, more preferably 4-8
mg Tropisetron 1-10 mg, more preferably 1-5 mg
[0031] Where a high daily dose is required, this may be
administered in several units of smaller dose.
[0032] 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, will be produced in addition to nausea and
vomiting. 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, in another preferred aspect, the
composition of the invention as defined above further includes an
opioid antagonist. 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.
[0033] 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-di-
hydroxymorphinan-6-one (naltrexone) and salts, particularly
acid-addition salts and, especially, the hydrochloride, thereof.
The preferred daily dose range for naloxone is 0.25-10 mg, more
preferably 0.5-2 mg, and for naltrexone is 10-100 mg, more
preferably 25-50 mg. Where a high daily dose is required this may
be administered in several units of smaller dose. According to
another aspect of the invention there is provided a process for
preparing any of the pharmaceutical compositions of the invention
as described above which comprises bringing a carrier into
association with the active ingredient and/or the anti-emetic
and/or the opioid antagonist.
[0034] In a further aspect, the invention provides the use of a
fast-dispersing dosage form designed to release active ingredient
rapidly in the oral cavity to deliver a dopamine agonist. A method
of administering a dopamine agonist to a patient which comprises
introducing into the oral cavity of the patient a composition as
previously defined is also provided.
[0035] As mentioned above, the composition of the invention can be
used to combat the effects of Parkinson's disease. Accordingly, the
invention also provides a composition as previously defined for use
in the treatment of Parkinson's disease. A method of treating
Parkinson's disease which comprises introducing into the oral
cavity of a patient a therapeutically effective amount of a
composition as previously defined is also provided.
[0036] In addition, dopamine agonists, especially apomorphine, can
be used to predict the likely response to levodopa in patients with
Parkinson's disease. Accordingly, the invention further provides a
composition as previously defined for use in the evaluation of
Parkinson's disease. A method of evaluating Parkinson's disease
which comprises introducing into the oral cavity of a patient a
selected amount of a composition as previously defined and
determining the clinical effect of the composition on the patient
is also provided.
[0037] In another aspect, the invention provides the use of a
composition as previously defined for the manufacture of a
medicament for the treatment and/or evaluation of Parkinson's
disease.
[0038] As previously mentioned, it is envisaged that the dopamine
agonist could be administered in conjunction with an anti-emetic
and/or opioid antagonist, if appropriate, but that the anti-emetic
and/or opioid antagonist could be administered by a variety of
routes and the individual elements could be administered in a
variety of sequences. According to another aspect of the invention
there is therefore provided a kit for co-administration of a
composition containing a dopamine agonist as previously defined and
an anti-emetic and/or opioid antagonist For instance, the kit may
comprise at least one fast-dispersing unit dosage form of a
dopamine agonist according to the invention, at least one unit
dosage form of an anti-emetic and, if the dopamine agonist is an
opium alkaloid, at least one unit dosage form of an opioid
antagonist together with instructions for the administration of the
unit dosage forms. In a preferred form of kit, the anti-emetic is
to be administered prior to the administration of the dopamine
agonist. For ease of administration, it is further preferred that
the anti-emetic and opioid antagonist, if present, be provided in
the form of fast-dispersing dosage forms of the type previously
defined. Accordingly, the kit may comprise a combination of
fast-dispersing dosage forms as previously defined, preferably with
instructions as to the sequence of administration. In a
particularly preferred form, the kit may comprise a blister pack
containing designated unit dosage forms of compositions as
previously defined. Preferably, the sequence of administration of
the designated unit dosage forms is marked on the blister pack. A
particularly preferred kit comprises fast-dispersing dosage forms
containing apomorphine and domperidone and/or naloxone.
[0039] According to another aspect of the invention there is
provided a method of co-administering a dopamine agonist and an
anti-emetic and/or opioid antagonist to a patient which comprises
introducing into the oral cavity of the patient a composition
containing a dopamine agonist as previously defined and
administering an anti-emetic and/or opioid antagonist to the
patient either orally or parenterally. It is preferred that the
anti-emetic and opioid antagonist, if present, are also provided in
the form of fast-dispersing dosage forms of the type previously
defined, either separately or in combination with the dopamine
agonist, which may also be introduced into the oral cavity of the
patient.
[0040] The invention is further illustrated by the following
examples.
EXAMPLE 1
[0041] Preparation of a Fast-Dispersing Dosage Form of
Apomorphine
[0042] (a) Preparation of Apomorohine Hydrochloride 2.0%
Dispersion
[0043] 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.
[0044] (b) Preparation of Apomorphine Hydrochloride 10 mg Units
[0045] 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 metre 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.
[0046] Each dosage unit had the following composition:
3 % by wt of Ingredient Weight (mg) 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 0.9 500.000 100.0 *Signifies removed during the
lyophilisation process
EXAMPLE 2
[0047] Comparative Pharmacokinetic Study
[0048] The objective of this study was to compare the
bioavailability of apomorphine hydrochloride following
administration by the oral route of a fast-dispersing dosage form
prepared by the method of Example 1 (Example 1) and administration
of a commercially available injectable formulation by the
subcutaneous route (subcutaneous) to 12 healthy volunteers. The
study was an open, randomised, comparative, 5-way cross-over
pharmacokinetic study.
[0049] Due to the emetic properties of apomorphine, subjects were
pre-treated with the anti-emetic domperidone. Following 2 days of
domperidone pre-treatment, subjects were randomised to receive the
following apomorphine treatments over 5 consecutive days:
[0050] 5 mg Apomorphine (half unit of Example 1)
[0051] 10 mg Apomorphine (one unit of Example 1)
[0052] 20 mg Apomorphine (two units of Example 1 administered
simultaneously)
[0053] 2.5 mg subcutaneous injection (Britaject) of apomorphine
into the abdominal wall
[0054] 10 mg Apomorphine (one unit of Example 1) followed 5 minutes
later by further 10 mg Apomorphine (one unit of Example 1).
[0055] Blood samples for pharmacokinetic analysis were taken
pre-dose and at intervals for 6 hours after each dose of
apomorphine
[0056] Assessment of the bioavailability of apomorphine was made
using the pharmacokinetic parameter AUC (area under the plasma
apomorphine concentration-time curve) Doses of 5 mg, 10 mg and 20
mg of Example 1 produced dose-related increase in bioavailability
as assessed by AUC (see Table I). Furthermore, giving two 20 mg
doses 5 minutes apart resulted in an increase in bioavailability
over the bioavailability of the 20 mg dose given at once (See FIG.
1).
4TABLE I The bioavailability of apomorphine given orally as Example
1 (5 mg to 20 mg), as two 10 mg doses 5 minutes apart and as a 2.5
mg subcutaneous injection. (Mean values) Dosage group AUC 2.5 mg
subcutaneous 831.0 5 mg (Example 1) 337.6 10 mg (Example 1) 504.8
20 mg (Example 1) 690.1 2 .times. 10 mg (Example 1) 908.6
[0057] In Example 2 it was shown that the overall absorption of
apomorphine, when administered from a rapidly disintegrating dosage
form, was increased when the 20 mg dose was administered as two 10
mg units taken five minutes apart rather than taking two 10 mg
units simultaneously. It is believed that the observed enhanced
absorption may be due to the-effect of the formulation on the pH of
the saliva of the mouth, in which the drug must be dissolved before
it can be absorbed pre-gastrically.
[0058] Apomorphine is a basic drug which is known to exhibit
optimal chemical stability in an acidic environment. Therefore
formulations of apomorphine normally include excipients such as
citric acid, tartaric acid or maleic acid to maximise chemical
stability.
[0059] These excipients would be expected to cause a fall in the
salivary pH which may affect the absorption of the drug. This
effect is surprisingly minimised by administering the dose over a
period of time.
[0060] According to another aspect of the invention there is
therefore provided a pharmaceutical product comprising a
therapeutic dose of a pharmaceutical composition containing a
dopamine agonist as previously defined in which the therapeutic
dose of the composition is divided into at least two portions and
the pharmaceutical product additionally comprises instructions to
administer said at least two portions sequentially with a specified
time period between administration of each portion.
[0061] The invention also provides a method of administering to a
patient a pharmaceutical product comprising a therapeutic dose of a
pharmaceutical composition containing a dopamine agonist as
previously defined in which said therapeutic dose of the
composition is divided into at least two portions which method
comprises introducing the at least two portions sequentially into
the oral cavity of the patient with a specified time period between
administration of each portion.
[0062] Preferably, the specified time period between administration
of each portion is from 2 to 15 minutes, more preferably from 5 to
10 minutes. It is also preferred that the instructions for
administration of the at least two portions are marked on a pack
containing the portions; Most preferably, the at least two portions
are contained in a blister pack and the instructions are preferably
marked on the blister pack.
[0063] In a further aspect, the invention provides a kit for the
administration of a composition containing a dopamine agonist as
previously defined which comprises at least first and second
designated unit dosage forms of the composition and instructions
specifying a time sequence for the sequential administration of the
at least first and second designated unit dosage forms.
[0064] The invention also provides a method of administering to a
patient a composition containing a dopamine agonist as previously
defined comprising at least first and second designated unit dosage
forms of the composition which method comprises sequentially
introducing said at least first and second designated unit dosage
forms into the oral cavity of the patient in accordance with a
specified time sequence.
[0065] It is preferred that the time sequence is such that a period
of from 2 to 15 minutes, more preferably from 5 to 10 minutes, is
required to elapse between administration of the first and second
designated unit dosage forms. Preferably, the instructions
specifying the time sequence for sequential administration of the
at least first and second designated unit dosage forms are marked
on a pack containing the designated unit dosage forms. It is
particularly preferred that the designated unit dosage forms are
contained in a blister pack. Preferably, the instructions are
marked on the blister pack.
[0066] It is especially preferred that the dopamine agonist
utilised in the pharmaceutical product or kit as previously defined
is apomorphine, N-propylnoraporphine or a salt thereof. Preferably,
each portion or designated unit dosage form contains from 2.5 to 20
mg, more preferably from 5 to 15 mg and especially 10 mg, of
apomorphine or a salt thereof.
[0067] A further aspect of this discovery that absorption of
apomorphine can be enhanced by administering the dose over a period
of time is that the pH of the saliva can be maintained within the
normal physiological range at the time of taking the apomorphine
formulation by the co-administration of an antacid formulation.
This could be either a specially prepared formulation or a
commerically available tablet or liquid formulation such as
Rennie.TM., Settlers.TM., Bisodol.TM., Aludrox.TM., Asilone.TM. or
Remegel.TM. The antacid would react directly with the acid
excipient and prevent the fall in pH of the saliva which is
believed to reduce the overall absorption of apomorphine from the
pre-gastric region of the gastro-intestinal tract.
[0068] According to a further aspect of the invention there is
therefore provided a pharmaceutical product or kit as previously
defined which further includes an antacid.
[0069] The invention also provides a method of administering a
dopamine agonist, a pharmaceutical product or designated unit
dosage forms containing a dopamine agonist as previously defined, a
method of co-administering a dopamine agonist and an anti-emetic
and/or opioid antagonist as previously defined and a method of
treating and/or evaluating Parkinson's disease as previously
defined all of which comprise the further step of introducing an
antacid into the oral cavity of the patient. The antacid may be
administered just before or after or simultaneously with
administration of the dopamine agonist.
[0070] An antacid for use in enhancing pre-gastric absorption of
the active ingredient from a composition containing a dopamine
agonist as previously defined is also provided.
EXAMPLE 3
[0071] Pre-Gastric Absorption Study
[0072] The objective of this study was to compare the
bioavailability of apomorphine hydrochloride 10 mg following
administration by the oral route as a fast-dispersing dosage form
(Example 1) placed into the mouth and allowed to disperse and when
encapsulated in a hard gelatin capsule and swallowed whole. The
study was an open, randomised, comparative, 2-way cross-over
pharmacokinetic study with 6 volunteers.
[0073] Due to the emetic properties of apomorphine, subjects were
pre-treated with the anti-emetic domperidone. Following 2 days of
domperidone pre-treatment, subjects were randomised to receive the
following apomorphine treatments over 2 consecutive days:
[0074] 10 mg Apomorphine (Example 1)
[0075] 10 mg Apomorphine encapsulated into a hard gelatin
capsule.
[0076] Blood samples for pharmacokinetic analysis were taken
pre-dose and at intervals for 6 hours after each dose of
apomorphine.
[0077] Assessment of the bioavailability of apomorphine was made
using the pharmacokinetic parameter AUC.
[0078] The doses of 10 mg (Example 1) produced a plasma profile
similar to that seen in Example 2 (see FIG. 2) However, the same
formulation when given encapsulated in a hard gelatin capsule gave
a significantly reduced plasma profile. This was seen clearly in
the pharmacokinetic parameter AUC, which indicated significantly
reduced absorption in the encapsulated group (Table II).
[0079] These results support the concept that apomorphine is
absorbed pre-gastrically from the fast-dispersing dosage forms of
Example 1 when placed into the mouth since, when the same
formulation was encapsulated (which would prevent pre-gastric
absorption), the amount of apomorphine detected in plasma was
significantly reduced.
5TABLE II The bioavailability of apomorphine given orally in the
form of Example 1 (10 mg) and 10 mg encapsulated in a hard gelatin
capsule (mean values) Dosage group AUC 10 mg (Example 1) 402.2 10
mg in a hard gelatin capsule 92.3
[0080] The following examples further exemplify formulations which
can be prepared using the process described in Example 1:
EXAMPLE 4
[0081]
6 % by weight of Ingredient Weight (mg) 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
[0082]
7 % by weight of Ingredient Weight (mg) 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
[0083]
8 % by weight of Ingredient Weight (mg) 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 Aspartarne EP/USNF 2.500 0.50 Total 500.000 100.00
*signifies removed during lyophilisation process.
EXAMPLE 7
[0084]
9 % by weight Weight of Ingredient (mg) 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
[0085]
10 % by weight Weight of Ingredient (mg) 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
[0086]
11 % by weight of Ingredient Weight (mg) 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
[0087]
12 % by weight of Ingredient Weight (mg) 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
[0088]
13 % by weight of Ingredient Weight (mg) 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
[0089]
14 % by weight of Ingredient Weight (mg) 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
[0090]
15 % by weight of Ingredient Weight (mg) 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
[0091]
16 % by weight of Ingredient Weight (mg) 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
[0092]
17 % by weight of Ingredient Weight (mg) 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.
* * * * *