U.S. patent application number 09/920698 was filed with the patent office on 2001-11-29 for compositions for nasal administration.
This patent application is currently assigned to West Pharmaceutical Services Drug Delivery. Invention is credited to Illum, Lisbeth, Watts, Peter James.
Application Number | 20010046519 09/920698 |
Document ID | / |
Family ID | 26312701 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010046519 |
Kind Code |
A1 |
Illum, Lisbeth ; et
al. |
November 29, 2001 |
Compositions for nasal administration
Abstract
There is provided a composition for the nasal delivery of a drug
suitable for the treatment of erectile dysfunction to a mammal
wherein the composition is adapted to provide an initial rise in
plasma level followed by a sustained plasma level of the drug.
Inventors: |
Illum, Lisbeth; (The Park,
GB) ; Watts, Peter James; (Gamston, GB) |
Correspondence
Address: |
AKIN, GUMP, STRAUSS, HAUER & FELD, L.L.P.
ONE COMMERCE SQUARE
2005 MARKET STREET, SUITE 2200
PHILADELPHIA
PA
19103
US
|
Assignee: |
West Pharmaceutical Services Drug
Delivery
|
Family ID: |
26312701 |
Appl. No.: |
09/920698 |
Filed: |
August 1, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09920698 |
Aug 1, 2001 |
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09586139 |
Jun 2, 2000 |
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09586139 |
Jun 2, 2000 |
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PCT/GB98/03572 |
Nov 27, 1998 |
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Current U.S.
Class: |
424/501 |
Current CPC
Class: |
A61P 15/10 20180101;
A61P 25/16 20180101; A61K 47/61 20170801; A61K 9/0043 20130101 |
Class at
Publication: |
424/501 |
International
Class: |
A61K 009/50 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 1997 |
GB |
9725519.4 |
Mar 13, 1998 |
GB |
9805253.3 |
Claims
We claim:
1. A composition for nasal delivery comprising a drug suitable for
the treatment of erectile dysfunction, wherein the composition is
adapted to provide an initial rise in plasma level followed by a
sustained plasma level of the drug.
2. A composition for nasal delivery comprising a drug useful in the
treatment of erectile dysfunction and one or more excipients,
wherein the composition is adapted to provide an initial rise in
plasma level followed by a sustained plasma level of the drug.
3. A composition according to claim 2, wherein the drug is a weak
base or a weak acid and the combination of drug with excipient
results in complexation as a result of an ion exchange process.
4. A composition according to claim 2, wherein the drug is a weak
base or a weak acid, and is combined with a block copolymer.
5. A composition according to claim 4, wherein the block copolymer
is selected from the group consisting of poloxamines, poloxamers
and polylactidepolyoxyethylene copolymers.
6. A composition according to claim 2, wherein the excipient is an
ion exchange polymeric material.
7. A composition according to claim 2, wherein the excipient
provides for controlled delivery of the drug to the nasal membrane
and comprises a polysaccharide and/or a block copolymer comprising
a polyoxyethylene block.
8. A composition according to claim 2, wherein the excipient is an
anionic polysaccharide selected from the group consisting of
xanthans, gellans, alginates, hyaluronic acid,
carboxymethylcellulose.
9. A composition according to claim 2, wherein the excipient is a
pectin.
10. A composition according to claim 2, wherein the excipient is a
carboxylated starch.
11. A composition according to claim 2, wherein the excipient is
chitosan.
12. A composition according to claim 1, wherein the composition is
a liquid.
13. A composition according to claim 2, wherein the composition is
a liquid system which is adapted to gel in the nasal cavity.
14. A composition according to claim 13, wherein the composition is
adapted to gel on contact with the cations present in the nasal
cavity.
15. A composition according to claim 14, wherein the composition
comprises a source of cations.
16. A composition according to claim 14, wherein the excipient
comprises pectin and/or gellan.
17. A composition according to claim 1, wherein the composition is
in the form of microspheres.
18. A composition according to claim 17, wherein the microspheres
are produced from carboxylated starch.
19. A composition according to claim 17, wherein the microspheres
are produced from chitosan.
20. A composition according to claim 1, wherein the composition
comprises a drug selected from the group consisting of the
alpha-adrenoreceptor antagonists, e.g. phentolamine,
phenoxybenzamine, yohimbine, moxislyte delaquamine; compounds with
central D.sub.2-receptor antagonist activity, e.g. apomorphine;
compounds that act primarily by blocking the re-uptake of serotonin
into nerve terminals, e.g. trazadone and chlorophenylpiperazine;
competitive and selective inhibitors of c-GMP type V
phosphodiesterases, e.g. sildenafil; L-arginine; papaverine, and
the pharmaceutically acceptable salts thereof.
21. A composition according to claim 20, wherein the composition
comprises a drug with central D.sub.2-receptor antagonist
activity.
22. A composition according to claim 21, wherein the composition
comprises apomorphine.
23. A method for the controlled delivery of a drug to the systemic
circulation of a mammal which comprises the nasal administration of
a composition according to claim 1, to the mammal.
24. A method of treatment of a disease in which the controlled
delivery of a drug to the circulation is desirable which comprises
the nasal administration of a composition according to claim 1, to
a mammal.
25. A method as claimed in claim 24, wherein the drug is
apomorphine and the disease is Parkinson's disease.
26. A method as claimed in claim 24, wherein the disease is
erectile dysfunction.
27. A method for treating a disease which comprises nasal
administration of a composition according to claim 1.
28. A method for treating erectile dysfunction which comprises
nasal administration of a composition according to claim 1.
29. The use of a composition according to claim 1, in the
manufacture of a medicament for the controlled delivery of a drug
useful in the treatment of erectile dysfunction to the systemic
circulation of a mammal.
30. The use of a composition according to claim 1, in the
manufacture of a medicament for nasal administration of a drug
useful in the treatment of erectile dysfunction.
31. The use of a composition according to claim 1, in the
manufacture of a medicament for treating erectile dysfunction.
32. A process for the preparation of a composition according to
claim 2 which comprises admixing the drug with the excipient.
33. A composition for nasal delivery comprising a drug useful in
the treatment of erectile dysfunction and an excipient comprising
an anionic or cationic polysaccharide or a block copolymer
containing a polyoxyethylene block.
34. A composition according to claim 33, wherein the drug is
apomorphine.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of International
Application No. PCT/GB98/03572 filed Nov. 27, 1998, the disclosure
of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] This invention relates to compositions for nasal
administration of drugs and particularly to compositions for nasal
administration of drugs for treating erectile dysfunction, such as
apomorphine. The invention also relates to the nasal administration
of drugs for treating erectile dysfunction.
[0003] Erectile dysfunction is a major medical problem in
middle-aged males. A variety of medical treatments has been
proposed including local injections as well as hormone therapy. The
prostaglandins have been especially useful in this regard.
[0004] Other drugs suitable for the treatment of dysfunction
include alpha-adrenoreceptor antagonists, e.g. phentolamine,
phenoxybenzamine, yohimbine, moxislyte delaquamine; compounds with
central D.sub.2-receptor antagonist activity, e.g. apomorphine;
compounds that act primarily by blocking the re-uptake of serotonin
into nerve terminals, e.g. trazadone and chlorophenylpiperazine;
competitive and selective inhibitors of c-GMP type V
phosphodiesterases, e.g. sildenafil; L-arginine; and
papaverine.
[0005] Presently, administration of the above drugs can often
involve the local injection of the penis with attendant problems of
compliance. A more discreet, non-invasive method for the treatment
of erectile dysfunction would be of considerable advantage.
[0006] A drug for erectile dysfunction could be given orally in
order to be absorbed from the gastrointestinal tract, but it is
well known by those skilled in the art that oral absorption can be
slow since the drug has to pass through the stomach into the small
intestine to the absorptive regions. The appearance of the drug in
the intestine can be delayed by food. Thus, oral absorption tends
to be erratic and unpredictable. Hence, this route of delivery is
not feasible. The buccal cavity, including the sublingual and
buccal tissues, is an alternative site for administration. However,
generally speaking drug absorption from this site is slow since the
tissues of the mouth are not intended for the efficient uptake of
substances, unlike the intestines. Moreover, drugs placed in the
mouth can be bitter as well as irritant.
[0007] The lungs offer another site for the delivery of drugs. The
lungs can provide rapid absorption, but administration needs to be
conducted with a device in the form of a nebulizer or inhaler and
can be limited by the dose. Many drugs are irritant when blown into
the lungs and can cause bronchospasm.
[0008] It is known that the nasal epithelium has good permeability
and a good blood supply and that drugs that are metabolised after
oral administration can be well absorbed from the nose since this
route avoids the first-pass metabolic effect in the liver. Hence,
the nasal administration of drugs for the treatment of erectile
dysfunction is potentially attractive and has been attempted.
However, side effects and adverse reactions were common.
[0009] It is known that the drug apomorphine (6aR)-5, 6, 6a,
7-tetrahydro-6-methyl-4H-dibenzo(d, e, g) quinoline- 10,11-diol
hemihydrate can be effective in the treatment of erectile
dysfunction (DanJou et al. Brit. J. Clin. Pharmacol. 26, 733,
1988). However, the drug is better known for its use in disease
conditions such as Parkinsonism where oral, rectal and nasal routes
have been reported. Intranasal apomorphine has been shown to be
useful in Parkinson's disease (Sam et al. Eur. J. Drug Metab.
Pharmacokinet. 20, 27, 1995; Dewey et al. Clin. Neuropharmacol. 19,
193, 1996), but is associated with transient nasal blockage and a
burning sensation. (Kleedorfer et al, Neurology 41, 761, 1991).
[0010] The extent of nasal absorption of apomorphine can be
enhanced using various agents such as those described by Merkus
that include cyclodextrins (WO-91/22445). The bioavailability,
defined as the quantity of drug appearing in the systemic
circulation as compared to a control in the form of a subcutaneous
injection, is stated to be about 40%.
[0011] While local reactions and side effects may be acceptable for
a patient receiving nasal apomorphine for the treatment of
Parkinson's disease, such side effects would be totally
inappropriate for an apparently healthy patient taking nasal
apomorphine for the treatment of erectile dysfunction.
[0012] Attention has been given to the route of administration of
apomorphine for use in erectile dysfunction with an emphasis on
convenience. Heaton et al. (Neurology, 45, 200-205) compared
different routes of administration in a study conducted in
patients. They reported that nasal administration of apomorphine
gave rapid onset of action but was associated with unacceptable
side effects such as yawning, nausea, vomiting, dizziness, blurred
vision, diaphoresis, pallor and mild hypertension and, therefore,
was not suitable. Their preferred system was a sublingual
formulation as further defined in U.S. Pat. No. 5,624,677 and
WO-95/28930. However, as discussed above, while sublingual
formulations can lead to the absorption of drugs, it is known that
such absorption can be slow and variable. Moreover, the quantity
absorbed may be limited due to the poor permeability of the oral
mucosal membranes in man. In addition, a green colouration of the
tongue following sublingual apomorphine has been reported together
with poor taste and mucosal ulceration.
[0013] Thus, the nasal administration of apomorphine has been
described in the prior art literature and in patents. The
formulations described were generally simple in nature and all
would have led to a pulsatile delivery of the drug resulting in a
sharp and high initial peak in the plasma level-time profile
leading to local reactions and side effects. In particular, none of
the nasal formulations described in the prior art comprised an
additive intended to modulate the rapid absorption of the drug.
[0014] In WO-94/27576 it is disclosed that the nasal delivery of
nicotine could be modified to provide a combination of a peak level
(to provide the so-called "buzz" effect of nicotine delivered by a
cigarette) and a subsequent controlled release phase. Thus,
WO-94/27576 deals with the problem of providing input of nicotine
into the bloodstream over a prolonged period of time. The reduction
of the plasma level-time profile in order to minimise side effects
and adverse reactions for drugs used in the treatment of erectile
dysfunction such as apomorphine is neither mentioned nor
suggested.
[0015] Ugowk et al (J. Control. Rel. 48, 1997, 302) has described
mucoadhesive nasal forms for apomorphine hydrochloride for the
treatment of Parkinson's disease. An attempt was made to
incorporate apomorphine into gelatin microspheres, but the
encapsulation efficiencies were reported to be sometimes very low.
Moreover, the drug was released rapidly. Ugowk et al also described
powder formulations of apomorphine together with polycarbophil or
carbomer (carboxypolymethylene) where 100 mg of apomorphine was
combined with 1 g of polymer and then freeze dried. The
compositions of the present invention were not described.
[0016] Thus, the prior art teaches that the nasal delivery of most
drugs for the treatment of erectile dysfunction tends to be
associated with unacceptable side effects.
[0017] Controlled release nasal formulations for the treatment of
erectile dysfunction have not been described previously.
[0018] As a result of investigations into this problem, the
applicant has realised that the adverse reactions and side effects
associated with the nasal administration of drugs for treating
erectile dysfunction such as apomorphine may be the result of an
inappropriate plasma level/time profile and, more specifically, a
result of an initial high peak plasma level. We have also realised
that such side effects may be reduced and even eliminated by
combining the drug with certain pharmaceutical excipients that
provide a controlled release effect such as polysaccharides and
block copolymers containing ethylene oxide (oxyethylene) moieties.
More particularly, we have now discovered controlled release nasal
formulations for drugs intended for the treatment of erectile
dysfunction that will provide an initial rise in plasma level of
the drug followed by a more sustained level of drug input. These
nasal formulations can provide a flatter plasma level/time profile
after nasal administration by which we mean a reduction in the peak
plasma level, but not necessarily a reduction in the area under the
plasma level versus time profile.
SUMMARY OF THE INVENTION
[0019] According to a first aspect of the present invention there
is provided a composition for nasal delivery comprising a drug
suitable for the treatment of erectile dysfunction, wherein the
composition is adapted to provide an initial rise in plasma level
followed by a sustained plasma level of the drug.
[0020] According to a second aspect of the present invention there
is provided a composition for nasal delivery comprising a drug
useful in the treatment of erectile dysfunction, e.g. apomorphine
or a salt thereof, and one or more excipients, e.g. in the form of
anionic or cationic polysaccharides depending on the drug or block
copolymers containing ethylene oxide moieties, wherein the
composition is adapted to provide an initial rise in plasma level
followed by a sustained plasma level of the drug.
[0021] It will be apparent to those skilled in the art that some of
the drugs described herein as being useful in the treatment of
erectile dysfunction are also known to be useful in the treatment
of other conditions and that the compositions of the invention
containing such drugs could also be used in the treatment of these
other conditions. A particular example is apomorphine for treating
Parkinson's disease.
[0022] With such compositions it is now possible to administer
drugs that are suitable for treating erectile dysfunction through
the nasal cavity to give a blood level versus time profile of the
drug in the systemic circulation that may provide an effective
erection in patients with erectile dysfunction, but without
significant adverse reactions and side effects. As discussed above,
a simple nasal spray containing such a drug is an unsatisfactory
dosage form since it provides a high peak level of the drug in the
blood initially followed by a rapid decline in this level leading
to adverse reactions and poor efficacy.
[0023] When drugs are administered using the nasal formulations of
the invention, the initial rise in drug plasma level is rapid,
although not as rapid as the rise that results when the same drugs
are administered using conventional nasal formulations. Moreover,
the peak plasma level of drug attained with the nasal formulations
of the invention is not as high as that attained with conventional
nasal formulations.
[0024] By "initial rise in plasma level of the drug" we mean that
the peak plasma level will typically be attained in a time less
than 45 minutes, preferably in less than 30 minutes and more
preferably in less than 15 minutes after nasal application. The
peak in the plasma level concentration versus time profile (e.g. in
ng/ml) will typically be reduced to 75% or less, preferably 50% or
less of the level obtained with an immediate release formulation of
the drug, e.g. as is obtained with conventional nasal spray
solutions which are not adapted to provide a controlled release
effect.
[0025] Each drug will have its own particular range of effective
concentration depending upon the properties of the drug. For
example, for apomorphine the "initial rise in plasma level" of the
drug should be to a level between 0.05 and 50 ng/ml, preferably
between 0.25 and 10 ng/ml and more preferably between 0.5 and 5.0
ng/ml in less than 30 minutes, preferably in less than 20 minutes
and more preferably in less than 10 minutes after nasal application
of the composition.
[0026] By a "sustained plasma level" of drug we mean that the
plasma level is typically maintained at a level that is necessary
for a clinical effect (effective concentration) for between 5 and
120 minutes, preferably between 10 and 60 minutes and more
preferably between 15 and 45 minutes.
[0027] In a preferred embodiment, the plasma level of drug will
remain at approximately the level attained after the initial rise
in plasma level for between 5 and 120 min, preferably between 10
and 60 min and more preferably between 15 and 45 min.
[0028] The drugs which are used in the compositions of the
invention may be weakly basic or weakly acidic. By "a weak base" we
mean drugs with a pKa less than 10 and by "a weak acid" we mean
drugs with a pKa more than 2.5.
[0029] Drugs which are suitable for use in the nasal compositions
of the invention include alpha-adrenoreceptor antagonists, e.g.
phentolamine, phenoxybenzamine, yohimbine, moxislyte delaquamine;
compounds with central D.sub.2-receptor antagonist activity, e.g.
apomorphine; compounds that act primarily by blocking the re-uptake
of serotonin into nerve terminals, e.g. trazadone and
chlorophenylpiperazine; competitive and selective inhibitors of
c-GMP type V phosphodiesterases, e.g. sildenafil; L-arginine; and
papaverine.
[0030] Pharmaceutically acceptable derivatives of the above
compounds, such as the pharmaceutically acceptable salts thereof
may also be used. A detailed review of these drugs is included in
the review entitled Drugs for the Treatment of Impotence by
Gascia-Reboll et al. Drugs and Aging 11, 140-151 (1997).
[0031] Preferred drugs include those with central D.sub.2-receptor
antagonist activity or the alpha-adrenoreceptor antagonists. Drugs
with central D.sub.2-receptor antagonist activity are of particular
interest, especially apomorphine.
[0032] A variety of pharmaceutically acceptable excipients can be
employed in the compositions of the invention including those that
form a complex with or entrap the drug. Particular materials
include the polysaccharides and PEGylated block copolymers, i.e.
block copolymers containing a block made up of repeating ethylene
oxide moieties.
[0033] Suitable excipients in the case of liquid compositions
include natural polymeric materials, such as sodium alginate,
xanthan, gellan gum, welan, rhamsan, agar, carageenan, dextran
sulphate, keratan, dermatan, pectin, hyaluronic acid and salts
thereof. Modified polysaccharide materials such as carboxymethyl
cellulose can also be employed as can block copolymers containing
one or more blocks made up of repeating ethylene oxide units. These
materials are given as examples and the list is not to be taken as
exhaustive.
[0034] In one method for preparing liquid compositions, the
excipient material such as a polysaccharide or a block copolymer
containing ethylene oxide moieties is dissolved in ultrapure water
or a buffer system or in ultrapure water to which has been added
various salts such as sodium chloride. The solution is stirred
overnight or until the material has dissolved. With apomorphine,
the drug may be dissolved in a similar aqueous system and added to
the solution of the excipient material. Alternatively, the
apomorphine may be dissolved directly in the excipient solution. A
suitable concentration of apomorphine in the final liquid
composition is in the range of from 1 mg/ml to 200 mg/ml,
preferably in the range of from 2 mg/ml to 100 mg/ml and more
preferably in the range of from 5 mg/ml to 50 mg/ml. The
concentration of excipient material needed is dependent on the type
of material used but is typically between 0.01% w/v and 50% w/v, by
which we mean from 0.01 to 50 g of excipient per 100 mls of the
liquid, e.g. water. A preferred concentration of the excipient
material is in the range 0.1% w/v to 50% w/v, i.e. 0.1 to 50 g of
excipient per 100 mls of the liquid, more preferably in the range
0.5% w/v to 50% w/v and particularly in the range 1.0% w/v to 30%
w/v.
[0035] For powder compositions, it is possible to use carboxylated
starch microspheres or positively charged microspheres available
from Perstorp (Sweden) and microspheres produced from natural
polymers such as carboxylmethyl cellulose, sodium alginate and
chitosan.
[0036] In one method for preparing powder systems, microspheres
having a mean diameter of between 0.5 .mu.m-300 .mu.m are suspended
in water or in water containing the dissolved drug and the
formulation freeze dried. If the microspheres are suspended in pure
water, then the drug is added to this suspension prior to freeze
dying. With apomorphine, the final concentration of apomorphine per
mg of microsphere is typically between 0.01 mg/mg and 5.0 mg/mg,
preferably between 0.02 mg/mg and 2.5 mg/mg and more preferably
between 0.025 mg/mg and 0.25 mg/mg. Weight ratios of drug to
microspheres in the range of from 1 part drug to 5 to 10 parts of
the microspheres are especially preferred.
[0037] In another method for preparing powder systems in the form
of microspheres, the drug such as apomorphine and the microspheres
are mixed mechanically in the dry state.
[0038] When drugs other than apomorphine are employed, the above
processes and amounts may be modified readily in accordance with
techniques well known to those skilled in the art.
[0039] It would also be possible to freeze dry a liquid composition
for reconstitution before use by the addition of water.
[0040] Preferred excipient materials for liquid compositions
include pectin, gellan gum, alginate, welan, rhamsan, xanthan and
carageenan, particularly pectin, gellan gum, alginate, welan and
rhamsan and especially pectin and gellan gum.
[0041] Gellan gum is the deacetylated form of the extracellular
polysaccharide from Pseudomonas elodae. Native/high-acyl gellan is
composed of a linear sequence of tetra-saccharide repeating units
containing D-glucuronopyranosyl, D-glucopyranosyl and
L-rhamnopyranosyl units and acyl groups.
[0042] Alginate is composed of two building blocks of monomeric
units namely .beta.-D-mannuronopyranosyl and
.alpha.-guluronopyranosyl units. The ratio of D-mannuronic acid and
L-guluronic acid components and their sequence predetermines the
properties observed for alginates extracted from different seaweed
sources.
[0043] Welan is produced by an Alcaligene species. Welan has the
same basic repeating unit as gellan but with a single glycosyl
sidechain substituent. The side unit can be either an
.alpha.-L-rhamnopyranosyl or an .alpha.-L-mannopyranosyl unit
linked (1->3) to the 4-0-substituted .beta.-D-glucopyranosyl
unit in the backbone.
[0044] Rhamsan is produced by an Alcaligenes species. Rhamsan has
the same repeating backbone unit as that of gellan but with a
disaccharide sidechain on 0-6 of the 3-O-substituted
.beta.-D-glucopyranosyl unit. The side chain is
.beta.-D-glucopyranosyl-(1-6)-.alpha.-D-glucopyranosyl unit.
[0045] Xanthan is produced by a number of Xanthomonas strains. The
polymer backbone, made up of (1->4)-linked
.beta.-D-glucopyranosyl units is identical to that of cellulose. To
alternate D-glucosyl units at the 0-3 position, a trisaccharide
side chain containing a D-glucoronosyl unit between two D-mannosyl
units is attached. The terminal .beta.-D-mannopyranosyl unit is
glycosidically linked to the 0-4 position of the
.alpha.-D-glucopyranosyluronic acid unit, which in turn is
glycosidically linked to the 0-2 position of an
.alpha.-D-mannopyranosyl unit.
[0046] Carageenan is a group of linear galactan polysaccharides
extracted from red seaweeds of the Gigartinaceae, Hypneaceae,
Solieriaceae, Phyllophoraceae and Furcellariaceae families.
[0047] Pectin is an especially preferred material and is obtained
from the dilute acid extract of the inner portion of the rind of
citrus fruits or from apple pomace. It consists of partially
methoxylated polygalacturonic acids. The gelling properties of
pectin solutions can be controlled by the concentration of the
pectin, the type of pectin, especially the degree of esterification
and the presence of added salts.
[0048] Mixtures of excipients can also be used, such as mixtures of
pectin or gellan with other polymers such as alginate, gelling of
the mixture being caused by the pectin or gellan gum. Other
combinations of gums can also be used, particularly where the
combination gives a synergistic effect, for example in terms of
gelation properties. An example is xanthan--locust bean gum
combinations.
[0049] A preferred excipient for liquid compositions is one that
allows the composition to be administered as a mobile liquid but in
the nasal cavity will cause the composition to gel, thereby
providing a bioadhesive effect which acts to hold the drug at the
absorptive surface for an extended period of time. The anionic
polysaccharides pectin and gellan are examples of materials which
when formulated into a suitable composition will gel in the nasal
cavity owing to the presence of cations in the nasal fluids.
[0050] The liquid compositions comprising pectin or gellan will
typically comprise from 0.01 to 20% w/v of the pectin or gellan in
water or an aqueous buffer system, by which we mean that the pectin
or gellan will be present in an amount of from 0.01 to 20 g per 100
mls of water or aqueous buffer. A preferred concentration for the
pectin or gellan in the water or aqueous buffer is in the range of
from 0.1% to 15% w/v, more preferably 0.1 to 5.0% w/v and
particularly 0.2% to 1% w/v.
[0051] For gelling to occur in the nasal cavity with a liquid
composition comprising an excipient which gels in the presence of
ions, such as pectin or gellan gum, it is likely to be necessary to
add monovalent and/or divalent cations to the composition so that
it is close to the point of electrolyte induced gelation. When such
a composition is administered to the nasal cavity, the endogenous
cations present in the nasal fluids will cause the mobile liquid
composition to gel. In other words, the ionic strength of the
composition is kept sufficiently low to obtain a low viscosity
formulation that is easy to administer, but sufficiently high to
ensure gelation once administered into the nasal cavity where
gelation will take place due to the presence of cations in the
nasal fluids.
[0052] Suitable cations for adding to the composition include
sodium, potassium, magnesium and calcium. The ionic concentrations
are chosen according to the degree of gelling required, and
allowing for the effect that ionised drug present may have on
gelling since certain drug molecules that are weakly basic and
positively charged such as apomorphine will also act as monovalent
cations and will tend to have an effect on the gelling properties
of the pectin or gellan system. For example, for a liquid
composition comprising 0.2% w/v of gellan, i.e. 0.2 g of gellan per
100 mls of liquid, the divalent ions calcium and magnesium give
maximum gel hardness and modulus at molar concentrations
approximately one fortieth ({fraction (1/40)}) of those required
with the monovalent ions sodium and potassium. A finite
concentration of each cation is required to induce gelation.
[0053] The ionic strength for a liquid nasal composition comprising
0.5% w/v of pectin or gellan gum can be in the range of 0.1 mM-50
mM for monovalent cations with the preferred range being 1 mM-5 mM
and in the range of 0.1 mM-5 mM for divalent cations with the
preferred range being 0.15 mM to 1 mM. For higher concentrations of
pectin or gellan gum the ionic strengths should be lowered
accordingly. The cations will compete with a positively charged
drug such as apomorphine for binding with the anionic
polysaccharide and the concentration of cations should be
controlled so that a sufficient amount of positively charged drug
will bind with the ion-exchanged anionic polysaccharide.
[0054] The complex between a basic drug such as apomorphine and the
ion-exchange anionic polysaccharide forms as a result of ionic
interaction between the negatively charged polysaccharide and the
positively charged drug. The pH of the composition must therefore
be such that the two species are well ionised. With apomorphine,
the pH should be kept in the range of from pH 3 to pH 8, preferably
in the range of from pH 4 to pH 6, by the presence of appropriate
buffers or acids. For these ion-exchange polysaccharides, the
positively charged drug such as apomorphine can be added either as
the base or as a salt. When the drug is used in its salt form it
will tend to ionise once in an aqueous environment and if it is in
base form the pH of the system can be controlled by the addition of
appropriate acids so as to ensure that the drug is ionised and able
to interact with the polysaccharide.
[0055] Block copolymers such as a poloxamer
(polyoxyethylene-polyoxypropyl- ene block copolymer) or a block
copolymer of polylactic acid and polyoxyethylene (PLA-PEG) may also
be used as the excipient in liquid compositions. The poloxamers can
be obtained from BASF as the Pluronic.TM. and Tetronic.TM. series
with different molecular weights and block structures. A preferred
block copolymer is Pluronic.TM. F127 also known as Poloxamer
407.
[0056] Other polymers which may be used as an excipient include
PLA-PEG copolymers which can be synthesised by the methods
described in EP-A-0166596 or by the methods described by Deng et al
(J. Polymer Sci. Part C Polymer letters, 24, 411, 1988), Zhu et al.
(J. Polym. Sci. Polm. Chem. 27, 2151, 1989) or Gref et al (Science,
263, 1600, 1994), PCT/WO95/03357. Water soluble linear tri-block
copolymers of PLA-PEG that gel when the temperature is raised are
especially preferred. These are described by Jeong et al. Nature.
388, 860, 1997. A suitable concentration of the block copolymer in
the liquid formulation is from 5 to 50% w/v, by which we mean from
5 to 50 g of copolymer per 100 mls of the liquid, e.g. water, with
a concentration between 10 and 30% w/v being particularly
preferred.
[0057] The liquid nasal compositions of the invention can also
contain any other pharmacologically-acceptable, non-toxic
ingredients such as preservatives, antioxidants and flavourings.
Benzalkonium chloride may be used as a preservative. It is also
known that apomorphine can demonstrate instability, probably due to
auto-oxidation. Thus, stabilising agents such as sodium
metabisulphite or ascorbic acid can be included in the
compositions.
[0058] When the formulations according to the present invention are
in the form of microspheres, polysaccharide microspheres may be
used including those which carry suitable anionic groups such as
carboxylic acid residues, carboxymethyl groups, sulphopropyl groups
and methylsulphonate groups or cationic groups such as amino
groups. Carboxylated starch microspheres are especially preferred.
Carboxylated starch microspheres (Cadexomer.TM.) are available from
Perstorp (Sweden).
[0059] Other suitable materials for the microspheres include
hyaluronic acid, chondroitin sulphate, alginate, heparin and
heparin-albumin conjugates, as described in Kwon et al. (Int. J.
Pharm. 79, 191, 1991).
[0060] Further materials that may be used for the microspheres
include carboxymethyl dextran (e.g. CM Sephadex.TM.), sulphopropyl
dextran (e.g. SP Sephadex.TM.), carboxymethyl agarose (e.g. CM
Sepharose.TM.), carboxymethyl cellulose, cellulose phosphate,
sulphoxyethyl cellulose, agarose (e.g. Sepharose.TM.), cellulose
beads (e.g. Sephacel.TM.) and dextran beads (e.g. Sephadex.TM.)
which are all available from Pharmacia, Sweden.
[0061] The term microsphere as used herein refers particularly to
substantially spherical particles which can be a monolithic solid
sphere or a small capsule. To ensure correct deposition in the
nasal cavity, the microspheres preferably have a mean diameter of
between 0.5 and 250 .mu.m, preferably between 10 .mu.m and 150
.mu.m and more preferably between 10 and 100 .mu.m as measured
using a conventional light microscope.
[0062] Microspheres can be made by procedures well known in the art
including spray drying, coacervation and emulsification (see for
example Davis et al. Microsphere and Drug Therapy, Elsevier, 1984;
Benoit et al. Biodegradable Microspheres: Advances in Production
Technologies, Chapter 3, Ed. Benita, S, Dekker, New York, 1996;
Microencapsulation and related Drug Processes, Ed. Deasy, Dekker,
1984, New York, pp 82, 181 and 225; U.S. Pat. Nos. 2,730,457 and
3,663,687).
[0063] In the spray drying process, the material used to form the
body of the microsphere is dissolved in a suitable solvent (usually
water) and the solution spray dried by passing it through an
atomisation nozzle into a heated chamber. The solvent evaporates to
leave solid particles in the form of microspheres.
[0064] In the process of coacervation, microspheres can be produced
by interacting a solution of a polysaccharide carrying a positive
charge with a solution of a polysaccharide carrying a negative
charge. The polysaccharides interact to form an insoluble coupling
that can be recovered as microspheres.
[0065] In the emulsification process, an aqueous solution of the
polysaccharide is dispersed in an oil phase to produce a water in
oil emulsion in which the polysaccharide solution is in the form of
discrete droplets dispersed in oil. The microspheres can be formed
by heating, chilling or cross-linking the polysaccharide and
recovered by dissolving the oil in a suitable solvent.
[0066] The microspheres can be hardened before combining with the
drug by well known cross-linking procedures such as heat treatment
or by using chemical cross-linking agents. Suitable agents include
dialdehydes, including glyoxal, malondialdehyde, succinicaldehyde,
adipaldehyde, glutaraldehyde and phthalaldehyde, diketones such as
butadione, epichlorohydrin, polyphosphate and borate. Dialdehydes
are used to cross-link proteins such as albumin by interaction with
amino groups and diketones form Schiff bases with amino groups.
Epichlorohydrin converts compounds with nucleophilic centres such
as amino or hydroxyl to epoxide derivatives. The cross-linkers used
for ion-exchange microspheres should not be directed towards the
negatively or alternatively positively charged groups required for
binding the drug.
[0067] For microsphere compositions of the invention, the drug such
as apomorphine is preferably in salt form to ensure that it is
ionised. The drug is sorbed to the microspheres by admixing with
the microspheres after their formation. This may be achieved by
suspending the microspheres in an aqueous buffer and then adding
the drug in solution. The microspheres can then be recovered by a
process of freeze drying.
[0068] The drug can be combined with the microspheres at different
ratios. A quantity of microspheres greater than that of the drug on
a weight to weight basis is preferred. The amount chosen will be
dictated by the dose of the drug and the complexation properties of
the microsphere.
[0069] It is possible to control the shape of the plasma level time
profile by the amount of anionic or cationic polysaccharide
material or polymer that is added to the nasal formulation
containing the drug useful in erectile dysfunction. Taking
apomorphine as the drug, a plasma level suitable for the treatment
of erectile dysfunction is believed to be from 0.5 to 5.0 ng/ml.
The duration of effect should be from 15 to 30 minutes. A suitable
nasal dose of apomorphine will be between 0.5 and 5.0 mg. A
preferred nasal dose will be between 1.0 and 3.0 mg.
[0070] The formulation, if in the form of a liquid, can be
administered using a simple nasal spray device available from
companies such as Valois or Pfeiffer.
[0071] Microspheres or other powder formulations can be
administered using a powder device. Suitable powder devices are
available from Bespak in the United Kingdom. Other suitable powder
devices are the nasal insufflators used for drugs such as
Rhinocort.TM. (marketed by Teijin in Japan). The device from Direct
Haler (Denmark) can also be used. Such nasal devices can be passive
with the patient having to draw a dose of the powder into the nasal
cavity from the device through their own inspiration or active with
powder being blown into the nasal cavity through some mechanical
process, e.g. using a rubber bulb or spring system.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0072] Those skilled in the art will also appreciate that many of
the currently available devices for the administration of dry
powders to the lung can easily be adapted to deliver the powder
formulations of this invention to the nose. Suitable devices
include those available from Dura, Valois, Glaxo-Wellcome, Norton,
Fisons, Leiras (RPR). These devices are well described in the prior
art and are known by names such as Ultrahaler.TM., Prohaler.TM. and
Easibreathe.TM.. The dry powder devices intended for lung delivery
can be modified by the attachment of a small nozzle. The device
from Orion in Finland is available with such a nasal nozzle
system.
[0073] In the drawings:
[0074] FIG. 1 is a schematic drawing of a Franz diffusion cell.
[0075] FIG. 2 is a graph showing the release of apomorphine from
liquid formulations prepared from Pectin and Pluronic.TM. F127 and
from a simple apomorphine solution as control.
[0076] FIG. 3 is a graph showing the plasma level versus time
profile expected for a liquid apomorphine formulation comprising a
gelling polysaccharide excipient following nasal administration to
a rat.
[0077] FIG. 4 is a graph showing the plasma level versus time
profile expected for a liquid apomorphine formulation comprising a
block copolymer excipient following nasal administration to a
rat.
DETAILED DESCRIPTION OF THE INVENTION
[0078] The present invention is now illustrated but not limited
with reference to the following examples.
[0079] The following examples provide details of the preparation
and release properties of nasal formulations useful for the
delivery of drugs intended for the treatment of erectile
dysfunction such as apomorphine. The release of the drug was
measured using a diffusion cell apparatus based on an original
design by Franz. Such Franz diffusion cells for measuring drug
release are familiar to the skilled person and are described in
WO-94/27576. The diffusion of the drug across an artificial
membrane in the form of cellulose nitrate into an electrolyte
solution chosen to simulate the ionic environment of the nasal
cavity was conducted at 37.degree. C. A diagram of the apparatus is
provided in FIG. 1.
[0080] The electrolyte fluid had the following composition:
[0081] Na.sup.+ions--150 mEq/1
[0082] K.sup.+ions--40 mEq/1,
[0083] Ca.sup.2+ions--8 mEq/1.
[0084] A 2 mg/ml aqueous solution of apomorphine was used as a
control. 20 mg of apomorphine were weighed into a 10 ml volumetric
flask and the flask contents made up to volume with water.
[0085] In each experiment a 50 .mu.l aliquot of the formulation was
applied to the membrane in order to measure diffusion across the
membrane.
EXAMPLE 1
Pectin Based Formulation
[0086] Into a 25 ml volumetric flask was weighed 250 mg of pectin
110 (obtained from Copenhagen Pectin A/S). 15 ml of ultrapure water
was then added and the solution stirred overnight on a magnetic
stirrer. The flask contents were made up to volume with ultrapure
water.
[0087] 10 mg of apomorphine (obtained from Sigma) were weighed into
a 5 ml volumetric flask. To the flask was added 3 ml of the 10
mg/ml pectin 110 solution. The mixture was stirred for 30 minutes
and the flask contents made to volume with the 10 mg/ml pectin 110
solution.
EXAMPLE 2
Pluronic.TM. F127 Formulation
[0088] Pluronic.TM. F127 (Poloxamer 407) was obtained from BASF.
Into a 100 ml conical flask was weighed 10 g of Pluronic.TM. F127.
50 ml of ultrapure water was then added and the solution left to
stir on a magnetic stirrer. The conical flask was sealed with
parafilm and was placed in the refrigerator at 5.degree. C. for 30
minutes. This ensures that the Pluronic.TM. F127 solution is in the
liquid state since solutions of this block copolymer are known to
gel when the temperature is raised.
[0089] 10 mg of apomorphine were weighed into a 5 ml volumetric
flask. To the flask was added 3 ml of the cooled, 200 mg/ml
Pluronic.TM. F127 solution. The mixture was allowed to stir and the
flask contents made to volume with the 200 mg/ml Pluronic.TM. F127
solution.
EXAMPLE 3
Measurement of Drug Release Kinetics
[0090] The Franz diffusion cell apparatus was used to measure
diffusion of drug across an artificial cellulose nitrate membrane
(0.45 .mu.m thickness) from the following formulations:
[0091] I. 2 mg/ml apomorphine (control solution)
[0092] II. 2 mg/ml apomorphine/10 mg/ml pectin 110
[0093] III. 2 mg/ml apomorphine/200 mg/ml Pluronic.TM. F127
[0094] In each case a 50 .mu.l aliquot of formulation was applied
to the membrane in order to measure diffusion of drug across the
membrane. The Pluronic.TM. F127 formulation had to be cooled for at
least 30 minutes at 5.degree. C. to keep the formulation in the
liquid state.
[0095] For each of the formulations I to III, two Franz diffusion
cell release profiles were obtained, the data absorbance vs time
were meaned, expressed as a percentage and plotted. The results are
illustrated in FIG. 2.
[0096] The control solution of apomorphine alone diffused rapidly
through the cellulose nitrate membrane with 100% of the drug
entering the Franz diffusion cell in 60 minutes. In contrast,
approximately 60% of the apomorphine was released from the pectin
110 system and approximately 80% of the apomorphine was released
from the Pluronic.TM. F127 after 60 minutes. After 120 minutes, 96%
and 92% of the apomorphine was released from the pectin 110 and
Pluronic.TM. F127 systems respectively.
EXAMPLE 4
A Michrosphere Based Formulation
[0097] Starch microspheres carrying carboxyl groups (Cadexomer.TM.)
were obtained from Perstorp Fine Chemical Companies, Sweden. The
microspheres had a particle diameter in the range of 53-106 micron
in the unswollen state. 5 g of a 10:1 weight ratio of carboxylated
to non-carboxylated starch microspheres were mixed with 20 mls of
an aqueous solution of apomorphine (pH adjusted to 7) at a
concentration of 5% w/v (i.e. 5 g of apomorphine per 100 mls of
solution). The system was freeze dried and 50 mg doses of the
powder were packed into gelatin capsules for administration by a
nasal insufflator device.
EXAMPLE 5
Preparation of Apomorphine Polymer Complex
[0098] An apomorphine/gellan complex was prepared as follows.
[0099] A gellan solution was prepared by adding 500 mg of gellan to
15 ml of water. The resulting mixture was stirred overnight on a
magnetic stirrer to dissolve the gellan in the water. The solution
was then made up to 25 ml with water.
[0100] An aqueous solution of apomorphine 10 mg/ml was added to the
gellan solution. A cloudy mixture resulted. This was stirred and
the precipitate allowed to settle. The slurry was centrifuged and
the recovered precipitate washed with deionized water to remove
excess drug. The precipitate was recovered once again by
centrifugation and freeze dried in a 100 ml round bottom flask at
-60.degree. C. for 24 hours.
[0101] A fluffy material was produced. This can be placed in
suspension in a suitable vehicle such as saline and then dosed
intranasally as a spray. The material can also be dosed as a powder
by physical admixture with adhesive microspheres such as starch
microspheres as described in PCT/GB88/00836.
EXAMPLE 6
Pharmacokinetic Evaluation
[0102] The beneficial properties of the formulations that comprise
this invention can be evaluated in a suitable animal model such as
the rat in order to determine the changed pharmacokinetic profile
of the drug as compared to a simple nasal solution.
[0103] Anaesthetised male Sprague-Dawley rats (body weight 250 g to
330 g) can be used in such experiments. The rats are starved for 12
hours prior to dosing. Anaesthesia is induced by intraperitoneal
administration of urethane (1.25 g/kg of either a 10% w/v or 40%
w/v solution) and maintained by additional doses of 1 mL of a 40%
w/v solution as required.
[0104] The animals are modified surgically so as to maintain
respiratory function and to prevent the nasal formulation reaching
the gastrointestinal tract. Blood samples are obtained by
cannulation of the jugular vein. This method has been described in
detail by Hirai (Int. J. Pharm. 1, 317, 1981) and modified by
Fisher et al. (J. Pharm. Pharmacol. 39, 357, 1987). The
formulations are dosed into the nasal cavity in a volume of 50
.mu.l. Blood samples are collected at suitable time intervals in
order to obtain a pharmacokinetic profile (e.g. 0, 2, 4, 6, 8, 10,
15, 20, 45, 60, 90, 120 mins post administration).
[0105] The blood samples are assayed for drug by standard HPLC. For
apomorphine, the method is based on HPLC with electrochemical
detection as described by Sam et al. (J. Chromat. of B. 658, 311,
1994). A dose of 0.5 mg of apomorphine is used for liquid
polysaccharide and microsphere formulations. This dose is chosen in
order to obtain sufficient concentration for analysis. For liquid
formulations based on gelling block copolymers a dose of 1 mg of
apomorphine is used. When employing a simple solution form of
apomorphine a sharp peak in the plasma level profile is found.
However, for the polysaccharide based systems in solution,
suspension or microsphere form a delayed peak of about 30 minutes
is found. The peak height is substantially reduced (for example
from 1400 ng/ml for the simple nasal solution to 350 ng/ml for the
polysaccharide liquid system described in Example 1.
[0106] For the poloxamer vehicle a similar delay in the peak height
is found and a delay in the time to maximum from less than 10
minutes to greater than 30 minutes. The plasma concentration is
reduced from about 1500 ng/ml for a simple nasal solution to about
750 ng/ml for the Poloxamer 407 (Pluronic.TM. F-127 system)
described in Example 2.
[0107] Representative curves are shown in FIGS. 3 and 4.
[0108] It will be clear to the skilled artisan that the
formulations described in the foregoing examples can be further
modified for ease of administration by the addition of other known
pharmaceutical excipients. Also other drugs useful in the treatment
of erectile dysfunction can be used in place of the
apomorphine.
* * * * *