U.S. patent application number 10/062020 was filed with the patent office on 2002-11-07 for nasal delivery of apomorphine.
This patent application is currently assigned to Nastech Pharmaceutical Company, Inc.. Invention is credited to Achari, Raja G., Ahmed, Shamim, Behl, Charanjit R., deMeireles, Jorge C., Liu, Tianquing, Romeo, Vincent D., Sileno, Anthony P..
Application Number | 20020165249 10/062020 |
Document ID | / |
Family ID | 23306601 |
Filed Date | 2002-11-07 |
United States Patent
Application |
20020165249 |
Kind Code |
A1 |
Achari, Raja G. ; et
al. |
November 7, 2002 |
Nasal delivery of apomorphine
Abstract
Intranasal delivery methods and compositions for the delivery of
dopamine receptor agonists are provided which are effective for the
amelioration of erectile dysfunction in a mammal without causing
substantial intolerable adverse side effects to the mammal. Nasally
administered compositions for treating male erectile dysfunction in
a mammal are also provided which include a therapeutically
effective amount of a dopamine receptor agonist which has been
dispersed in a system to improve its solubility and/or
stability.
Inventors: |
Achari, Raja G.;
(Millington, NJ) ; Ahmed, Shamim; (Central Islip,
NY) ; Behl, Charanjit R.; (Hauppauge, NY) ;
deMeireles, Jorge C.; (Syosset, NY) ; Liu,
Tianquing; (Central Islip, NY) ; Romeo, Vincent
D.; (Massapequa Park, NY) ; Sileno, Anthony P.;
(Brookhaven Hamlet, NY) |
Correspondence
Address: |
Woodcock Washburn LLP
46th Floor
One Liberty Place
Philadelphia
PA
19103
US
|
Assignee: |
Nastech Pharmaceutical Company,
Inc.
|
Family ID: |
23306601 |
Appl. No.: |
10/062020 |
Filed: |
January 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10062020 |
Jan 31, 2002 |
|
|
|
09334304 |
Jun 16, 1999 |
|
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60096545 |
Aug 14, 1998 |
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Current U.S.
Class: |
514/289 |
Current CPC
Class: |
A61P 15/10 20180101;
A61K 9/0043 20130101; A61K 31/00 20130101; A61K 31/473 20130101;
A61K 31/44 20130101 |
Class at
Publication: |
514/289 |
International
Class: |
A61K 031/4745 |
Claims
What is claimed is:
1. A method of ameliorating male erectile dysfunction in a mammal
comprising nasally administering a therapeutically effective amount
of a dopamine receptor agonist to said mammal before, during or
after sexual activity which is sufficient to induce an erection
without causing substantial intolerable adverse side effects to
said mammal.
2. The method of claim 1, wherein said dopamine receptor agonist is
selected from the group consisting of apomorphine, chemically
modified equivalents and pharmaceutical salts thereof.
3. A pharmaceutical composition for treating male erectile
dysfunction in a mammal comprising a therapeutically effective
amount of a dopamine receptor agonist in combination with a nasal
delivery system, wherein said pharmaceutical composition does not
cause substantial intolerable adverse side effects in said
mammal.
4. The pharmaceutical composition of claim 3, wherein said dopamine
receptor agonist is apomorphine.
5. The pharmaceutical composition of claim 4, wherein said
apomorphine is dispersed in an aqueous or non-aqueous
formulation.
6. The pharmaceutical composition of claim 4, wherein said nasal
delivery system comprises a buffer to maintain the pH of said
dopamine receptor agonist, a pharmaceutically acceptable thickening
agent and a humectant.
7. The pharmaceutical composition of claim 6, further comprising
one or more pharmaceutical excipients.
8. The pharmaceutical composition of claim 7, further comprising a
pharmaceutically acceptable preservative.
9. The pharmaceutical composition of claim 6, wherein said buffer
is selected from the group consisting of acetate, citrate,
prolamine, carbonate and phosphate buffers.
10. The pharmaceutical composition of claim 6, wherein said
thickening agent is selected from the group consisting of methyl
cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl
cellulose, carbomer, polyvinyl alcohol, alginates, acacia,
chitosans and combinations thereof.
11. The pharmaceutical composition of claim 6, wherein said
humectant is selected from the group consisting of sorbitol,
glycerol, mineral oil, vegetable oil and combinations thereof.
12. A method of treating erectile dysfunction in a male mammal
comprising nasally administering the composition according to claim
3.
13. The pharmaceutical composition of claim 3, wherein said
dopamine receptor agonist is selected from the group consisting of
apomorphine, chemically modified equivalents and pharmaceutical
salts thereof.
14. The pharmaceutical composition of claim 13, wherein said
chemically modified equivalents comprise a pro-drug.
15. A nasally administered pharmaceutical composition comprising a
therapeutically effective amount of a dopamine receptor agonist
dispersed in a buffer to maintain its pH, a pharmaceutically
acceptable thickening agent and a humectant, wherein sand nasally
administered pharmaceutical composition does not cause substantial
intolerable adverse side effects when administered to said
mammal.
16. The nasally administered pharmaceutical composition of claim
15, wherein said dopamine receptor agonist is selected from the
group including apomorphine, chemically modified equivalents and
pharmaceutical salts thereof.
17. The nasally administered pharmaceutical composition of claim
16, wherein said chemically modified equivalents comprise a
pro-drug.
18. A method of treating impotence and male erectile dysfunction in
a human in need of such treatment comprising administering to a
nasal membrane of said human an effective amount of a composition
according to claim 15.
19. A method of treating male erectile dysfunction without causing
substantial intolerable adverse side effects in a mammal comprising
administering into a nasal cavity of said mammal a therapeutically
effective dosage of a dopamine receptor agonist in combination with
a nasal delivery system comprising a pharmaceutically acceptable
buffer, a thickening agent and a humectant.
20. The method of claim 19, wherein said dopamine receptor agonist
is selected from the group consisting of apomorphine, chemically
modified equivalents and pharmaceutical salts thereof.
21. The method of claim 20, wherein said chemically modified
equivalents comprise a pro-drug.
22. A method of administering a therapeutically effective amount of
a dopamine receptor agonist to a mammal through a nasal membrane
thereof comprising delivering to said nasal membrane a
therapeutically effective amount of said dopamine receptor agonist
which does not cause substantial intolerable adverse side effects
in said mammal, wherein said dopamine receptor agonist is dispersed
in a nasal delivery system comprising a pharmaceutically acceptable
a buffer, a thickening agent and a humectant.
23. The method of claim 22, wherein said dopamine receptor agonist
is effective for the treatment of male erectile dysfunction in a
mammal.
24. An intranasal dosage unit for treating impotency or erectile
dysfunction in a mammal comprising an effective amount of a
dopamine receptor agonist in combination with an intranasal carrier
comprising a buffer, wherein said dosage unit does not cause
substantial intolerable adverse side effects in said mammal and an
erection is produced in said mammal within about 60 minutes of
administering said dosage unit to a nasal mucosa of said
mammal.
25. The intranasal dosage unit of claim 24, wherein said erection
is produced within about 45 minutes.
26. The intranasal dosage unit of claim 24, wherein said erection
is produced within about 30 minutes.
27. The intranasal dosage unit of claim 24, wherein said erection
is produced within about 15 minutes.
28. The intranasal dosage unit of claim 24, wherein said erection
is produced in less than about 15 minutes.
29. The intranasal dosage unit of claim 24, wherein said intranasal
carrier is an aqueous solution.
30. The intranasal dosage unit of claim 29, wherein said aqueous
solution is selected from the group consisting of aqueous gels,
aqueous suspensions, aqueous liposomal dispersions, aqueous
emulsions, aqueous microemulsions and combinations thereof.
31. The intranasal dosage unit of claim 24, wherein said intranasal
carrier is a non-aqueous solution.
32. The intranasal dosage unit of claim 31, wherein said
non-aqueous solution is selected from the group consisting of
non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal
dispersions, non-aqueous emulsions, non-aqueous microemulsions and
combinations thereof.
33. The intranasal dosage unit of claim 24, wherein said intranasal
carrier is a powder formulation.
34. The intranasal dosage unit of claim 33, wherein said powder
formulation is selected from the group consisting of simple powder
mixtures, powder microspheres, coated powder microspheres,
ribosomes and combinations thereof.
35. The intranasal dosage unit of claim 24, further comprising an
excipient having bio-adhesive properties.
36. The intranasal dosage unit of claim 24, wherein said buffer is
selected to have a pH of from about 3 to about 10.
37. The intranasal dosage unit of claim 24, further comprising a
humectant.
38. The intranasal dosage unit of claim 37, wherein said humectant
is selected from the group consisting of soothing agents, membrane
conditioners, sweeteners and combinations thereof.
39. A nasally administered pharmaceutical composition for treating
male erectile dysfunction in a mammal comprising a therapeutically
effective amount of a dopamine receptor agonist which has been
dispersed in a system to improve its solubility.
40. The nasally administered pharmaceutical composition of claim
39, wherein said dopamine receptor agonist is selected from the
group consisting of apomorphine, chemically modified equivalents
and pharmaceutical salts thereof.
41. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises glycerin.
42. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises a glycol derivative.
43. The nasally administered pharmaceutical composition of claim
42, wherein said glycol derivative is propylene glycol.
44. The nasally administered pharmaceutical composition of claim
42, wherein said glycol derivative is polyethylene glycol.
45. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises a sugar alcohol.
46. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises propylene glycol and
glycerin.
47. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises ascorbic acid and water.
48. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises sodium ascorbate and water.
49. The nasally administered pharmaceutical composition of claim
39, wherein said system comprises sodium metabisulfite and
water.
50. A nasally administered pharmaceutical composition for treating
male erectile dysfunction in a mammal comprising a therapeutically
effective amount of a dopamine receptor agonist which has been
dispersed in a system to improve its stability.
51. The nasally administered pharmaceutical composition of claim
50, wherein said dopamine receptor agonist is selected from the
group consisting of apomorphine, chemically modified equivalents
and pharmaceutical salts thereof.
52. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises glycerin.
53. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises a glycol derivative.
54. The nasally administered pharmaceutical composition of claim
53, wherein said glycol derivative is propylene glycol.
55. The nasally administered pharmaceutical composition of claim
53, wherein said glycol derivative is polyethylene glycol.
56. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises a sugar alcohol.
57. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises propylene glycol and
glycerin.
58. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises polyethylene glycol 400.
59. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises ascorbic acid and water.
60. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises sodium ascorbate and water.
61. The nasally administered pharmaceutical composition of claim
50, wherein said system comprises sodium metabisulfite and water.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates generally to intranasal
delivery methods and dosage forms. More particularly, methods and
dosage forms for the safe and reliable intranasal delivery of
apomorphine to ameliorate erectile dysfunction in a mammal are
provided.
[0002] Apomorphine is a potent dopamine receptor agonist which has
a variety of uses. For example, it has been effectively used as an
adjunctive medication in the treatment of Parkinson's disease which
is complicated by motor fluctuations (T. van Laar et al., Arch.
Neurol., 49: 482-484 (1992)). In particular, apomorphine has been
used for relieving "off-period" symptoms in Parkinson patients with
such response fluctuations. In the study by van Laar et al., the
intranasally applied apomorphine used to achieve the results
reportedly included an aqueous solution of apomorphine
hydrochloride (HCL) at a concentration of 10 mg/ml. This
formulation is also used for parenteral application and is
published in different Pharmacopeia's.
[0003] Also, U.S. Pat. No. 5,756,483 issued to Merkus (hereinafter
"the '483 patent") which is hereby incorporated by reference,
discloses the intranasal delivery of a variety of compositions,
including apomorphine in combination with a cyclodextrin and/or a
polysaccharide and/or a sugar alcohol for treating Parkinson's
disease. The '483 patent, however, discloses very narrow dosage
ranges of 0.1 to 2 mg of apomorphine per nostril which is
specifically tailored for the amelioration of the "off-period"
symptoms of Parkinson's disease.
[0004] Further, U.S. Pat. No. 5,770,606 issued to El-Rashidy et al.
(hereinafter "the '606 patent"), which is hereby incorporated by
reference, discloses the delivery of apomorphine in a sublingual
dosage unit for alleviating psychogenic impotence or erectile
dysfunction with no substantial undesirable side effects. The '606
patent further includes results from a study conducted by the
inventors on the effect of apomorphine delivered intranasally on
erectile dysfunction. The study suggested that intranasal delivery
of apomorphine at concentrations of 2.5 mg to 3.5 mg was effective
for eliciting an erection in patients suffering from erectile
dysfunction, however, since the study participants suffered
extensive and serious side effects including hypotension, nausea,
vomiting, impaired vision, diaphoresis and ashen coloring, it was
concluded that intranasal delivery of apomorphine to treat erectile
dysfunction was insufficiently safe and reliable to be a viable
commercial product.
[0005] Accordingly, it is one of the purposes of this invention,
among others, to provide a safe and reliable intranasal delivery
system for apomorphine that ensures delivery of therapeutic amounts
of the drug into the bloodstream which is fast acting, easily
administered and causes no substantial adverse side effects.
SUMMARY OF THE INVENTION
[0006] It has now been discovered that this and other purposes can
be achieved by the present invention, which provides for a method
for ameliorating male erectile dysfunction in a mammal. This method
includes the nasal administration of a dopamine receptor agonist to
the mammal before, during or after sexual activity in an amount
sufficient to induce an erection without inducing substantial
intolerable side effects in the mammal. Preferably, the dopamine
receptor agonist is apomorphine.
[0007] The present invention also provides for a pharmaceutical
composition for treating male erectile dysfunction in a mammal
without causing substantial intolerable adverse side effects that
includes a therapeutically effective amount of a dopamine receptor
agonist in combination with a nasal delivery system. Preferably,
the dopamine receptor agonist is selected from the group consisting
of apomorphine, chemically modified equivalents and pharmaceutical
salts thereof and even further preferably, the dopamine receptor
agonist is apomorphine. The chemically modified equivalents of
apomorphine preferably include a pro-drug. Further, it is
preferable that apomorphine is dispersed in an aqueous or
non-aqueous formulation.
[0008] In addition, the nasal delivery system of the pharmaceutical
composition can include a buffer to maintain the pH of the dopamine
receptor agonist, a pharmaceutically acceptable thickening agent
and a humectant. The pharmaceutical composition can further include
one or more pharmaceutical excipients and even further include a
pharmaceutically acceptable preservative.
[0009] The buffer of the nasal delivery system can be selected from
the group including acetate, citrate, prolamine, carbonate and
phosphate buffers.
[0010] The thickening agent of the nasal delivery system can be
selected from the group including methyl cellulose, xanthan gum,
carboxymethyl cellulose, hydroxypropyl cellulose, carbomer,
polyvinyl alcohol, alginates, acacia, chitosans and combinations
thereof.
[0011] The humectant of the nasal delivery system can be selected
from the group including sorbitol, glycerol, mineral oil, vegetable
oil and combinations thereof.
[0012] The present invention also provides a method of treating
erectile dysfunction in a male mammal including nasally
administering a pharmaceutical composition including a
therapeutically effective amount of a dopamine receptor agonist in
combination with a nasal delivery system wherein the pharmaceutical
composition does not cause substantial intolerable adverse side
effects in the mammal.
[0013] The present invention also provides for a nasally
administered pharmaceutical composition that includes a
therapeutically effective amount of a dopamine receptor agonist
dispersed in a buffer to maintain its pH, a pharmaceutically
acceptable thickening agent and a humectant, wherein said nasally
administered pharmaceutical composition does not cause substantial
intolerable adverse side effects when administered to a mammal. The
dopamine receptor agonist of the nasally administered
pharmaceutical composition is selected from the group including
apomorphine, chemically modified equivalents and pharmaceutical
salts thereof. It is further preferable that chemically modified
equivalents of apomorphine include a pro-drug.
[0014] The present invention also provides for a method of treating
impotence and male erectile dysfunction in a human in need of such
treatment including administering to a nasal membrane of the human
an effective amount of a nasally administered pharmaceutical
composition including a therapeutically effective amount of a
dopamine receptor agonist dispersed in a buffer to maintain its pH,
a pharmaceutically acceptable thickening agent and a humectant,
wherein the nasally administered pharmaceutical composition does
not cause substantial intolerable adverse side effects when
administered to the human.
[0015] Another preferred method of the present invention also
provides for treating male erectile dysfunction in a mammal without
causing substantial intolerable adverse side effects. This method
includes administering into a nasal cavity of the mammal a
therapeutically effective dosage of a dopamine receptor agonist in
combination with a nasal delivery system. The nasal delivery system
includes a pharmaceutically acceptable buffer, a thickening agent
and a humectant. The dopamine receptor agonist is selected from the
group including apomorphine, chemically modified equivalents and
pharmaceutical salts thereof. Preferably, chemically modified
equivalents of apomorphine include a pro-drug.
[0016] Another preferred method of the present invention is a
method for administering a therapeutically effective amount of a
dopamine receptor agonist to a mammal through a nasal membrane
without causing substantial intolerable adverse side effects. This
method includes delivering to the nasal membrane of a mammal a
dopamine receptor agonist dispersed in a nasal delivery system
which includes a pharmaceutically acceptable buffer, a thickening
agent and a humectant. Preferably, the dopamine receptor agonist is
effective for the treatment of male erectile dysfunction in a
mammal.
[0017] The present invention also provides for an intranasal dosage
unit for treating impotency or erectile dysfunction in a mammal
which does not cause substantial intolerable adverse side effects.
The dosage unit includes an effective amount of a dopamine receptor
agonist in combination with an intranasal carrier. The intranasal
carrier includes a buffer. The buffer pH is selected to enhance
absorption of the dopamine receptor agonist and to produce an
erection within about 60 minutes of administering the dosage unit
to a nasal mucosa of the mammal. Preferably, an erection is
produced within about 45 minutes, more preferably within about 30
minutes, most preferably within about 15 minutes, and even further
preferably in less than about 15 minutes.
[0018] The intranasal carrier of the intranasal dosage unit is
preferably an aqueous solution. Further, the aqueous solution can
be selected from the group including aqueous gels, aqueous
suspensions, aqueous liposomal dispersions, aqueous emulsions,
aqueous microemulsions and combinations thereof.
[0019] Alternatively, the intranasal carrier of the intranasal
dosage unit is a non-aqueous solution. The non-aqueous solution can
be selected from a group including non-aqueous gels, non-aqueous
suspensions, non-aqueous liposomal dispersions, non-aqueous
emulsions and non-aqueous microemulsions and combinations
thereof.
[0020] The intranasal carrier of the intranasal dosage unit can
also be a combination of an aqueous solution and a non-aqueous
solution.
[0021] Alternatively, the carrier of the intranasal dosage unit is
a powder formulation. The powder formulation can be selected from a
group including simple powder mixtures, powder microspheres, coated
powder microspheres, liposomal dispersions and combinations thereof
Preferably, the powder formulation is powder microspheres. The
powder microspheres are preferably formed from various
polysaccharides and celluloses selected from the group including
starch, methylcellulose, xanthan gum, carboxymethylcellulose,
hydroxypropyl cellulose, carbomer, alginate polyvinyl alcohol,
acacia, chitosans and combinations thereof.
[0022] The intranasal dosage unit can also include an excipient
having bio-adhesive properties. Preferably, the buffer of the
intranasal dosage unit is selected to have a pH of from about 3 to
about 10 and more preferably from about 3.5 to 7.0.
[0023] Preferably, the intranasal dosage unit includes a humectant.
A humectant can be selected from the group consisting of soothing
agents, membrane conditioners, sweeteners and combinations
thereof.
[0024] The present invention also provides for a nasally
administered pharmaceutical composition for treating male erectile
dysfunction in a mammal including a therapeutically effective
amount of a dopamine receptor agonist which has been dispersed in a
system to improve its solubility. The dopamine receptor agonist of
this composition is selected from the group consisting of
apomorphine, chemically modified equivalents and pharmaceutical
salts thereof. The system of this composition includes one of the
following or combinations thereof: a glycol derivative; a sugar
alcohol; glycerin; propylene glycol and glycerin; polyethylene
glycol 400; ascorbic acid and water; sodium ascorbate and water; or
sodium metabisulfite and water. Preferred glycol derivatives
include propylene glycol and polyethylene glycol. Preferred sugar
alcohols include mannitol and xylitol.
[0025] The present invention also provides for a nasally
administered pharmaceutical composition for treating male erectile
dysfunction in a mammal including a therapeutically effective
amount of a dopamine receptor agonist which has been dispersed in a
system to improve its stability. The dopamine receptor agonist of
this composition is selected from the group consisting of
apomorphine, chemically modified equivalents and pharmaceutical
salts thereof. The system of this composition includes one of the
following or combinations thereof: a glycol derivative; a sugar
alcohol; glycerin; propylene glycol and glycerin; polyethylene
glycol 400; ascorbic acid and water; sodium ascorbate and water; or
sodium metabisulfite and water. Preferred glycol derivatives
include propylene glycol and polyethylene glycol. Preferred sugar
alcohols include mannitol and xylitol.
[0026] These and other advantages of the present invention will be
appreciated from the detailed description and examples which are
set forth herein. The detailed description and examples enhance the
understanding of the invention, but are not intended to limit the
scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The present invention is directed to compositions and
methods for treating sexual dysfunction in a mammal. In particular,
a method is provided for ameliorating male erectile dysfunction in
a mammal by nasally administering to the mammal a therapeutically
effective amount of a dopamine receptor agonist before, during or
after sexual activity which is sufficient to induce an erection
without causing substantial adverse side effects in the mammal.
[0028] For purposes of the present invention, the phrase "erectile
dysfunction" is intended to encompass certain medically related
symptoms resulting in the inability of a male to perform sexually,
including penile dysfunction, as well as male impotence. As used
herein, the term "impotence" is intended to mean the inability of a
male to achieve and/or sustain a penile erection sufficient for
vaginal penetration and intercourse.
[0029] As used herein, a "dopamine receptor agonist" is intended to
encompass those members of the dopamine receptor agonist family
which are able to ameliorate male erectile dysfunction when
administered to a mammal. Apomorphine is an example of such a
composition. Thus, the present invention is intended to encompass
apomorphine and its functional equivalents including pharmaceutical
salts and chemically modified equivalents thereof, including for
example pro-drug forms of apomorphine. Apomorphine can be
represented by the formula: 1
[0030] and in the present invention can exist in a free base form
or as an acid addition salt. For the purposes of the present
invention, apomorphine hydrochloride is preferred; however, other
pharmacologically acceptable moieties thereof can be utilized as
well. The term "apomorphine" as used herein includes the free base
form of this compound as well as pharmacologically acceptable acid
addition salts thereof. In addition to the hydrochloride salt of
apomorphine, other pharmacologically acceptable acid addition salts
of apomorphine include the hydrobromide, the hydroiodide, the
bisulfate, the phosphate, the acid phosphate, etc.
[0031] For the purposes of the present invention, apomorphine or a
similarly acting dopamine receptor agonist is administered nasally
in an amount sufficient to excite cells in the mid-brain region of
the patient but without substantial adverse side effects.
[0032] This cell excitation is believed to be part of a cascade of
stimulation that is likely to include neurotransmission with
serotonin and oxytocin. Because dopamine receptors agonists act
directly on regions of the mid-brain, the present invention also
contemplates the use of such agonists for improving the sexual
desire in both male and female mammals, as well as the amelioration
of erectile dysfunction in males as set forth above.
[0033] The dopamine receptors in the mid-brain region of a patient
can be stimulated to a degree sufficient to cause an erection by
the nasal administration of apomorphine so as to maintain an
adequate plasma concentration of apomorphine. The amount of
apomorphine nasally administered is an amount sufficient to cause
an erection but is low enough not to cause substantial intolerable
adverse side effects. As used herein, "substantial intolerable
adverse side effects" include those effects caused by either the
delivery system or the dopamine receptor agonist which are
incompatible with the health of the user or which are so unpleasant
as to discourage the continued use of the composition. Such effects
include, for example, hypotension, nausea, vomiting, impaired
vision, diaphoresis and ashen coloring.
[0034] Apomorphine is nasally administered about 30 to about 45
minutes prior to sexual activity, preferably about 15 to about 20
minutes prior to sexual activity, and more preferably less than 15
minutes prior to sexual activity.
[0035] The compositions according to the present invention can be
administered, for example, as a nasal spray, nasal drop,
suspension, gel, ointment, cream or powder. The administration of a
composition can also include using a nasal tampon or a nasal sponge
containing a composition of the present invention.
[0036] The dopamine receptor agonist can also be brought into a
viscous basis via systems conventionally used, for example, natural
gums, methylcellulose and derivatives, acrylic polymers (carbopol)
and vinyl polymers (polyvinylpyrrolidone). In the present
compositions, many other excipients known in the art can be added
such as preservatives, surfactants, co-solvents, adhesives,
antioxidants, buffers, viscosity enhancing agents and agents to
adjust the pH and the osmolarity.
[0037] The amount of dopamine receptor agonist administered to a
patient will vary according to the delivery system used, and the
age and weight of the patient. There are two critical parameters
for selecting the appropriate dosage levels of the dopamine
receptor agonist. First, the dosage level must be effective for
achieving an erection in the patient and second, the dosage level
must not cause substantial intolerable adverse side effects to the
patient.
[0038] The onset of substantial intolerable adverse side effects,
for example, nausea and/or vomiting, can be obviated or delayed by
nasally delivering a dopamine receptor agonist at a controlled
dissolution rate so as to provide circulating serum levels and
mid-brain tissue levels of the dopamine receptor agonist sufficient
for an erection and without inducing nausea and/or vomiting. When
it is necessary to administer higher doses of a dopamine receptor
agonist, for example, doses above about 2 mg, the likelihood of a
substantial intolerable adverse side effect onset can be reduced by
concurrently administering a ganglionic agent capable of inhibiting
the ganglionic response, for example, nicotine or lobeline
sulfate.
[0039] Other antiemetic agents that can be used in accordance with
the present invention include metoclopramide; phenothiazines such
as chlorpromazine, prochlorperazine, pipamazine, thiethylperazine
and oxypendyl hydrochloride; serotonin (5-hydroxytryptamine or
5-IIT) agonists such as domperidone, odansetron and histamine
antagonists including buclizine hydrochloride, cyclizine
hydrochloride and dimenhydrinate; parasympathetic depressants such
as scopolamine; metopimazine; trimethobenzamide; benzquinamine
hydrochloride; and diphenidol hydrochloride.
[0040] As set forth previously, the nasal delivery systems that can
be used with the present invention can take various forms including
aqueous solutions, non-aqueous solutions and combinations thereof.
Aqueous solutions include, for example, aqueous gels, aqueous
suspensions, aqueous liposomal dispersions, aqueous emulsions,
aqueous microemulsions and combinations thereof. Non-aqueous
solutions include, for example, non-aqueous gels, non-aqueous
suspensions, non-aqueous liposomal dispersions, non-aqueous
emulsions, non-aqueous microemulsions and combinations thereof.
[0041] The various forms of the delivery system set forth above can
include a buffer to maintain the pH of the dopamine receptor
agonist, a pharmaceutically acceptable thickening agent and a
humectant. Desirably, the pH of the buffer is selected to maintain
the dopamine receptor agonist in a non-ionized form. In particular,
the pH of the buffer is selected to optimize the absorption of the
dopamine receptor agonist across the nasal mucosa. The particular
pH of the buffer, of course, can vary depending upon the particular
nasal delivery formulation as well as the specific dopamine
receptor agonist composition selected. Buffers that are suitable
for use in the present invention include acetate, citrate,
prolamine, carbonate and phosphate buffers.
[0042] With respect to the non-aqueous formulations set forth
above, suitable forms of buffering agents can be selected such that
when the formulation is delivered into the nasal cavity of a
mammal, selected pH ranges are achieved therein upon contact with,
e.g., a nasal mucosa.
[0043] In the present invention, the pH of the compositions should
be maintained from about 3.0 to about 10.0. Compositions having a
pH of less than about 3.0 or greater than about 10.0 can increase
the risk of irritating the nasal mucosa of a recipient. Further, it
is preferable that the pH of the compositions be maintained from
about 3.0 to about 7.0.
[0044] The viscosity of the compositions of the present invention
can be maintained at a desired level using a pharmaceutically
acceptable thickening agent. Thickening agents that can be used in
accordance with the present invention include methyl cellulose,
xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose,
carbomer, polyvinyl alcohol, alginates, acacia, chitosans and
combinations thereof. The concentration of the thickening agent
will depend upon the agent selected and the viscosity desired. Such
agents can also be used in a powder formulation discussed
above.
[0045] The compositions of the present invention can also include a
humectant to reduce or prevent drying of the mucus membrane and to
prevent irritation thereof. Suitable humectants that can be used in
the present invention include sorbitol, mineral oil, vegetable oil
and glycerol; soothing agents; membrane conditioners; sweeteners;
and combinations thereof. The concentration of the humectant in the
present compositions will vary depending upon the agent
selected.
[0046] In the present invention, other optional ingredients can
also be incorporated into the nasal delivery system provided that
they do not interfere with the action of the dopamine receptor
agonist or significantly decrease the absorption of the dopamine
receptor agonist across the nasal mucosa. Such ingredients include
pharmaceutically acceptable excipients and preservatives.
[0047] To extend shelf life, preservatives can be added to the
present compositions. Suitable preservatives that can be used with
the present compositions include benzyl alcohol, parabens,
thimerosal, chlorobutanol and benzalkonium chloride and preferably
benzalkonium chloride is used. Typically, the preservative will be
present in a composition in a concentration of up to about 2% by
weight. The exact concentration of the preservative, however, will
vary depending upon the intended use and can be easily ascertained
by one skilled in the art.
[0048] The present invention provides for the compositions as
described above which are administered nasally to a mammal to treat
erectile dysfunction. For purposes of the present invention,
"administered nasally" or "nasal administration" is intended to
mean that the dopamine receptor agonists are combined with a
suitable delivery system for absorption across the nasal mucosa of
a mammal, preferably, a human.
[0049] A preferred embodiment of the present invention provides for
a nasally administered pharmaceutical composition that includes a
therapeutically effective amount of a dopamine receptor agonist
dispersed in a buffer to maintain the pH of the agonist, a
pharmaceutically acceptable thickening agent and a humectant. As
used herein, "therapeutically effective amount" means a unit dosage
of the present dopamine receptor agonist which is able to be
combined with a pharmaceutically acceptable nasal delivery system
and absorbed through the nasal mucosa of a mammal to produce an
erection in about 1 hour, preferably in about 45 minutes, more
preferably in about 30 minutes, and most preferably in 15 minutes
or less which renders the intended physiological effect which is to
induce a penile erection in a mammal with penile erectile
dysfunction without causing substantial intolerable adverse side
effects to the mammal. Preferably, the dopamine receptor agonist is
selected from a group including apomorphine, chemically modified
equivalents which include a pro-drug and pharmaceutical salts
thereof.
[0050] Another preferred embodiment of the present invention
provides for a method of treating impotence and male erectile
dysfunction in a human in need of such a treatment. This method
includes administering into a nasal cavity of a mammal for
absorption through the nasal mucosa thereof a therapeutically
effective dosage of a dopamine receptor agonist as previously set
forth in combination with a nasal delivery system. The dopamine
receptor agonist is preferably selected from a group including
apomorphine, chemically modified equivalents which include a
pro-drug and pharmaceutical salts thereof. For purposes of the
present invention, the nasal delivery system can include a
pharmaceutically acceptable buffer, a thickening agent and a
humectant.
[0051] In another preferred embodiment of the present invention, a
method is provided for administering a therapeutically effective
amount of a dopamine receptor agonist to a mammal through a nasal
membrane without causing substantial intolerable adverse side
effects in the mammal. This method includes delivering to a nasal
membrane of a mammal a dopamine receptor agonist which is dispersed
in a nasal delivery system that includes a pharmaceutically
acceptable buffer, a thickening agent and a humectant. In this
method, the dopamine receptor agonist is effective for the
treatment of a sexual dysfunction in a mammal, particularly
impotence and/or erectile dysfunction in a male mammal.
[0052] Another preferred embodiment of the present invention
provides for an intranasal dosage unit for treating impotency in a
mammal and which does not cause substantial intolerable adverse
side effects in the mammal. The intranasal dosage unit includes an
effective amount of a dopamine receptor agonist in combination with
a pharmaceutically acceptable intranasal carrier. This carrier
includes a buffer. The pH of the buffer is selected as set forth
above to facilitate dopamine receptor agonist absorption through
the nasal mucosa so an erection is achieved in about 60 minutes,
preferably in about 45 minutes, more preferably in about 30 minutes
and most preferably in 15 minutes or less after administration.
[0053] The following examples are provided to assist in further
understanding the invention. The particular materials and
conditions employed are intended to be further illustrative of the
invention and are not limiting upon the reasonable scope
thereof.
[0054] A series of experiments were performed to illustrate
features and advantages of the present invention. Several
conditions were common to each experiment. For example, in Examples
1-4, apomorphine was administered to healthy male subjects who did
not suffer from erectile dysfunction. Further, none of the subjects
took any medication for two weeks prior to these experiments.
[0055] The following examples show that apomorphine can be nasally
administered without causing substantial intolerable adverse
effects. A different dosage of apomorphine was administered in each
experiment to determine a preferred range of dosages having minimal
adverse effects.
EXAMPLE 1
[0056] TABLE 1 shows the results of an experiment in which 1.0 mg
of apomorphine HCL was nasally administered to nine male
subjects.
1 TABLE 1 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE
DEGREE SEVERITY OF THE SYMPTOM Mild to Mild, not moderate,
Moderate, Severe, TOTAL troublesome, not Moderate, somewhat
extremely NUMBER or of very troublesome, somewhat severe,
troublesome, OF SUBJECTS SYMPTOMS short of short troublesome,
troublesome, or constantly EXPERIENCING EXPERIENCED duration
duration or persistent or persistent present SYMPTOMS Nasal Burning
2 0 0 0 0 2 Sneezing 1 0 1 0 0 2 Unusual Taste 2 0 0 0 0 2 Nausea 1
1 0 0 0 2 Tearing of Eyes 1 0 0 0 0 1 Lightheadedness 1 0 0 0 0 1
Tiredness 3 0 0 0 0 3 Congestion 1 0 0 0 0 1 Sweating 1 0 0 0 0
1
[0057] It should be noted that some of the subjects of this
experiment suffered from more than one symptom and one subject did
not suffer from any symptoms.
[0058] As shown in TABLE 1, the symptoms suffered by the subjects
in this experiment were generally not troublesome and of very short
duration. One subject, though, suffered from moderate sneezing and
another subject suffered from mild to moderate nausea. The adverse
effects with nasal administration of 1.0 mg of apomorphine HCL were
minimal and the severity of the adverse effects were generally not
troublesome.
EXAMPLE 2
[0059] TABLE 2 shows the results of an experiment in which 0.5 mg
of apomorphine HCL was nasally administered to three male
subjects.
2 TABLE 2 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE
DEGREE OF SEVERITY OF THE SYMPTOM Mild to Mild, not moderate,
Moderate, Severe, TOTAL troublesome, not Moderate, somewhat
extremely NUMBER or of very troublesome, somewhat severe,
troublesome, OF SUBJECTS SYMPTOMS short of short troublesome,
troublesome, or constantly EXPERIENCING EXPERIENCED duration
duration or persistent or persistent present SYMPTOMS Nasal Burning
2 0 0 0 0 2 Nasal Pain 1 0 0 0 0 1 Unusual Taste 1 0 0 0 0 1
[0060] One of the subjects of this experiment did not suffer any
symptoms and two of the three subjects in this experiment suffered
mild symptoms which were not troublesome and were of very short
duration. The results of this experiment show minimal adverse
effects with nasal administration of 0.5 mg of apomorphine HCL.
[0061] The results of this experiment also show that nasal
administration of apomorphine HCL was effective for inducing an
erection. In particular, one of the three subjects experienced an
erection while another felt the beginning of an erection.
EXAMPLE 3
[0062] TABLE 3 shows the results of an experiment in which 2.0 mg
of apomorphine HCL was nasally administered to nine male
subjects.
3 TABLE 3 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE
DEGREE OF SEVERITY OF THE SYMPTOM Mild to Mild, not moderate,
Moderate, Severe, TOTAL troublesome, not Moderate, somewhat
extremely NUMBER or of very troublesome, somewhat severe,
troublesome, OF SUBJECTS SYMPTOMS short of short troublesome,
troublesome, or constantly EXPERIENCING EXPERIENCED duration
duration or persistent or persistent present SYMPTOMS Nasal Burning
1 0 0 0 0 1 Sneezing 0 1 0 0 0 1 Unusual Taste 4 0 0 0 0 4 Nausea 3
0 0 0 0 3 Lightheadedness 2 0 0 0 0 2
[0063] It should be noted that some of the subjects of this
experiment suffered from more than one symptom and one subject did
not suffer from any symptoms.
[0064] Eight of the nine subjects in this experiment suffered from
symptoms of mild degree as shown in TABLE 3. Further, the symptoms
suffered by all of the subjects were not troublesome. The results
of this experiment show very minimal adverse effects with nasal
administration of 2.0 mg of apomorphine HCL.
[0065] The results of this experiment also show that nasal
administration of apomorphine HCL was effective for inducing an
erection. In particular, three of the nine subjects of this
experiment had a partial erection while one subject felt an
erection.
EXAMPLE 4
[0066] TABLE 4 shows the results of an experiment in which 4.0 mg
of apomorphine HCL was nasally administered to two male
subjects.
4 TABLE 4 NUMBER OF SUBJECTS EXPERIENCING SYMPTOMS GIVEN BY THE
DEGREE OF SEVERITY OF THE SYMPTOM Mild to Mild, not moderate,
Moderate, Severe, TOTAL troublesome, not Moderate, somewhat
extremely NUMBER or of very troublesome, somewhat severe,
troublesome, OF SUBJECTS SYMPTOMS short of short troublesome,
troublesome, or constantly EXPERIENCING EXPERIENCED duration
duration or persistent or persistent present SYMPTOMS Sneezing 0 0
0 1 0 1 Nausea 0 1 0 0 0 1 Lightheadedness 0 1 0 0 0 1
[0067] One subject of this experiment did not suffer any symptoms
while the other subject experienced mild to moderate nausea and
lightheadedness, which were not troublesome and were of very short
duration, and moderate sneezing, which was somewhat troublesome. In
particular, this subject felt like vomiting, felt lightheaded for
twenty minutes after apomorphine was administered and sneezed four
times. It is known in the art that the emetic effect of high
dosages of apomorphine includes vomiting and therefore, it is
believed that this subject suffered these symptoms due to the
higher dosage of apomorphine.
[0068] The results of this experiment do not show substantial
adverse effects with nasal administration of 4.0 mg of apomorphine
HCL.
[0069] Examples 1-4 show that apomorphine can be nasally
administered at different dosages without substantial adverse
effects and further, adverse effects are minimal with a dosage of
apomorphine of equal to or less than 2.0 mg.
EXAMPLE 5
[0070] TABLE 5 shows the solubility and stability of apomorphine
hydrochloride dispersed in several different systems.
5TABLE 5 System Solubility Solubility Improved # Composition of
System pH (mg/mL) Enhancement % Stability * 1 Water 3.6 20.9 -- --
2 Propylene Glycol -- 84.5 304.3 Yes 3 Glycerin -- 37.4 78.9 Yes 4
50% Propylene Glycol + 50% Glycerin -- 67.9 224.9 Yes 5
Polyethylene Glycol 400 -- 19.9 None Yes 6 1.8% Ascorbic Acid + 2.3
25.0-30.0 19.6-43.5 Yes 98.2% Water 7 0.2% Sodium Ascorbate + 99.8%
5.0 20.0-25.0 0-19.6 Yes Water 8 0.5% Sodium Metabisulfite + 99.5%
3.1 249 19.1 Yes Water * Based on color change.
[0071] TABLE 5 shows the composition of several systems in which
apomorphine HCL has been dispersed. System #1 includes water and
served as a control for comparison with System #2-System #8. TABLE
5 also shows the solubility of apomorphine HCL after it has been
dispersed in the above systems. It also shows that the stability of
apomorphine HCL has been improved after it has been dispersed in
the above systems. The improved stability of apomorphine HCL was
determined based on the color change of apomorphine HCL. For
instance, a reduced degree of color formation after dispersion of
apomorphine HCL in a system would signify improved stability.
[0072] As shown in TABLE 5, the solubility of apomorphine HCL
clearly improves significantly when it is dispersed in the
compositions of System #2-System #4. Further, the solubility of
apomorphine HCL improved moderately when it was dispersed in the
compositions of System #6-System #8.
[0073] Apomorphine HCL exhibited improved stability when dispersed
in each of System #2-System #8.
[0074] The results of this experiment demonstrate that a
pharmaceutical composition according to the present invention and
including apomorphine dispersed in different systems as shown
above, can improve the solubility and stability of apomorphine.
[0075] Thus, while there have been described what are presently
believed to be the preferred embodiments of the present invention,
those skilled in the art will realize that other and further
embodiments can be made without departing from the spirit and scope
of the invention, and it is intended to include all such further
modifications and changes as come within the true scope of the
claims set forth herein.
* * * * *