U.S. patent application number 10/351198 was filed with the patent office on 2003-07-17 for transmucosal phosphodiesterase inhibitors for the treatment of erectile dysfunction.
Invention is credited to Doherty, Paul C. JR., Place, Virgil A., Smith, William L..
Application Number | 20030134861 10/351198 |
Document ID | / |
Family ID | 23854316 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030134861 |
Kind Code |
A1 |
Doherty, Paul C. JR. ; et
al. |
July 17, 2003 |
Transmucosal phosphodiesterase inhibitors for the treatment of
erectile dysfunction
Abstract
A pharmaceutical formulation is provided for treating erectile
dysfunction in a mammalian male individual. The pharmaceutical
formulation includes a phosphodiesterase inhibitor or a
pharmaceutically acceptable salt, ester, amide or derivative
thereof, that is administered transmucosally within the context of
an effective dosing regimen. Preferred modes of administration
include transbuccal, sublingual and transrectal routes. A kit for
the administration of the pharmaceutical formulation is also
provided.
Inventors: |
Doherty, Paul C. JR.;
(Cupertino, CA) ; Place, Virgil A.; (Kawaihae,
HI) ; Smith, William L.; (Mahwah, NJ) |
Correspondence
Address: |
REED & EBERLE LLP
800 MENLO AVENUE, SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
23854316 |
Appl. No.: |
10/351198 |
Filed: |
January 24, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10351198 |
Jan 24, 2003 |
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09467094 |
Dec 10, 1999 |
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6548490 |
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09467094 |
Dec 10, 1999 |
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09181070 |
Oct 27, 1998 |
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6037346 |
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09181070 |
Oct 27, 1998 |
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08958816 |
Oct 28, 1997 |
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Current U.S.
Class: |
514/252.16 ;
514/234.5; 514/249; 514/252.17; 514/262.1; 514/263.3; 514/263.38;
514/266.1; 514/266.22; 514/267; 514/269; 514/308; 514/345 |
Current CPC
Class: |
A61K 9/0031 20130101;
A61K 31/4015 20130101; A61K 31/50 20130101; A61P 43/00 20180101;
A61K 9/0034 20130101; A61K 31/426 20130101; A61K 31/4709 20130101;
A61P 15/10 20180101; A61K 31/4745 20130101; A61K 31/5025 20130101;
A61K 31/496 20130101; A61K 31/519 20130101; A61K 31/343 20130101;
A61K 45/06 20130101; A61K 31/505 20130101; A61K 31/5513 20130101;
A61K 31/444 20130101; A61K 31/00 20130101; A61K 31/52 20130101;
A61K 9/006 20130101; A61K 31/501 20130101; A61K 31/437 20130101;
A61K 31/4164 20130101; A61K 31/4439 20130101; A61K 31/381 20130101;
A61K 31/502 20130101; A61K 31/522 20130101; A61P 25/02 20180101;
A61K 31/40 20130101; A61K 31/4166 20130101; A61K 9/0056 20130101;
A61K 31/538 20130101; A61P 9/00 20180101; A61K 31/549 20130101;
A61K 31/4704 20130101 |
Class at
Publication: |
514/252.16 ;
514/249; 514/263.3; 514/266.1; 514/267; 514/266.22; 514/269;
514/345; 514/262.1; 514/234.5; 514/263.38; 514/308; 514/252.17 |
International
Class: |
A61K 031/56; A61K
031/5377; A61K 031/497; A61K 031/522; A61K 031/517; A61K
031/519 |
Claims
What is claimed is:
1. A pharmaceutical formulation for treating erectile dysfunction
in an individual and suitable for transmucosal drug administration,
comprising a therapeutically effective amount of a
phosphodiesterase inhibitor, a carrier suitable for transmucosal
drug administration, and, optionally, a permeation enhancer.
2. The formulation of claim 1, wherein the formulation comprises a
solid dosage form for application to buccal mucosa, and the carrier
is suitable for transbuccal drug delivery.
3. The formulation of claim 2, wherein the carrier is a
hydrolyzable polymer.
4. The formulation of claim 3, wherein the dosage form further
comprises an adhesive suitable for affixing the dosage form to the
buccal mucosa.
5. The formulation of claim 2, wherein the phosphodiesterase
inhibitor represents approximately 1 wt % to 30 wt % of the buccal
solid dosage form.
6. The formulation of claim 2, wherein the buccal solid dosage form
contains at least one additional component selected from the group
consisting of disintegrants, diluents, binders, lubricants,
flavoring, colorants, and preservatives.
7. The formulation of claim 1, wherein the formulation comprises a
dosage form for application to sublingual mucosa, and the carrier
is suitable for sublingual drug delivery.
8. The formulation of claim 7, wherein the sublingual dosage form
completely disintegrates in less than five minutes after
administration.
9. The formulation of claim 7, wherein the sublingual dosage form
contains at least one additional component selected from the group
consisting of binders, disintegrators, wetting agents, and
lubricants.
10. The formulation of claim 1, wherein the formulation comprises a
dosage form for application to rectal mucosa, and the carrier is
suitable for transrectal drug delivery.
11. The formulation of claim 10, wherein the transrectal dosage
form completely disintegrates within approximately 3 hours
following administration.
12. The formulation of claims 11, wherein the transrectal dosage
form is a rectal suppository.
13. The formulation of claim 12, wherein the rectal suppository
further includes at least one additional component selected from
the group consisting of stiffening agents, antioxidants, and
preservatives.
14. The formulation of claim 1, wherein the phosphodiesterase
inhibitor is a Type III phosphodiesterase inhibitor.
15. The formulation of claim 14, wherein the Type III
phosphodiesterase inhibitor is selected from the group consisting
of bipyridines, imidazolones, imidazolines, dihydropyridazinones,
dihydroquinolones, mixed Type III-Type IV inhibitors, anagrelide,
bemoradan, ibudilast, isomazole, lixazinone, motapizone, olprinone,
phthalazinol, pimobendan, quazinone, siguazodan and trequinsin.
16. The formulation of claim 15, wherein the Type III
phosphodiesterase inhibitor is a bipyridine.
17. The formulation of claim 16, wherein the bipyridine is selected
from the group consisting of amrinone and milrinone.
18. The formulation of claim 15, wherein the Type III
phosphodiesterase inhibitor is an imidazolone.
19. The formulation of claim 18, wherein the imidazolone is
selected from the group consisting of piroximone and enoximone.
20. The formulation of claim 15, wherein the Type III
phosphodiesterase inhibitor is a dihydroquinolinone.
21. The formulation of claim 20, wherein the dihydroquinolinone is
selected from the group consisting of cilostamide, cilostazol,
vesnarinone and OPC 3911.
22. The formulation of claim 1, wherein the phosphodiesterase
inhibitor is a Type IV phosphodiesterase inhibitor.
23. The formulation of claim 22, wherein the Type IV
phosphodiesterase inhibitor is selected from the group consisting
of pyrrolidinones, quinazolinediones, xanthine derivatives, phenyl
ethyl pyridines, tetrahydropyrimidones, diazepine derivatives,
oxime carbamates, naphthyridinones, benzofurans, naphthalene
derivatives, purine derivatives, imidazolidinones, cyclohexane
carboxylic acids, benzamides, benzothiophenes, pyridopyridazinones,
etazolate, S-(+)-glaucine, substituted phenyl compounds, and
substituted biphenyl compounds.
24. The formulation of claim 23, wherein the Type IV
phosphodiesterase inhibitor is a pyrrolidinone.
25. The formulation of claim 24, wherein the pyrrolidinone is
selected from the group consisting of rolipram, R020-1724 and RS
33793.
26. The formulation of claim 25, wherein the pyrrolidinone is
rolipram.
27. The formulation of claim 1, wherein the phosphodiesterase
inhibitor is a Type V phosphodiesterase inhibitor.
28. The formulation of claim 27, wherein the Type V
phosphodiesterase inhibitor is selected from the group consisting
of zaprinast; MY 544; dipyridamole; sildenafil;
pyrazolopyrimidinones; griseolic acid derivatives;
2-phenylpurinones; phenylpyridone derivatives; pyrimidines;
pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones;
imidazoquinoxalinones or aza analogues thereof; phenylpyridones;
1C-351 (ICOS);
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3
(2H)pyridazinone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-qu-
inazolinyl]-4-piperidine-carboxylic acid, monosodium salt;
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-met-
hyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin;
cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
-b]purin-4-one;
3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;
4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)
propoxy)-3-(2H)pyridazinone;
1-methyl-5-(5-morpholinoacetyl-2-n-propoxyph-
enyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piper-
idinecarboxylic acid, monosodium salt; pyrrolo[1,2-c]imidazolone
derivatives;
1-phenylmethyl-N-[[4-ethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-
-yl)]pyrimidin-5-yl]-1H-imidazol-2-carboxamide;
1-phenylmethyl-N-[4-ethyl--
2-(1H-imidazol-1-yl)pyrimidin-5-yl-]H-imidazol-2-carboxamide;
4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-methylimidazo[5,1-h]p-
teridin-6(5H)-one; and
9-ethyl-2(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-meth-
yl-4-(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one.
29. The formulation of claim 28, wherein the Type V
phosphodiesterase inhibitor is zaprinast.
30. The formulation of claim 28, wherein the Type V
phosphodiesterase inhibitor is a pyrazolopyrimidinone.
31. The formulation of claim 28, wherein the Type V
phosphodiesterase inhibitor is sildenafil or a pharmaceutically
acceptable salt thereof.
32. The formulation of claim 1, wherein the phosphodiesterase
inhibitor is selected from the group consisting of pentoxifylline,
papaverine, doxazosin, prazosin, terazosin, trimazosin and
hydralazine.
33. The formulation of claim 1, further comprising an additional
active agent.
34. The formulation of claim 33, wherein the additional active
agent is a vasoactive agent.
35. The formulation of claim 33, wherein the additional active
agent is a smooth muscle relaxant.
36. The formulation of claim 1, wherein the daily dose of the
formulation is in the range of approximately 5 mg to 100 mg.
37. The formulation of claim 36, wherein the phosphodiesterase
inhibitor in the daily dose of the formulation is in a range of
approximately 0.1 to 500 mg.
38. A kit to assist an individual in administering a drug used for
the treatment of erectile dysfunction comprising: a pharmaceutical
formulation comprising a selected phosphodiesterase inhibitor; a
container for housing the pharmaceutical formulation during storage
and prior to use; and instructions for carrying out drug
administration in a manner effective to treat erectile
dysfunction.
39. The kit according to claim 38, wherein the pharmaceutical
formulation is for buccal administration.
40. The kit according to claim 39, wherein the phosphodiesterase
inhibitor is housed in a buccal storage unit with a bioerodible
polymeric carrier.
41. The kit according to claim 38, further comprising a venous flow
control device.
42. The kit according to claim 41, wherein the venous flow control
device comprises a flexible tubing having integral fastening means.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. Ser.
No. 09/467,094, filed Dec. 10, 1999, which is a
continuation-in-part of U.S. Ser. No. 09/181,070, filed Oct. 27,
1998, which is a continuation-in-part of U.S. Ser. No. 08/958,816,
filed Oct. 28, 1997, the disclosures of which are hereby
incorporated by reference.
TECHNICAL FIELD
[0002] This invention relates generally to methods and
pharmaceutical compositions for treating erectile dysfunction; more
particularly, the invention relates to transmucosal (e.g., buccal,
sublingual and transrectal), phosphodiesterase inhibitors that are
used to treat erectile dysfunction.
BACKGROUND
[0003] Impotence is the consistent inability to achieve or sustain
an erection of sufficient rigidity for sexual intercourse. It has
recently been estimated that approximately 10 million American men
are impotent (R. Shabsigh et al., "Evaluation of Erectile
Impotence," Urology 32:83-90 (1988); W. L. Furlow, "Prevalence of
Impotence in the United States," Med. Aspects Hum. Sex. 19:13-6
(1985)). Impotence is recognized to be an age-dependent disorder,
with an incidence of 1.9 percent at 40 years of age and 25 percent
at 65 years of age (A. C. Kinsey et al., "Age and Sexual Outlet,"
in Sexual Behavior in the Human Male; A. C. Kinsey et al., eds.,
Philadelphia, Pa.: W. B. Saunders, 218-262 (1948)). In 1985 in the
United States, impotence accounted for more than several hundred
thousand outpatient visits to physicians (National Center for
Health Statistics, National Hospital Discharge Survey, 1985,
Bethesda, Md., Department of Health and Human Services, 1989 DHHS
publication no. 87-1751). Depending on the nature and cause of the
problem, treatments include psychosexual therapy, hormonal therapy,
administration of vasodilators such as nitroglycerin and
-adrenergic blocking agents ("-blockers"), oral administration of
other pharmaceutical agents, vascular surgery, implanted penile
prostheses, vacuum constriction devices and external aids such as
penile splints to support the penis or penile constricting rings to
alter the flow of blood through the penis.
[0004] A number of causes of impotence have been identified,
including vasculogenic, neurogenic, endocrinologic and psychogenic.
Vasculogenic impotence, which is caused by alterations in the flow
of blood to and from the penis, is thought to be the most frequent
organic cause of impotence. Common risk factors for vasculogenic
impotence include hypertension, diabetes, cigarette smoking, pelvic
trauma, and the like. Neurogenic impotence is associated with
spinal-cord injury, multiple sclerosis, peripheral neuropathy
caused by diabetes or alcoholism and severance of the autonomic
nerve supply to the penis consequent to prostate surgery. Erectile
dysfunction is also associated with disturbances in endocrine
function resulting in low circulating testosterone levels and
elevated prolactin levels.
[0005] Impotence can also be a side effect of various classes of
drugs, in particular, those that interfere with central
neuroendocrine control or local neurovascular control of penile
smooth muscle. Krane et al., New England Journal of Medicine
321:1648 (1989). Penile erection requires (I) dilation of the
arteries that regulate blood flow to the lacunae of the corpora
cavernosum, (2) relaxation of trabecular smooth muscle, which
facilitates engorgement of the penis with blood, and (3)
compression of the venules by the expanding trabecular walls to
decrease venous outflow.
[0006] Trabecular smooth muscle tone is controlled locally by
adrenergic (constrictor), cholinergic (dilator) and nonadrenergic,
noncholinergic (dilator) innervation, and by endothelium-derived
vasoactive substances such as vasoactive intestinal polypeptide
(VIP), prostanoids, endothelin and nitric oxide. High sympathetic
tone (noradrenergic) is implicated in erectile dysfunction, and, in
some patients, the disorder can be successfully treated with
noradrenergic receptor antagonists. See, e.g., Krane et al.,
supra.
[0007] There is also evidence that dopaminergic mechanisms are
involved in erectile function. For example, pharmacologic agents
that elevate the level of brain dopamine or stimulate brain
dopamine receptors increase sexual activity in animals (see, e.g.,
Gessa & Tagliamonte, Life Sciences 14:425 (1974); Da Prada et
al., Brain Research 57:383 (1973)).
[0008] Administration of L-DOPA, a dopamine precursor, enhances
sexual activity in male rats. L-DOPA has been used in the treatment
of Parkinsonism and is known to act as an aphrodisiac in some
patients (Gessa & Tagliamonte, supra; Hyppa et al., Acta
Neurologic Scand. 46:223 (Supp. 43, 1970)). Specific dopamine
agonists have been studied for their effects on erectile function.
Apomorphine, (n-propyl)norapo-morphine, bromocryptine, amantidine,
fenfluramine, L-DOPA and various other pharmacological activators
of central dopaminergic receptors have been found to increase
episodes of penile erection in male rats (Benassi-Benelli et al.,
Arch. int. Pharmacodyn. 242:241 (1979); Poggioli et al., Riv. di
Farm. & Terap. 9:213 (1978); Falaschi et al., Apomorphine and
Other Dopaminomimetics, 1: 117-121 (Gessa & Corsini, Eds.,
Raven Press, N.Y.)). In addition, U.S. Pat. No. 4,521,421 to
Foreman relates to the oral or intravenous administration of
quinoline compounds to treat sexual dysfunction in mammals.
[0009] The currently available dopamine agonists, with few
exceptions, have found limited use in the treatment of erectile
dysfunction because of their peripheral side effects. These effects
include nausea and vomiting, postural hypotension, arrhythmias,
tachycardia, dysphoria, psychosis, hallucinations, drowsiness and
dyskinesias (See, e.g., Martindale The Extra Pharmacopoeia, 31 st
Ed., pages 1151-1168).
[0010] The invention described herein provides a means to avoid the
above-mentioned problems encountered with previously known methods
for treating erectile dysfunction. Specifically, the invention
relates to methods and formulations for effectively treating
erectile dysfunction by transmucosally, e.g., buccally,
sublingually or transrectally, administering a selected active
agent, wherein the active agent is an inhibitor of a
phosphodiesterase.
[0011] Phosphodiesterases are a class of intracellular enzymes
involved in the metabolism of the second messenger nucleotides,
cyclic adenosine monophosphate (cAMP), and cyclic guanosine
monophosphate (cGMP) (see, e.g., Doherty, "Oral, Transdermal, and
Transurethral Therapies for Erectile Dysfunction" in Male
Infertility and Dysfunction, Hellstrom, ed., Chapter 34 (New York,
N.Y.: Springer-VerlagHellstrom, 1997)). Numerous phosphodiesterase
inhibitors have previously been described in the literature for a
variety of therapeutic uses, including treatment of obstructive
lung disease, allergies, hypertension, angina, congestive heart
failure and depression (see, e.g., Goodman and Gilman's The
Pharmacological Basis of Therapeutics Ninth Edition, Chapter 34).
Oral and parenteral administration of phosphodiesterase inhibitors,
as alluded to above, have also been suggested for the treatment of
erectile dysfunction (Doherty, supra; see also PCT Publication Nos.
WO 96/16644, and WO 94/28902). The phosphodiesterases have been
classified into seven major families, Types I-VII, based on amino
acid or DNA sequences. The members of the family vary in their
tissue, cellular and subcellular distribution, as well as their
links to cAMP and cGMP pathways. For example, the corpora cavernosa
contains: Type III phosphodiesterases, which are cAMP-specific cGMP
inhibitable; Type IV phosphodiesterases, the high affinity,
high-specificity cAMP-specific form; and Type V phosphodiesterases,
one of the cGMP-specific forms.
[0012] The invention, as noted above, is directed to transmucosal
administration of pharmacologically active agents to treat erectile
dysfunction. The agents are preferably, although not necessarily,
Type III, Type IV or Type V phosphodiesterase inhibitors.
Surprisingly, it has now been found by the inventors herein that
transmucosal and particularly buccal, sublingual or transrectal
administration of these phosphodiesterase inhibitors as disclosed
herein is highly effective in treating erectile dysfunction,
including vasculogenic impotence. Transmucosal and particularly
buccal, sublingual or transrectal administration of
phosphodiesterase inhibitors to treat erectile dysfunction
accordingly represents an important advance in the treatment of
impotence and other erectile disorders.
SUMMARY OF THE INVENTION
[0013] It is a primary object of the invention to provide
pharmaceutical formulations for treating erectile dysfunction that
have a therapeutically effective amount of a selected
phosphodiesterase inhibitor and that are administered
transmucosally.
[0014] It is another object of the invention to provide the
pharmaceutical formulation for transbuccal administration.
[0015] It is a further object of the invention to provide the
pharmaceutical formulation for application to the sublingual
mucosa.
[0016] It is still another object of the invention to provide the
pharmaceutical formulation for application to the rectal
mucosa.
[0017] It is another object of the invention to provide the
pharmaceutical formulation with a Type III phosphodiesterase
inhibitor.
[0018] It is a further object of the invention to provide the
pharmaceutical formulation with a Type IV phosphodiesterase
inhibitor.
[0019] It is yet another object of the invention to provide the
pharmaceutical formulation with a Type V phosphodiesterase
inhibitor.
[0020] It is yet another object of the invention to provide a kit
capable of use by an individual for self-administration of a
phosphodiesterase inhibitor as provided herein.
[0021] Additional objects, advantages and novel features of the
invention will be set forth in part in the description that
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
[0022] In one aspect of the invention, a method is provided for
treating an individual prone to erectile dysfunction, e.g.,
vasculogenic erectile dysfunction, the method comprising
transmucosally administering to the individual a pharmaceutical
formulation containing a phosphodiesterase inhibitor.
Administration of the pharmaceutical formulation is carried out
within the context of a predetermined dosing regimen such that the
agent is effective in the treatment of erectile dysfunction. The
method is especially useful in the treatment of vasculogenic
impotence, although other types of erectile dysfunction may also be
treated using the present formulations, e.g., neurogenic,
endocrinologic and psychogenic impotence. Drug delivery is
preferably effected through the buccal mucosa, sublingual mucosa or
transrectal mucosa but the drug may also be administered through
other mucosal surfaces of the body. For buccal administration, the
active agent is typically although not necessarily administered by
affixing a buccal dosage unit to the buccal mucosa of the
individual undergoing treatment, and allowing the dosage unit to
remain in place until drug delivery is complete. Alternatively,
buccal administration may be effected by the application to the
buccal mucosa of a cream, ointment or paste containing the active
agent. For sublingual administration, the active agent is typically
although not necessarily administered by placing a sublingual
tablet under the tongue of the individual undergoing treatment, and
allowing the tablet to remain in place until tablet disintegration
and thus drug delivery is complete. For transrectal administration,
the active agent is typically although not necessarily administered
by placing a suppository within the rectum and allowing the dosage
unit to remain in place until melting of the carrier and thus drug
delivery is complete. Alternatively, transrectal administration may
be effected using a cream, ointment or solution (e.g., enema)
containing the active agent.
[0023] In another aspect of the invention, a pharmaceutical
formulation is provided for carrying out the present method for
treating erectile dysfunction. The pharmaceutical formulation
comprises an effective amount of a phosphodiesterase inhibitor, a
carrier or vehicle suited to transmucosal administration and,
optionally, a permeation enhancer. The formulation may contain one
or more additional active agents, e.g., dopaminergic drugs, smooth
muscle relaxants, vasoactive drugs, and additives, e.g.,
excipients, surfactants, preservatives (e.g., antioxidants),
stabilizers, chelating agents, enzyme inhibitors, antibacterial
agents, binders, diluents, lubricants, and the like, as will be
appreciated by those skilled in the art of drug formulation
preparation and delivery. Buccal formulations will generally
although not necessarily comprise a solid dosage unit containing
the active agent, a hydrolyzable (or "bioerodible") polymeric
carrier, and a means for affixing the dosage unit to the buccal
mucosa. The latter may represent a separate adhesive component in
the formulation, or the polymeric carrier itself may serve as an
adhesive. Sublingual formulations comprise a dosage form for
application to the sublingual mucosa and a carrier suitable for
sublingual drug delivery. Thus, sublingual formulations will
generally although not necessarily comprise a solid dosage unit
containing the active agent and one or more vehicles and a
lubricant. Transrectal formulations comprise a dosage form for
application to the rectal mucosa and a carrier suitable for
transrectal drug delivery. Thus, transrectal formulations in the
form of a suppository will generally although not necessarily
comprise a solid dosage unit containing the active agent and one or
more suppository bases.
[0024] In another aspect, a kit is provided to assist an individual
in drug administration to carry out the method of the invention.
Generally, the kit will include the following components: a
pharmaceutical formulation comprising the phosphodiesterase
inhibitor to be administered; a container housing the
pharmaceutical formulation during storage and prior to use; and
instructions for carrying out drug administration in a manner
effective to treat erectile dysfunction. When the kit is for
assisting an individual in buccal drug administration,
specifically, the kit will include at least the following: a buccal
dosage unit comprising the active agent and a bioerodible polymeric
carrier; a container housing the dosage unit prior to use; and
written instructions for carrying out administration of the active
agent for the intended therapeutic purpose.
DETAILED DESCRIPTION OF THE INVENTION
[0025] Definitions:
[0026] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
drugs or drug delivery systems, as such may vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to be
limiting.
[0027] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a phosphodiesterase inhibitor"
includes a mixture of two or more such compounds, reference to "a
permeation enhancer" includes mixtures of two or more enhancers,
and the like.
[0028] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
[0029] The term "erectile dysfunction" is intended to include any
and all types of erectile dysfunction, including: vasculogenic,
neurogenic, endocrinologic and psychogenic impotence ("impotence"
is used here in its broadest sense to indicate a periodic or
consistent inability to achieve or sustain an erection of
sufficient rigidity for sexual intercourse; see U.S. Pat. No.
5,242,391 to Place et al., cited supra); Peyronie's syndrome;
priapism; premature ejaculation; and any other condition, disease
or disorder, regardless of cause or origin, which interferes with
at least one of the three phases of human sexual response, i.e.,
desire, excitement and orgasm (see Kaplan, Disorders of Sexual
Desire (New York, N.Y. Brunner Mazel Book Inc., 1979)).
[0030] The terms "treating" and "treatment" as used herein refer to
reduction in severity and/or frequency of symptoms, elimination of
symptoms and/or underlying cause, prevention of the occurrence of
symptoms and/or their underlying cause, and improvement or
remediaton of damage. The present method of "treating" erectile
dysfunction, as the term is used herein, thus encompasses both
prevention of the disorder in a predisposed individual and
treatment of the disorder in a clinically symptomatic
individual.
[0031] The term "phosphodiesterase inhibitor" as used herein is
intended to mean an agent that is capable of inhibiting or
selectively reducing the activity of any one or more
phosphodiesterases.
[0032] The terms "active agent," "drug" and "pharmacologically
active agent" are used interchangeably herein to refer to a
chemical material or compound that induces a desired effect. In the
preferred embodiment herein, the terms refer to a phosphodiesterase
inhibitor which is capable of being delivered transmucosally.
Included are derivatives and analogs of those compounds or classes
of compounds specifically mentioned which also induce the desired
effect.
[0033] "Penetration enhancement" or "permeation enhancement" as
used herein relates to an increase in the permeability of the
mucosal tissue to the selected pharmacologically active agent,
i.e., so that the rate at which the drug permeates therethrough is
increased.
[0034] "Carriers" or "vehicles" as used herein refer to carrier
materials suitable for transmucosal drug administration. Carriers
and vehicles useful herein include any such materials known in the
art which is nontoxic and does not interact with other components
of the composition in a deleterious manner.
[0035] By "transmucosal" drug delivery is meant administration of a
drug to the mucosal surface of an individual so that the drug
passes through the mucosal tissue and into the individual's blood
stream. A preferred form of transmucosal drug delivery herein is
"buccal" or "transbuccal" drug delivery which refer to delivery of
a drug by passage of a drug through an individual's buccal mucosa
and into the bloodstream. Another preferred from of transmucosal
drug delivery herein is "sublingual" or "transublingual" drug
delivery which refer to delivery of a drug by passage of a drug
through an individual's sublingual mucosa and into the bloodstream.
An additional preferred form of transmucosal drug delivery herein
is "rectal" or "transrectal" drug delivery which refer to delivery
of a drug by passage of a drug through an individual's rectal
mucosa and into the bloodstream.
[0036] By an "effective" amount of a drug or pharmacologically
active agent is meant a nontoxic but sufficient amount of the drug
or agent to provide the desired effect, i.e., treatment of erectile
dysfunction.
[0037] Active Agents for Treatment of Erectile Dysfunction:
[0038] In order to carry out the method of the invention, a
selected phosphodiesterase inhibitor is administered transmucosally
to an individual prone to erectile dysfunction.
[0039] The active agent herein may be any agent which is effective
to inhibit the activity of a phosphodiesterase. Suitable
phosphodiesterase inhibitors include, but are not limited to,
inhibitors of the Type III phosphodiesterases (the
cAMP-specific-cGMP inhibitable form), the Type IV phosphodiesterase
(the high affinity-high specificity cAMP form) and the Type V
phosphodiesterases (the cGMP specific form). Additional inhibitors
that may be used in conjunction with the present invention are
cGMP-specific phosphodiesterase inhibitors other than Type V
inhibitors.
[0040] Examples of Type III phosphodiesterase inhibitors that may
be administered herein include, but are not limited to, bipyridines
such as milrinone and amrinone; imidazolones such as piroximone and
enoximone; imidazolines such as imazodan and 5-methyl-imazodan;
dihydropyridazinones such as indolidan and LY181512 1
[0041] dihydroquinolinone compounds such as cilostamide,
cilostazol, vesnarinone and OPC 3911 2
[0042] other compounds such as anagrelide, bemoradan, ibudilast,
isomazole, lixazinone, motapizone, olprinone, phthalazinol,
pimobendan, quazinone, siguazodan and trequinsin; and mixed Type
III and Type IV inhibitors such as benafentrine,
cis-6-[p-acetamidophenyl]-1,2,3,4,4a,10b-
-hexahydro-8,9-dimethoxy-2-methylbenzo-[c][1,6]-naphthyridine, EMD
54622
(5-[1-(3,4-dimethoxybenzoyl)-4,4-dimethyl-1,2,3,4-tetrahydrochinolin-6-yl-
]-6-methyl-3,6-dihydro-1,3,4-thiadiazin-2-one), Org 20241
(N-hydroxy-4-[3,4-dimethoxyphenyl]-thiazole-2-carboxim idamide),
Org30029
(N-hydroxy-5,6-dimethoxybenzo-[b]-thiophene-2-carboximidamide),
saterinone, tolafentrine and zardaverine. Preferred Type III PDE
inhibitors herein are bipyridines, imidazolones, imidazolines,
dihydropyridazinones and dihydroquinolinone compounds. Of these,
the inhibitors that are particularly preferred herein are
milrinone, amrinone, piroximone, enoximone, imazodan,
5-methyl-imazodan, indolidan, cilostamide, cilostazol and
vesnarinone. The inhibitors may be used alone or in combination; if
in combination, they may be administered either simultaneously or
sequentially.
[0043] Examples of Type IV phosphodiesterase inhibitors that may be
administered herein include, but are not limited to: pyrrolidinones
such as rolipram
(4-(3-cyclopentyloxy-4'-methoxyphenyl)-2-pyrrolidinone)) and
rolipram derivatives such as R020-1724
(4-(3-butyloxy-4-methoxyphenyl)-im- idazolidinone) and RS 33793
(8-(3-nitrophenyl)-6-(3-methyl-2-butenyl)pyrid-
o[2,3a]pyrazin-5-one); quinazolinediones such as nitraquazone
(3-[3'-nitrophenyl] N-ethylquinazoline-2,6-dione), CP-77059
(1-(carbomethoxyphenyl)-3-benzylpyrido[2,3d]pyrimidine-2,4(1H,3H)dione),
RS-25344 (1-(3-nitrophenyl)-3-(4-pyridylmethyl)-1,2,3,4-tetrahydro
pyrido(2,3-d) pyrimidine-2,4-dione)) and other nitraquazone
analogs; xanthine derivatives such as denbufylline
(1,3-di-n-butyl-7-[2'-oxopropyl- ]xanthine), XT-44
(1-n-butyl-3-n-propylxanthine), arofylline (LAS 31025;
1-propyl-3-(4-chlorophenyl)-xanthine) and BRL 61063 3
[0044] phenyl ethyl pyridines such as CDP 840
(4-(1-(3-cyclopentyloxy-4-me- thoxyphenyl)-2-phenylethyl) pyridine)
and compounds disclosed in WO 97/22585 to Guay et al.;
tetrahydropyrimidones such as atizoram (CP 80633) 4
[0045] diazepine derivatives such as C11018 5
[0046] and compounds disclosed in WO 97/36905 to Pascal et al.;
oxime carbamates such as filaminast (PDA-641); naphthyridinones
such as RS 17597 6
[0047] benzofurans such as
2-butyl-7-methoxy-benzofuran-4-carboxylic acid
(3,5-dichloro-pyridin-4-yl)-amide,
2-benzyl-7-methoxy-benzofuran-4-carbox- ylic acid
(3,5-dichloro-pyridin-4-yl)-amide, 7-methoxy-2-phenethyl-benzofu-
ran-4-carboxylic acid (3,5-dichloropyridin-4-yl)-amide and
5-(2-butyl-7-methoxy-benzofuran-4-yl)-tetrahydro-pyrimidin-2-one,
phenyldihydrobenzofurane compounds such as those disclosed in U.S.
Pat. No. 5,902,824; 4-substituted benzofurane compounds such as
those disclosed in EP 819688AI; substituted furans as disclosed in
Perrier et al. Bioorg. Med. Chem. Lett. 9:323-326 (1999);
naphthalene derivatives such as T 440 7
[0048] purine derivatives such as V-12294A 8
[0049] imidazolidinones such as 1,3-dimethyl-2-imidazolidinone
(DMI); cyclohexane carboxylic acids such as ariflo (SB 207499,
(c-4-cyano-4-[3'-cyclopentyloxy-4'-methoxyphenyl]-r-1-cyclohexanecarboxyl-
ic acid)); benzamides such as piclamilast (RP73401;
N-(3,5-dichloro-4-pyridyl)-3-cyclopentoxy-4-methoxy benzamide);
benzothiophenes such as tibenelast (LY 186655); pyridopyridazinones
such as 9
[0050] substituted phenyl compounds, as disclosed in U.S. Pat. No.
5,891,896 to Warrellow et al.; substituted biphenyl compounds as
disclosed in U.S. Pat. No. 5,877,190 to Dhainaut et al.; etazolate;
and S-(+)-glaucine ((S)-(+)-1,2,9,10-tetramethoxyaporphine).
[0051] Examples of Type V phosphodiesterase inhibitors include, but
are not limited to, zaprinast, MY5445, dipyridamole, and
sildenafil. Other Type V phosphodiesterase inhibitors are disclosed
in PCT Publication Nos. WO 94/28902 and WO 96/16644.
[0052] The compounds described in PCT Publication No. WO 94/28902
are pyrazolopyrimidinones. Examples of the inhibitor compounds
include
5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H--
pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-morphol
inoacetyl-2-n-propoxyphenyl)
1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propy-
l-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-allyloxy-5-(4-methyl-
-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazol-
o[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl-
)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-on-
e,
5-[2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl)phenyl]-1-methy-
l-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[5-[4-(2-hydroxyethyl)-1-piperazinylsulfonyl]-2-n-propoxyphenyl]-1-meth-
yl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-
-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, and
5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihy-
dro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
[0053] The phosphodiesterase inhibitors described in PCT
Publication No. WO 96/16644 include griseolic acid derivatives,
2-phenylpurinone derivatives, phenylpyridone derivatives, fused and
condensed pyrimidines, pyrimidopyrimidine derivatives, purine
compounds, quinazoline compounds, phenylpyrimidinone derivative,
imidazoquinoxalinone derivatives or aza analogues thereof,
phenylpyridone derivatives, and others. Specific examples of the
phosphodiesterase inhibitors disclosed in WO 96/16644 include
1,3-dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one,
2-(2-propoxyphenyl)-6-purinone,
6-(2-propoxyphenyl)-1,2-dihydro-2-oxypyri- dine-3-carboxamide,
2-(2-propoxyphenyl)-pyrido[2,3-d]pyrimid-4(3H)-one,
7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydro-pyrimido[4,5-d]pyrimid-
ine, 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide,
1-ethyl-3-methylimidazo[1,5a]quinoxalin-4(5H)-one,
4-phenylmethylamino-6-chloro-2-(1-imidazoloyl)quinazoline,
5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-propyloxy]-4,5-dhydro-4-oxo-
-pyrido[3,2-e]-pyrrolo[1,2-a]pyrazine,
5'-methyl-3'-(phenylmethyl)-spiro[c-
yclopentane-1,7'(8'H)-(3'H)-imidazo[2,1-b]purin]4'(5'H)-one,
1-[6-chloro-4-(3,4-methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine--
4-carboxylic acid, (6R,
9S)-2-(4-trifluoromethyl-phenyl)methyl-5-methyl-3,-
4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]-purin-4-one,
1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-d]-pyrimid-4-one,
1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimi-
d-4-one, 2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidazole,
and
2-(4-carboxypiperidino)-4-(3,4-methylenedioxy-benzyl)amino-6-nitroquinazo-
line, and 2-phenyl-8-ethoxycycloheptimidazole.
[0054] Still other Type V phosphodiesterase inhibitors useful in
conjunction with the present invention include: IC-351 (ICOS);
4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3
(2H)pyridazinone;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-qu-
inazolinyl]-4-piperidine-carboxylic acid, monosodium salt;
(+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-met-
hyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin;
cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1-
-b]purin-4-one;
3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate;
4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)
propoxy)-3-(2H)pyridazinone;
1-methyl-5-(5-morpholinoacetyl-2-n-propoxyph-
enyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one;
1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyll-4-piper-
idinecarboxylic acid, monosodium salt; pyrrolo[1,2-c]imidazolone
derivatives (as described in U.S. Pat. No. 4,937,258 to Shaw);
1-phenylmethyl-N-[[4-ethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)]pyrimidi-
n-5-yl]-1H-imidazol-2-carboxamide;
1-phenylmethyl-N-[4-ethyl-2-(1H-imidazo-
l-1-yl)pyrimidin-5-yl]-1H-imidazol-2-carboxamide (see U.S. Pat. No.
5,318,975 to Lis);
4,9-diethyl-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)-7-me-
thylimidazo[5,1-h]pteridin-6(5H)-one; and
9-ethyl-2(2-ethyl-4-methyl-1H-im-
idazol-1-yl)-7-methyl-4-(2-propyl)imidazo[5,1-h]pteridin-6(5H)-one
(see U.S. Pat. No. 5,602,252 to Davey); Pharmaprojects No. 4516
(Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects
No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069
(Schering Plough); GF-196960 (Glaxo Wellcome); and Sch-51866.
[0055] Other phosphodiesterase inhibitors that may be
co-administered with the Type III PDE inhibitor include nonspecific
phosphodiesterase inhibitors such as aminophylline, enprofylline,
isbufylline, IBMX, papaverine, pentoxifylline, theobromine and
theophylline, and direct vasodilators such as hydralazine.
[0056] The active agents may be administered, if desired, in the
form of salts, esters, amides, prodrugs, derivatives, and the like,
provided the salt, ester, amide, prodrug or derivative is suitable
pharmacologically, i.e., effective in the present method. Salts,
esters, amides, prodrugs and other derivatives of the active agents
may be prepared using standard procedures known to those skilled in
the art of synthetic organic chemistry and described, for example,
by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and
Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For
example, acid addition salts are prepared from the free base using
conventional methodology, and involves reaction with a suitable
acid. Generally, the base form of the drug is dissolved in a polar
organic solvent such as methanol or ethanol and the acid is added
thereto. The resulting salt either precipitates or may be brought
out of solution by addition of a less polar solvent. Suitable acids
for preparing acid addition salts include both organic acids, e.g.,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. An acid
addition salt may be reconverted to the free base by treatment with
a suitable base. Particularly preferred acid addition salts of the
active agents herein are halide salts, such as may be prepared
using hydrochloric or hydrobromic acids. Conversely, preparation of
basic salts of acid moieties which may be present on a
phosphodiesterase inhibitor molecule are prepared in a similar
manner using a pharmaceutically acceptable base such as sodium
hydroxide, potassium hydroxide, ammonium hydroxide, calcium
hydroxide, trimethylamine, or the like. Particularly preferred
basic salts herein are alkali metal salts, e.g., the sodium salt,
and copper salts. Preparation of esters involves functionalization
of hydroxyl and/or carboxyl groups which may be present within the
molecular structure of the drug. The esters are typically
acyl-substituted derivatives of free alcohol groups, i.e., moieties
which are derived from carboxylic acids of the formula RCOOH where
R is alkyl, and preferably is lower alkyl. Esters can be
reconverted to the free acids, if desired, by using conventional
hydrogenolysis or hydrolysis procedures. Amides and prodrugs may
also be prepared using techniques known to those skilled in the art
or described in the pertinent literature. For example, amides may
be prepared from esters, using suitable amine reactants, or they
may be prepared from an anhydride or an acid chloride by reaction
with ammonia or a lower alkyl amine. Prodrugs are typically
prepared by covalent attachment of a moiety which results in a
compound that is therapeutically inactive until modified by an
individual's metabolic system.
[0057] Pharmaceutical Formulations and Modes of Administration:
[0058] The active agent is administered transmucosally to treat
erectile dysfunction, and is accordingly administered in a
pharmaceutical formulation suitable for transmucosal drug
administration.
[0059] The pharmaceutical compositions may be in the form of solid,
semi-solid or liquid dosage forms, such as, for example, buccal
tablets, sublingual tablets, rectal suppositories, suspensions,
creams, ointments, solutions, lotions, pastes or the like,
preferably in unit dosage form suitable for single administration
of a precise dosage. The compositions comprise an effective amount
of the phosphodiesterase inhibitor in combination with a
pharmaceutically acceptable carrier and, in addition, may include
other pharmaceutical agents, adjuvants, diluents, buffers, etc.
[0060] For solid compositions, conventional nontoxic solid carriers
include, for example, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, talc, cellulose,
glucose, sucrose, magnesium carbonate, and the like. Liquid
pharmaceutically administrable compositions can, for example, be
prepared by dissolving, dispersing, etc., an active compound as
described herein and optional pharmaceutical adjuvants in an
excipient, such as, for example, water, saline, aqueous dextrose,
glycerol, ethanol, and the like, to thereby form a solution or
suspension. If desired, the pharmaceutical composition to be
administered may also contain minor amounts of nontoxic auxiliary
substances such as wetting or emulsifying agents, pH buffering
agents and the like, for example, sodium acetate, sorbitan
monolaurate, triethanolamine sodium acetate, triethanolamine
oleate, etc. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington: The Science and Practice of Pharmacy,
Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995).
[0061] Depending on the particular phosphodiesterase inhibitor
administered, it may be desirable to incorporate a permeation
enhancer in the formulation in order to increase the rate at which
the active agent permeates through the mucosal tissue to which it
is applied, e.g., the buccal mucosa, sublingual or rectal mucosa.
Examples of suitable permeation enhancers include dimethylsulfoxide
("DMSO"), dimethyl formamide ("DMF"), N,N-dimethylacetamide
("DMA"), decylmethylsulfoxide ("DMSO"), polyethylene glycol
monolaurate ("PEGML"), glycerol monolaurate, lecithin, the
1-substituted azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Nelson Research & Development Co., Irvine,
Calif.), SEPA.RTM. (available from Macrochem Co., Lexington,
Mass.), alcohols (e.g., ethanol), surfactants as discussed above,
including, for example, Tergitol.RTM., Nonoxynol-9.RTM. and
TWEEN-80.RTM., and lower alkanols such as ethanol.
[0062] The formulations may additionally include one or more enzyme
inhibitors effective to inhibit drug-degrading enzymes which may be
present at the site of administration. Such enzyme inhibiting
compounds may be determined by those skilled in the art by
reference to the pertinent literature and/or using routine
experimental methods. Additional optional components include
excipients, binders, fillers, lubricants (e.g., stearates such as
magnesium stearate), preservatives (e.g., antioxidants), chelating
agents, solubilizing agents (e.g., surfactants), and the like, as
will be appreciated by those skilled in the art of drug formulation
preparation and delivery.
[0063] Transmucosal drug may involve administration of any type of
formulation or dosage unit suitable for application to the mucosal
tissue. For example, the selected active agent may be administered
in an ointment, cream, paste, or the like, or in a solid dosage
form unit to be placed under the tongue (sublingual formulations),
affixed to the buccal mucosa as an adhesive tablet or patch (buccal
formulations), or placed within or near the rectum (transrectal
formulations).
[0064] Preferred buccal dosage forms will typically comprise a
therapeutically effective amount of the selected phosphodiesterase
inhibitor and a bioerodible (hydrolyzable) polymeric carrier that
may also serve to adhere the dosage form to the buccal mucosa. The
buccal dosage unit is fabricated so as to erode gradually over a
predetermined time period, wherein drug delivery is provided
essentially throughout. The time period is typically in the range
of approximately 0.5 hours to 24 hours. Buccal drug delivery, as
will be appreciated by those skilled in the art, avoids the
disadvantages encountered with oral drug administration, e.g., slow
absorption, degradation of the active agent by fluids present in
the gastrointestinal tract and/or first-pass inactivation in the
liver. The "therapeutically effective amount" of phosphodiesterase
inhibitor in the dosage unit will of course depend on the potency
of the agent and the intended dosage, which, in turn, is dependent
on the particular individual undergoing treatment, the specific
indication, and the like. Suitable doses of specific
phosphodiesterase inhibitors will be known to those skilled in the
art, or may be deduced from the literature in combination with the
teaching of the present disclosure. By way of example, a typical
daily dosage of sildenafil citrate for treatment of sexual
dysfunction as discussed herein is in the range of about 25 to 100
mg, although more or less may be effective. The dosage unit will
generally contain from approximately 1.0 wt. % to about 60 wt. %
active agent, preferably on the order of 1 wt. % to about 30 wt. %
active agent. With regard to the bioerodible (hydrolyzable)
polymeric carrier, it will be appreciated that virtually any such
carrier can be used, so long as the desired drug release profile is
not comprised, and the carrier is compatible with the
phosphodiesterase inhibitor to be administered and any other
components that may be present in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic
(water-soluble and water-swellable) polymers that adhere to the wet
surface of the buccal mucosa. Examples of polymeric carriers useful
herein include acrylic acid polymers and co, e.g., those known as
"carbomers" (Carbopol.RTM., which may be obtained from B. F.
Goodrich, is one such polymer). Other suitable polymers include,
but are not limited to: hydrolyzed polyvinylalcohol; polyethylene
oxides (e.g., Sentry Polyox.RTM. water soluble resins, available
from Union Carbide); polyacrylates (e.g., Gantrez.RTM., which may
be obtained from GAF); vinyl polymers and copolymers;
polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and
cellulosic polymers such as hydroxypropyl methylcellulose, (e.g.,
Methocel.RTM., which may be obtained from the Dow Chemical
Company), hydroxypropyl cellulose (e.g., Klucel.RTM., which may
also be obtained from Dow), hydroxypropyl cellulose ethers (see,
e.g., U.S. Pat. No. 4,704,285 to Alderman), hydroxyethyl cellulose,
carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl
cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose
acetate butyrate, and the like.
[0065] Other components may also be incorporated into the buccal
dosage forms described herein. The additional components include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like.
Examples of disintegrants that may be used include, but are not
limited to, cross-linked polyvinylpyrrolidones, such as
crospovidone (e.g., Polyplasdone.RTM. XL, which may be obtained
from GAF), cross-linked carboxylic methylcelluloses, such as
croscarmelose (e.g., Ac-di-sol.RTM., which may be obtained from
FMC), alginic acid, and sodium carboxymethyl starches (e.g.,
Explotab.RTM., which may be obtained from Edward Medell Co., Inc.),
methylcellulose, agar bentonite and alginic acid. Suitable diluents
are those which are generally useful in pharmaceutical formulations
prepared using compression techniques, e.g., dicalcium phosphate
dihydrate (e.g., Di-Tab.RTM., which may be obtained from Stauffer),
sugars that have been processed by cocrystallization with dextrin
(e.g., co-crystallized sucrose and dextrin such as Di-Pakg, which
may be obtained from Amstar), lactone, calcium phosphate,
cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered
sugar and the like. Binders, if used, are those that enhance
adhesion. Examples of such binders include, but are not limited to,
starch, gelatin and sugars such as sucrose, dextrose, molasses, and
lactose. Particularly preferred lubricants are stearates and
stearic acid, and an optimal lubricant is magnesium stearate.
[0066] Preferred sublingual dosage forms include sublingual
tablets, creams, ointments and pastes. The tablet, cream, ointment
or paste for sublingual delivery comprises a therapeutically
effective amount of the selected phosphodiesterase inhibitor and
one or more conventional nontoxic carriers suitable for sublingual
drug administration. The sublingual dosage forms of the present
invention can be manufactured using conventional processes. The
sublingual dosage unit is fabricated to disintegrate rapidly. The
time period for complete disintegration of the dosage unit is
typically in the range of from about 10 seconds to about 30
minutes, and optimally is less than 5 minutes.
[0067] Other components may also be incorporated into the
sublingual dosage forms described herein. The additional components
include, but are not limited to binders, disintegrators, wetting
agents, lubricants, and the like. Examples of binders that may be
used include water, ethanol, polyvinylpyrrolidone, starch solution
gelatin solution, and the like. Suitable disintegrators include dry
starch, calcium carbonate, polyoxyethylene sorbitan fatty acid
esters, sodium lauryl sulfate, stearic monoglyceride, lactose, and
the like. Wetting agents, if used, include glycerin, starches, and
the like. Particularly preferred lubricants are stearates and
polyethylene glycol. Additional components that may be incorporated
into sublingual dosage forms are known, or will be apparent, to
those skilled in this art; for example, see Remington: The Science
and Practice of Pharmacy, 19th edition (Mack Publishing, 1995).
[0068] Preferred transrectal dosage forms include rectal
suppositories, creams, ointments, and liquid formulations (enemas).
The suppository, cream, ointment or liquid formulation for
transrectal delivery comprises a therapeutically effective amount
of the selected phosphodiesterase inhibitor and one or more
conventional nontoxic carriers suitable for transrectal drug
administration. The transrectal dosage forms of the present
invention can be manufactured using conventional processes. The
transrectal dosage unit can be fabricated to disintegrate rapidly
or over the period of several hours. The time period for complete
disintegration is preferably in the range of from about 10 minutes
to about 6 hours, and optimally is less than 3 hours.
[0069] Other components may also be incorporated into the
transrectal dosage forms described herein. The additional
components include, but are not limited to, stiffening agents,
antioxidants, preservatives, and the like. Examples of stiffening
agents that may be used include, for example, paraffin, white wax
and yellow wax. Preferred antioxidants, if used, include sodium
bisulfite and sodium metabisulfite.
[0070] Ointments, as is well known in the art of pharmaceutical
formulation, are semisolid preparations that are typically based on
petrolatum or other petroleum derivatives. Creams containing the
selected active agent, are, as known in the art, viscous liquid or
semisolid emulsions, either oil-in-water or water-in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also called the "internal"
phase, is generally comprised of petrolatum and a fatty alcohol
such as cetyl or stearyl alcohol. The aqueous phase usually,
although not necessarily, exceeds the oil phase in volume, and
generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant. The specific ointment or cream base to be
used, as will be appreciated by those skilled in the art, is one
that will provide for optimum drug delivery. As with other carriers
or vehicles, an ointment base should be inert, stable,
nonirritating and nonsensitizing. The ointment or cream is applied
to a suitable mucosal surface.
[0071] Pastes are semisolid dosage forms in which the active agent
is suspended in a suitable base. Depending on the nature of the
base, pastes are divided between fatty pastes or those made from a
single-phase aqueous gels. The base in a fatty paste is generally
petrolatum or hydrophilic petrolatum or the like. The pastes made
from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base. The paste is applied
to a suitable mucosal surface.
[0072] Suppositories are solid dosage forms in which the active
agent is carried in a suitable base. Specifically shaped for
insertion into body orifices, the suppository melts, softens or
dissolves resulting in effective delivery of the active agent. The
suppository base can be an oleaginous base, water-soluble base, or
mixture of both. The base must remain a solid at room temperature
but melt, soften or dissolve at body temperature. Thus, suitable
suppository bases include, for example, cocoa butter, glyceryl
monostearate and polyethylene glycol. The suppository is made using
conventional techniques including molding, compression, or hand
rolling. The suppository is inserted into a body orifice having a
suitable mucosal surface.
[0073] Enemas are liquid dosage forms in which the active agent is
solubilized or suspended in a suitable liquid carrier. As will be
readily apparent to those skilled in the art, the selection of the
liquid carrier is dependent upon the stability and chemical
reactivity of the active agent. Suitable liquid carriers for enemas
include, for example, sodium chloride solution. Alternative
carriers, additional components and methods of preparing enemas are
known to those skilled in the art or disclosed in Remington: The
Science and Practice of Pharmacy, referenced above.
[0074] Additional pharmacologically active agents may be delivered
along with the primary active agent, i.e., the phosphodiesterase
inhibitor. Vasoactive agents, particularly vasodilators, are
preferred additional agents. Suitable vasoactive agents include,
but are not limited to, nitrovasodilators such as: nitroglycerin;
linsidomine, particularly linsidomine chlorhydrate ("SIN-I");
molsidomine; organic nitrates such as isosorbide dinitrate,
erythrityl tetranitrate and amyl nitrate; sodium nitroprusside;
S-nitrosothiols such as S-nitroso-N-acetyl-d,l-penicillami- ne
("SNAP"), S-nitroso-N-cysteine and S-nitroso-N-glutathione
("SNO-GLU"); and diazenium diolates ("NONOates") such as
(Z)-1-{N-methyl-N-[6-(N-methy-
l-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate,
(Z)-1-[N-(3-ammoniopropyl)-
-N-(n-propyl)amino]diazen-1-ium-1,2-diolate,
(Z)-1-{N-[3-aminopropyl]-N-[4-
-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate and
sodium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate. Other
suitable vasoactive agents include, for example, long and short
acting-blockers such as phenoxybenzamine, dibenamine, doxazosin,
terazosin, phentolamine, tolazoline, prazosin, trimazosin,
alfuzosin, tamsulosin and indoramin; ergot alkaloids such as
ergotamine and ergotamine analogs, e.g., acetergamine,
brazergoline, bromerguride, cianergoline, delorgotrile,
disulergine, ergonovine maleate, ergotamine tartrate, etisulergine,
lergotrile, lysergide, mesulergine, metergoline, metergotamine,
nicergoline, pergolide, propisergide, proterguride and terguride;
antihypertensive agents such as diazoxide, hydralazine and
minoxidil; vasodilators such as nimodipine, pinacidil, cyclandelate
and isoxsuprine; chlorpromazine; haloperidol; yohimbine; Rec
15/2739; trazodone; naturally occurring prostaglandins such as
PGE.sub.0, PGE.sub.1, PGA.sub.2, PGB.sub.1, PGF.sub.1,
19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2,
PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3,
PGF.sub.3; semisynthetic or synthetic derivatives of natural
prostaglandins, including carboprost tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost,
sulprostone and tiaprost; and vasoactive intestinal peptide.
Prazosin, prostaglandin E.sub.0, prostaglandin E.sub.1 and
prostaglandin E.sub.2 are particularly preferred vasoactive agents
to be co-administered with the active agent.
[0075] The amount of active agent administered and the dosing
regimen used, will, of course, be dependent on the particular drug
selected, the age and general condition of the subject being
treated, the severity of the subject's condition, and the judgment
of the prescribing physician. A typical daily dose of an active
agent as administered transmucosally, e.g., buccally, sublingually,
or transrectally, is generally in the range of approximately 0.1 to
500 mg, with 5 mg to 100 mg representing an optional dosage range
for most active agents. Depending on the half-life of the drug and
the availability via the chosen route of administration, the dosing
regimen can be modulated in order to achieve satisfactory
therapeutic results.
[0076] Kits:
[0077] The invention also encompasses a kit for patients to carry
out the present method of treating premature ejaculation using
transmucosal, e.g., buccal, sublingual, and transrectal drug
therapy. The kit contains the pharmaceutical formulation to be
administered, a container, preferably sealed, for housing the
formulation during storage and prior to use, and instructions for
carrying out drug administration in an effective manner. The
formulation may consist of the drug in unit dosage form. The kit
may contain multiple formulations of different dosages of the same
agent. The kit may also contain multiple formulations of different
active agents. The instructions may be in written or pictograph
form, or can be on recorded media including audio tape, video tape,
or the like.
[0078] Use in Conjunction With Venous Flow Control ("VFC")
Device:
[0079] In an alternative embodiment of the invention, a
pharmaceutical formulation containing the selected
phosphodiesterase inhibitor is administered transmucosally in
combination with use of a venous flow control device such as that
described in U.S. Pat. No. 5,855,548 to Place for "Venous Flow
Control Element for Maintaining Penile Erection," assigned to
VIVUS, Inc. (Mountain View, Calif.). Preferred devices are formed
from a length of flexible tubing having an integral fastening
means, so as to provide for readily adjustable venous flow control
when applied to the penis. The device is applied to the base of the
penis prior to and during sexual intercourse, such that it
effectively enhances retention of blood within the penis without
substantially obstructing arterial inflow or becoming too
constrictive during the erectile process. In this embodiment, a kit
will include the venous flow control device in addition to the
components noted above, along with instructions for using the
device.
[0080] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the foregoing description as well as the examples
which follow are intended to illustrate and not limit the scope of
the invention. Other aspects, advantages and modifications within
the scope of the invention will be apparent to those skilled in the
art to which the invention pertains. All patents, patent
applications, and publications mentioned herein are hereby
incorporated by reference in their entireties.
EXAMPLE 1
[0081] Preparation of transmucosal paste: A transinucosal
formulation is prepared containing zaprinast, a Type V
phosphodiesterase inhibitor. 10 g of bulk zaprinast is placed in a
mortar and a pestle is used to grind the solid into a fine powder.
About 10 g of a previously weighed out quantity of 100 g of
OPABASE.RTM. (Colgate-Hoyt Laboratories, Norwood, Mass.) is
combined with the zaprinast powder on an ointment tile. The
zaprinast powder and ORABASE.RTM. are levigated together using a
spatula. The remaining ORABASE.RTM. is added to the ointment tile
and levigated with the previously mixed components to produce a
smooth, consistent formulation. The resulting formulation is a 10%
zaprinast transmucosal formulation.
[0082] This procedure can be used with various phosphodiesterase
inhibitors, ointment bases and additional components, e.g.,
enhancers or the like.
EXAMPLE 2
[0083] Preparation of transmucosal paste: A transmucosal
formulation is prepared containing sildenafil citrate, a Type V
phosphodiesterase inhibitor. About 5 g of bulk sildenafil citrate
is placed in a mortar and a pestle is used to grind the solid into
a fine powder. About 5 g of a previously weighed out quantity of
100 g of ORABASE.RTM. is combined with the sildenafil citrate
powder on an ointment tile. The sildenafil citrate powder and
ORABASE.RTM. are levigated together using a spatula. The remaining
ORABASE.RTM. is added to the ointment tile and levigated with the
previously mixed components to produce a smooth, consistent
formulation. The resulting formulation is a 5% sildenafil citrate
transmucosal formulation.
EXAMPLE 3
[0084] Preparation of buccal dosage form: 10 g of zaprinast and 90
g of gelatin are mixed and pulverized in a mill. After the mixing
is complete, 20 g of concentrated glycerin, 10 g of lactose and 20
g of mannitol are added and the components are mixed until uniform.
150 mg aliquot portions of the mixture are compression-molded to
provide a buccal dosage unit. Each buccal unit contains 10 mg of
zaprinast.
EXAMPLE 4
[0085] Preparation of a buccal dosage form: 10 g of sildenafil
citrate and 90 g of gelatin are mixed and pulverized in a mill.
After the mixing is complete, 20 g of concentrated glycerin, 10 g
of lactose and 20 g of mannitol are added and the components are
mixed until uniform. 150 mg aliquot portions of the mixture are
compression-molded to provide a buccal dosage unit. Each buccal
unit contains 10 mg of sildenafil citrate.
EXAMPLE 5
[0086] Preparation of a buccal dosage form: 10 g of milrinone (a
Type III phosphodiesterase inhibitor) and 90 g of gelatin are mixed
and pulverized in a mill. After the mixing is complete, 20 g of
concentrated glycerin, 10 g of lactose and 20 g of mannitol are
added and the components are mixed until uniform. 150 mg aliquot
portions of the mixture are compression-molded to provide a buccal
dosage unit. Each buccal unit contains 10 mg of milrinone.
EXAMPLE 6
[0087] Preparation of a buccal dosage form: 10 g of rolipram (a
Type IV phosphodiesterase inhibitor) and 90 g of gelatin are mixed
and pulverized in a mill. After the mixing is complete, 20 g of
concentrated glycerin, 10 g of lactose and 20 g of mannitol are
added and the components are mixed until uniform. 150 mg aliquot
portions of the mixture are compression-molded to provide a buccal
dosage unit. Each buccal unit contains 10 mg of rolipram.
EXAMPLE 7
[0088] 10074] Preparation of a sublingual tablet: 1.0 g of
zaprinast, 1.0 g of mannitol, 2.0 g of microcrystalline cellulose,
and 10 mg of magnesium stearate are blended in a suitable mixer and
then compressed into sublingual tablets. Each sublingual tablet
contains 10 mg of zaprinast.
EXAMPLE 8
[0089] Preparation of a sublingual tablet: 1.0 g of sildenafil
citrate, 1.0 g of mannitol, 2.0 g of microcrystalline cellulose,
and 10 mg of magnesium stearate are blended in a suitable mixer and
then compressed into sublingual tablets. Each sublingual tablet
contains 10 mg of sildenafil citrate.
EXAMPLE 9
[0090] Preparation of a rectal suppository: A pharmaceutical
formulation containing a Type V phosphodiesterase inhibitor for
transrectal administration is prepared by mixing 10 to 100 mg
zaprinast with polyethylene glycol, molecular weight approximately
4000, and heating the mixture to a temperature just high enough to
produce a zaprinast-polymer melt. The zaprinast-polyethyleneglycol
mixture can then be poured into a mold suitable to provide a
zaprinast rectal suppository, and allowed to cool. The suppository
so provided is a unit dosage form suitable for transrectal
administration.
EXAMPLE 10
[0091] Preparation of a rectal suppository: A phannaceutical
formulation containing an a Type V phosphodiesterase inhibitor for
transrectal administration is prepared by mixing to 100 mg
sildenafil citrate with polyethylene glycol, molecular weight
approximately 4000, and heating the mixture to a temperature just
high enough to produce a sildenafil citrate-polymer melt. The
sildenafil citrate-polyethyleneglycol mixture can then be poured
into a mold suitable to provide a sildenafil citrate rectal
suppository, and allowed to cool. The suppository so provided is a
unit dosage form suitable for transrectal administration.
EXAMPLE 11
[0092] An effective phosphodiesterase-inhibiting dose may be
determined using the following procedures.
[0093] Buccal administration: Patients with penile vascular
insufficiency are given a single dose of 0.5 g of a
phosphodiesterase inhibitor (e.g., zaprinast) transbucally in a
buccal dosage form. Prior to and approximately 3 hours after
administering the inhibitor, blood samples are taken and assayed
for plasma phosphodiesterase activity using, for example,
high-performance liquid chromatography with fluorimetric detection
as described by Lee et al, J. Chromatography 421:237-244 (1987).
This procedure is repeated at 24 hour intervals with dosage
adjusted as necessary.
[0094] Sublingual administration: The same procedures described for
determining an effective phosphodiesterase-inhibiting dose for
buccal administration are followed except that a suitable dosage
form is administered sublingually.
[0095] Transrectal administration: The same procedures described
for determining an effective phosphodiesterase-inhibiting dose for
buccal administration are followed expect that a suitable dosage
form is administered transrectally.
EXAMPLE 12
[0096] The pharmaceutical formulations of Examples 1-10 can be used
to treat erectile dysfunction in individuals in which the
dysfunction is associated, for example, vascular insufficiency.
Dosage may be adjusted using the methodology of Example 11. In all
instances, the individuals are expected to respond positively,
although variations in the intensity and duration of erection may
be observed depending on dose, formulation, and environment.
Generally, between approximately 5 and 90 minutes following drug
administration, it is expected that an erection may be
achieved.
* * * * *