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Description  |
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TECHNICAL FIELD
This invention relates to the treatment of erectile disfunction and more
particularly to the treatment of impotence, priapism and Peyronie's
syndrome.
BACKGROUND OF THE INVENTION
As used herein, the term "erectile dysfunction" refers to certain disorders
of the cavernous tissue of the penis and the associated facia which
produce impotence, the inability to attain a sexually functional erection;
priapism, the persistent and often painful erection of the penis; and
Peyronie's syndrome, a condition characterized by fibrosis of the
cavernous tissue and associated painful and distorted erection of the
penis. Erectile dysfunctions, particularly impotence, affect a substantial
number of patients. For example, impotence is estimated to affect
approximately 10 million American men and can result from any of numerous
physiological or psychological factors which cause the blood flow to and
from the penis to remain in balance thereby preventing retention of
sufficient blood to cause rigid dilation of the corpus cavernosa and
spongiosa. As used herein, the term "impotence" is used in its broadest
sense as the inability to attain a sexually functional erection when
desired.
Treatments for impotence include psychosexual therapy, hormonal therapy,
administration of vasodilators such as nitroglycerin and
.alpha.-adrenergic blocking agents (hereafter "s-blockers"), vascular
surgery, implanted penile prostheses, vacuum 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. See Robert J. Krause, et
al., Impotence, N. Eng. J. Med. Vol. 321, No. 24, Dec. 14, 1989 for a
general discussion of the current state of the art.
Originally Dr. Latorre and later Dr. R. Verag of Paris demonstrated that
impotence could be physiologically treated by the direct injection of a
vasoactive drug into a patient's epigastric artery and thereafter
thousands of patients have treated their impotence by self injection of
such drugs directly into the corpora cavernosa. Forward, 1.sup.er
Symposium International Sur L'Erection Pharmacologique, 17-19 Nov. 1989,
Paris, p 2; R. Virag, et al, Intracavernous Injection of Papaverine as a
Diagnostic and Therapeutic Method in Erectile Failure, Angiology, 35, pp
79-87, 984; (See also, U.S. Pat. Nos. 4,127,118, 4,766,889 and 4,857,059
which are incorporated herein by reference). The drugs most commonly used
include .alpha.-blockers, such as the long acting phenoxybenzamine and the
short acting phentolamine, smooth muscle relaxants such as papaverine,
prostaglandins having a vasoactive function such as prostaglandin-E.sub.1
(PGE.sub.1) and combinations of such drugs having different receptor
effects to enhance therapy. Erection producing intracavernous injection
doses of papaverine are typically in the range of about 7.5 to 160 mg, of
phentolamine are in the range of about 0.1 to 10 mg of and of PGE.sub.1
are in the range of about 2.5 to 50 micrograms. See for example, Kurkle,
et al, Injection Therapy for Impotence Urol. Clin. of America, Vol. 15,
No. 4, Nov. 88, pp 625-629 and N. Ishii, et al, Intra Cavernous Injection
of Prostaglandin E for the Treatment of Erectile Impotence, J. of Urol.,
Vol. 141, Feb. 1989, pp 323-325. Vasoactive intestinal peptides at doses
of 10-100 .mu.g have also been reported as producing erection on
intracavernous injection. See also, H. Handelsman, Diagnosis and Treatment
of Impotence, U.S. Dept. of Health Services, Agency for Health Care Policy
and Research, April 1990, for a summary of intracavernal injection and
other treatment of impotence.
Although intracavernous injection of vasoactive drugs can produce a
relatively rapid onset of erection in patients suffering from impotence
attributable to venous leakage or arterial insufficiency; patients often
find the injections psychologically disturbing, painful, traumatic or
inconvenient as evidenced by a high discontinuance rate. See S. Althouf,
et al, Why Do So Many People Drop Out From Auto-Injection Therapy for
Impotence?, Journal of Sex & Marital Therapy, Vol. 15, No. 2, 1989, pp
121-129. Adverse side effects including priapism, corporeal nodules and
diffuse fibrosis, drug tolerance, bruising and hematomas. Swelling and
ulceration of penile skin at the injection site have also been reported.
Nevertheless, because of the relatively innocuous intervention involved and
the high failure rate of penile prostheses, the pharmacological approach
to the treatment of impotence is still quite advantageous to a large
number of patients and could be even more so if the side effects could be
avoided. The administration of vasodilators via the male urethra has been
disclosed in Voss, U.S. Pat. No. 4,801,587 and Kock, EPA 0357581 to
produce erections as has the transurethral administration of testosterone,
S. M. Milco, Bulletins et Memoirs de la Societa Roumaine D'Endocrinologie,
Vol. 5, pp 434-437 (Dec. 1939), strychnine and another drug (citation to
be provided). It has also been suggested that cocaine administered
transurethrally could contribute to an erection although the reported side
effects were catastrophic, JAMA, Vol. 259, No. 21, page 3176 (1988).
Priapism is less common than impotence and can be attributed to various
causes. It has been associated with diseases producing intravascular
agglutination or sludging, such as leukemia, and pharmacological priapism
has been reported in a small percentage of patients who are treated for
impotence by intracavernous injection. Priapism has been treated by
intracavernous injection of vasoconstrictors such as .alpha.-adrenergic
receptor agonists (hereafter ".alpha.-agonist"). The reported effective
doses of the .alpha.-agonist, phenylephrine, are in the range of about 0.1
to 2 mg.
Peyronie's syndrome is a condition of unknown etiology characterized by
fibrosis of the cavernous tissues and painful and distorted erections. The
current treatment consists of injection of steroids and other
anti-inflammatory agents into the site of the fibrosis.
With respect to administration of drugs directly to the penis, medicated
catheters such as described in U.S. Pat. No. 4,640,912 have been used to
prevent or treat localized infections and irritation of the urethra and
bladder; a nitroglycerin coated, erection inducing condom is disclosed in
U.S. Pat. No. 4,829,991; the transurethral administration of certain drugs
is suggested in U.S. Pat. Nos. 4,478,822, 4,610,868, 4,640,912 and
4,746,508; and medicated urethral suppositories, inserts or plugs,
typically containing anti-infective agents or spermicides are disclosed in
U.S. Pat. Nos. 1,897,423, 2,584,166, 2,696,209 and 3,373,746, for example.
As noted above, Voss, Kock, Milco, and others disclose introducing agents
into the urethra to induce erections.
According to our invention, we have provided methods and dosage forms for
the treatment of erectile dysfunctions which are painless, capable of
rapidly, safely and effectively producing erection of the penis in the
case of impotence, detumescence of the penis in the case of priapism and
administration of anti-inflammatory drugs to fibrotic sites in the case of
Peyronie's syndrome without the above described adverse side effects and
with a high degree of patient acceptability.
BRIEF DESCRIPTION OF THE INVENTION
We have found that the above-described erectile dysfunctions can be safely
and effectively treated by the transurethral administration of the
appropriate therapeutic drug or combination of therapeutic drugs (as used
herein the term "agent" refers to a drug or a combination of drugs capable
of producing the desired therapeutic effect) and have provided
compositions and penile inserts adapted to be easily and painlessly
inserted into the urethra, which compositions or inserts carry the
appropriate therapeutic agent in an amount sufficient to produce the
desired result.
In one preferred embodiment of this invention the therapeutic agent is
applied as a coating on a penile insert configured to prevent complete
insertion and to facilitate removal.
In another preferred embodiment of this invention, the agent is contained
in a gel, cream, ointment or suppository for example which may be
deposited in the urethra from a specially designed inserter.
BRIEF DESCRIPTION OF THE DRAWINGS
This invention and the advantages thereof will be readily apparent from the
following description of the invention with reference to the accompanying
drawings wherein:
FIG. 1 is a cross sectional view of one embodiment of this invention;
FIG. 2 is a cross sectional view of another embodiment of this invention:
FIG. 3 is an exploded view of a penile insert according to the invention
and its container;
FIG. 4 is a side view, partly in section, of an inserter/container assembly
for introducing a composition containing a dose of agent into the urethra;
FIG. 5 is a top view of the inserter/container of FIG. 4; to
FIG. 6 is a side view of another inserter construction for introducing a
dose into the urethra;
FIG. 7 is a cross-section through the inserter of FIG. 6 in the filling
position; and
FIG. 8 is a cross-section through the inserter of FIG. 6 in the loaded
position.
DESCRIPTION OF THE INVENTION INCLUDING THE BEST MODE
In its broadest aspect, this invention contemplates the treatment of
erectile dysfunction by the transurethral administration of an agent,
therapeutically effective with respect to the dysfunction, directly into
the blood supplying the corpus cavernosum via the cross circulation with
the spongiosa surrounding the urethra. The erectile dysfunctions which may
be so treated include impotence, for which the therapeutic agent is one or
more drugs capable of producing a vaso-dilatory or other erection inducing
effect. Suitable vaso-dilatory agents include nitrates such as
nitroglycerin and isosorbide dinitrate, long and short acting
.alpha.-blockers such as phenoxybenzamine, dibenamine, doxazosin,
terazosin, phentolamine, tolazoline, prazosin and trimazosin; adenosine,
ergot alkaloids, chlorpromazine, haloperidol, yohimbine, verapamil and
other calcium blockers, natural and synthetic vasoactive prostaglandins
and analogs thereof such as PGE.sub.1, including alprostadil, misoprostol
and enprostil, for example, prostaglandin E.sub.2, minoxidil, vasoactive
intestinal peptides or any other agent which is capable of producing an
erection when administered transurethrally. For example, dopamine agonists
such as apomorphine and bromocriptine, testosterone, cocaine, strychnine,
and opioid antagonists such as naltrexone have been reported to induce
erection and they may also be useful according to this invention. See S.
Lal et al, Apomorphine: Clinical Studies on Erectile Impotence and
Yawning, Prog. Neuro-Psychopharmacology, Vol. 13, 1989, pp 329-339 and A.
Fabbri et al, Endorphins in Male Impotence, Evidence for Naltrexone
Stimulation of Erectile Activity in Patient Therapy,
Psychoneuroendocrinology, Vol. 14, No. 1 & 2, pp 89, 103-111.
We have found that combinations of two or more drugs can exhibit a
synergistic effect and preferred combinations are combinations of
.alpha.-blockers and prostaglandin particularly prazosin, doxazosin or
terazosin with PGE.sub.1, such as alprostadil, misoprostol or enprostil.
With respect to priapism, the therapeutic agent may be one or s more
vasoconstrictor drugs. Suitable vasoconstrictors include a receptor
agonists such as epinephrin, phenylethylamine, norepinephrine, dopamine,
metaraminol, phenylephrine, methoxamine, ephedrine, phenylpropanolamine,
mephentermine and propylhexedrine, for example, .beta.-blockers such as
butoxamine, dichloroisoproterenol, zopropranolol, alprenolol, bunolol,
nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, metoprolol,
atenolol, acebutolol, bevantolol, pafenolol, and tolamolol, for example,
and any other agent which is capable of producing a detumescent effect
when applied transurethrally.
With respect to Peyronie's syndrome, the therapeutic agent may be one or
more anti-inflammatory drugs such as corticosteroids including cortisone,
hydrocortisone, tetrahydrocortisone, prednisone, prednisolone,
methylprednisolone, fludrocortisone, desoxycortisol, corticosterone,
triamcinolone, paramethasone, betamethasone, dexamethasone and
beclomethasone, for example, non-steroidal anti-inflammatories such as
salicylic acid, aspirin, diflunisal, methyl salicylate, phenylbutazone,
oxyphenbutazone, apazone, phenacetin, acetaminophen, indomethacin,
sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ibuprofen,
naproxen and fenoprofen, for example, and other drugs such as testosterone
which may be capable of producing an anti-inflammatory effect on fibrous
tissue within the corpus cavernosum when administered transurethrally.
It is preferred that the agent be rapidly delivered through the urethra in
order to bring about a rapid onset of the desired effect. To that end the
agent containing material may be caused to contact the urethra along a
sizable portion, about 2-3 cm, of its length rather than localizing it at
one site along the urethra. Also, the agent should be applied at least 1
cm into the penis and past the point where the transition from the
epidermal character of the glans has been completed. It has been found
that rapid absorption can also be obtained when a small, rapidly releasing
dosage form such as a gel, cream, ointment or suppository or a coating is
deposited between the proximal portion of the fossa navicularis including
the valves of navicularis and the distal portion of the pendulous urethra.
This appears to be the optimum location for rapid absorption of the agent
and although it varies from individual to individual it is generally at a
depth of 2-5 cm in the penis.
In all of the dosage forms contemplated herein, it is desirable that the
volume of agent-containing material that is deposited in the urethra
remain within the urethra and in contact with the wall of the urethra
until complete absorption of the agent has occurred and that the material
be deposited in a manner that permits relatively rapid absorption of the
agent. Dosages in the range of 50-100 mg (approximately 50--100 .mu.l in
liquid volume) tended to exhibit observable spillage prior to complete
absorption. Accordingly, the amount of drug-containing material retained
in the urethra should be less than about 100 mg and preferably less than
about 50 mg. Adequate lubrication has been obtained with as little as 5-10
.mu.l of lubricating carriers such as polyethylene glycol (PEG) 1000 and
1450.
The dose of agent can be contained in any of the fluid or semi-fluid
solutions, suspensions, dispersions, ointments, pastes or gels selected
from the numerous formulations of such types known to the art but
preferably comprises a formulation in which the agent is dispersed in a
pharmaceutically acceptable carrier which rapidly releases the agent
within the urethra. These formulations can also contain pharmaceutically
acceptable antioxidants such as BHT, for example, and other stabilizing
agents as is known to the art as may be required to extend shelf life.
Such a dose can be easily introduced into the urethra from a flexible tube,
squeeze bottle, pump or aerosol spray single or multiple dose
administrator, for example. The agent may also be contained in rapidly
releasing coatings or suppositories which are rapidly dissolved absorbed,
melted or bioeroded in the urethra. Urethral permeation enhancers for the
agent may also be included in the agent containing compositions. In
certain embodiments which are to illustrated in FIGS. 1 and 3, the agent
is included in a coating on the exterior surface of a penile insert.
In the presently preferred embodiments of the invention, the agent is
contained in a dose of predetermined volume which is deposited as a
suppository into the urethra at the desired location.
Referring now to FIG. 1, a penile insert 1 comprises a shaft portion 2
which is sized to be easily and comfortably inserted into the male
urethra. Means are also provided to prevent complete insertion of the
inserter into the urethra in a manner that would make removal difficult.
The means may simply be a portion of the shaft of adequate length to be
gripped and not released during use. It is preferable however that the end
of shaft 2 is provided with an enlarged terminal portion 3 configured to
prevent complete insertion into the urethra and to facilitate removal of
the device after the agent has been delivered. The internal end of shaft
portion 2 is preferably provided with a rounded, blunted end to prevent
discomfort on insertion and is typically from about 3 to 5 millimeters in
diameter and from about 2 to 12 centimeters in length.
The insert itself may be made from any pharmacologically acceptable
material and although it may be rigid, it is preferred that the device be
relatively soft and flexible for purposes of comfort, merely having
sufficient rigidity to facilitate insertion. For this purpose various
pharmaceutically acceptable natural or synthetic rubber or polymeric
materials such as natural rubber, silicone rubber, ethylene vinyl acetate
(EVA) copolymers, polyethylene, polypropylene, polycarbonate, polyester,
polyurethane, polyisobutylene polymers, and polyoxyethylene polymers such
as Delrin.RTM. manufactured by Du Pont, for example, are suitable.
Polypropylene is particularly useful, especially where the product is to
be radiation sterilized.
Although the therapeutic agent and optionally a permeation enhancer may be
dispersed throughout the body of the insert 1, it is preferable that the
agent be concentrated on the urethra-contacting surfaces of the device in
order to permit rapid absorption of the agent and any permeation enhancer.
As shown in FIG. 1, the shaft portion 2 of the insert 1 is provided with
an agent-containing coating 4 which comprises the desired agent dose and,
if used, a permeation enhancer, dispersed throughout a rapidly releasing
carrier. The coating 4 may be applied to the insert by means of dip
coating in an appropriate agent-containing bath, spray coating, heat melt
coating, evaporation of a fixed volume of a solution or suspension of the
agent in a volatile vehicle or by co-extrusion of an agent-containing
layer onto the surface of shaft 2, for example.
To facilitate insertion, coating 4 preferably has lubricating properties
and may contain dispersant materials such as PEG, propylene glycol,
glycerine, polyvinyl pyrrolidine (PVP), polyvinyl alcohol (PVA), hydroxy
alkyl celluloses or cyclodextrins, for example, which are or become
slippery upon insertion into the urethra. Materials such as glycerol
monolaurate, polyethylene glycol monolaurate, and glycerol monolaurate,
for example, may combine permeation enhancing properties with lubricating
properties.
To facilitate adherence of the drug coatings to the penile insert, the
surfaces to which the coatings are applied may be slightly roughened.
Also, to provide a visual indication of complete agent release, the
coating, instead of being clear and transparent, can be selected to
provide a different visual appearance from that of the uncoated insert.
This can be accomplished with the use of dyes or pigments or can be a
property of the agent or coating material itself.
In use, the device would be inserted slowly (about 5-10 seconds) into the
urethra up to the terminal portion 3 and either maintained in place until
the agent is absorbed (about 30-45 seconds) and then slowly removed, or
more preferably, particularly with shorter devices (about 2-5 cm in
length), the device 1 would be inserted into the urethra up to portion 3
and then, while compressing the penis around shaft 2, gently but firmly
rotated and reciprocated to wipe all the agent-containing material from
the surface of the device prior to removal.
When the agent dose is formed from a water soluble material such as PEG it
is also preferable that the patient urinate shortly before administration
of the dose. The residual urine in the urethra cause the dose to dissolve
more rapidly producing more rapid drug absorption.
Referring now to FIG. 2, a combination insert/container 10 is shown in
which the insert 11 is provided with a tapered agent-carrying shaft
portion 12 which terminates in a plug portion 13 which may also be
provided with sealing ridges 13a. Plug element 13 terminates in cap
portion 14 which may be larger than plug 13 and preferably of a square or
other polygonal configuration to make it easy to rotate insert 11 for
removal from its container 15. Container 15 is generally tubular in shape
closed at one end and of sufficient length to receive the insert up to
contact with cap 14. The interior diameter of container 15 and the
exterior diameter of plug 13 with sealing ridges 13a are selected to
provide a sliding seal that is sufficient to prevent insert 1 from falling
out of the container and the passage of contaminants into the container
while permitting removal of the insert with the application of a
reasonable force on cap 14.
Referring now to FIG. 3, another embodiment of the invention is shown in
which the penile insert 20 comprises a shaft portion 22 adapted to be
received within the male urethra and a terminal portion 23 in the form of
a tubular cap adapted to enclose the glans and, if more agent delivering
surface is required, some portion of the shaft of penis 17. The
body-contacting surface of insert 20 is provided with an agent-containing
coating 24 similar to that described with respect to FIG. 1 which coating
is applied to the shaft 22 and such other portion of the interior of the
terminal portion 23 as is desired. The embodiment of FIG. 3 may be used
with respect to less potent agents which require an administration rate
greater than can be obtained directly through the urethra. Thus the
portion of the coating 24 which contacts the glans and the shaft of the
penis also provides for the administration of the agent directly through
the skin of the penis in addition to the transurethral administration.
In use, the device would be inserted into the urethra 16 and in contact
with the skin of penis 17 and maintained in place until all the agent has
been released from coating 14. In FIG. 3 a constrictive, typically
elastic, band 18 is applied around the base of the penis 17 while the
insert 20 is in place to constrict the penis and prevent the flow of blood
therefrom. This constrictive band can also be used with respect to the
embodiments of FIGS. 1, 2, 4 and 5. It is useful in impotence where it
will prevent the flow of blood from corpus cavernosum thereby assisting in
the maintenance of the erection and, in Peyronie's syndrome where it will
cause the anti-inflammatory drug to remain in the corpus cavernosum for an
extended period of time. The constricting bands would not normally be used
when the device of this invention is used to treat Priapism where it is
desired to increase, rather than retard, the flow of blood from the penis.
In the practice of this invention it is desirable that the entire dose of
the agent be reproducibly deposited in contact with the urethra at the
desired location within the urethra. Because the coatings on the inserts
of FIGS. 1-3 are in contact with the urethra during the insertion and
removal procedure, it is possible that some of the coating may be
deposited at non-optimum locations or that all of the coating may not be
removed prior to withdrawal of the insert. In order to obtain a more
precise control of the dose administered and the site of application, the
dose can be contained within the insert where it is protected from contact
with the urethra during insertion and means can be provided to positively
displace the entire dose from the insert into the urethra at the desired
depth of application.
Referring now to FIGS. 4 and 5 another embodiment of this invention is
shown for use when the agent is contained in an ointment, paste,
suppository, cream or gel formulation of the type described above rather
than as a coating on the shaft of an inserter. The dosage
inserter/container 25 comprises a container 26 closed at one end and
receiving inserter 27 in the other end. Although container 26 can be
cylindrical in configuration it is preferred to form container 26 into a
more volume efficient flattened configuration such as elliptical or
rectangular because there is no need to maintain a large clearance between
the exterior of inserter 27 and the interior of container 26, to prevent
inadvertent removal of any coating on inserter 27. Inserter 27 comprises a
shaft portion 28 having an external configuration similar to that of the
inserter shown in FIGS. 1 and 2 but provided with a longitudinal bore
which receives the piston portion 29 of plunger 30, the agent-containing
dose 31 in the form of an ointment, paste, suppository, cream or gel
having sufficient viscosity to enable it to remain, without spillage,
within the cavity formed between the tip of piston 29 and the end of the
bore. The bore may communicate with the urethra through the single outlet
shown in FIG. 4 through which the dose is ejected by movement of piston
29. Alternatively, the end of the inserter could be provided with a
multiplicity of small holes distributed about the tip through which the
dose could be extruded in small streams into contact with the urethra.
Preferably, means are provided to prevent unintentional activation of
plunger 30 which in its simplest form could be a frangible bead or bond
which resists relative motion of plunger 30 with respect to shaft portion
28 until a predetermined force is applied. A more positive means is
illustrated in FIGS. 4 and 5 wherein shaft portion 28 terminates in a plug
portion 32 configured to form a sliding seal with the interior of
container 26. The plug portion 32 terminates in cap portion 33 provided
with receptacle means 34 configured to receive plunger 30 when plunger 30
is in a first position and to be incapable of receiving plunger 30 when in
a second position and being of sufficient depth to allow displacement of
piston 29 over sufficient travel to fully displace dose 31 from the
inserter. In FIGS. 4 and 5 the receptacle 34 is shown as a slot across cap
33. Plunger 30 is mounted transverse to slot 34 and maintained in this
first position by a frangible bond 35. Cap 33 is likewise sealed to
container 26 by a similar frangible bond 36. These frangible bonds can be
formed by any suitable technique which include adhesive bonding, heat or
sonic welding or the application of some form of "shrink wrap" material,
for example.
This configuration is readily adaptable to automated filling together with
precise control of the quantity of dose 31 and provides for positive
administration of the desired quantity of agent at the desired site of
application.
Prior to use the device is protected from inadvertent displacement of dose
31 by means of the frangible seal 35 and inadvertent removal of the
inserter by means of frangible seal 36. In use, frangible seal 35 would be
broken by rotating plunger 30 from its first position to a second position
where it is in alignment with receptacle 34 and frangible seal 36 would be
broken to remove the inserter 27 from container 26. The inserter would
then be placed into the urethra to the depth of plug 32 and plunger 30
depressed into receptacle 34 to completely eject dose 31 into the urethra
at the desired point of application. The inserter 27 would then be removed
leaving the dose 31 within the urethra.
The materials used to form the inserter/container 25 are the same as those
which can be used in fabricating the devices of FIGS. 1 and 2 for example
and when these materials are thermoplastic the formation of the frangible
bonds 35 and 36 by sonic fusion is a preferred technique.
In order to assure the complete displacement of dose 31 by piston 29,
relatively precise tolerances must be maintained with respect to the
internal and external diameters of the bore through shaft portion 28 and
of the piston 29, respectively. FIGS. 6, 7 and 8 describe a device in
which manufacturing tolerances can be more relaxed while still maintaining
positive displacement of the entire dose to the urethra at the desired
position. Inserter 40 of FIGS. 6, 7 and 8 comprises a sleeve 41 which is
preferably slightly thinner or otherwise weakened about the periphery of
its distal end 42 such that this portion is more flexible than the
remainder of sleeve 41 so that it will deform preferentially at this
location. Sleeve 41 is also preferably provided with a thickened terminal
portion 43. Sleeve 41 is sized to be received within the male urethra and
preferably terminates at a shoulder 44 on handle 45, shoulder 44 being of
sufficient diameter to prevent insertion into the urethra. Sleeve 41 may
be formed as a unit with handle 45 or it may be formed separately and
bonded or otherwise attached to shoulder 44. Handle 45 is provided with a
central bore having a diameter corresponding to the interior of sleeve 41
and piston 46 is slidably received within sleeve 41 and handle 45. The
distal end of piston 46 is firmly connected to the interior portion of the
end portion 43 of sleeve 41. When piston 46 is moved to a position where
it completely fills sleeve 42, the inserter has the configuration shown in
FIG. 6. However, when piston 46 is withdrawn slightly from the position of
FIG. 6, the end 43 of sleeve 41 will be withdrawn with the piston, to form
a cup shaped cavity into which a suppository 47, preferably spherical,
comprising the agent dose can be received. Upon further withdrawal to the
position shown in FIG. 8, tile peripheral portion 42 of the end of sleeve
41 will have been withdrawn by piston 46 into the sleeve 41 causing it to
surround and envelope suppository 47.
In operation, the spherical suppositories 47 would be fabricated in the
frozen condition by any of the conventional techniques used for the
manufacture of spherical granules of predetermined size. Equipment for
manufacturing small spherical particles is known to the art and includes
rotary processing, multiple-step extrusion and spheronization equipment.
Suitable equipment is available, for example, from Niro-Aeromatic, Inc. of
Colombia, Md.
To load the inserter, piston 46 would be moved to the position shown in
FIG. 7 and the frozen suppository 47 deposited in the cup shape receptacle
so formed. The piston 46 would then be withdrawn to the position shown in
FIG. 8 completely enclosing and enveloping the suppository 47 within the
retroverted tip 42 of the sleeve. In use, the loaded inserter would be
inserted into the male urethra until shoulder 44 abuts the meatus and
plunger 46 moved forward to the position shown in FIG. 6 thereby releasing
suppository 47 from the tip of the inserter and depositing it at the
desired depth.
Inserter 40 may be made from any of the materials described in connection
with the embodiments of FIGS. 1-4 and may be provided with means for
preventing inadvertent actuation as described with respect to FIGS. 4 and
5. For example, after the inserter is loaded with the suppository as shown
in FIG. 8, sonic bonds could be formed between the handle 45 and the
piston 46 or a cap-like structure similar to that of FIGS. 4 and 5 could
be employed.
Although the configurations shown in FIGS. 4-8 are preferred
configurations, other inserter/container configurations can be used and
any mechanism by which a predetermined quantity of drug can be introduced
from the inserter at a predetermined depth in the urethra is suitable for
use with this invention. As with the other devices of this invention, the
agent in dose 31 can be one or more drugs. However, when a combination of
drugs is required to produce the desired therapeutic effect, it is also
possible to sequentially administer separate doses of each individual
drug, each of which can then be titrated by the physician and/or patient
to produce the desired effect.
The embodiments of this invention can either be manufactured under sterile
conditions thereby eliminating the need for post manufacturing
sterilization or they can be manufactured under non-sterile conditions and
then subsequently sterilized by any suitable technique such as radiation
sterilization.
The penile inserts and injectors of this invention can be manufactured by
typical plastic forming and coating process and solvent evaporation known
to the art which include molding, extrusion, heat forming, dip coating,
spray, coating, heat melt coating and solvent evaporation. Although
prototype devices of FIG. 1 were made from EVA rods which were heat formed
by hand into the configuration of FIG. 1 on a hot plate to flatten the
exterior end and blunt the interior end, components forming the various
embodiments of this invention can be made in quantity in conventional
injection molding equipment.
Molded parts which require coating can be coated by any suitable process.
Dip coating, with control of the temperature and viscosity of the bath and
the dwell time of the article to be coated in the bath, coupled with air
wiping for added precision is capable of producing quite reproducible
coatings within the requirements of this invention. Depositing a known
volume of a solution or suspension of the agent/dispersant in a volatile
carrier onto the shaft in the presence of a warm air stream also produces
coating in a reproducible manner as does the application of a known volume
of a melt containing the agent to a cool inserter shaft.
PEG based coating and suppository formulations are particularly suitable to
this invention because they are solid at refrigerator or ambient
temperatures, have lubricating properties, dissolve in the urethra to
allow rapid absorption of the active agent therein dispersed and some
lower molecular weight PEGs also melt at urethral temperatures.
PEGs of varying molecular weight from about 400-8000 including mixtures of
PEG can be used according to this invention. All PEGs will dissolve in the
urethra whereas only the lower molecular weight species will melt.
Temperatures in the flacid penis are normally in the range of
30.degree.-32.degree. C., at or above the melting point of PEGs up to
about molecular weights of 600. PEG 1000 melts at about
37.degree.-40.degree. C. PEG 1450 melts at about 43.degree.-46.degree. C.
and higher molecular weight PEGs melt at higher temperatures. PEGs as a
class, are highly water soluble, about 70-80% by weight in water at
20.degree. C. and even higher at the temperatures within the urethra.
At 70.degree. C. the viscosity of a 50--50 blend of PEG 1450 and PEG 400 is
such that approximately 100 mg of a dip mixture was reproducibly left on a
10 cm long by 3.5 mm diameter EVA rod after a single dip. By varying the
molecular weight of the PEGs and/or their ratios and/or the temperature of
the bath, the viscosity of the bath and the resultant weight of the
coating can be adjusted. For example, a 1:2 weight ratio mixture of PEG
600 and PEG 1000 will have a melting point of about 32.degree. C. and
could be expected to yield a coating of approximately 50 mg at a bath
temperature within the range of about 50.degree.-80.degree. C.
PEG 1450 is available as a flake material at room temperature which on
melting and cooling forms a smooth coating on the insert of this
invention. At bath temperatures in the range of 60.degree. C. to
80.degree. C. coatings of about 50 mg can be obtained from a single dip.
As another example, at 70.degree. C., PEG 1450 deposited on the 2 cm of the
tip equals about 50 mg. The slower dissolution of the higher molecular
weight PEG allows controlled deposit on a limited area. As the system is
inserted into the urethra the slower melt of PEG 1450 allows minimal
deposition in the distal urethra and maximum at the depth of full
insertion.
Doses such as coatings and suppositories formed from the lower molecular
weight PEGs need to be stored under refrigeration when high ambient
temperatures are anticipated. Doses formed from PEG 1450 and above,
however, have physical stability even when carried exposed to high summer
temperatures.
Another approach to forming the desired coating on the shaft 12 of the
inserter is to micropipette a known quantity of the agent and dispersant
in solution or suspension in a volatile solvent onto the shaft 12 which is
maintained in a downwardly inclined position in the presence of a warm air
stream to permit rapid evaporation of the solvent before any of the liquid
can drop from the shaft. This approach is particularly suitable when both
the agent and the dispersant are mutually soluble in the volatile carrier.
As an example, PGE.sub.1 together with a lubricating dispersant such as
propylene glycol, PEG, glycerin, PVP, PVA, cyclodextrin or hydroxyalkyl
cellulose for example, would be dissolved in weight ratios of dispersant
to agent of 1:1-10:1 in alcohol at a concentration such that a small
volume, approximately 10 .mu.l for example, of the alcoholic solution
contains the desired dose of the agent. This predetermined quantity of
solution would be introduced from a micropipette onto the surface of the
inserter in the presence of a warm air stream and would evaporate rapidly
to form the desired coating. The volume of solution is not critical but
should be selected based on the size of the insert and the viscosity of
the solution such that a relatively even coating of the solvent solution
on the shaft is obtained without any spillage prior to evaporation of the
volatile solvent. Melted PGE.sub.1 containing the agent can also be
micropipetted in a similar manner onto a cool inserter shaft to provide
reproducible doses of single or multiple drugs.
Preferably, the total weight of the dose should be minimized consistent
with the maintenance of lubricating properties. At about the 50-100 mg
level, the capacity of the urethra to receive and retain the agent
containing dose and rapidly absorb the agent appears to be reached as some
spillage of the dose was observed. Accordingly, dose weights should be
less than about 100 mg and preferably | | |
