BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a method and a transdermal drug delivery device for treating erectile dysfunction, More specifically, a device comprising the patch applied to the glans penis of circumcised penis, the support for attaching the patch to the head of the penis said glans penis and the rings constricting the base part of the penis.

Description of the Prior Art

It is medically well known that there are many causes of male impotence, for example, psychogenic, neurogenic, vascular, endocrine disorder or the problem of corpus cavernosa. As used herein, the term erectile dysfunction refers to certain disorders of the cavernous tissue of the penis and associated facia which produce impotence, the inability to attain a sexually functional erection; the persistent and often painful erection of the penis, a condition characterized by fibrosis of the cavernous tissue and associated painful and distorted erection of the penis.

However, in case of psychological treatment, most patient is accompanied by rejection symptoms. Internal medical and hormone therapy are likely to cause side effects. The vacuum tumescence device may have an inconvenience and trouble in using the jelly and device.

The artificial erection method using the penile prosthesis, reconstruction of corpus cavernosu arteria and vein ligation are accompanied with fear on the surgical operation. In case of self-injection method of vasodilating agents, continuous treatment is difficult on account of pain at injection, rejection symptoms on injection and fibrosis of injection portion.

With respect to administration of drugs directly to the penis, medicated catheters such as descrioed in U.S.Patent 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. Patent 4,829,991; the transdermal administration of certain drugs is suggested in U.S. Patent 4,478,822, 4,610,868, 4,640,912, 4,746,508, 5,242,391; and medicated urethral suppositories, inserts or plugs, typically containing anti-infective agents or spermicides are disclosed in U.S. Patent 1,897,423, 2,584,166, 2,696,209 and 3,373,746, for example. As conventional pharmaceutical formulation, spray urethral insertion formulation have been used.

However, the urethral insertion formulation made by dispersing the drug in the high molecular hydrogel is an erection-producing formulation by inserting hydrogel containing a drug into the urethra. In case of this formulation, there exists a trouble in using a special device in order to insert hydrogel into the urethra. In particular, there is serious apprehension about infection during the treatment, and the weak mucous membrane of urethra is easily infected.

Furthermore, a conventional spray formulation or

ointment is an erection-producing formulation by applying or spraying the drug onto the penile shaft or glans. However, such formulation cannot maintain a sufficient erection which is necessary for sexual intercourse when the anatomic structure of the penis is observed.

There are many patents describing devices for administration drugs through the skin; U.S.Patent 3,598,122, 3,598,123, 3,742,951, 4,031,894, 4,060,084, 4,144,317, 4,201,211 and 4,379,454. Such transdermal drug delivery devices are commonly in the form of a laminated composite that includes a reservoir layer containing the drug, a pressure sensitive adhesive layer for attaching layer for attaching the composite to the skin, and a backing layer that forms the upper layer of the device. Depending upon the particular drug and drug formulation involved, the reservoir layer may be a matrix in which the drug formulation is dispersed or a layer in the form of a walled container which holds the drug formulation. Container type reservoirs are often formed as a pocket between the backing layer and drug-permeable basal membrane through which the drug pas-ses to the skin.

U.S. Pat. No. 5,333,621 combines a conventional condom with transdermal delivery device having a vasodilator for generating the erection of the penis for sexual intercourse. The transdermal medication device delivers the vasodilator especially to the skin surface of penile shaft.

The penis is composed of three cylindrical masses of erectile tissue, the dorsally paired corpora cavernosa and the unpaired corpus cavernosum urethra. Each corpus

cavernosum is surrounded by a dense capsule or tunica albuginea composed of collagenous fibers.

As can be seen from the said anatomic structure of penis, the penile shaft of the penis using a patch in U.S. Pat. No. 5,333,621 cannot deliver the drug to the corpus cavernosum through the tunica albuginea which is a fibrous tough collagen membrane having a thickness of o.5 to 2.2 mm. Therefore, the patch disclosed in the above patent is nothing but a simple formulation disregarding the anatomic structure of the penis.

In other words, a patch disclosed in U.S. Pat. No. 5,333,621 is nothing but a common system by simply combining a patch with the condom for applying it to the penile shaft without considering any special method or means to maximize or increase the penetration of the drug through the tunica albuginea. Furthermore such patch using a condom may cause the side effects including allergy due to the condom to the male as well as the female, and may not give the orgasm during the sexual intercourse. Therefore, such patch system may not apply to the persons having the rejection symptoms on the use of condom.

The glans penis of the penis practically has no tunica albuginea which is a main barrier for inhibiting the penetration of drug through the skin contrary to the penile shaft in view of anatomic aspect, and has only fibrous tissue between sinusoid and epidermis.

The present invention is characterized in that a patch is applied directly to the glans penis to deliver the drug to the corpus cavernosum, thereby providing a patch device for treating the erectile dysfunction.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method and device for treatment of erection dysfunction which are painless, safely and effectively producing erection of the penis without the adverse side effects and with a high degree of patient acceptability in the case of male impotence.

The another object of the present invention is to provide a transdermal drug delivery device for treating erectile dysfunction comprising the cylinder or multi- reservoir type patches applied to the glans penis in circumcised penis, the condom type or adhesive band type support for attaching the patch to the glans, and rings constricting the base part of the penis body.

First characteristic of the present invention is to apply the patch device to the glans penis in circumcised penis, where the glans is appropriate site for absorbing the drugs because the glans penis has practically no tunica albuginea and only a minimal amount of fibrous tissue between the sinusoid and epidermis.

Second characteristic of the present invention is the shape of the patch device classified into two types, a cylinder type and multi-reservoir type patches. Furthermore multi-reservoir type patch said container type reservoir comprises multi reservoirs containing pharmaceutically active drug.

Further functional characteristic of multi-reservoir type patches are delivering the various compositions of medication by inserting different drugs to each reservoir and convenience of attaching the patch to the glans due

to its flexibility.

Third characteristic of the present invention is the ring constricting the base part of the penis body, consisting of two rings having different constricting power, one of which shall be removed before the sexual intercourse.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a perspective view applied multi-reservoir type patch device of the present invention to glans penj s in the circumcised penis.

Fig. 2 is a schematic view of cylinder type patch of the present invention. Fig. 2(A) is a cross-sectional view of cylinder type reservoir patch taken along line I - I in Fig. 2.

Fig. 2(B) is a cross-sectional view of cylinder type reservoir patch taken along line I - I in Fig. 2.

Fig. 3 is a schematic view of the condom type support and a constricting ring of the cylinder type patch device.

Fig. 4 shows the various types constricting rings of the present invention.

Fig. 5(A) is a perspective view of one multi-reservoir type patch of the present invention.

Fig 5(B) is a perspective view of another multi- reservoir type patch of the present invention.

Fig. 6(A) is a cross-sectional view of multi-reservoir type patch with an adhesive band type support of the present invention taken along line II - II in Fig. 5(A).

Fig. 6(B) is a perspective view of an adhesive band

type support.

Fig. 7 is the graphs measured by rigiscan showing the rigidity and circumference change of the penis applied our invention device to human penis. Fig. 7(A) is the graphs measured by rigiscan showing the rigidity and circumference change of the penis only applied to two constricting rings.

Fig. 7(B) is the graphs measured by rigiscan showing the rigidity and circumference change of the penis only applied to our invention patch device.

(Refference numeral)

20 : Multi-reservoir type patch

21 : Release liner 22 : Rate control membrane

23 : Backing layer

24 : Reservoir layer

25 : Space between multiple reservoir

26 : Fist heat-sealing region 27 : Second heat-sealing region

28 : Adhesive band type support

29 : Adhesive layer

30 : Constricting ring I 40 : Constricting ring II 41 : Magic tape type constricting ring

42 : Hook type Constricting ring

43 : Hold elastic type constricting ring

44 : Silicon oil insertion type constricting ring

45 : air insertion type constricting ring 60 : Multi-reservoir type patch II

70 : Release liner

100 : Cylinder type patch

101 : Backing layer

102 : Reservoir layer

103 : Rate controlling membrane 104 : Release liner

200 : Condom type support

201 : Backing layer

202 : Matrix layer

203 : Release liner 401 : Elastic band

402 : Negative part of magic tape

403 : Positive part of magic tape

404 : Hold elastic band

405 : Hold part 406 : Hook

407 : Insert silicon oil or air

408 : Oil inserting hole

DETAILED DESCRIPTION OF THE INVENTION

In reference to the drawings, the present invention can be explains in detail.

As shown in Fig. 1, the multi-reservoir type patch device of the present invention comprises a multi- reservoir type patches (20, 60) applied to the glans penis of the circumference penis, an adhesive band type support (28) for attaching the patch to the glans and two constricting ring (30, 40) for constricting the base part of the penis body. As shown in Fig. 2, the cylinder type patch device of the present invention comprises a cylinder type

patch(lOO), a condom type support(200) having constricting ring I (30) in the entrance of condom and a constricting ring II (40) for constricting the base part of the penis. Figs. 2(A) and 2(B) show the cross-sectional views of reservoir patch and matrix patch of cylinder type taken along line I - I , respectively.

Referring to Fig. 2(A), the reservoir patch of cylinder type consists of a drug and light impermeable backing layer(101), a reservoir layer containing pharmaceutically active drugs (102), a rate controlling membrane (103) of drug release, and a release liner (104) to be removed before use. More specifically, the backing layer(101) is made by polyester film or polyester film coated with aluminum membrane impermeable to drugs and light. The rate controlling membrane (103) is characterized in dense and microporous membrane controlling the drug release rate to the skin. The material of release liner(104) is same as that of the backing layer.

Referring to Fig. 2(B), this matrix patch of cylinder type consists of a drug and light impermeable backing layer(201), a polymer matrix containing medication(202) , and a release liner(203) to be removed before use. The polymer matrix(202) is attached to the glans penis of the circumcised penis.

As shown in Fig. 3, the condom type support(200) fixes the patch to the glans penis of the circumcised penis. The material of support is selected from elastomer, polyurethane, natural or synthetic rubber. Further, the constricting ring(30) exists in the entrance of condom

type support(200) in order to assist penile erection.

Fig. 4 shows the various types of constricting rings (40) used in this invention. The types of constricting rings are magic tape type(41), hook type(42), hold elastic type(43) and silicon oil insertion type(44), or air insertion type (44). Among them, silicone oil insertion(44) or air insertion type (44) is more effective and convenient ring for use. It is generally required two constricting rings to assist penile erection of the penis. During the penile erection, one of two rings is removed before sexual intercourse.

Fig. 5(A) and Fig. 5(B) shows two types of multi- reservoir type patch. As shown in these Figs., multi- reservoir type patch consists of multiple reservoirs containing pharmaceutically active drugs, a drug impermeable release liner(21), a rate control membrane(22) for controlling the drug release rate, multiple reservoir layer(24) containing medication, and a drug impermeable backing layer (23). There exist heat- sealing space (25)among multiple reservoir where the patch can be easily bent due to heat-sealing space between multiple reservoirs. Using these heat-sealing spaces (25), the patch can be easily attached to the conically shaped glans. The structure of multi-reservoir type patch is shown in Fig. 6 in more detail.

Fig. 6(A) Shows a schematic view super imposing the components of multi-reservoir type patch device taken along line II - II in Fig. 5(A).

An adhesive band type support(28) coated with pressure sensitive adhesive (29) is used for attaching the multi- reservoir type patch to the glans penis of the

circumcised penis.

In Fig 6(B), release liner(70) is removed just before using the support(28).

The method for manufacturing the multi-reservoir type patch device of the present invention can be described as follows.

The drug impermeable backing film is laid on the mold having multiple ^* reservoir shape. Using vacuum, the backing film is formed as multi-reservoir shape with heat- treatment. the drug is loaded in the multiple reservoirs before the first heat-sealing with the rate controlling membrane. The second heat-sealing is carried out upon laying the release liner to the rate controlling membrane. There are two characteristics in the multi-reservoir type patch.

One is to deliver the various compositions of medication by inserting different drugs to each reservoir. It is possible to get multiple administration effect by each reservoir, where compose of different drug medication. The other is the convenience of attaching the patch to the conically shaped glans, because the heat- sealing spaces among multiple reservoir let it bent easily for attachment. Use of transdermal drug delivery device for treatment erectile dysfunction of the invention is as follows. The penile erection is induced by attaching the patch to the glans penis of the circumcised penis with support and two rings; one ring is removed during penile erection. After achieving enough erection, the patch and support are removed just before the sexual intercourse; and having

sexual intercourse with only one ring.

The drugs applied to this patch for penile erection are as follows.

In general, vasodilators, smooth muscle relaxants, alpha-blockers, dopamine agonists, opioid agonists, potassium channel opener, calcium blockers, alpha- adrenaline agonists, bronchodilators, specific phosphodiesterase HIinhibitors and/or vasoactive intestinal peptides can be applied. More specifically, phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, tolazoline, haloperidol, adenosine, ergot alkaloids, chlorpromazine, yohimbin and/or verakpamil can be used as alpha-blockers.

Ditiazem, nifedipine, nicardipine, nimodipine and/or verapamil can be used as calcium blockers. Further, PGE 1, alprostadil, misoprostol and/or PGE 2 as natural and synthetic vasoactive prostaglandins; apomorphine, bromocriptine as dopamine antagonists; adenosine, amylnitrate, dipyridamole, erythrityl tetranitrate, ethaverine hydrochloride, isosobide dinitrate, isoxsuprine hydrochloride, milrinone lactate, niacine, niacinamide, nicotinyl alcohol, nitroglycerine, nylindrin hydrochloride, papaverine hydrochloride, pentaerythritol tetranitrate, pentaerythritol phenobarbital, pentoxifylline, pinacidil, sodium fluoride and/or tolaxoline hydrochloride as vasodilating agents can be used.

Aminophylline, amobarbital, ephedrine aminophylline, ephedrine, phenobarbital, potassium iodide aminophylline, guaifenesin aminophylline, potassium iodide butabarbital, pseudoephedrine, theophylline dextrose, theophylline

dyphylline, hydroxazine hydrochloride, iodinated glycerol and/or theophylline anhydrous can be used as smooth muscle relaxants.

The effect of the transdermal drug delivery device of this invention can be described with following Examples.

Composition of applied medicine

Prostaglandin El (PGE 1) was used as an active ingredient. 10 - 70 % by weight of enhancer selected from Cio to C^g fatty acid or fatty alcohol and 20 -

40 % by weight of triacetin as stabilizer were included in the composition.

Application to the patients or volunteers For the human application of transdermal drug delivery device of the present invention, erectile dysfunction patients and patients under the spinal anesthesia were selected. Spinal anesthetic patients were selected for removing the mental effects occurred by conscious patients during the experiment.

Rigiscan was used for measuring the rigidity and circumference change of the penis. During the experiment, audio-visual sexual stimulation was given to the patients or volunteers continuously.

(Comparative Example)

Application to two constricting rings without patch Two constricting rings without patch were applied to the patients under the spinal anesthesia. The rigidity and circumference change of the penis especially at the tip and base part of the penis body was

measured with two rings.

Fig. 7 (A)-(a) showed the changes of rigidity at the tip part of the penis. During 20 to 50 minutes, the rigidity was approximately 30 to 40 %. After removing one restricting ring at 40 minutes, the rigidity of the penis was suddenly declined. The circumference change of the tip part of the penis was shown to Fig. 7 (A) -(b).

In initial stage, the circumference changed from 5 cm to 7 ~ 8 cm for 10 to 35 minutes. Then the circumference declined irregularly.

Fig. 7 (A)-(c) showed the change of rigidity at the base part of the penis. For 10 to 20 minutes. 40 to 50 % of rigidity was shown. After 20 minutes, the rigidity declined suddenly. Then circumference change at the tip part of the penis show irregular small change in Fig. 7 (A)-(c)

As a conclusion, application two rings to volunteer could not solve the erectile dysfunction, because the base part of the penis did not show enough rigidity for sexual intercourse.

Application to only multi-reservoir type patch A multi-reservoir type patch was attached to the patient under the spinal anesthesia. Multi-reservoir type patch containing medication was attached to the glans penis using an adhesive band type support. After a lapse of 40 minutes, enough erection was not detected for sexual intercourse. Applying only multi- reservoir type patch could not solve the erectile dysfunction.

(Example)

Application to multi-reservoir type patch with two constricting rings to the volunteer

Multi-reservoir type patch containing medication with two constricting rings was applied to the patient under the spinal anesthesia.

As shown in Fig. 7(B)-(a), 60 to 80 % of constant rigidity were measured at the tip part of the penis for

35 to 90 minutes. The circumference change showed from 6 cm to 8~9 cm for 40 to 90 minutes as shown in Fig. 7(B)-

(b) .

At the base part of the penis, 60 to 80 % of rigidity was shown for 35 to 90 minutes in Fig. 7(B)-(c). Further, the circumference change showed from 6 cm to 7~9 cm for 40 ~ 90 minutes.

Therefore, as shown in Fig. 7(B), sufficient rigidity and circumference changes were measured at the tip and the base of the penis for sexual intercourse.

As a conclusion, the multi-reservoir type patch with two constricting rings was required for sufficient penile erection.

The drug penetrated glans transferred to the corpus cavernosa through the erectile tissue and small veins. Migration time of sufficient drug to the corpus cavernosa was required 40 minutes. During this time, two constricting rings delay the drug loss as the blood flows through the superficial emissary vein.

As described in above, the transdermal drug delivery patch device for treating erectile dysfunction according to the present invention may be produced and maintained sufficient erection and rigidity for sexual intercourse.

Furthermore, in case of using the patch device of the invention, it may be overcome pain and trouble by injection and there is not serious apprehension about infection and wound occurrence of the weak mucous membrane of urethra during the treatment.

Application to multi-reservoir type patch with two constricting rings to the impotence patient

During 40 minutes, the rigidity at the tip and the base of the penis was measured in 20 to 30 %. After a lapse of 40 minutes, the rigidity of the penis was suddenly induced at the moment of cutting one ring. After one hour, 60 to 70 % of rigidity enough to sexual intercourse were shown. Therefore, the device comprising a patch, an adhesive band type support and two rings was appropriate for enough penile erection.