Treatment of erectile dysfunction

America

EPIGRAPH: PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF SEXUAL DISORDERS IN HUMAN HUMAN PATIENTS AND DEVICES FOR ADMINISTRATION

INVENTORS: VIRGIL A. PLACE, ROBERT M. GALE and RANDALL G. BERGGREN.

Claim of right of priority under Article 4 of the Paris Convention of 20 March 1883.

in the United States of America on S, 5 April 1990 under No.⁹ 07/514.397

INPI MOD. 113 n F, 0732

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The present invention relates to a process for the preparation of transurethrally administered pharmaceutical compositions for the treatment of sexual disorders in human male patients, which comprise either vasodilating agents, namely nitrates, ergot alkaloids or prostaglandins, or vasoconstricting agents. in particular substituted benzyl or benzene alcohols, or steroidal or non-steroidal anti-inflammatory agents which are administered transurethrally by use of specific administration devices.

The therapeutic agents to be employed depend on the sexual disorder to be treated. Thus, vasodilating agents are used in the treatment of impotence; vasoconstrictor agents are used for the treatment of priapism and anti-inflammatory agents are intended for the treatment of Peyronie's syndrome.

The device for administering the transurethral compositions comprises a simple insert for placement within the urethra (1) which has a quick release coating (4) of the pharmaceutical composition on its outer surface or is in the form of an inserter (27) containing a load of therapeutic agent (31) to be displaced into the urethra by mechanical means similar to embolus.

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The therapeutic agents to be employed depend on the sexual disorder to be treated. Thus, vasodilating agents are used in the treatment of impotence; vasoconstrictor agents are used for the treatment of priapism and anti-inflammatory agents are intended for the treatment of

Peyronie.

The device for administering the transurethral compositions comprises a simple insert for placement within the urethra (1) which has a quick release coating (4) of the pharmaceutical composition on its outer surface or is in the form of an inserter (27) containing a load of therapeutic agent (31) to be displaced into the urethra by mechanical means similar to embolus.

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J. Med, Vol. 321, N^Q 24, 14 December 1989 for general background information.

In 1980 Dr, R, Verig de Paris demonstrated for the first time that impotence could be treated physiologically by direct injections of a vasoactive drug into the patient's gastric artery and subsequently thousands of patients treated for their own importance. injection of these drugs directly into the tissues of the corpora cavernosa.

See hello^s Symposium International Sur L'Erection Pharmacologique, 17-19 November 1989, Paris, p, 2; R, Virag et al., Intracavernous Injection of Papaverine as a Diagnostic and Therapeutic Method in Erectile Failure, Angiology, 35 pp79-87, 1984 (see also U.S. Pat.² 4277/118, 4,766,889 and 4,857,059, which were incorporated herein by reference).

The most commonly used drugs include alpha-blocking agents such as long-lasting phenoxybenzamine and short-term phentolamine, soft muscle relaxants such as papaverine, prostaglandins that have a vasoactive function such as prosglandine— (PGE1 |) and the consinations of these drugs that have different effects as a receptor in order to encourage therapy. The intracavernous injection doses of erection producing papaverine are typically in the range of about 7.5 to 160 mg, those of phenolamine are in the range of about 0.1 to 10 mg, and those of PGE4 ( prostaglandin - E ·) 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^and 4, Nov. 88, pp 625-629 and N. Ishir et al., Intra Cavernous Infection of Prostaglandin and for the Treatment of Erectile Impotence, J. of Urol., Vol. 141, Feb 1989, pp 323-325. Vasoactive intestinal peptides, in doses of 10 to 100 æg, have also been referred to as erection producers when administered by intracavernous injection.

See also M. Mandelsman, Diagnosis and Treatment of Impotence, in vasoactive doses at doses of XO to X00 µg, have also been referred to as erection producers when administered by intracaveraous injection.

See also M. Mandelsman, Piagnosis and Treatment of Impotence, U.S. Pept. of Health Services, Agency for Health Care Policy and Research, April 1990, on an overview of intracaveraous injection and other impotence treatment

Although intracaveraous infection of vasoactive drugs can produce a relatively rapid erection reaction in patients suffering from impotence attributed to venous effusion or arterial insufficiency, patients often find psychologically disruptive infections, intolerance, traumatic or inconvenient as is ividen®. due to the high number of dropouts. See S. Althouf, et al., Rays By Many People or Out Of Self-Injection Therapy for Impotence, Journal of Sex and Marital Therapy, Vol. 15, No. 2 1989, pp. 121-129. Adverse side effects include pirapism, lumps in the body and scattered fibrosis, drug wasting, bruising and bruising. »Swelling and ulceration of the skin of the penis at the site of injection has also been reported.

However, due to the relatively innocuous intervention involving it and the high deficiency attributed to penile prostheses, the pharmacological route in the treatment of impotence is still considered to be advantageous for a large number of patients who could have even greater acceptability if could avoid side effects.

Priapism is less common than impotence and can be attributed to several causes. Diseases have been associated with intravascular agglutination or coagulation such as leukemia, and pharmacological priapism has been observed in a small percentage of patients who have been treated with impotence by intracavernous injection. 0 Priapism has been treated by intracavernous injection of vasoconstrictors such as alpha-adrenergic receptor agonist agents (hereinafter referred to as alpha-agonist). Said effective doses of the agonist, phenyleferin, are in the range of about 0.1 to 2 mg.

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Peyronie's syndrome is a condition of unknown etiology characterized by fibrous degeneration of the cavernous tissues and leading to painful and deficient erections. Current treatment consists of administering an injection of steroids and other anti-inflammatory agents at the site of fibrous degeneration.

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With regard to drug delivery directly to the penis, catheters have been used with medicaments as described in U.S. Pat.⁹ 4,640,912 to prevent or treat localized infections of the urethra and bladder; U.S. Patent No.⁹ No. 4,829,991 refers to a nitroglycerin-coated condom which causes erection and transurethral administration of certain drugs is suggested in U.S. Pat.⁹s, 4,478,822, 4,610,868, 4,640,912 and 4,746,508; and urethrally administered suppositories, inserts or tampons, typically containing anti-infectious agents or spermicides have been disclosed in U.S. Pat.^ss 1,897,423, 2,584,166, 2,696,209 and 3,373,746, for example. As mentioned above, Kock and Milco report introducing agents into the urethra to cause erections.

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According to the invention methods and dosage forms have been provided for the treatment of sexual disorders, which are painless and are capable of rapidly, safely and effectively producing penile erection in case of impotence penile depletion in case of priapism. , and administration of antiinflammatory drugs at sites where fibrous degeneration with respect to 'Peyronie's syndrome occurs, without the adverse side effects described above and with a high degree of patient acceptability.

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Brief Description of the Invention

We have found that the above described sexual disorders can be safely and effectively treated by transurethral administration of the appropriate therapeutic drug or combination of therapeutic drugs (when used herein, and the term agent, refers to a drug or combination of drugs capable of the desired therapeutic effect) and penis compositions and inserts have been provided adapted to be easily inserted into the urethra and painlessly, combination of these inserts incorporating the appropriate therapeutic agent in an amount sufficient to produce the desired result.

In a preferred embodiment of this invention the therapeutic agent is applied as a coating or in the form of an insert for insertion into the urethra, configured to prevent its complete insertion and to facilitate its 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 spherical inserter.

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specifically designed for this purpose.

Brief Description of the Drawings

This invention, and its respective advantages, will be immediately apparent from the following description of the invention, with reference to the accompanying drawings, in which:

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Figure 1 is a cross-sectional view of one embodiment of this invention;

Figure 2 is a cross-sectional view of another embodiment of this invention;

Figure 3 is an enlarged view of a urethral insert according to the invention and its container;

Figure 4 is a partially sectional side view of a container / inserter assembly for introducing a composition containing a dose of agent into the urethra; and

Figure 5 is a top view of the inserter / container of Figure 4.

Description of the Invention, including Best Mode

In the broadest sense, the invention relates to the treatment of sexual disturbance by the transurethral administration of an agent, which is therapeutically effective with respect to the disorder, directly into the bloodstream entering the corpora cavernosum by transverse circulation with: , the spongy tissues surrounding the urethra.

Sexual disorders which may be treated in this manner include impotence, for which the therapeutic agent consists of one or more drugs capable of producing a vasodilatory action or other type of erectile effect. Usable vasodilating agents include nitrates such as nitroglycerine and isosorbite dinitrate, short- and long-acting alpha-blocking agents such as phenoxybenzamine, dibenamide, doxazonin, terazosin, pentolamine tolazoline, prazonin and trimazosine; adenosine, ergotic alkaloids, chlorpromazine, haloperidol, johimbane, verapamil and other calcium blocking agents, natural and synthetic vasoactive prostaglandins and their analogues, such as prosta glandins - Ej (PGEj)_f alprostadil and misoprostol, for example vasoactive intestinal peptides or any other agent that is capable of producing an erection when administered transurethrally. For example, dopamine agonist agents such as apomorphine and bromocriptine and opioid antagonist agents such as naltrexone have been preferred for erection and may also be used in accordance with this invention. See S. Lai et al Apomorphine: Clinical Studies on Erectile Impotence and Yawning, Prog, Neuro-Psychopharmacology, vol 13, 1989, pp. 329-339 and A. Fabbri et al., Endorphines in Male Impotence, Evidence for Naltrexone Stimulation of Erectile Activity in Patient Therapy, Psyhconeuroendocrinology, vol. 14, no^s 1 and 2, pp. 89, 103-111.

With respect to priapism, the therapeutic agent may consist of one or more vasoconstrictor drugs. Usable vasoconstricting agents include alpha-receptor agonist agents such as epinephrine, penylethylamine,

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pinephrine, dopamine, metaraminol, phenylephrine, methoxamine, ephedrine, phenylpropanolamine, mephentremine and propylbexedrene, for example, blocking agents such as butoxamine, dichloroisoproterenol, propranolal, alprenolal, Ouolol, nadolol, oxprenolol, penbolol thiololol, penprolol , metoprolol, atenolol, acebutolol, bevantolol, pafenolol, and tolamol, for example, and any other agent which is capable of producing a dehumidifying effect, when applied transurethrally.

In addition to Peyronie's syndrome, the therapeutic agent may be one or more antiinflammatory drugs, such as corticosteroids, which include cortisone, hydroxide cortisone, tetrahydrocortisone, prednisone, prednisolone, methylprednisolone, fludrocortisol, corticosterone, deoxycholone, , betamethasone, dexometa sona and beclomethasone, for example non-steroidal anti-inflammatory agents such as salicylic acid, aspirin, diflunisal, methyl salicylate, phenylbutazone, oxyphenebutazone, apazone, phenacetin, acetaminophen, indomethacin, sulindac, mefenamic acid sodium meclofenamate, tolmetia, ibuprofen, naproxen and fenoprofen, for example, and how can other drugs be able, produce an anti-inflammatory effect on fibrous tissue within the corpora cavernosum when administered transurethrally, it is said that the agent is rapidly released through the urethra, in order to provide a rapid reaction of the desired effect. To this end, the agent containing the active product is brought into contact with the urethra over an extended portion, which is about 2 to 5 cm in length, rather than locally placed at a single point on the urethra. The agent should also be applied at least within the penis and after the point at which the transition of the epidermal character of the glans is complete.

In all dosage forms referred to herein it is desirable that the volume of the agent-containing material that is deposited in the urethra remain therein until complete absorption of the agent has occurred and the material is deposited in a manner that allows for relatively low absorption. quick^-'agent. Volumes in the range of 50 to 100 mg (approximately 50 to 100 µl) tended to show visible shrinkage before complete absorption. Accordingly, it is preferable that the amount of drug-containing material retained in the urethra be less than about 50 µl. Proper lubrication was obtained with a small amount of 5-10 µm of lubricating carriers such as polyethylene glycol (PEG) 1000 and 1450.

The dose of agent may be contained in the form of solutions, suspensions, dispersions, ointments, pastes or gels, both fluid and semi-fluids of the numerous formulations of such types known in the art but preferably comprises a formulation wherein the agent is dispersed in a pharmaceutically acceptable carrier which readily releases the agent into the urethra and which can be readily introduced into the urethra. of a single or multiple dose dispensing device in the form of a flexible tube, tablet, pump or aerosol spray, for example. 0 The agent may also be contained in quick release coatings or suppositories which are absorbed, fused or biodegraded in the urethra. In the agent-containing composition, urethra permeation promoting agents may also be included. In certain embodiments shown in Figures 1 and 3, the agent is included in a coating placed on the outer surface of the insert for introduction into the urethra.

In another embodiment, shown in Figures 4 and 5, the agent is contained in a volume dose,

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which is deposited into the urethra at the desired location as a suppository.

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Referring now to Figure 1, an insert into the urethra (1) comprises a small diameter rod-shaped portion (2) sized to be easily and comfortably inserted into the urethra of male humans. Means have also been 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 cylindrical rod of suitable size to be secured and not released during use. It is preferable, however, that the end of the stem (2) be provided with an enlarged end portion (3) configured to prevent complete insertion into the urethra and facilitate removal of the device after the agent has been administered. The inner end of the rod (2) is preferably provided with a rounded end to prevent insertion discomfort and is typically about 3 to 5 millimeters in diameter and about 2 to 12 centimeters in length.

The insert itself can be made from any pharmacologically acceptable material and, although it may be rigid, a device that is relatively soft and reliable for comfort is preferred, provided it is nevertheless rigid enough to facilitate insertion. For this purpose various pharmaceutically acceptable materials, polymeric or synthetic materials such as natural rubber, silicone rubber, ethylene vinyl acetate (EVA) copolymers, polyethylene, polypropylene, polycarbonate, polyester, polyurethane, polysobutylene polymers, are suitable. and polyoxymethylene polymers, such as Delrin (r), manufactured by Du Pont, for example.

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Polypropylene is particularly useful, especially in cases where the product is radiation sterilized.

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Although the therapeutic agent and, optionally, a permeation accelerating agent may be dispersed throughout the insert body (1), it is preferable that the agent be concentrated on the surfaces of the device that are in contact with the urethra in order to allow rapid absorption of the agent and any penetration accelerator. As shown in Figure 1, the cylindrical stem (2) of the insert (1) is provided with an agent-containing coating (4) comprising the desired agent dose and, if a permeation accelerating agent is used, dispersed by a rapid release carrier. 0 coating (4) is applied to the insert by dip coating in a bath containing a suitable agent, by spray coating, hot melt coating, evaporation of a fixed volume of a solution or suspension of the agent in a volatile vehicle, or by coextruding a layer containing the agent onto the stem surface (2), for example.

For ease of insertion, coating (4) preferably has lubricating properties and may contain dispersion-assisting materials such as PEG, propylene glycol, glycerine, pilivinyl pyrrolidine (PVP), polyvinyl alcohol (PVA) or hydroxyalkylcelluloses, or cyclodextrins for example. , which are or become sliding after insertion into the urethra. Materials such as glycerine monolaurate, polyethylene monolamate, and glycerol monolamate can combine penetration accelerating agent properties with lubricating properties.

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In order to facilitate adherence of drug coatings to the insert for introduction into the urethra, the surfaces to which the coatings apply may be slightly roughened.

To provide a visual indication of complete drug release, the coating, instead of being clear and transparent, may also be chosen to have a different visual appearance from that of the uncoated insert. This may be accomplished with the use of coloring or pigmented substances, or may be a property of the drug or of the coating material itself.

When used, the slide should be inserted slowly (about 5 to 10 seconds) into the urethra to the terminal portion (3) and or held in position until the agent is absorbed (about 30 to 45 seconds) and then removed. slowly, or more preferably, particularly with smaller devices (about 2 to 5 cm in length), device (1) should be inserted into the urethra up to the portion (3) θ then, While wrapping the penis around the stem (2), the device is rotated from the displaced back and forth gently but firmly to wipe the agent-containing material from the surface of the device before removing it. .

Referring now to Figure 2, an insert / container combination is shown, wherein the insert (11) is provided with a tapered rod portion (12) which has an active agent, which terminates in a piston-shaped portion (12). 13) and which may also be provided with sealing edges (13a). The piston shaped element (13) terminates in a cap (14) which may be larger than the piston (13) and preferably with the

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/ 4 square or other, polygonal configuration, so that it is easy to rotate the insert (11) for removal of its insert (15) »

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The container (15) is generally tubular in shape with a "closed end" and sufficient length to receive the insert until contact with the lid (14). 0 The inner diameter of the container (15) and the outer diameter of the piston (13) with the sealing edges (15a) are chosen so as to provide a sliding seal that is sufficient to prevent the container insert (1) of lime. and preventing the passage of contamination elements into the container while allowing removal of the insert by applying a reasonable force exerted on the lid (14).

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Referring now to Figure 3, another embodiment of the invention is shown wherein the insert for insertion into the urethra (20) comprises a cylindrical hasshaped portion (22) adapted to be received within the urethra of beings. a human end, and a tubular cap-shaped end portion (23) adapted to surround the gin and also, if a larger agent-releasing surface is required, a body part of the penis (17), The surface of the insert (20) which is in contact with the body is provided with an agent-containing coating (24), similar to that described in Figure 1, with this coating being applied to the stem (22) and another part of the interior of the terminal portion (23) as desired. The embodiment of Figure 3 may be used reactively to less potent agents which require a greater degree of administration than can be obtained directly from the urethra. Thus, the lining portion 24 which contacts the lip and body of the feet also provides the winnowing of the lobe.

directly through the skin of the penis, in addition to transurethral administration.

When used, the device should be inserted into the urethra (16) and in contact with the skin of the penis (17) and held in place until all agent has been released from the coating (14). Referring to Figure 3, a constrictive and typically elastic band (18) is applied around the base penis (17) while the insert (2) remains in position to tighten the penis and prevent blood from flowing from it. . This constrictive band can also be used with respect to the embodiments of Figures 1, 2, 4 and 5. It is useful in impotence states where it will prevent the flow of blood from the corpora cavernosa, thus helping to maintain erection and the syndrome. and Peyronie, in which he will take anti-inflammatory drugs to remain in the corpora cavernosa for an extended period of time. Constrictive strips are not generally used when the device of this invention is used to treat priapism, where blood flow from the penis must be increased rather than slowed down.

Referring now to Figures 4 and 5, another embodiment of this invention is depicted for use when the agent is contained in a formulation of the above type of ointment, paste, suppository, cream or gel, and not as a coating of the nail. an inserter. The insert / container dosage form (25) comprises a container (26) closed at one end and receiving an insert (27) at the other end. Although the container 26 may have a cylindrical configuration / it is preferred to form the container 26 with a more volume efficient flat configuration such as an elliptical or rectangular configuration because there is no need to maintain a large clearance between the outside. insert (27) and the interior of container (26) so as to prevent inadvertent removal of any liner on insert (27), 0 The insert (27) comprises a rod portion (28) which has an external configuration similar to that of the insert shown in Figures 1 and 2, but has a longitudinal cavity which receives the piston portion (29) of the plug (30), the dose containing agent (31) in the form of an ointment, paste, suppository, cream or gel having sufficient viscosity to allow it to remain without leakage into the cavity formed between the tip of the plunger 29 and the hole.

Preferably, means are provided to prevent unintended activation of the plug (30), which in its simplest form could be a fragile part or connection resisting movement of the plug (30) relative to the Rod (28) until a predetermined force is applied. A more effective means is shown in Figures 4 and 5 wherein the rod (28) terminates in a piston (32) configured to form a sliding seal with the interior of the container (26). The piston portion (32) terminates in a cap (33) provided with receptacle means (34) configured to receive the plug (30) when it is in a first position to be unable to receive the plug (30) when it is found. in a second position and of sufficient depth to allow displacement of the piston (29) in one piece; sufficient stroke to completely displace the inserter dose (31). In Figures 4 and 5 the receptacle (34) is shown as a slot through the lid (33). The plug (30) s is transversely mounted with respect to the groove (34) and is held in this first position by means of a fragile connection (35). The lid (33) is likewise, fixed to the container (26) by a similar breakable connection (36). These fragile bonds may be formed by any suitable technique including adhesive bonding, sonic welding or

18$

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heat, or the application of some form of peelable shell material, for example.

This configuration is easily adaptable to automatic filling, together with precise control of the dose amount of agent (31) and provides effective delivery of the desired amount of drug to the desired application site.

Prior to use, the device is protected from negligent dose shifting (31) by means of a break seal (35) and negligent removal of the inserter by a cheek seal (36). When the seal (35) is used it should be broken by turning the cap (30) from its first position to the second position, which is in alignment with the receptacle (34), and the seal (36) should be broken to remove the seal. inserter (27) from the container (26). 0 The inserter should then be placed into the urethra to the depth of the plunger (32) and the plug (30) is fitted into the receptacle (34) so ​​as to fully inject the dose of drug (31) into the urethra at the desired point of the injection. application, the inserter (27) may then be removed, leaving the drug load (31) within the urethra.

The materials used to form the inserter / container (25) are the same as those that can be used in the manufacture of the devices of Figures 1 and 2, for example, and when these materials are thermoplastic, the formation of the fragile bonds (35). ) and (36) by sonic fusion is the preferred technique.

Although the configuration represented in Figures 4 and 5 is

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In a preferred embodiment, other intrinser / container configurations may be used and any mechanism by which a predetermined amount of drug may be introduced from the inserter into the urethra to a predetermined depth is suitable for use therewith. invention. Like the other devices of this invention, the agent contained in dose 31 may be one or more drugs. However, when a combination of drugs is required to produce the desired therapeutic effect, it is also possible to administer sequentially separate doses of each individual drug, each of which may be prescribed by the physician and / or the patient to produce the desired effect. .

Embodiments may either be manufactured under sterilization conditions thereby eliminating the need for sterilization after manufacture, or may be manufactured under non-sterilization conditions after manufacture, or may be manufactured under non-sterilization conditions, thereby eliminating the need for sterilization. sterilization after manufacture, or may be manufactured under non-sterilization conditions and then further sterilized by any suitable technique, such as radiation sterilization.

Urethral inserts and injectors of this invention may be manufactured by any typical plastic molding and solvent evaporation and coating process known in the art, including molding, extrusion, hot forming, coating dipping, spray coating, hot melt coating and solvent evaporation. Although the prototypes of the devices of Figure 1 were made from ethylene vinyl acetate rods, which were manually hot-formed to the configuration of Figure 1, on a hot plate to flatten out the outer end and round the inside out 20 tf , the components of the embodiments of Figures 2 and 4 have been made in large amount by conventional injection molding equipment.

Molded parts in need of coating may be coated by any suitable method. Insertion coating, by controlling the temperature and viscosity of the bath and the time it takes for the article to be coated in the bath, coupled with air removal for greater accuracy is capable of producing very reproducible coatings within the requirements of this article. invention. Arrangement of a known volume of a dispersant / agent solution or suspension in a votive carrier on the rod in the presence of a hot air stream also produces coating in a reproducible manner, as is the case with the application of a melt containing contain the agent on a cold inserter stem.

Polyethylene glycol based coating formulations are particularly suitable for this invention because they remain solid at refrigerator or room temperature but melt at or below body temperature, have lubricating properties and dissolve in the urethra to allow rapid absorption of the active drug dispersed therein. The viscosity at 70 ° C of a 50 by 50 mixture of polyethylene glycol 1450 and polyethylene glycol 400 is such that approximately 100 mg of a dipping mixture was reproducibly applied to a 10 cm long ethylene - vinyl acetate rod per 3.5 mm in diameter. diameter after a single dip.

However, by varying the molecular weight of the polyethylene glycols and / or their proportions and / or the temperature of the bath, the viscosity of the bath and the resulting coating weight may be adjusted. For example, a mixture of polyethylene glycol 600 and polyethylene glycol 1000 in a 1: 2 weight ratio will have a melting point of about 32 ° C and a coating of approximately 50 mg can be expected at a bath temperature of about 1 ° C. polyethylene glycol 1450 is obtained as a flocculent material at room temperature which, when subjected to cooling, forms a soft coating on the insert of this invention. At bath temperature of the order of 60 to 50 ° C, coatings of about 50 mg can be obtained in a single dip.

As another example at 70 ° C polyethylene glycol 1450 deposited on two cm of rod and equal to about 50 mg.

Slower dissolution of the higher molecular weight polyethylene glycol allows for a controlled deposit in a limited area. How system is insend⁰ Inside the urethra, the slower melting of polyethylene glycol 1450 allows a minimal deposition of the urethra and maximum depth and complete insertion.

Coatings formed from lower molecular weight polyethylene lenses need to be reinforced and cooled when high ambient temperatures are expected. Coatings formed from polyethylene glycol 1450, however, remain physically stable even when exposed to high summer temperatures.

In another hypothesis for forming the desired coating on the inserter shaft (12) and depositing by means of a micropipette a known amount of the depersant agent in solution or suspension in a volatile solvent on the rod (12). which is held in an inclined position towards the shaft in the presence of a hot air stream so as to ^The allow rapid evaporation of the solvent before any of the liquids fell off the stem.

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This application form is particularly suitable when both the agent and dispersant are mutually soluble in the volatile carrier.

As an example, prostaglandins - Ej together with a lubricant dispersant such as propylene glycol PEG, glycerin PVP, PVA, hydroxyalkylcellulose or cyclodextrins, for example should be dissolved in weight ratios of dispersant to agent of 1: 1 - 10. : 1 in alcohol, with a concentration such that a small volume, approximately 10 µl, for example, of the alcohol solution contains the desired dose of the agent, This predetermined amount of solution should be introduced from a micropipette onto the surface of the inserter in the presence of a hot air stream and will evaporate rapidly to form the desired coating.

The volume of the solution is not accurate but should be chosen based on the size of the insert and the viscosity of the solution so that a relatively uniform coating of the solvent solution is obtained on the rod without any spillage before evaporation of the volatile solvent. . The fused agent-containing PEG2 may also be applied by a micropipette in a similar manner onto a cold insert rod to provide reproducible doses of single or multiple drugs.

Preferably, the total coating weight will be reduced consistently with the persistence of lubricating properties, and coating weights of less than 50mg are preferred. Similar amounts are also separated when the dosage form is in the form of a solution, dispersion, ointment, paste, gel or suppository for example.

At a level of about 50 to 100 mg, the ability of the urethra to receive the agent-containing material and rapidly absorb the agent appears to have been achieved, as some shedding of the coating material has been observed.

Once the weight of the coating or dose containing the agent is chosen, the concentration of the agent in the vehicle should be suitably chosen to provide the desired total dose within the dosage form or coating.

Unit dosages for prostaglandins - E1 are in the range of from about 10 to 1000 yag, with about 50 to 500 µg being preferred, papaverine dosage units are in the range of 1 to 20 mg and the dosage units of Phentolamine, Prazosine and Doxazosin are in the range of about 50 and 1000 µg per dose, with about 100 and 400 µg being preferred. Combinations of two or more drugs, such as prostaglandins E1 and alpha-blocking agents, have been found to potentiate the erectile effect, thus allowing their efficacy to be achieved at lower doses of both drugs.

If the agent is a combination of drugs, they may all be included in a single dosage form. However, when the agent comprises more than one drug, it will be preferable to sequentially administer each drug from a dosage form containing only one drug.

It is always preferable to use the minimum effective dose in any medical intervention, and it has been anticipated that the dosage forms of this invention should be provided in varying and increasing doses. Initially the patient will experience which

If the effective dosage is for him, use the minimum dose, and when administration is required until the desired effect is obtained thereafter, the patient should choose an effective dosage that is close to the determined high dosage, or may continue to be dosed. Use lower multiple doses.

The following examples of this invention are presented.

EffElPle 1 an EVA rod (with ²3% va) with&gt; .5 mm in the form of an insert having a hash approaching .... ente D one in length, with a blunt and spherical end and a head approximately 4 am thick and thin. of diameter, a hot plate. It was prepared and heated to 70 ° C in an immersion bath comprising a mixture of 5 ° C.^{/ l 0} at ps 00 sdepolyethylene glycol 1450 and polyethylene glyc 400, _and enough c and the agent to sharpen_Lgo to the desired concentration. The top suspended insert was dipped into the dip bath and removed.

the total weight of the coating thus obtained was aprori * .i-damen ·

I'll give you 100mg. Nine inserts are prepared and have rev. team »having approximately 50 µg of prostitute&gt; landinn._χ and nine insertO3 having coatings containing approximately 10 µg prostaglandins E1 and 10 µg / Ag hydrochloride termine. When used by a helpless man volunt '^: four doses of 50 µg of prostaglandin were required. stop and achieve a minimum easing. Dosafc..i's firms combined^Ί staglandins d; prasonin produced a reaction&gt;

It is not only strong in normal but also powerless volunteers, such as the administration of a lower total dose and two uses in a shorter period of time. There was a slight sensation in the urethra of the ureter on the part of the

<img file="PT97441B_D0024.tif" />

normal with the devices using the Prazosin Hydrochloride, but not for impotent patients. 'Using base form of Prazosin instead of chlworldrate may eliminate this feeling.'

EXAMPLE 2

An ethylene-vinyl acetate rod (24% vinyl acetate) 5 mm in diameter and approximately 10 cm in length was flattened at one end and flattened by manipulation on a hot plate. » gel, comprising 9 mg of 95% ethanol, 1 æg propylene glycol, J, 2 mg hydroxypropylcellulose and 2 mg prostaglandins E. Prepared and applied by dipping onto the dipstick rod with a total load of about 500 µm. mg The residual ethanol on the dipstick was allowed to evaporate. The prostaglandin load Ej. was about 200 µg / per unit. The erection of the penis occurred in a normal human within ten minutes after insertion of two rods into the ure. for a total dose of prostaglandin-Ej of 400 µg »

EXAMPLE 5

An ethylene * vinyl acetate (28% vinyl acetate) rod 5 mm in diameter and approximately 10 cm long, with a rounded end and a flat head, was coated with 500 µg of S-shaped prozoaine; and in a mixture of PEG (1: 2 PEG 600s PEG 1,000) tense one paa. melting temperature of approximately 52 ° C. The initial imiosisence will occur within a few minutes after insertion into the urethra of the male patient, with the maximum effect occurring within about fifteen minutes. Both the intensity and duration of the effect will be higher in patients with normal vascularization, whose impotence is due to deficiency. neurological disease *

For patients with severe vascular impairment, the administration of a single drug may have an incomplete action, requiring additional doses or the use of visible drug formation *

EXAMPLE 4

Insects for introduction into the urethra, configured as in Example 3, are coated with a mixture of 20 µg prostaglandins E² and 200 µg doxazoxin hydrochloride in the polyethylene glycol mixture described in Example 3. Patients with low vascular deficiencies severity will reach sexual response with this dose in several minutes, which will last approximately 30 minutes.

EXAMPLE 5

I

The urethral inserts configured as in Example 3 are coated with 100 µg penilephrine in approximately 50 mg of the polyethylene glycol mixture of Example 3, or with approximately 100 µg adrenaline contained in the polyelin glycol mixture of Example 3. . The inserts thus manufactured are inserted into the urethra of a patient suffering from priapism, due to either pharmacological or other causes. * If no swelling is achieved within approximately five to ten minutes, application should be be repeated at intervals of approximately ten minutes until such time as it occurs. Additional small doses are administered in this manner to avoid excessive systemic dosing when circulation balance is restored.

EXAMPLE 6

The urethral inserts configured as in Example 3 are coated with 100 µg triamcinoloma acetonite in approximately 50 mg of the polyethylene glycol mixture of Example 3 and in 50 mg polyethylene glycol having a molecular weight of about 2000 to 8000, or 50 µg of fluokinonide in approximately 50 mg of the polyethylene glycol mixture of Example 3 and in 50 mg of polyethylene glycol having a molecular weight of from about 200 to 8000. These inserts are inserted daily into the urethra of a patient suffering from Peyronie's disease and allowed to remain in the urethra for approximately twenty minutes to provide the steroid at the local therapeutic concentration in the corpora cavernosa. This method limits the trauma associated with the local injection of the antiinflammatory agent, which may itself instill the fibrotic process that the therapeutic agent intends to correct. If you don't observe me | After single dose treatment, multiple doses may be used for twenty minutes each until an effective dose level can be established.

EXAMPLE 7

The inserts for introduction into the urethra, as shown in Figure 1, are immersion coated with a mixture of polyethylene glycol 1450 at a temperature of 70 ° C containing 16 µg of prostaglandins-E4. Immersion to a depth of 2 cm in this solution leaves a total mass of 50 mg at a distance of 2 cm contains 500 µg of prostaglandins. 0

I

<img file="PT97441B_D0025.tif" />

Insertion time is about 1 second and storage time is 3 minutes at room temperature of about 20 ° C.

<img file="PT97441B_D0026.tif" />

This system was stable when exposed to the summer temperatures of Woschington, DC, and provided adequate insertion lubrication at slow insertion for a period of approximately 5 to 10 seconds. Approximately 30 seconds after total insertion, the system was then slowly removed within 10 seconds, and the entire lining within the urethra was released after this process.

The erection occurs in a normal male subject about 15 minutes.

apcis

<img file="PT97441B_D0027.tif" />

EXAMPLE 8 insert for insertion into the urethra, as shown in Figure 2, was injection molded from a polyoxymethylene polymer to provide a rod portion (12) approximately 3 cm long having a cone shape. approximately 3 mm in diameter at the piston end to approximately 2.5 mm

JM at the tip. Prostaglandins E together with an equal amount of propylene glycol as lubricant / dispersing agent were dissolved in ethyl alcohol with a prostaglandins-E concentration of 400 µg per 10 µl solution. Ten µl of this solution was applied by means of a micropipette onto the slanting rod of the slant at approximately 45 ° in vertical elevation in the presence of a hot air stream to evaporate the alcohol and provide a thin coating of the slurry. prostaglandin Ej in the disparate element on the insert stem. The insert was then placed into its container. 0 insert has been inserted in

<img file="PT97441B_D0028.tif" />

<img file="PT97441B_D0029.tif" />

<img file="PT97441B_D0030.tif" />

The urethra is rotated and simultaneously moved back and forth vigorously to clean prostaglandins-Ej from the insert surface for approximately 20 seconds. Similar inserts were used in two other individuals and functional erections were obtained for approximately 10 minutes and lasted approximately 30 minutes. - This product had a relatively short shelf life._upossibly due to prostaglandin unevenness. It would therefore be preferable to manufacture and package the device in a low humidity and nitrogen medium.

EXAMPLE 9

An insert for introduction into the urethra was manufactured as described in Example 8, except for the drug alprostadil (PBE), which was mixed with a gamma-type cyclodexphrine, in a ratio of 1 part alprostadil to 4 parts cyclodextrin. This product may have a longer shelf life than the product of Example 8. |

EXAMPLE 10

---- ,

Inserts configured as shown in Figures 1 and 2 were tried on impotent male males, where impotence is associated with diabetes, post-coronary artery disease (vascular insufficiency) and post radical tectectomy, and with individuals. normal elderly and normal healthy dividends, using various active drugs and combinations thereof. Overall, 3 patients responded positively, although variations in erection intensity and duration were observed, which depended on the dose of the formulation and the environment. Analyzes of the returned used systems showed residual drug loads of about 0 to 50%, indicating that the application technique is important in the use of the inserter. The preferred insertion technique, which is associated with substantially complete removal of the drug from the inserter, involves a slow insertion to a maximum depth greater than 5 to 10 seconds, followed by a back and forth motion of a rotation of the inserter to a length of approximately 3 cm, while maintaining pressure on the penis to maintain close contact between the urethra and the inserter shaft for about 20 seconds and then slowly removing the inserter while maintaining compression on the penis. This technique effectively cleans the inserter surface and provides substantial complete distribution of the agent.

EXAMPLE 11

An inserter configured as shown in Figure 4 has been injection molded to provide a rod portion approximately 3 cm long, having an elongated conical shape approximately 3 mm in diameter at the plunger end to approximately 2 µm. 5 mm at the end, with a central hole of 1.5 mm.

The plunger is inserted into the center bore to a depth that leaves a 1.5 mm cavity in the tip. The inserter is inverted and molten PEG 1450 containing 400 µg alprostadil is poured into the cavity and allowed to solidify therein. After solidification a suppository weighing about 2.9 µg contains about 15%, a weight of alprostadil, was formed. Alternatively, a 1.5 mm long solid PEG 1450 cylinder suppository containing 400 µg alprostadil may be introduced into the rod and moved to the end of the inserter and then inserted into the rod. plug into a hole of 1.5 mm.

<img file="PT97441B_D0031.tif" />

<img file="PT97441B_D0032.tif" />

Inserter is molded from polypropylene. The inserter is then placed inside a polypropylene container and an ultrasonic connection is formed between the insertion piston portion and the container and between the plug, which has been placed transversely with respect to the slot in the lid. The device may then be sterilized by radiation. In use, the connections between the cap and cap, and the cap and container will break and the inserter assembly is removed from the container, the cap should be rotated in alignment with the slot in the cap, the inserter stem it will be inserted into the penis until the plunger starts, and the plug will be compressed into the groove to inject the agent load into the urethra. The device should then be removed.

After the general description of the invention, it is obvious that various modifications become apparent to those skilled in the art which may be made without departing from the scope of this invention, which is limited only by the following claims.