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    • 专利摘要:
    Improved drug compositions and methods useful in treating male erectile dysfunction. In a buffer containing L-arginine and glycine, an optimized mixture of pentolamin mesylate, papaverine hardochloride, and alprostadil drugs are injected into the penile tissue to cause erectile men's erection.
    公开号:KR20040043996A
    申请号:KR1020020072485
    申请日:2002-11-20
    公开日:2004-05-27
    发明作者:포돌스키조셉에스.
    申请人:조나겐, 아이엔씨.；
    IPC主号:
    专利说明:

    Improved compositions for the treatment of Male Erectile Dysfunction
    [1] The present invention relates to improved compositions and methods of treatment of drugs useful for treating male erectile dysfunction. More specifically, the present invention is directed to treating erectile dysfunction and special compositions comprising one or more of the following pharmaceutically active agents, α-adrenergic antagonists, phosphodiesterase inhibitors and prostaglandins, in a new buffer. For administering such compositions to mammals (including humans).
    [2] Erectile dysfunction is a common medical condition that adversely affects about 200,000 men in the United States alone. Erectile dysfunction in men has been defined as the inability to achieve or maintain an erection sufficient for sexual intercourse (Impotence, National Institutes of Health Consensus Development Panel on Impotence Conference, JAMA 1993, 270, 83-90). A prominent etiology for this disease is the malfunction of the arteries associated with cardiovascular disease. Male erectile dysfunction is often associated with depression, anxiety, and self-degradation, adversely affecting the quality of life. Although male erectile dysfunction represents an important clinical problem, treatment for this disease remains uncertain and insufficient.
    [3] One of the minimally invasive treatments available involves the use of a vacuum shrink device in the penis to cause an erection. The physiological function of the penis is that blood flows through deep arteries in tissues and through veins close to the skin surface. By placing a plastic cylinder across the axis of the penis and limiting the flow of venous blood from the penis and employing a vacuum pump, the corpus cavernosum penis tissue is congested with trapped blood and an erection occurs. Common patient complaints indicate that the device interferes with sexual intercourse, has a short shelf life and can cause tissue damage, such as necrosis, in the penis with prolonged use.
    [4] Penile implants are another treatment for erectile dysfunction. This therapy requires surgical implantation of a mechanical device into the penis (eg U.S. Pat. No. 5,065,744 to Zumanowshky). The device may be a radially expandable rod or tube inflated with a solution that can be operated on to the patient to achieve an erection. Although this method does not affect the ability to urinate, inject sperm or have orgasm, the surgery required to implant the prosthesis can cause pain, infection, and scarring. Recent insights into the physiological mechanisms of penile erection have led to the development of other therapies for the treatment of erectile dysfunction. Initial research has shown that during sexual arousal, nitric oxide (NO) molecules are released into the surrounding tissue from the nerve endings and endothelial cells of the genital organs. These nitric oxide molecules then cause the enzyme guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which lowers intracellular calcium levels in the surrounding medium and relaxes smooth muscle cells. In the penis, the relaxation of the smooth muscle cells of the corpus cavernosum causes increased blood flow into the spaces of the corpus cavernosum, which leads to greater pressure within the corpus cavernosum, leading to stiffening of the penis.
    [5] Pharmacological drugs that inhibit the destruction of cGMP will then have the potential to sustain or promote an erection during sexual stimulation. The drug sildenafil (Viagra ™ , Pfizer, Inc.) is one such pharmacological drug that has shown some success in this way when administered orally (Terrett, NK et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819). -1824)
    [6] Other forms of oral therapies available to treat erectile dysfunction include the α-adrenergic antagonist atatipamezole (Farmos Orion), the dopaminergic antagonist apomorphine (Pentech Pharmaceuticals), Sildenifil (Pfizer, Inc.), a phosphodiesterase inhibitor, and centrally acting drugs such as pentolamin compositions (Vasomax ™ , Zonagen), which are also α-adrenergic antagonists / vasodilators .
    [7] These drugs appear to work by expanding arteries, relaxing and harmonizing penile tissue (smooth muscle cells), inducing blood into the penis, and causing an erection. However, some oral therapies may have drawbacks in terms of efficacy and side effects. Therefore, in such a case, it may be beneficial to directly treat erectile dysfunction or improve erectile ability by directly administering the drug on / in the penis itself. This mode of administration can also minimize the dosage of the necessary drug.
    [8] One other route for administering such vascular agonists is by dermal administration to the penis. Compound alprostadil (prostaglandin E1) is formulated as a cream (Macrochem) that is absorbed into penile tissue. Alprostadil is shown to bind to specific receptors in penile tissue and is accompanied by an increase in cellular cyclic adenosine monophosphate (cAMP) levels. Physiological mechanisms, like the cGMP described above, result in a decrease in intracellular calcium and relaxation of smooth muscle cells in the cytoplasm. The effects of these vasodilatation nerves lead to rapid artery inflow and dilation of the spaces of oriental vessels within the penis. This action then restricts the outflow of the veins from the penis, indicating stiffness of the penis. Another vascular agonist, papaverine hydrochloride, is formulated into patches (PharmaPatch, Pharmedia) for application to the skin of the penis and to maintain cGMP levels in similar types of mechanisms as described above causing erections. It acts as a non-specific phosphodiesterase inhibitor. These external treatments of the skin surface of the penis are disadvantageous and adversely affect the contact of the drug during sexual intercourse.
    [9] The aforementioned pharmacological drugs and route of administration represent therapies for the treatment of erectile dysfunction that can be successful for about 75-80% of 200,000 men with erectile dysfunction. However, for the remaining 20-25%, other treatments are often necessary, including intrathecal and / or intracavernosal injections.
    [10] Two FDA-Approved Available Injection Therapies Currently Pharmacia-Upjohn; and Edex ™ , Schwartz Pharma), all of which use alprostadil as the active ingredient. Caaverject Is commercially available as lyophilized powder containing the active ingredient alprostadyl in the main drug of lactose, sodium citrate, and benzyl alcohol. When reconstituted with water, Caverject Is injected into the space of the corpus cavernosum of the penis. Similarly EDEX ™ is a lyophilized flour comprising alprostadyl, α-cyclodextrin, and anhydrous lactose. It also reconstructs with water before being injected into the cavernous space of the penis. Urethral suppositories of alprostadil (MUSE ™ , Vivos, Inc.) have also been recently introduced on the market but have shown disappointing clinical results (Biotech. Newswatch, June 15,1998, 4-5). Not all men who suffer from erectile dysfunction respond with Alprostadil treatment alone.
    [11] In order to treat these individuals who do not respond to alprostadil, Zorgniotti et al. (Incorporated by J. Urol. 133: 39-41 (1985) as a reference) have been given intravenous carbenosal injection of a combination of papaverine hydrochloride and fentolamine mesylate. Has quickly demonstrated temporary penile swelling and can be accompanied by an erection in response to sexual stimulation.
    [12] Similarly, Althof et al. (J.Sex Marital Ther. 17 (2): 101-112 (1991), incorporated by reference) are approximately 84 of patients injected with intracavernosal injections of papaverine hydrochloride and pentolamin mesylate. Reported an increase in erection. However, 25% of patients progressed to fibrotic nodules, 30% had abnormal liver function, and 19% experienced penile tissue injuries, with a high dropout rate (57%) in this study. In another study using the same compound of pentolamin mesylate and papaverine hydrochloride, intracavernosal injection of this compound caused significant penile fibrosis in injected patients (see Larsen, EK et al., J. Urol. 137,292). -293 (1987)). The most common intracavernosal injection drugs are compounds of alprostadil, papaverine and pentolamin known as "Trimix." The major side effects of intracavernosal injections are prolonged erections and fibrosis, which can cause penile deflection, nodules, and plaques.
    [13] Therefore, there is a need for other safe and effective treatment of erectile dysfunction that can minimize the drawbacks of the currently available therapies described above.
    [14] Compositions and methods are provided for the treatment of male erectile dysfunction. When injected into the corpus cavernosum, the compositions of the present invention help to trigger, promote and maintain an erection of the penis. The compositions comprise one or more α-adrenergic antagonists, prostaglandins and any phosphodiesterase inhibitors. Preferred phosphodiesterase inhibitors include papaverine hydrochloride. Class V phosphodiesterase inhibitors such as, for example, Sildenifil (Pfizer) are more preferred. Alprostadil is the preferred prostaglandin. Any pharmaceutically salts, hydrates, hemihydrates, esters or other pharmaceutically acceptable forms of the aforementioned pharmaceutically active agents that are pharmaceutically acceptable are also within the scope of the present invention. The compositions of the present invention may further comprise a buffer comprising one or more substrates for nitric oxide synthase.
    [15] One embodiment of the present invention includes fentolamine mesylate, alprostadil and papaverine hydrochloride (Trimix). Preferably the trimix further comprises a buffer comprising one or more substrates for the nitric oxide synthase. Preferred buffers include glycine, arginine, and mixtures thereof. More preferably, the buffer comprises a mixture of glycine, L-arginine, mannitol, and benzyl alcohol in water, which when combined with the active ingredients results in an injectable mixture of about 6-8 pH. Another embodiment includes pentolamin mesylate and alprostidyl. Preferably this embodiment further comprises the aforementioned buffers.
    [16] Any of the foregoing buffers may also include other constraints, carriers, and the like. One advantage of using the buffers of the present invention in conjunction with the active drugs described above is the resulting improved solubility aspect of the pharmaceutically active drug. The buffers also provide substrates for the enzyme nitric oxide synthase, have been shown to play a role in erectile reactions and may require lower dosages for efficacy.
    [17] The present invention provides, by way of non-limiting example, an improved composition comprising one or more vascular agonists pentolamin mesylate, papaverine hydrochloride, and alprostadil (or salts of these pharmacoagonists that meet any pharmaceutically criteria). The purpose. Another aspect of the invention is directed to a composition comprising one or more vascular agonists such as papaverine, phentolamine, and alprostadil in a buffer comprising glycine, L-arginine, or a mixture of glycine and L-arginine. It is done. Use of the composition of the present invention by improved solubility aspects of the vasoactive agent in the buffers of the present invention reduces the incidence of fibrous nodules and prolonged erection in the penis caused by deposition of the vasoactive agent at the injection site and reservoir formation . Without wishing to be bound by theory, it has also been believed that the presence of other substrates for L-arginine or nitric oxide synthase in the compositions of the present invention may lower the dosage of the active drug required to effectively treat erectile dysfunction.
    [18] The invention is described with respect to fentolamine as α-adrenergic antagonists and in particular phentolamine mesylate or phentolamine hydrochloride. Pentolamine can exist in hydrated forms, including solvated as well as unsolvated forms, including hemihydrate. Generally solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for this invention.
    [19] Pentolamin can also make salts that meet the pharmaceutically standard with organic and inorganic acids. Examples of suitable acids for salt formation include sulfonics, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, as well as hydromic acids such as hydrochloric and hydrobromic Other acids such as ascorbic, maleic, methanesulphonic, toluenesulphonic acid, and other minerals and carboxylic acids known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to prepare the salt in the traditional manner. The free base forms can be regenerated by treating the salt with dilute aqueous base solution such as aqueous sodium hydroxide, potassium chlorate, ammonia and sodium bicarbonate. The base forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for the present invention.
    [20] When the composition according to the invention comprises only α-adrenergic antagonists or phosphodiesterase inhibitors or prostaglandins as pharmaceutically active agents, the composition adds a buffer comprising a substrate of nitric oxide synthase such as arginine. Will contain as. When the composition of the present invention comprises two or more pharmaceutically active agents described above, the composition optionally comprises buffers comprising a substrate of nitric oxide synthase.
    [21] One exemplary embodiment includes an α-adrenergic antagonist (e.g. pentolamin mesylate), a phosphodiesterase inhibitor (e.g. papaverine hydrochloride or sildenifil), and a prostaglandin (e.g. alprostadil) in a buffer. ) Is a composition comprising. Active ingredients pentolamin mesylate, papaverine hydrochloride, and alprostadil are present in the composition in a weight ratio ranging from about 0.1: 1.0: 001 to about 5: 30: 0.02. Preferably the weight ratio of pentolamin mesylate: papaverine hydrochloride: alprostadyl is about 1: 30: 0.01. More preferably, the weight ratio of fentolamine mesylate: papaverine hydrochloride: alprostadyl is about 5: 7.5: 0.005.
    [22] Dosages of the vasoactive components of the invention range from about 0-40 μg / ml alprostadil, about 0-50 mg / ml papaverine, and about 0-10 mg / ml pentolamin at about 0.5 ml total volume. to be. Preferred dosages of the compositions of the invention range from about 1-5 mg / ml pentolamin, about 0-30 mg / ml papaverine, 5-20 μg / ml alprostadil in about 0.5 ml total volume. More preferably, the amount is about 5 mg / ml pentolamin, about 7.5 mg / ml papaverine, 0.005 mg / ml alprostadil in about 0.5 ml total volume.
    [23] Another exemplary embodiment is a composition optionally comprising an α-adrenergic antagonist (eg pentolamin mesylate), and prostaglandin (eg alprostadyl) in a buffer. The active ingredients pentolamin mesylate and alprostadil are present in the composition in a weight ratio ranging from about 0.1: 0.001 to about 5: 0.02. Preferably the weight ratio of pentolamin mesylate: alprostadyl is about 5: 0.005.
    [24] In this embodiment the dosage of the vasoactive component of the invention is about 0-40 μg / ml alprostadyl and about 0-10 mg / ml pentolamin in about 0.5 ml total volume. Preferred dosages range from about 1-5 mg / ml pentolamin and about 5-20 μg / ml alprostadil at about 0.5 ml total volume. More preferably, the amount is about 5 mg pentolamin and about 0.005 mg / ml alprostadil in about 0.5 ml total volume.
    [25] For a composition of the invention comprising only phentolamine as a vascular agent that combines with a buffer such as a buffer containing arginine and / or glycine, the preferred dosage is about 1.25 mg / ml at about 0.5 ml total volume. A preferred dosage for a composition comprising only papaverine as a vasoactive agent in combination with a buffer comprising arginine and / or glycine is about 7.5 mg / ml in about 0.5 ml total volume. In compositions comprising only alprostadyl as a vascular agonist in combination with a buffer comprising arginine and / or glycine, the preferred dosage is about 5 μg / ml at about 0.5 ml total volume.
    [26] Compositions comprising only two vasogonists in a buffer according to the invention are also contemplated by the invention.
    [27] The active ingredients are administered into a buffer which increases their solubility and / or provides a substrate for nitric oxide synthase. The buffer preferably comprises glycine, mannitol, and benzyl alcohol in water. In this buffer, the content of glycine is preferably in the range of about 1% to about 2% by weight. More preferably the buffer comprises L-arginine, glycine, and other pharmaceutically acceptable excipients such as mannitol and benzyl alcohol in water. The weight ratio of L-arginine to glycine in this preferred buffer is about 1:20. The pH of the composition in the buffer is about 3-9. The preferred pH range for the composition in the buffer is about 6 to about 8. Neutral pH is most preferred.
    [28] Also included in the present invention is a method for treating male erectile dysfunction comprising administration of a pharmaceutically effective amount of a composition comprising one or more α-adrenergic antagonists, phosphodiesterase inhibitors, and prostaglandins. Preferably the composition in this method comprises pentolamin mesylate, papaverine hydrochloride, and alprostadil in a buffer. The route of administration in this method of treatment is one of the components consisting of oral, dermal application, subcutaneous intraperitoneal, intramuscular, and penis (including penile cavernosal). The preferred route of administration is by intracavernosal injection.
    [29] One composition used in this method of treatment preferably comprises pentolamin mesylate, papaverine hydrochloride, and alprostadil in a weight ratio ranging from about 0.1: 0.0: 0.001 to about 5: 30: 0.02. Preferably pentolamin mesylate, papaverine hydrochloride, and alprostadil are present in the composition in a weight ratio of about 1: 30: 0.01. More preferably pentolamin mesylate, papaverine hydrochloride, and alprostadil are present in the composition in a weight ratio of about 0.5: 7.5: 0.005.
    [30] Dosages of vascular agonists useful in this method of treatment are about 0-40 μg / ml alprostadil, about 0-50 mg / ml papaverine, and about 0-10 mg / ml pentolamin in about 0.5 ml of total volume. Preferred dosages of the vascular agonists range from about 1-5 mg / ml pentolamin, about 0-30 mg / ml papaverine, and about 5-20 μg / ml alprostadil in about 0.5 ml of total volume. More preferably, the dose used in this method is about 5 mg / ml pentolamin, about 7.5 mg / ml papaverine, and about 0.005 mg / ml alprostadil in about 0.5 ml total volume.
    [31] In a method of using a composition containing only phentolamine as the vasoactive agent, the preferred dosage ratio is from 0.5 ml of total volume to about 1.25 mg / ml. In a method of using a composition containing only papaverine as an vascular agent, the preferred dosage ratio is from 0.5 ml to about 7.5 mg / ml of total volume. In a method of using a composition containing only alprostadyl as the vasoagent, the preferred dosage ratio is from 0.5 ml to about 5 μg / ml total volume.
    [32] Other compositions used in this method include α-adrenergic antagonists (eg pentolamin mesylate), and prostaglandins (eg alprostadyl). The active ingredients, pentolamine mesylate and alprostadil, are present in the composition in a weight ratio ranging from about 0.1: 0.001: to about 5: 0.02. Preferably the weight ratio of pentolamin mesylate: alprostadyl is about 5: 0.005.
    [33] Dosages of the vasoactive components of the invention range from about 0-40 μg / ml alprostadil and about 0-10 mg / ml pentolamin in about 0.5 ml of total volume. Preferred dosages range from about 1-5 mg / ml pentolamin and 5-20 μg / ml alprostadil at a total volume of about 0.5 ml. More preferably, the dose is about 5 mg pentolamin and about 0.005 mg / ml alprostadil in about 0.5 ml of the total volume.
    [34] The buffer used to dissolve the active ingredients in the previous methods includes a mixture of glycine, mannitol, and benzyl alcohol in water. The glycine content of this buffer preferably ranges from about 1% to about 2% by weight. More preferably, the buffer comprises a mixture of glycine, L-arginine, mannitol, and benzyl alcohol in water. The weight ratio of glycine to L-arginine in this preferred buffer is about 1:20. The pH of the composition of the invention in the buffer is from about 3 to about 9. The preferred pH range for the composition in the buffer is about 6 to about 8. Neutral pH is most preferred.
    [35] The invention also aims at the unit dosage form of any of the compositions described herein.
    [36] The invention is further illustrated by the following examples. Example 1 describes an experiment to evaluate the increased solubility of the active ingredients pentolamine, papaverine, and alprostadil in a buffer comprising glycine and arginine. Example 2 demonstrates the improved ability of a composition to induce erection of the penis in rabbits by injection of a corpus cavernosum of a composition comprising phentolamine mesylate, papaverine hydrochloride, and alprostadil in a buffer at various pHs. . Example 3 describes how the improved compositions of the invention can be used to treat erectile dysfunction in humans. Examples 4 and 5 demonstrate the safety and effectiveness of improved compositions when used in the treatment of erectile dysfunction in humans.
    [37] The foregoing details and examples are intended to illustrate the invention and are not intended to limit the scope of the invention as defined in the appended claims.
    [38] Example 1
    [39] Solubility of Pentolamine-Papaberine in Glycine-Arginine Buffer
    [40] Papaverine is poorly soluble in the presence of pentolamin at physiological pH (<1 mg / ml). In this state, papaverine can precipitate, making a solid drug precipitate at the injection site. Precipitation of this solid papaverine can act as a reservoir of drugs that continue to affect erections beyond the time of increasing the risk of sustained erections and the development of nodules / cytosis in the penis.
    [41] To address this problem, buffers containing glycine, arginine, or a mixture of glycine and L-arginine were prepared to increase the solubility of the active ingredients papaverine and pentolamin and provide a substrate for nitric oxide synthase. . A series of saturated solutions containing pharmaceutically active ingredients in a buffer at various pHs were prepared, filtered to determine the concentration of dissolved pentolamin and papaverine active ingredients and then high performance liquid chromatography (HPLC) and ultraviolet wavelengths. The analyzer was analyzed.
    [42] At a ratio of about 6 to 1, a saturated solution of papaverine hydrochloride and solid pentolamin mesylate is added to a buffer containing about 0.1 M glycine and about 2 mM L-arginine in the amounts shown in Table 1 and with an initial pH of 8.2. 0.1 N NaOH solution was used to adjust the pH to the indicated value. These solutions are shaken for about 10 minutes for maximum dissolution of the drug in the buffer and left overnight at room temperature. The samples are then filtered through a 0.45μ PETE filter to remove undissolved drug and analyzed by HPLC to determine how much each drug has dissolved in the solution at various pH values. HPLC was performed using a C18 column with phase buffer (5 mM NaH 2 PO and 5 mM octane sulfonic acid, pH 3) capable of moving at 30 ml acetonitrile at a flow rate of 1.5 ml / minute. The detection wavelength was 210 nm. Standard curves of both fentolamine and papaverine were prepared, and the concentration of fentolamine-papaberine mixtures in the samples was determined by measurement of the peak area. The results are shown in Table 1 below.
    [43] Solubility of Active Drugs in Buffer pHPapaverine (mg / ml)Pentolamine (mg / ml) Added to bufferIn solutionAdded to bufferIn solution 3.916636.811112.12 4.35607.75109.88 5.04600.7106.5 7.48600.17104.97 7.65600.2106.99
    [44] The data demonstrate that the solubility in glycine-arginine buffer at pH 3.91 for papaverine is about 36.81 g / ml. In contrast, the solubility in glycine-arginine buffer at pH 7.48 was only 0.2 mg / ml. Thus, the use of a buffer containing glycine and L-arginine at a pH of about 3-5 increases the solubility of papaverine in contrast to buffers with pH greater than 7.0. Similarly, the solubility of fentolamine in mixtures is generally greater at low pH. However, there was an increase in the solubility of pentolamin at pH7.65. Increased solubility of the vasoagent in the buffers of the present invention reduces the likelihood that the drugs form a reservoir at the injection site.
    [45] Example 2
    [46] Intracavernosal Injection of Trimix Formulations
    [47] Four New Zealand white rabbits were used in this study to determine the effect of intracavernosal injection of two compositions of the composition of the present invention. The composition included a trimix of alprostadil, pentolamin mesylate, and papaverine hydrochloride. Detailed compositions are listed in Table 2 below. The contents of Compositions A and B are similar except that Composition B does not contain L-arginine.
    [48] Composition of Injectable Trimix CompositionComposition A (per ml)Composition B (per ml) Alprostadil20 µg20 µg Pentolamin mesylate5mg5mg Papaverine HCI30mg30mg L-arginine0.35mgnone Glycine7.5mg7.5mg Mannitol24mg24mg Benzyl alcohol84mg8.4mgFinal pH: 3.98Final pH: 4.01 Sterile filteredSterile filtered
    [49] Two of the rabbits underwent intracavernosal injection of solution A and the other two underwent intracavernosal injection of solution B. In preparation for these injections, rabbits were anesthetized by intramuscular injection of ketamine (35 mg / kg) and xylazine (5 mg / kg). Anesthesia was maintained with a large pill injection in 0.2 ml vein of the required pentobarbital (25 mg / ml). A 20-gauge angiocatheter entered the carotenoid artery for on-line measurement of arterial pressure in tissues. A 23 gauge mini catheter was placed into the cavernous body to measure intracavernosal pressure during erection. Baseline arterial blood pressure and intracavernosal pressure were recorded. Once the baseline was established, either 0.2 ml of Solution A or Solution B was injected into the corpus cavernosum. The effects of intracavernosal drug administration on intracavernosal pressure and tissue arterial pressure have been recorded continuously. If sufficient penile erection did not occur, additional intracavernosal injections were made.
    [50] The results indicate that the first rabbit injected with 0.2 ml of Solution A into the corpus cavernosum experienced sufficient penile erection lasting more than 30 minutes. Intracavernosal pressure, a measure of hyperemia, increased from about 30 mm Hg to about 63 mm Hg (91% of mean tissue arterial pressure after injection). The only side effect recognized was non-hazardous hypotension lasting approximately 10 seconds. There was no effect on heart rate.
    [51] A second rabbit injected with 0.2 ml of Solution A intracavernosal also experienced sufficient penile erection lasting about 4 minutes. Post-injection cavernosal pressure rises from about 35 mm Hg to about 69 mm Hg (83% of average cystemic arterial pressure). The rabbit was second injected with 0.2 ml of Solution A into the cavernous corpus cavernosum, causing another sufficient penile erection that lasted more than 30 minutes. After the second intracavernosal injection, the intracavernosal pressure increased from about 45 mm to about 81 mm Hg (96% of mean cystic arterial pressure). The only side effect recognized was non-hazardous transient hypotension lasting approximately 8 seconds. There was no effect on heart rate.
    [52] The third rabbit received an intracavernosal injection of 0.2 ml of Solution B and caused a partial erection lasting 3 minutes. The first injection increased intracavernosal pressure from about 36 mm Hg to about 50 mm Hg (60% of mean cystemic arterial pressure). The second injection resulted in sufficient penis erection lasting longer than 30 minutes. After the second intracavernosal injection, the intracavernosal pressure increased from about 28 mm Hg to about 65 mm Hg (96% of mean tissue arterial pressure). The only side effect recognized was non-hazardous transient hypotension lasting approximately 6 seconds. There was no effect on heart rate.
    [53] The fourth rabbit received two injections of 0.2 ml solution B each, failed to cause an erection, causing a non-hazardous increase in cavernous cavernous pressure of only about 15 mm Hg to about 33 mm Hg. A third injection of 0.2 ml solution B resulted in partial erections that increased the intracavernosal pressure from about 30 mm Hg to about 45 mm Hg (64% of the average cystic arterial pressure). The fourth injection of 0.2 ml solution B caused an erection of sufficient penis lasting about 15 minutes. After the fourth injection, the cavernosal pressure increased from about 42 mm Hg to about 65 mm Hg (88% of mean tissue arterial pressure). Transient, non-hazardous hypotension lasting about 5-8 seconds after each injection was observed. There was no change in heart rate.
    [54] These experiments demonstrate that intracavernosal administration of Solution A or Solution B caused erection of the penis in rabbits. An erectile response to Solution A occurred after one injection in the first rabbit and after two injections in the second animal. An erectile response to Solution B occurred after two injections in the first animal and four injections in the second animal. Thus, both Solution A and Solution B, which contain the active ingredients in one buffer of glycine or glycine-arginine, pentolamin mesylate, papaverine hydrochloride, and alprostadyl, provide effective treatment of male erectile dysfunction. However, using Solution A to erect rabbits required fewer injections. Solution A, which contains glycine as well as L-arginine, therefore appears more effective than solution B as an erectile dysfunction treatment.
    [55] Example 3
    [56] Treatment of Erectile Dysfunction in Humans
    [57] While the foregoing examples illustrate the effect of erectile dysfunction in rabbits of trimixes of alprostadyl, pentolamin mesylate and papaverine hydrochloride in buffers with or without arginine, these compositions also treat the treatment of erectile dysfunction in humans. Also useful. The dose of active drug suitable for administration to a human can be predetermined as one of ordinary skill in the art. For example, a suitable base-line dose is Zorgniotti, et al., Who demonstrated that intracavernosal injections of 30 mg papaverine (1 ml total volume) combined with 0.5 to 1 mg pentolamin resulted in penile erection in response to sexual stimulation. J. Urol. 133: 39-41, 1985).
    [58] The dosages of the active agents in the compositions and methods of the present invention range from about 0 to about 40 μg / ml alprostadil, from about 0 to about 5 mg / ml papaverine, from about 0 to about 10 mg / ml in total volume of about 0.5 ml. Pentolamin range. Preferred dosages of the compositions of the invention range from about 0.5 ml of total volume to about 1-5 mg / ml pentolamin, about 7.5-30 mg / ml papaverine, about 5-20 μg / ml alprostadil. More preferably, the dose of the composition of the invention is from about 0.5 ml of total volume to about 5 mg / ml pentolamin, about 7.5 mg / ml papaverine, and about 0.005 mg / ml alprostadil. Erectile response can be measured by one of several criteria well known in the art.
    [59] According to the invention, the use of other nitric oxide synthesizing substrates in cooperation with vascular agonists comprising arginine or pentolamin and / or alprostadyl and / or papaverine is preferred for arginine or other nitric oxide synthase substrates. Enhances or restores sexual response or responsiveness in men who suffer from erectile dysfunction when compared to a composition free of alcohol. Due to the presence of arginine or other nitric oxide synthase substrates, it is possible to use smaller dosages of vasoactive agents that are more cost effective and with fewer side effects.
    [60] Example 4
    [61] Intracacular Cavernous Injection in Humans
    [62] Randomized, double-blind, placebo controlled experiments were designed to compare the pharmacodynamics and stability of the following trimix compositions.
    [63] Trimix 1 per mlTrimix 2 (per ml) Prostaglandin E10.01mg0.005mg Pentolamin mesylate1.0mg5.0mg Papaverine HCI30.0mg7.5mg L-arginine0.35mg0.35mg Glycine7.5mg7.5mg Mannitol24mg24mg Benzyl alcohol8.4mg8.4mg Final pH4.014.01
    [64] Viagra Sixty-five male patients who failed oral treatment were treated with the following compositions in each of the four or more experimental periods.
    [65] curePapaverine Dose (mg / ml)Pentolamine dose (g / ml)Alprostadil Dose (mg / ml) 1 (placebo)000 2 (caverject)000.02 3 (Trimix 1)30One0.01 4 (trimix 2)7.550.005
    [66] The placebo for the experiment was only arginine (0.35 mg / ml). The treatment sequence in which each patient was dosed was randomized and double-blinded with each patient receiving a single batch of blinded therapy.
    [67] The experimental drug was administered by injection into the corpus cavernosum of 0.5 ml (treatments 1, 3 and 4) or 1.0 ml (treatment 2) through the dorsal side of the penis using a needle in the form of a 26 or 27 gauge insulin. Each patient completed self-assessment of erectile response at 0, 5, 10, 20, 30, 45, 60, 75, 90 and 120 minutes after injection. the results are as follow.
    [68] Therapeutic compositionPatients with sufficient erection (n = 65)efficiency(%) One00 21726 32234 42742
    [69] As the fentolamine concentration increased, the efficiency of the composition also increased. Efficiency was defined as the percentage of patients who could achieve sufficient erection after injection. These data are surprising in that phentolamine injected alone alone causes swelling and does not cause sufficient erection.
    [70] Example 5
    [71] Optimization of Composition in Caverject Failure
    [72] The following experiment shows the most improved dosage of Caverject (20 μg alprostadil) injections in men who failed treatment. A randomized, double-blind, four-way cross-in-office trial of 40 patients with severe erectile dysfunction was performed. First In-Office Caverject After injection (Visit 1), patients received a single intracavernosal injection of 0.5 ml of one of the following compositions containing 0.35 mg / ml L-arginine during the next four office visits (at least one week apart).
    [73] curePapaverine Dosage (mg / ml)Pentolamine Dosage (mg / ml)Alprostadil Dosage (mg / ml) Bimix 1050.010 Bimix 2050.040 Trimix 37.550.005 Trimix 43050.010
    [74] Post-dose patient self-assessment of the erectile response, main symptom questionnaire, blood pressure measurement and investigation of side effects were conducted at various time points up to two hours before and after dosing. Database operating procedures and statistical analyzes were conducted and interpreted consistently with FDA regulations and ICH guidelines. The first efficacy parameter was self-assessment of patients with erection scores ranging from 1 (no evidence of expansion) to 4 (sufficient stiffness). The second parameters are the maximum erectile response from each treatment, the time from injection to satisfactory response, the duration of the erectile response sufficient for vaginal penetration, and the percentage of erectile response sufficient for vaginal penetration. Safety was assessed based on the investigation of treatment-unexpected adverse events (AEs) (frequency, intensity, duration of treatment and related). The results are as follows and the erectile response rate is a percentage of patients with grade 3 erections (deemed sufficient for sexual intercourse).
    [75] cureErectile reaction rate (%)Incidence of penis pain (%) Caverject (Visit 1)041 Bimix 14328 Bimix 24643 Trimix 34619 Trimix 45128
    [76] There were some differences in the rate of erection between different Bimix and Trimix formulations, but the differences were not statistically significant (p = 0.317).
    [77] Although there were no severe or severe AEs reported, there was an incidence of penile pain that showed a clear alprostadil dose-response relationship. The majority of AEs were mild for all treatments.
    [78] Erectile response rates indicate that patients with severe ED can be treated well evenly with one intracavernosal injection of Bimix or Trimix containing arginine. The effectiveness of Bimix formulations containing arginine is surprising given that reaction rates that are statistically equivalent to Trimix compositions are achieved without papaverine at the same concentration of pentolamin and alprostadil (Bimix 1 vs Trimix 4). The effectiveness of Bimix compositions containing arginine may prove beneficial for patients suffering from severe erectile dysfunction. By removing papaverine from the treatment regimen, patients with severe erectile dysfunction may experience less formation of nodules associated with repeated injections of papaverine.
    [79] In summary, these data demonstrate that patients who fail initial oral or other infusion therapies can benefit from the improved compositions described herein. However, the compositions and methods of the present invention can also be used as the first course of treatment for erectile dysfunction. The foregoing detailed description is intended to illustrate the invention and is not intended to limit the scope of the invention as defined in the appended claims. Other variations are still possible within the spirit and scope of the invention and can be readily presented to those skilled in the art.
    [80] The compositions of the present invention, when injected into the corpus cavernosum, help to trigger, promote and maintain an erection of the penis.
    [81] According to the invention, the use of other nitric oxide synthesizing substrates in cooperation with vascular agonists comprising arginine or pentolamin and / or alprostadyl and / or papaverine is preferred for arginine or other nitric oxide synthase substrates. Enhances or restores sexual response or responsiveness in men who suffer from erectile dysfunction when compared to a composition free of alcohol. Due to the presence of arginine or other nitric oxide synthase substrates, it is possible to use smaller dosages of vasoactive agents that are more cost effective and with fewer side effects.
    [82] One advantage of using the buffers of the present invention in conjunction with the active agents described above is the resulting improved solubility aspect of the pharmaceutically active agents.
    [83] The improved solubility aspects of the vasoactive agent in the buffers of the present invention make use of the compositions of the present invention to reduce the occurrence of fibrous nodules and prolonged erection in the penis caused by deposition of the vasologic agonist at the injection site and reservoir formation. .
    [84] The buffers may also provide substrates for the enzyme nitric oxide synthase, play an erectile response and may require lower dosages for efficacy.
    [85] That is, patients who fail initial oral therapy or other infusion therapy may benefit from the improved compositions described herein.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] Fentolamine and alprostadil in a buffer, said buffer comprising a substrate for nitric oxide synthase.
    [2" claim-type="Currently amended] The method of claim 1,
    The pentolamin is fentolamine mesylate, fentolamine hydrochloride, or a salt of fentolamine to meet the pharmaceutical criteria.
    [3" claim-type="Currently amended] The method of claim 2,
    The weight ratio of pentolamin mesylate to alprostadil is about 0.5 to 0.005 to about 5: 0.02.
    [4" claim-type="Currently amended] The method of claim 3,
    The weight ratio of pentolamin mesylate to alprostadil is about 5 to 0.005.
    [5" claim-type="Currently amended] The method of claim 2,
    The fentolamine mesylate and alprostadil are at concentrations of about 0-10 mg / ml fentolamine and about 0-40 μg / ml alprostadil.
    [6" claim-type="Currently amended] The method of claim 5,
    The fentolamine mesylate and alprostadil are at concentrations of about 1-5 mg / ml pentolamin and about 5-20 μg / ml alprostadil.
    [7" claim-type="Currently amended] The method of claim 6,
    Fentolamine mesylate and alprostadil are at concentrations of about 5 mg / ml pentolamin and about 0.005 mg / ml alprostadil.
    [8" claim-type="Currently amended] The method of claim 2,
    Pentolamine mesylate and alprostadil are present in a total volume of 0.5 ml.
    [9" claim-type="Currently amended] The method of claim 2,
    And the substrate for nitric oxide synthase is L-arginine.
    [10" claim-type="Currently amended] The method of claim 9,
    Wherein said buffer further comprises benzyl alcohol and mannitol.
    [11" claim-type="Currently amended] The method of claim 2,
    And the substrate for nitric oxide synthase is a mixture of L-arginine and glycine.
    [12" claim-type="Currently amended] The method of claim 10,
    Wherein the buffer comprises glycine and L-arginine in a weight ratio of about 1 to 20.
    [13" claim-type="Currently amended] The method of claim 2,
    And wherein the buffer has a pH range of about 3 to about 5.
    [14" claim-type="Currently amended] The method of claim 2,
    The substrate for nitric oxide synthase is glycine.
    [15" claim-type="Currently amended] The method of claim 2,
    Wherein the composition in the buffer has a pH range of about 3 to about 9. 9.
    [16" claim-type="Currently amended] The method of claim 2,
    Wherein the composition in the buffer has a pH range of about 7.
    [17" claim-type="Currently amended] 17. A method for treating male erectile dysfunction comprising administering a pharmacologically effective amount of the composition according to any one of claims 1 to 15 or 16.
    [18" claim-type="Currently amended] Use of a composition according to any one of claims 1 to 15 or 16 for the manufacture of a medicament for the treatment of erectile dysfunction.
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    同族专利:
    公开号 | 公开日
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-11-20|Application filed by 조나겐, 아이엔씨.
    2002-11-20|Priority to KR1020020072485A
    2004-05-27|Publication of KR20040043996A
    优先权:
    申请号 | 申请日 | 专利标题
    KR1020020072485A|KR20040043996A|2002-11-20|2002-11-20|Improved compositions for the treatment of Male Erectile Dysfunction|
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