JP2001233770A - Combination of oral drugs for treating erectile dysfunction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject combination tolerant to sildenafil therapy and intended for patients worrying about erectile dysfunction(ED). SOLUTION: This combination comprises 10-100 mg of sildenafil and an additional medicament effective for improving the blood circulation through the spongy tissue. The combination has the following advantages: both cyclic adenosine monophosphate and cyclic guanosine monophosphate levels rise simultaneously and the NO tissue level of the spongy tissue rises as well; and furthermore, this combination is effective for the change in the stream of local blood during erection and also partially influences the brain's dopamine receptor interfering in the central path of erection.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to erectile dysfunction (E)
D) Drugs used as oral drugs and combinations of the drugs.

[0002]

The most recent treatment for ED has been greatly improved with the use of oral Sildenafil citrate in the range of 10 to 100 mg / tablet per treatment. With the repeated use of sildenafil, cardiotoxicity and side effects such as gastritis and hypotension have become significant problems. It has been reported that the response is very high when compared to other drugs administered for the above-mentioned diseases, but there are some that are immune unresponsive to sildenafil treatment.

[0003]

SUMMARY OF THE INVENTION The present invention has been made in view of the above, and provides a drug combination for patients suffering from erectile dysfunction (ED) resistant to sildenafil treatment. The purpose is to:

[0004]

SUMMARY OF THE INVENTION The above object is attained by the following method.
0 mg of sildenafil is effective in improving the blood circulation of the corpus cavernosum, and additionally increases the tissue levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate and NO (nitric oxide) in the corpus cavernosum. Achieved by a combination of drugs consisting of a drug.

[0005] The drug of the present invention is not only
Used in case of intolerance side effects.

In order to guarantee the effectiveness of the designed drug, the present invention is based on the effect of reducing the increase in venous drainage penile blood pooling from the corpus cavernosum of the penis. At the same time, the drug not only induces the bioeffects of nitric oxide on the corpus cavernosum of the penis, but also cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (c
GMP) levels are increased by inhibiting phosphodiesterase type 5.

[0007]

DETAILED DESCRIPTION OF THE INVENTION Clinical Trials Patients suffering from ED are clinically evaluated and
As an immune-unresponsive animal to 0 mg sildenafil, he was treated with drugs to overcome the dilemma. An early successful evaluation of the treatment led to a detailed analysis for various studies of ED and Sildenafil Negative ED (EDSN) in claims 1 to 17.

[0008] lotios, tablets, capsules,
Solutions, suspensions, lubricants, ointments, sprays, creams, transdermal systems, gels,
It is preferred to utilize the combination of drugs in a pharmacological formulation such as a liquid.

[0009] It is important according to the invention that patients are resistant to 100 mg of sildenenafil when treated by the reaction of a positively responding drug, and that they report improved clinical conditions for their ED.

[0010] Patients afflicted with ED have a wide range of illnesses such as coronary artery disease, diabetes mellitus, renal or hepatic failure, radical prostate surgery or transurethral surgery, and suffer from depression with or without antidepressants. Troubled or
It suffers from a wide variety of drugs, pathologies that cause spinal or brain injury, or ED. There is complex metabolic and vascular disease responsible for ED, inward flow of blood into the corpus cavernosum is measured at low levels in defective biosynthesis, and / or damage to phosphodiesterase type 5 in corpus cavernosum of the penis Increases the rate of conversion of nitric oxide with or without enzymatic activity. In addition to the complex diseases described above, the increased outward flow from the corpus cavernosum to the prostatic chamber and further to the penile vein can be explained. Clinical results Effective not only locally (meaning the corpus cavernosum) but also locally (meaning the area of the prostatic chamber). To increase the inward velocity and decrease the circulating outward velocity from the penis at the same time. From a number of drugs investigated to satisfy the designed drug effect, alpha sympathiomimetica apparently reduces venous drainage from the corpus cavernosum (it is locally effective in the area of the prostatic chamber) , Medium effect
effect) was recorded by including dopamine, whereas a minor effect was observed when injected into the corpus cavernosum in the presence of prostaglandin E1.

It was surprising to measure the elevated tissue levels of NO in the corpus cavernosum, as well as the direct or indirect elevation of cGMP and cAMP, as well as the changing inward / outward flow conditions.

[0012] Thus, the medicament mechanism is that NO induced by inhibition of phosphodiesterase type 5 in the corpus cavernosum.
Is described as decreased venous clearance from the corpus cavernosum.

Examination of many drug combinations by taking cavernosograms diagnostics reveals that reduced venous drainage during erection is a major cause of therapeutic efficacy in sildenafil immune unresponsiveness I understand. Compounds For example, in the present application, drug combinations include sildenafil of the following chemical structure:

[0014]

Embedded image The dosage range of the present invention includes 10 μg of Suprarenin having the following chemical structure:

[0015]

Embedded image Alpha symphathicomics
195 to 215% after infusion into the corpus cavernosum in urodynamic procedures of the prostate and bladder outlet areas of patients suffering from priapism, as monitored by video as imetics)
The range showed an extreme increase in the urodynamic pressure profile. The above measurement is adjunctant
It demonstrates significant changes in muscle tone in the prostate region that continuously affect venous blood flow from the corpus cavernosum. Patients suffering from ED who received 100 mg of sildenafil in response to a full erection did not reach that value in their urodynamic pressure profile.

[0016]

[Table 1] Table 1 shows the effect of the combination of the drug containing sildenafil and pseudoephedrine hydrochloride. The respective structural formulas are shown below.

[0017]

Embedded image In a two compartment formulation, the concentration of sildenafil varies in the range of 10-100 mg, and that of pseudoephedrine hydrochloride is 20-60 mg.
Range.

Interestingly, without a nitro drug for MAOI (monoamine oxidase inhibitor) selected for a novel combination treatment of coronary heart disease or ED, patients with sildenafil-negative ED (EDSN) will receive 50 mg of sildenafil 4
A response rate of 7 to 10 was shown when ingesting 0 mg of pseudoephedrine hydrochloride.

Changes in the extended release of the drug by including various standard formulations improve the response rate of 8/10 patients.

Synthetic products from the same content of sildenafil and phenylephrine or pseudoephedrine showed the same rate of successful treatment. Administration of extended release of synthetic products is 8
It stabilizes the rate of successful treatment in 10/10 patients and shows an increase in intercourse rate after 12 hours.

[0021]

[Table 2] Standard treatments for ED and EDSN use 50 mg sildenafil and 40 mg phenylephrine or pseudoephedrine, with and without extended release formulation, with the intended precoital 3
Should be taken between 0 and 90 minutes. The therapeutic effect is the next 16
It disappears within 0 minutes.

According to pharmacokinetic studies, the above formulation reaches a maximum plasma (plasma) concentration 45 to 90 minutes after oral administration. Medium time for absorption is 65 + / 2
5 minutes. The change in extended release pharmacokinetics for the formulation used in the improved activity stage results in 25 + / 10 minutes.

The mechanism of action is a direct and indirect backslash in the erectile corpus cavernosum, reducing venous flow and increasing prostatic urethral muscle tone.

The physiology of the drug increases the enzyme activity of adenylate cyclase, whereas metabolic processing by phosphodiesterase is inhibited. CAMP in the corpus cavernosum
And high levels of cGMP increase the inflow of blood into the corpus cavernosum, resulting in sustained smooth muscle relaxation.

The present invention solves the above problems by combining the following drugs. 1. Combination of 10-100 mg sildenafil of the following two chemical structures with 10-60 mg pseudoephedrine hydrochloride, which are binary or their synthetic products.

[0026]

Embedded image 2. 10 which is binary or their synthetic product
Combination of １００100 mg sildenafil with 5-100 mg Midodrin having the following chemical structure:

[0027]

Embedded image 3. 10 which is binary or their synthetic product
~ 100 mg of sildenafil and the following chemical structure: alpha sympathicomi
metica).

[0028]

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[0029]

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[0030]

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[0031]

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[0032]

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[0033]

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[0034]

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[0035]

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[0036]

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[0037]

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[0038]

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[0039]

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[0040]

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[0041]

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[0042]

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[0043]

Embedded image 4. 10-100 mg sildenafil of the following chemical structure, which is a binary or synthetic product thereof:
Combination with 0.5-50 mg of Ethylephrine.

[0044]

Embedded image 5. 10-100 mg sildenafil of the following chemical structure, which is a binary or synthetic product thereof:
Combination with 0.5 to 100 mg oxilofurin.

[0045]

Embedded image 6. 10-100 mg sildenafil of the following structure, which is a binary or synthetic product thereof,
In combination with 00 mg foredrin.

[0046]

Embedded image 7. 10 which is binary or their synthetic product
A combination of 100 mg of sildenafil with 0.2 to 10 mg of ergotoxin and its dihydro derivative having the following chemical structure.

[0047]

Embedded image 8. Combination of 10-100 mg sildenafil with the following chemical structure and 0.5-200 mg norphenephrine, which are binary or synthetic products thereof.

[0048]

Embedded image 9. 10-100 mg sildenafil of the following chemical structure, which is a binary or synthetic product thereof:
Combination with 0.1-300 mg of alpha receptor antagonist.

[0049]

Embedded image 10. 10-100 mg of sildenafil, which is a binary or synthetic product of the following chemical structure, and L-arginine ginsenoid
id).

[0050]

Embedded image The chemical reaction of the above synthesis product is free of sildenafil
This is possible by approaching N, and its specific examples are given below.

[0051]

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[0052]

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[0053]

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[0054]

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[0055]

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[0056]

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[0057]

Embedded image The above reaction process refers to the international Beilstein registration number,
The novel compound bond can be confirmed by 4533683, and the chemical reaction can be confirmed by Reaction ID 1865533.

Further, biological studies of the synthetic compounds described above
Ogiso, T; Iwai, M; Tanino, T; Ikeda, K; Paku, T; H
oribe, Y; Suzuki, H; J Pharm. Sci 1988, 87 594.

In order to improve the resorption in a time-dependent manner, the following formulation is proposed. The tablets are 1) saliva, 2)
Includes various surface coatings that are resistant to gastric acid, 3) duodenal fluid, 4) intestinal fluid. In addition, tablets also have multiple skins with various components (pellets) that control the release time of the drug. Acid stable pellets are absorbed 2 hours after ingestion,
Acid-alkali resistant pellets are absorbed 4 hours after ingestion. However, the kinetic function can also include various pellets of many ingredients to ensure a tune time for the drug to take effect. List of Prior Art The following list is a list of prior art and citations that are believed to be relevant to the present specification. 1. Pfizer Institute, March 1998 (No.69 / 54
85/00/0) information on sildenafil products. 2. J. Urol. 155 p. 808-815 1998 3. J. Urol. 155 p. 913-914 19964. Int. J. Impot. Res. 9 (3) p. 115-121 1997 5. J. Urol. 160 (2) p. 389-393 199
8 6. Eur. Urol. 32 (2) p. 184-189 1997 7. Wien Med. Wochenschr. 147 (4-5) p. 102-104
1997 8. J. Urol. 158 (1) p. 234-237 1998 9. J. Sex. Maital Ther. 24 (1) 1998

Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court II (Reference) A61K 31/4985 A61K 31/4985 31/50 31/50 31/513 31/513 31/517 31/517 31/522 31 / 522 45/06 45/06 47/16 47/16 A61P 15/10 A61P 15/10 // (A61K 31/522 (A61K 31/522 31: 137) 31: 137) (A61K 31/522 (A61K 31 / 522 31:48) 31:48) F-term (reference) 4C076 AA06 AA09 AA11 AA16 AA22 AA24 AA36 AA53 AA99 BB01 CC17 DD51 FF68 4C084 AA02 AA17 AA19 AA27 AA30 MA02 MA13 MA17 MA22 MA23 MA28 MA35 MA37 MA52 MA70 NA05 NA11 ZA812 ZC541 ZC542 4C086 AA01 AA02 BC35 BC41 BC42 CB06 GA02 GA07 GA12 MA02 MA04 MA10 MA13 MA17 MA22 MA23 MA28 MA35 MA37 MA52 MA70 NA05 NA06 NA12 ZA81 ZC20 ZC54 4C206 AA01 AA02 FA14 GA07 MA02 MA12 MA33 MA48 MA37 MA37 MA43 MA37 MA57 MA37 MA57

Claims (18)

[Claims] 1. Sildenafil of 10 to 100 mg,
A second component drug in a therapeutically effective range, including an increase in circulating inward blood flow to the corpus cavernosum, simultaneously with a decrease in circulating outward blood flow from the corpus cavernosum, erectile A combination of drugs that simultaneously increase cAMP, cGMP and NO levels in isolated corpus cavernosum. 2. A drug combination according to claim 1 comprising a second component that is in the range of 1 to 100 mg phenylephrine. 3. The drug combination according to claim 1, comprising a therapeutically effective range of a second component that is alpha-sympathic mimicticum. 4. The drug combination according to claim 1, comprising a second component which is in the range of 0.5 to 50 mg of ethylenephrine. 5. A drug combination according to claim 1 comprising a second component which is in the range of 0.5-100 mg oxilofurin. 6. The drug combination according to claim 1, comprising a second component that is in the range of 1-100 mg foredrin. 7. The drug combination according to claim 1, comprising in the range of 0.2 to 10 mg ergotoxin and a second component which is a dihydro derivative thereof. 8. The drug combination according to claim 1, comprising a second component which is norfenefrin in the range of 0.5 to 200 mg. 9. The composition of claim 1, comprising a second component that is an alpha receptor antagonist in the range of 0.5-300 mg.
Combinations of the described drugs. 10. A drug set according to any one of claims 2 to 9, comprising a second component which synthesizes sildenafil via an ester or amide bond and produces a novel synthetic product from the two components. Fit. 11. The drug combination according to claim 1, comprising a second component made in a two-compartment formulation. 12. The method according to claim 1, wherein the additional components include formulations for all types of extended release standards to ensure time-correlated release of a single drug from the drug combination. Combinations of the drugs described in the item. 13. A drug combination according to any one of the preceding claims, wherein the drug combination integrates additional compounds that extend the time and modulate the release of the drug. 14. The drug combination according to claim 1, wherein the extended release of the drug is achieved without breaking the tablet or capsule. 15. L-Arginine and 10-100 mg as an orally administrable formulation or as a synthetic product with or without additional ingredients for extended release
Combinations of drugs containing sildenafil. 16. An augmentation that reduces venous drainage not only from the erect corpus cavernosum but also from the prostatic urethra and pelvic regions, and largely comprises a serotonin agonist or serotonin antagonist or apomorphine pharmaceutically active drug combination. Nitric oxide, cAMP and c in the corpus cavernosum with and without additional components for release
Drugs that simultaneously increase the tissue content of GMP. 17. An extension that reduces venous drainage not only from the erectile corpus cavernosum but also from the prostatic urethra and pelvic regions, and largely comprises a serotonin agonist or serotonin antagonist or apomorphine pharmaceutically active drug combination. Nitric oxide, cAMP and c in the corpus cavernosum with and without additional components for release
Drugs taken by Transdermal that simultaneously increase the tissue content of GMP and are as effective as the combination of drugs used. 18. The medicament according to any one of claims 1 to 17, wherein the medicament is made of rotoios, tablets, capsules, solutions, suspensions, lubricants, ointments, sprays, creams, transdermal systems, gels, liquids. Combination.