WO2012000634A1

WO2012000634A1 - Pharmaceutical composition for the treatment of erectile dysfunction

Info

Publication number: WO2012000634A1
Application number: PCT/EP2011/003145
Authority: WO
Inventors: Georg Bambach
Original assignee: Georg Bambach
Priority date: 2010-06-29
Filing date: 2011-06-27
Publication date: 2012-01-05

Abstract

Pharmaceutical product for treatment of erectile dysfunction, comprising quinine and sildenafil, vardenafil or tadalafil as the potency-enhancing active substance.

Description

PHARMACEUTICAL COMPOSITION FOR TREATMENT

OF EFFECTIVE DYSFUNCTION

The invention relates to a pharmaceutical agent for the treatment of erectile

Dysfunction, which is an integral part of impotence.

Erectile dysfunction is known to cause a patient to be unable to achieve the erection necessary for sexual intercourse.

This dysfunction can be age-related, with a significant percentage of men becoming impotent as they age.

In addition to age-related impotence, impotence may also be produced by surgical procedures such as radical retropubic prostatectomy and destruction of neurovascular bundles of nerves passing through the small basin, rectal surgery, or prostate radiation in prostate cancer.

Destruction of the nerve tracts during prostatectomy is particularly problematic unless special attention is paid to the neurovascular nerve tracts.

Finally, time-related potency disorders occur, which are also due to alcohol consumption. Thus, it has been found that the intake of alcohol leads to significant potency disorders, even if previously been taken potency increasing agents, such as sildenafil and the like.

Finally, the effect of potentiating agents, such as sildenafil, diminishes with increasing age of impotent men, so that they must take ever higher doses of sildenafil in order to achieve the desired sexual function.

Known impotence eliminating agents are called "Viagra" =

INN: SILDAFENIL commercially and from the European patents EP 463756 and

CONFIRMATION COPY 702555 known. Combination agents which treat sildenafil with a further active ingredient can be taken from WO 00/54774 and EP 1 81 1 988.

The latter patent cites numerous other patents and publications dealing with the alleviation or elimination of erectile dysfunction. However, there is still a need for such drugs which can further alleviate this problem.

Furthermore, scientific studies (J. Pharm Pharmacol Vol. 61, 2007, pp 1637) with sildenafil and u.a. Quinine at the hepatic cytochrome P450 in terms of hepatic degradation of sildenafil known. Similarly, combinations of sildenafil with other drugs are also known, which in turn are to be influenced by quinine (but without reference to sildenafil) (US 7754767 and WO 2007/070779).

The present invention has for its object to provide a further drug with which the effect of already known drugs for the relief of erectile dysfunction can be increased.

According to the teaching of the invention, it has surprisingly been found that the addition of quinine and its usual salts with acids claimed the effect of

Drugs for the relief of erectile dysfunction can increase.

definitions:

"Quinine" is the chemical compound (8S, 9R) -6'-methoxycinchonan-9-ol.

According to the invention, all isomeric forms are also covered by this general formula, preferably quinidine. Likewise, quinine is not just pure

Compound, but also the corresponding hydrate forms, such as the

Trihydrate.

By "salts with acids" are meant the following salts: salts of organic and inorganic acids, such as chloride, dichloride, hydrochloride, sulphate, disulphate, hydrosulphate and the corresponding hydrate forms for this purpose, for example hydrochloride dihydrate, sulphate dihydrate, disulphate heptahydrate, bromides, citrates, hydrocitrates, magnesium citrates, phosphates, acid phosphates, lactates, tartrates, acid tartrates and other salts of acids which are usually used pharmaceutically to form salts with acids.

The hydrochloride dihydrate and the sulfate dihydrate of quinine are preferably used according to the invention.

"Sildenafil" is the chemical compound 1 - {[3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) 4-ethoxyphenyl] sulfonyl-4-methylpiperazine and its salts with acids as defined above Sildenafil citrate is preferred.

"Tadalafil" means (6R, 12aR) -6- (1,3-benzodioxol-5-yl) -2-methyl-1,2,3,4,6,7,12,12a, octahydropyrazino [2 ', 1 ': 6, 1] pyrido [3,4-b] indole-1,4-dione.

Also, this compound can be used as a salt with an acid as mentioned above.

"Vardenafil" has the following IUPAC nomenclature: l - {[3- (5-Methyl-4-oxo-7-propyl-3,4-dihydroimidazo [5, 1-fj [1,2,4] triazine-2-one) yl) -4-ethoxyphenyl] sulfonyl} -4-ethylpiperazine.

Also, this compound can be advantageously used in the form of a salt with an acid as defined above.

The three drugs mentioned can be used in erectile dysfunction to adjust the erection for sexual intercourse during sexual arousal of the patient. The degree and duration of the erection essentially depends on how much blood flows into or drains out to the erectile tissue of the penis. The effect of the blood supply to the penis, ie to the corpus cavernosum, has been described in a large number of publications, so that it need not be discussed further here. Essential in the Control is the cyclic guanosine monophosphate cGMP, which is formed in the state of erection and cleaved by the enzyme phosphodiesterase-5 (PDE-5). This cleavage is prevented by blocking the enzyme PDE-5 by the three drugs mentioned above, so that the cGMP can freely control the erection of the penis by the inflow of blood to the corpus cavernosum.

It is already known that the effect of sildenafil can be improved or the dosage amount can be saved by adding arginine.

This was explained by the fact that arginine releases nitric oxide, which can lead to dilatation of the blood vessels.

The three aforementioned active substances sildenafil, tadalafil and vardenafil are usually used in doses of 20-25 mg, 50 mg and 100 mg according to the needs of the patient. In the present case, it has been found that the addition of quinine or quinine dihydrochloride can reduce the dosage amount by up to 50% without limiting the effect of the drug to remedy erectile dysfunction.

This applies in particular to the consumption of alcoholic beverages, since it has frequently been observed that even the intake of said active substances does not lead to the desired success. The addition of quinine appears to block this undesirable effect of alcoholic beverages, as far as erectile dysfunction is concerned.

The active ingredient quinine itself is in pharmacy more than 100 years ago known pharmaceutical agent for the control of malaria or even today for combating leg cramps. It acts as a muscle-tonic in calf cramps and is usually without effect in the fight against erectile dysfunction. Only the inventive combination of quinine or its chloride or sulfate salts with sildenafil, tadalafil and vardenafil leads to the unexpected

Increase in rectification of erectile dysfunction (ED). In summary, it can be shown that when using sildenafil, tadalafil and vardenafil alone The occurrence of these phenomena can be significantly intensified by the addition of quinine and can last for a longer period than the sole

Drug ingestion.

According to the invention, the active ingredient ratio, based on the weight of quinine / ED removal agent, is in a range from 1: 100 to 10: 1, preferably 1: 5 to 5: 1, in particular 0.5: 1 to 2.5: 1.

All weights and ratios relate to the active ingredients alone, but not to their salts with acids.

The combination of quinine / sildenafil uses 1-200 mg of quinine and 10-100 mg of sildenafil per dosage form (tablet). Quinine levels of 10-150 mg and sildenafil levels of 10-80 mg are preferred.

The following quantities of quinine and vardenafil can be used in one tablet as a dosage form: 1 -200 mg quinine and 10-100 mg vardenafil. Quinine levels of 10-150 mg and vardenafil levels of 10-80 mg are preferred.

The same abovementioned amounts can be used for the combination of quinine and tadalafil.

According to the invention, a pharmaceutically acceptable carrier may be present in the compositions. These carrier materials include binders, auxiliaries or carrier materials themselves.

The carrier is chosen according to the purpose, d. H. in the form of oral tablets, capsules, either solid-filled, semi-solid or liquid-filled, powders, oral gels, elixirs, solutions, syrups, suspensions and the like.

For oral administration in the form of tablets or capsules, the active ingredients, quinine and sildenafil may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, Magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, ethyl alcohol (for liquid forms) and the like.

Optionally, suitable binders, lubricants, disintegrating agents,

Disinfectants and coloring matters are also incorporated into the mixture.

Common binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate,

Carboxymethyl cellulose, polyethylene glycols and waxes.

Suitable lubricants are, for example, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include starch, methyl cellulose, guar gum and the like.

Disinfectants include benzalkonium chloride and the like.

Oral administration of the agent of the invention is preferred. In this respect, tablets or capsules are used.

In addition, the agents of the invention may be formulated in sustained-release form. Accordingly, coated tablets are formulated which permit sustained release of the drug.

Usually, the human oral dose containing the agent according to the invention is max. Administered 1 x / day.

The dosage form refers to an agent formulated in a delivery system, for example, tablet, capsule, oral gel, powder for dissolution or suspension in conjunction with inactive ingredients. Capsule refers to a particular container or enclosure made of methylcellulose, polyvinyl alcohol, denatured gelatins or starches. It can be used equally hard capsules and soft capsules for the purposes of the invention.

Tablet relates to a compressed or shaped solid dosage form containing the active

Contains components with appropriate diluents. The tablet is usually prepared by compressing the ingredients of the invention or granulated mixtures previously obtained by wet granulation, dry granulation or by

Compaction have been obtained.

Oral gels refer to the active ingredients and a carrier that is dispersed or solubilized in a hydrophilic semi-solid matrix.

Powders for dissolving concern powder mixtures containing the active ingredients and the carrier as well as suitable diluents which can be suspended in water or juices.

Diluents are substances that usually make up the major proportion of the dosage form. Common diluents include sugars such as lactose, sucrose, mannitol and sorbitol.

Starches can be derived from wheat, corn, rice and potatoes. As cellulose microcrystalline cellulose can be used.

The amount of such diluents in the mixture may range from about 2 to about 98 percent by weight based on the total agent.

Disintegrating substances which are added to the mixture according to the invention help in breaking up (disintegrating) the mixture and in releasing the substances. Such disintegrants include starches, cold water-soluble modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as guar, karaya, tragacanth and agar, cellulose derivatives such as methyl cellulose and

Sodium carboxymethyl cellulose, microcrystalline celluloses, optionally cross-linked, alginates, such as alginic acid and sodium alginate, lime substances, such as bentonites or effervescent mixtures. The proportion of these disintegrants in the mixture may range from about 1 to about 15 percent by weight based on the mixture.

Binders concern substances which have a binding effect on the substances usually present in granules and hold them together in the mixture.

Binders add binding forces to those already present in the mixture

Connecting means or other carrier means.

Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potato, natural gums such as acacia, gelatin and

Tragacanth, derivatives derived from algae, such as alginic acid, sodium alginate,

Ammonium calcium alginate, cellulosic materials such as cellulose, methylcellulose,

Sodium carboxymethylcellulose and hydroxypropyl methylcellulose, PVP, as well as inorganic substances such as magnesium aluminum silicate. The amount of binder in the mixture may be in a range of 2-98% by weight based on the

Total mixture are.

Lubricants are those substances that help release the finished tablet from the tablet press by reducing friction.

Suitable lubricants include metallic stearates such as magnesium stearate,

Calcium stearate or potassium stearate, stearic acid, refractory waxes and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate,

Sodium oleate, PEGs. These lubricants are usually used in the last step before compression, since they must be present on the surface of the granules. The The amount of lubricant ranges from 0.5 to about 5 percent by weight based on the total mixture.

Numerous methods for producing tablets are known and familiar to the person skilled in the art. Such methods include dry methods, such as the direct

Grouting and coarse pressing of granulated products, or wet methods or other special procedures.

"Therapeutically effective amount" means the amount of active ingredients sufficient for the desired therapeutic effect.

The amount of therapeutic dose of the active ingredients may vary depending on the condition of the patient and the route of administration. The dosage form as well as the dose and the dose frequency may vary depending on the age,

Body weight and depend on the patient himself. The dose may be administered orally in one or more dosage units.

The preparation of an agent according to the invention is explained on a tablet. This is done by compression and molding, optionally with one or more

Auxiliaries produced. Compressed tablets can be made by pressing in a machine, the active ingredients in free-flowing form, such as powders or granules, optionally mixed with a binder, lubricants, inert

Diluents, surfactants and dispersants are mixed. Molded tablets can be made by molding in a special machine by moistening a mixture of powdered active ingredients with an inert liquid diluent.

The following describes tablets made by compression or molding. For this purpose, microcrystalline cellulose, gelatin, magnesium stearate, fumed silica, cross carmelose and sodium magnesium stearate are used as auxiliaries, the tablets usually consisting of a core and a film coating. The examples mention only the active ingredients, which are then compressed with the above aids to a tablet. The amounts mentioned in the examples are each based on the pure active substance, but not on the salt of the acid.

example 1

Sildenafil as citrate 20 mg / tablet

Quinine as sulfate (Ph. Eur.) 50 mg

According to Example 1, further tablets are formulated containing 50 and 100 mg

Sildenafil and 100 or 150mg quinine included.

Example 2

Tadalafil 20 mg / tablet

Quinine as in Example 1 30 mg / tablet

As in Example 2, a 40 mg tablet of tadalafil is formulated with 20 mg of quinine.

Example 3

Vardenafil (as hydrochloride trihydrate) 20 mg

Quinine according to Example 1 10 mg

According to Example 3, the amount of vardenafil remains the same, the amount of quinine is increased to 30 mg per tablet.

Example 4

Sildenafil as in Example 1 20 mg

Quinine as in Example 1 10 mg Example 5

Sildenafil as in Example 1 20mg

Quinine as in Example 1 20 mg

Examples 6-10

Examples 1-5 are repeated in place of quinine, each with the same amount of quinidine.

In all combinations of quinine or quinidine on the one hand and Sildenafil, Vardenafü and Tadalfil it was found that on the one hand the effect of impotence reducing drugs could be increased, so that their amount could be reduced by up to 50% and on the other hand even the loss of effect of these substances (eg Consumption of alcoholic beverages) could be lifted.

Claims

claims

A pharmaceutical composition for the treatment of erectile dysfunction containing quinine or an isomer thereof, optionally as a pharmaceutically acceptable salt thereof, and a drug selected from sildenafil, vardenafum or tadalafil or a pharmaceutically acceptable salt thereof, together with a

pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1, characterized in that to pharmaceutically acceptable salts of salts of organic and inorganic acids, such as chloride, dichloride, hydrochloride, sulfate, disulfate, hydrosulfate and the corresponding hydrate forms for this purpose, for example Hydrochloriddihydrat, sulfate dihydrate, Disulfatheptahydrat, bromides, Citrates, hydrocitrates,

Magnesium conduction, phosphates, acid phosphates, lactates, tartrates, acid tartrates belong.

3. Pharmaceutically acceptable agent according to claim 1 or 2, characterized

characterized in that the weight ratio of quinine / drug is in a range of 1: 100 to 10: 1, preferably 0.5: 1 to 2.5: 1 by weight.

4. Pharmaceutical agent according to one of claims 1 to 3, characterized

in that one tablet contains as dosage form 10-100, preferably 10-80 mg sildenafil, vardenafil or Tadalfil and 1-200, preferably 10-150 mg quinine.