WO2019097278A1

WO2019097278A1 - Pharmaceutical composition for erectile dysfunction that includes an active substance which prevents pain

Info

Publication number: WO2019097278A1
Application number: PCT/IB2017/057189
Authority: WO
Inventors: Ciro Eduardo SILVA RIAÑO
Original assignee: CAICEDO PINTO, David
Priority date: 2017-11-16
Filing date: 2017-11-16
Publication date: 2019-05-23

Abstract

The present invention relates to compositions and the dosage form thereof for treating sexual dysfunction in pain-sensitive humans. More specifically, the invention relates to the use of compositions comprising lidocaine hydrochloride as a fast and long-lasting pharmacological action as an anaesthetic for pain-sensitive individuals during the application of active substances for treating male erectile dysfunction based on the active substances alprostadil, phentolamine, papaverine and atropine, as pharmaceutically acceptable salts thereof, on an aqueous injectable pharmaceutical support comprising disodium EDTA, an organic acid, a sulfite salt and an inorganic chloride salt to additionally prevent irritation. The subject matter and purpose of this invention comprises a pharmaceutical composition for erectile dysfunction which also includes an active substance for pain prevention.

Description

PHARMACEUTICAL COMPOSITION FOR ERECTILE DYSFUNCTION

WHAT INCLUDES AN ACTIVE THAT PREVENTS PAIN

D E S C R I P C I O N

OBJECT OF THE INVENTION.

The present invention relates to compositions and their dosage form for the treatment of sexual dysfunction in pain sensitive humans.

More particularly, this invention relates to the use of compositions comprising lidocaine hydrochloride as a fast and long-lasting pharmacological action as an anesthetic for pain-sensitive individuals during the application of active ingredients for the treatment of male erectile dysfunction based on the active ingredients of alprostadil. , phentolamine, papaverine and atropine in their pharmaceutically acceptable salts on an aqueous injectable pharmaceutical carrier comprising disodium EDTA, an organic acid, a sulfite salt and an inorganic salt in its chloride form to further prevent irritation. The object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction that also includes an active that prevents pain.

FIELD OF THE INVENTION.

The present invention relates to compositions and their dosage form for the treatment of sexual dysfunction in pain sensitive humans. More particularly, this invention relates to the use of compositions comprising lidocaine hydrochloride as fast and long-lasting pharmacological action as an anesthetic for pain-sensitive individuals during the application of active ingredients for the treatment of male erectile dysfunction based on the active ingredients of alprostadil, phentolamine, papaverine and atropine in their pharmaceutically acceptable salts on an aqueous injectable pharmaceutical carrier. comprising disodium EDTA, an organic acid, a sulfite salt and an inorganic salt in its chloride form to further prevent irritation.

BACKGROUND OF THE INVENTION

The normal erection takes place as a result of a coordinated vascular episode in the penis. This is normally triggered in the nervous system and consists of the vasodilatation and relaxation of the smooth muscle in the penis and its contribution to the arteries. The arterial inflow produces the dilation of the substance of the cavernous body. The venous outlet is occluded by this dilation, which allows high blood pressures maintained in the penis sufficient to produce and maintain rigidity. The muscles of the peritoneum also help to create and maintain the rigidity of the penis. The erections are produced mainly in the nervous system by thoughts, fantasies and / or sexual stimulation and can be reinforced locally by reflex mechanisms.

Impotence or male erectile dysfunction is defined as the inability to reach and maintain an erection sufficient for a satisfactory sexual act and intercourse. Impotence in a given case can come from psychological disorders, physiological abnormalities in general, neurological disorders, hormonal deficiencies or a combination of the above.

As used in the present description, psychogenic impotence is defined as functional impotence without an organic base functional determinant and apparent.

It can be characterized by the inability to have an erection in response to some stimuli. The current diagnosis and professional thinking about the etiology of male erectile dysfunction have focused on the severity of the disease, that is, mild, moderate and severe. A diagnostic method employs oral medication as a means of distinguishing dysfunctional patients who may respond to oral medications from those who need more direct intervention, i.e., such as intracavernous injection or surgery.

Currently the treatment of dysfunction is commonly done orally, with medications such as sildenafil, which is a selective inhibitor of phosphodiesterase with positive results, but with systemic side effects (headache, easy reddening, indigestion). among others) and the waiting for the drug to reach the action site after its systemic distribution. It also carries all the problems associated with blood pressure, since in all patients it can not be administered.

During normal erections of the penis, when the inflow of blood to the corpus cavernosum occupies the sinusoidal spaces, the trabecular tissue compresses the small cavernous veins against the thick fibrous tissue that surrounds the body to maintain an erection. To mediate these changes in blood circulation, nitric oxide is released from parasympathetic postsynaptic neurons and, to a lesser extent, endothelial cells and a-adrenergic neurons are inhibited in arterial and trabicular smooth muscle. Nitric oxide, which diffuses easily, stimulates the increased formation of cyclic guanosine monophosphate (GMP) in the corpus cavernosum by guanylate cyclase to relax smooth muscle cells. In that sense, the technique has revealed the use of papaverine to improve blood flow in patients with circulation problems and works by relaxing the blood vessels so blood can flow easily through the corpus cavernosum of the penis. In that sense, an effective solution, is the intracavernosal administration that allows an immediate interaction of the assets and therefore its effective treatment. Alprostadil is an E1 protagladine (PGE1, alprostadil) that belongs to the family of eicosanoids, which represent a large group of oxygenated metabolites of polyunsaturated 20 fatty carbon acids, including prostagladins, thromboxanes, leukotrienes, lipoxins, epoxiecosatrienic acids, hepoxilins, leukotrienes, lipoxins, epoxieicosatrienic acids, hepoxilins and other compounds. The natural precursor of eicosanoids is the free arachidonic acid that binds to phospholipids of the adherent membrane and is released by the enzyme phospholipase A2. Physiological eicosanoids that exist in almost all tissues and are shown to be modulators or mediators of a considerable number of physiological processes. All these effects are mediated eicosanoids through specific cellular receptors, which have been identified in platelets and smooth muscle cells. In the field of urology and andrology, they are used especially in the management of impotence.

In this regard, suitable supports have also been defined for the parenteral delivery of the active ingredients against male erectile dysfunction, based on PGE1 and others. For example, patent CO / 2013/236844, of the same inventors herein, relate a pharmaceutical composition for erectile dysfunction comprising for a volume of 3.35ml_, the active or pharmaceutically acceptable salts thereof of alprostadil in an amount of 0.0013%; papaverine in an amount of 0.007%; phentolamine in an amount of 0.116%; and, atropine in an amount of 0.033%, wherein said composition additionally comprises an aqueous pharmaceutical carrier effective against irritation including disodium EDTA in an amount of 0.0014%; methyl paraben in an amount of 0.01% and propyl paraben in an amount of 0.001 g; sodium bisulfite in an amount of 0.05 g; sodium chloride in an amount of 0.001 g; and, 98% ethanol in an amount of 5%. In that This sense has been approved by virtue of the support that it shows through studies, the possibility of preventing irritability and therefore the consequent pain, however, it has been shown that the pain even when the treatment against erectile dysfunction is adequate, is still significant.

Although in the market there are already compositions containing alprostadil, phentolamine (in their salts) such as in US Patent No. US6124461 to Shoemaker, these are found with an emulsifier which can be polyethylene glycol, its doses are not easily standardized and have a pH between 4.5-5.2; producing irritation at the time of administration to the patient. Other formulations such as US application No. US20040102475 of Podolski, use as buffer arginine or glycine with mannitol and benzyl alcohol, with a pH between 3-7 and preferably 3-5, producing irritation and pain to the patient. However, these developments of the new compositions of intracavernosal injection, produces certain pains in sensitive individuals, making it necessary to seek new compositions for erectile dysfunction that also includes an asset that prevents pain.

Therefore, the object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction that also includes an active that prevents pain.

OBJECT OF THE INVENTION.

Accordingly, a first object of the present invention is to avoid the disadvantages of prior art. Particularly, the main object of the present invention is to create a pharmaceutical composition for erectile dysfunction which also includes an active which prevents pain.

Another no less important object is that the formulation is non-irritating during application. The present invention meets these needs and provides other advantages related to the administration of the product, which includes an anesthetic, thus avoiding pain during its application.

The novel features that are considered as the basis of the invention are set forth in particular in the appended claims and the additional advantages thereof, will be better understood on the following detailed description with the preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

More particularly, this invention relates to the use of compositions comprising lidocaine hydrochloride as a fast and long-lasting pharmacological action as an anesthetic for pain-sensitive individuals during the application of active ingredients for the treatment of male erectile dysfunction based on the active ingredients of alprostadil. , phentolamine, papaverine and atropine in their pharmaceutically acceptable salts on an aqueous injectable pharmaceutical carrier comprising disodium EDTA, an organic acid, a sulfite salt and an inorganic salt in its chloride form to further prevent irritation.

The object and purpose of the present invention comprises a pharmaceutical composition for erectile dysfunction that also includes an active that prevents pain.

For the effect, according to the present invention, it has been highlighted the fact of including a local anesthetic, which can be applied intravenously in the cavernous body of the penis. The concentration of the anesthetic to be used according to the present invention is preferably order of 0.009 mg to 0.1 mg, preferably 0.01 mg per milliliter in the dosage form.

Said anesthetic according to the present invention comprises:

1 - Lidocaine hydrochloride C14.H22N2O

This anesthetic has a pharmacological, rapid, long-term action in individuals sensitive to local anesthetics of this type. Lidocaine hydrochloride is rapidly absorbed after parenteral administration, since no constrictor vessel is administered in its formulation, to allow rapid de-alkylation in the liver by the action of mixed-function oxidases to monoethylglycine xylidine, since about 75% of the glycine xylidine is secreted in the urine as the metabolite 4-hydroxy-2-dimethylalanine.

The administrative dose is low and its function is to lower the pain in the area of the application, so that it allows to maintain the erection since it exerts a vasodilator action. Being such a low dose and local action, decreases the adverse effects that may occur when the doses are high that can cause drowsiness, dizziness, buzzing and can significantly affect the central nervous system of the individual. The clinical application of lidocaine hydrochloride has great amplitude as a local anesthetic.

According to the present invention, the amount applied to the individual must be low, taking care to avoid the lack of sensitivity and taking care of the vital functions of the penis.

The advantages according to the present invention, is that it allows to modify neurophysiological reactions such as pain and stress that is suffered when a general anesthesia is performed. Infiltration anesthesia is the direct application of an injection that contains the local anesthetic in the tissues, the recommended concentration depends on the age, the weight of the individual and the pharmacological action sought.

The fundamental advantage of the formulation of the present invention is that it includes infiltration anesthesia achieving satisfactory general bodily functions without strong secondary problems in the individual because the lidocarna hydrochloride is soluble in water.

The composition of the present invention seeks a locally injectable pharmaceutical form in the penis, so that its use is allowed in patients with some level of diabetes, heart problems and that due to their age or physical condition does not allow a normal erection.

Based on the present invention it is possible to decrease the pain of the application in the penis, without interfering with the main action in the treatment of erectile dysfunction.

According to the present invention, it also relates to compositions containing the active ingredients useful in the treatment of male erectile dysfunction, such as: 2-prostaglandin PG1 C2OH ₃₄ 0 ₃

3-Papavehna HCI C ₂ oH ₂ N04

4-Phentolamine Mesylate CI ₇ H ₁₉ N30CH403S

5-Atropine (form CIS AND TRANS) C17H23NO3

These assets have a high speed of action, are not irritating and have an effect of greater duration compared to other compositions already existing according to the prior art. According to the present invention, preferably the compositions are for injectable use.

Papaverine is a potent and non-specific, muscle relaxant, and is a non-selective phosphodiesterase cAMP inhibitor of phosphodiesterase, causing penile vasodilation. It has a relatively short half-life (1-2 hours) and is metabolized in the liver. After intracavernous injection, the maximum serum concentration is several times less than after the extracavernosal injection. A meta-analysis of the main studies published on the use of reports of papaverine that is effective in 53% of men with erectile dysfunction according to the doctor for the ability to produce an erection of sufficient rigidity for the sexual act.

For its part, phentolamine is a competitive inhibitor of a1 and a2-adrenergic receptors and is believed to act by inhibiting arterial constriction in the corpus cavernosum. Its main salt to be used is the Mesylate.

Atropine sulfate has been used as an intracavernous injection. At low doses (10 sup -8 m), this anticholinergic agent decreases the inhibition of adrenergic and cholinergic excitation of the non-adrenergic, non-cholinergic neuroeffector systems that control neurogenic smooth muscle relaxation of the smooth muscle. However, in high pharmacological doses (10 sup -3 m.) Of atropine sulfate causes the release of endothelium-derived relaxing factor.

Thus, the present invention is providing immediate action compositions for intracavernosal, intraurethral local use without causing pain in addition to irritation, as well as physicochemically stable compositions.

The compositions further comprise an aqueous pharmaceutical carrier comprising an organic acid, a sulfite salt, disodium EDTA and an inorganic salt in its chloride form and with a final pH between 3-8, preferably between 4-7. The compositions may be present in liquid, solid form (lyophilized powder) or arranged in a pharmaceutical carrier such as a hydrophilic gel or ointment or a cream base of an acrylic acid polymer such as carbopol®.

The manufacturing process comprises the following stages of mixing the condoms with the active ingredients and their subsequent cold filtration for the respective packaging or lyophilization of the product.

The compositions of the present application are in polyvalent form, where they are used as drugs: and in their salts pharmaceutically acceptable, solvated (water, alcohols) or not solvated, hydrated or not hydrated. The active ingredients can also be found in their base form.

Pharmaceutical composition for erectile dysfunction according to the present invention comprises for each 1 mL of sterile water CSP, the concentration of the anesthetic of lidocaine hydrochloride can comprise doses between 0.1 mg to 0.001 mg, preferably between 0.008 mg to 0.05 mg and more preferably from 0.01 mg to 0.02 mg. The dosage form also comprises for the same proportion of each 1 mL of sterile water CSP, the active or pharmaceutically acceptable salts thereof of alprostadil or protaglandin E1 in an amount for the 60% concentration of 0.045 mg to 0.050 mg, preferably 0.048. mg, for the 40% concentration of 0.030 mg to 0.035 mg, preferably 0.032 mg and for the 20% concentration of 0.010 mg to 0.020 mg, preferably 0.016 mg. For its part, papaverine is present for the same formulation in an amount of 0.5 mg to 0.9 mg, preferably 0.7 mg; phentolamine in an amount of 1.0 mg to 1.9 mg, preferably 1.5 mg; and, atropine in an amount of 1.0 mg to 1.5 mg, preferably of 1.1 mg. Said composition additionally comprises an aqueous pharmaceutical carrier.

The preferred salts are for each of the active ingredients; Papaverine hydrochloride, phentolamine hydrochloride or mesylate and Atropine sulphate hydrated or unhydrated.

The compositions further comprise an aqueous pharmaceutical carrier comprising disodium EDTA; sulfite salts, among which are: polyols or alcohols 98% ethanol. sodium sulfite, magnesium sulphite or sodium metabisulfite and an inorganic salt in magnesium or sodium metabisulfite and an inorganic salt in the form of potassium chloride, sodium chloride, magnesium chloride or calcium chloride. The compositions may further comprise other pharmaceutically acceptable ingredients such as preservatives, antioxidants, tonicity agents, among others. The final pH is between 3-8, preferably between 4-7. It additionally comprises an aqueous pharmaceutical carrier which for the formulation illustrated above for 1 mL of sterile water CSP, includes disodium EDTA in an amount of 4 mg to 5 mg, preferably 4.2 mg; Sodium methyl paraben in an amount of 8 mg to 9 mg, preferably 8.3 mg and sodium propyl paraben in an amount of 0.70 mg to 0.90 mg, preferably 0.83 mg; sodium metabisulfite in an amount of 3 mg to 6 mg, preferably 5 mg; and, sodium chloride in an amount of 7 mg to 12 mg, preferably 9 mg. The pharmaceutical composition as defined above, comprises sterile water CSP in a proportion to form an injectable pharmaceutical form.

The treatment methods comprise intracavernous, intraurethral administration, in the concentrations previously contemplated for administration at time intervals: every 6, 8, 12, 24 or 48 hours.

Thus, according to the formulation of the present invention, for a 1 milliliter of sterile water C.S.P the formulation will comprise the ratio of Table 1, for each PGE1 concentration of 20%, 40% and 60%.

Table 1.

Example: Injectable solution. This example illustrates the preparation of dosage forms for intracavernous administration of a lidocaine hydrochloride pool and the active ingredients of alprostadil, phentolamine, papaverine and atropine in their pharmaceutically acceptable salts on an aqueous injectable pharmaceutical carrier to prevent pain and irritation.

Comparative test was carried out with patients with the different formulations defined in the present invention according to the concentration of 20%, 40% and 60% of alprostadil to measure the irritability and pain compared with the compositions of the market and those of the present invention with the composition described above intracavernosa. This patient study includes information received by the Q.F.U.N. Ciro H Silva R. Card No. 04011712809904271 under the reference "Report on the master injectable product for male impotence". Said report comprises:

Patient No.1:

The young patient of 45 years. He informed that when applying the product in the cavernous part of the penis, he achieved the erection of the penis, but he did not present pain after injection that causes its application. During intercourse and after patient No. 1, there is no pain at the point of injection. The concentration of lidocaine did not affect the erection and had a normal ejaculation. As a patient, he recommends it for people who They may have severe pain in the first application or in later applications.

Patient No.2:

The patient is older than 65 years and is a user of male impotence products more than six years ago. It was changed to the injectable product because it does not present an increase in the cardiac heart rate, it does not present sweating. In the application with lidocaine did not present pain after its application and during intercourse I do not present any pain. I do not affect his erection and I present a normal ejaculation.

Patient No.3

The patient is older than 58 years and is a user of male impotence products more than three years ago. He switched to the injectable product because he has heart problems and the products on the market affect him. In the application with lidocaine did not present pain after its application and during intercourse I do not present any pain. I do not affect his erection and I present a normal ejaculation.

In that order of compositions, the preferable composition according to the present invention comprises an injectable pharmaceutical composition for erectile dysfunction which comprises for each 1 ml_ of sterile water CSP, the concentration of the anesthetic of lidocaine hydrochloride preferably of 0.01 mg in combination with the pharmaceutically acceptable salts of alprostadil or protaglandin E1 in an amount for the 60% concentration of 0.048 mg, for the 40% concentration of 0.032 mg and for the 20% concentration of 0.016 mg; papaverine present for the same formulation in an amount of 0.7 mg; phentolamine in a amount of 1.5 mg; atropine in an amount of 1.1 mg; and as aqueous support, disodium EDTA in an amount of 4.2 mg; sodium paraben, in an amount of 8.3 mg and sodium propyl paraben in an amount of 0.83 mg; sodium metabisulfite in an amount of 5 mg; and, sodium chloride in an amount of 9 mg.

Only some preferred embodiments of the invention have been illustrated by way of example. In this regard, it will be appreciated that the compositions and their dosage form for the treatment of sexual dysfunction in pain-sensitive humans, as well as the configurative arrangements can be chosen from a plurality of alternatives without departing from the spirit of the invention according to following claims.

Claims

1. Injectable pharmaceutical composition for erectile dysfunction

CHARACTERIZED BECAUSE it comprises for each 1 ml_ of sterile water C.S.P .: lidocaine hydrochloride in an amount of 0.01 mg, in combination with protaglandin E1 or its pharmaceutically acceptable salts in a concentration of 60% with an amount of 0.048 mg; papaverine in an amount of 0.7 mg; phentolamine in an amount of 1.5 mg; and, atropine in an amount of 1.1 mg; wherein the composition additionally comprises an aqueous pharmaceutical carrier.

2. Injectable pharmaceutical composition for erectile dysfunction

CHARACTERIZED BECAUSE it comprises for each 1 ml_ of sterile water C.S.P .: lidocaine hydrochloride of 0.01 mg, in combination with protaglandin E1 or its pharmaceutically acceptable salts in a concentration of 40% with an amount of 0.032 mg; papaverine in an amount of 0.7 mg; phentolamine in an amount of 1.5 mg; and, atropine in an amount of 1.1 mg; wherein the composition additionally comprises an aqueous pharmaceutical carrier.

3. Injectable pharmaceutical composition for erectile dysfunction

CHARACTERIZED BECAUSE it comprises for each 1 ml_ of sterile water C.S.P .: lidocaine hydrochloride of 0.01 mg, in combination with protaglandin E1 or its pharmaceutically acceptable salts in a concentration of 20% with an amount of 0.016 mg; papaverine in an amount of 0.7 mg; phentolamine in an amount of 1.5 mg; and, atropine in an amount of 1.1 mg; wherein the composition additionally comprises an aqueous pharmaceutical carrier.

4. Injectable pharmaceutical composition for erectile dysfunction of the 1, 2 or 3 characterization BECAUSE the aqueous pharmaceutical support comprises disodium EDTA in an amount of 4.2 mg; sodium paraben, in an amount of 8.3 mg and sodium propyl paraben in an amount of 0.83 mg; sodium metabisulfite in an amount of 5 mg; and, sodium chloride in an amount of 9 mg.