WO2014119985A2

WO2014119985A2 - Pharmaceutical composition comprising a selective phosphodiesterase enzyme inhibitor in oral gel form

Info

Publication number: WO2014119985A2
Application number: PCT/MX2014/000028
Authority: WO
Inventors: Miguel Ángel GARCIA PÉREZ; Gabriel MARCELÍN JIMÉNEZ; Concepción Albina VÁZQUEZ FLORES; Ricardo David ÁVILA CEDILLO; Alionka Citlalli P. ANGELES MORENO; Octavio CARO RODRÍGUEZ
Original assignee: Garcia Pérez Miguel Ángel
Priority date: 2013-01-31
Filing date: 2014-01-28
Publication date: 2014-08-07
Also published as: WO2014119985A3; MX2013001279A

Abstract

The invention concerns a novel stable, semi-solid composition for oral administration comprising at least one selective phosphodiesterase enzyme inhibitor and/or at least one pharmaceutically acceptable excipient. Once administered orally, the composition maintains sustained release, doubling the length of time for which the active ingredient remains in the organism and prolonging the therapeutic effect of the selective phosphodiesterase enzyme inhibitor. The semi-solid composition can be used for selective phosphodiesterase enzyme inhibition, for example, in a non-restrictive manner, for controlling or treating erectile dysfunction, with a therapeutic effect lasting for up to eight hours.

Description

PHARMACEUTICAL COMPOSITION WITH A SELECTIVE INHIBITOR OF THE

ENZYM PHOSPHODESTERASE IN THE FORM OF ORAL GEL

FIELD OF THE INVENTION

The present invention relates to a novel stable semi-solid composition for oral administration comprising at least one selective phosphodiesterase enzyme inhibitor and / or at least one pharmaceutically acceptable excipient. The composition once administered orally, maintains a sustained release, doubling the time of permanence of the active ingredient in the body and prolonging the therapeutic effect of the selective phosphodiesterase enzyme inhibitor.

The use of the semi-solid composition is for the selective inhibition of the phosphodiesterase enzyme for example in a non-limiting manner, for the control or treatment of erectile dysfunction, with a therapeutic effect of up to 8 hours. BACKGROUND

Sexuality is the set of physical, psychological, functional, social and cultural attributes that identify sex itself and its sexual behavior, whether or not they are related to sexual organs or procreation. The exercise of sexuality is one of the most basic and vital expressions of the human species. It evolved with man, from brutality and pleasure in primitive times, to the most sophisticated eroticism of the contemporary world; mainly from the discovery and massive use of methods for birth control.

According to the Mexican Association for Sexual Health AC, sexual dysfunctions are a series of syndromes in which the erotic processes of the sexual response are undesirable for the individual or for the social group and that occur recurrently and persistently . Among the determinants of these dysfunctions are: the biological constitution, misinformation, the psychological nature, the nature of the couple's relationship and the social and cultural environment, dysfunctions of physiological origin, among others.

Some of the sexual dysfunctions known today are: hypoactive sexual desire syndrome, male erectile dysfunction, female anorgasmia syndrome, premature ejaculation syndrome, vaginismus syndrome, sexual avoidance syndrome and sexual distress disorder (sexual phobia), delayed ejaculation, orgasmic insensitivity, dyspereunia, female anorgasmia, orgasmic insensitivity, among others.

Male erectile dysfunction is defined as the inability of a man to obtain a penile erection as part of a complete multifaceted process of male sexual function, thus removing the sine qua non condition from sexual life and giving equal importance to other aspects of male sexual behavior (Álvarez E, 2009). It has been shown that erectile dysfunction (ED) is a frequent pathology that affects the quality of life, not only of the man who suffers from it, but also of his partner and therefore of his environment.

In a recent review of epidemiological studies on erectile dysfunction suggests that approximately 5% to 20% of men have moderate to severe erectile dysfunction. The difference in the reported incidence is probably due to ^c differences in the methodology and to the ages and socioeconomic status of the study populations. Erectile dysfunction has risk factors in common with cardiovascular disease, such as lack of exercise, obesity, smoking, diabetes, hypercholesterolemia and metabolic syndrome. The risk of suffering from erectile dysfunction can be reduced by modifying these risk factors, especially with exercise or weight loss. - Another risk factor is radical prostatectomy (PR) in any of its forms (open, laparoscopic or robotic). , due to the risk of damage to the cavernous nerves, poor oxygenation of the cavernous bodies and vascular insufficiency. About 25-75% of men who undergo PR experience post-operative erectile dysfunction. Patients who are candidates for radical proteactetomy with nerve conservation, by preserving the cavernous nerves, the recovery of erectile function after PR can be guaranteed (Wespes E, 2009).

To maintain a normal erection, the integrity of the vascular, neurological, endocrinological and psychological systems is needed. The different phases of penile erection induced by sexual stimulation are called the male sexual cycle and consist of:

Phase I flaccidity: Sympathetic tone is predominant, there is arterial flow and muscle contraction trabecular of the corpora cavernosa with low blood volume in the sinusoids of the corpora cavernosa.

Phase II of filling or tumescence: in response to parasympathetic stimulation, blood flow is increased by arterial dilation, the resistance of sinusoidal spaces is decreased by relaxation. When the sinusoids expand, there is an understanding of the intracavernous and subalbugineous venous flexes retaining blood inside the cavernous bodies causing penis expansion and complete erection.

Phase III of complete erection: the pressure of the bodies is slightly lower than the systolic pressure and the penis is fully expanded and the blood flow in and out is low (approximately 3-5 mL / min).

Phase IV of rigid erection: intracavernous pressure can reach systolic pressure several times due to the compression of the ischiocavernosus muscles at the base of the penis and the total closure of the arterial and venous flow. This phase occurs during intercourse and masturbation when direct stimulation of the penis generates the cavernous bulb reflex. If the stimulation is interrupted or there is muscular fatigue, the intracavernous pressure drops and the penis returns to the full erection phase.

Phase V Ejaculation: is induced by rhythmic contractions of the ischiocavernosus muscles and especially Cavernous bulb that propel semen through the urethral lumen.

Phase VI of detumescence: the return of muscle tone after orgasm or the cessation of stimulation induces arterial concentration, the opening of venous circuits and detumescence occurs by progressive escape of blood from the corpora cavernosa.

The phases described explain why the erection is an essential vascular phenomenon that depends on the balance between the blood supply where the erection depends on a central control and a peripheral control, in the central control the most important organ is the brain: the stimuli Sexuals are integrated into the hypothalamus and the message is transmitted, to the penis, via the spinal cord and sacral center of the erection.

Erection is continually inhibited by sympathetic basal tone, anti-erection messages are mediated by norepinephrine and sympathetic stimuli. Pro-erection messages are mediated by dopamine and descend by spinal cords and stimulate the parasympathetic. There is therefore a constant balance between pro and antirection factors and when appropriate sexual arousal occurs, parasympathetic activity increases and sympathetic activity decreases. Peripheral erection control It depends on the balance between neuronal and local factors.

The neuronal elements with contractile action are norepinephrine and neuropeptide and, which act on the cells of the arterial and trabecular smooth muscle of the corpora cavernosa.

The relaxing action factors on smooth muscle are acetylcholine (AC), nitric oxide (ON), released by the action of AC, vasoactive intestinal polypeptide (PIV) and CGRP (its English name: calcitonin gene related peptide). Local contractile action factors are endothelin 1 and prostaglandin F2 alpha. The relaxing ones are ON and prostaglandin El (PGE1) (Álvarez E, 2009).

Various factors are involved in erectile function

(physical and psychic) so it is classified as:

Organic: for vascular, neurological, hormonal or local lesions.

Psychogenic: by central inhibition of the erectile mechanism without physical injuries.

Mixed: when the presence of an organic anomaly does not imply that it is the only reason, nor the exclusion of concomitant psychogenic causes.

Some risk factors are: age, diabetes, cardiovascular disease, smoking, secondary to drugs, secondary to drug use, endocrine abnormalities, penile abnormalities, chronic renal failure, liver failure, neurological pathology, COPD, affective disorders, regional surgery or trauma in that area, among others.

To perform a diagnosis of erectile dysfunction, an international index test for erectile dysfunction is performed, which is simple, fast, with good sensitivity and specificity; It allows classifying ED as mild, moderate and severe. Afterwards, the history of the problem or sexual history is reviewed where the start date, form of establishment is established, questions are asked about penile stiffness, maintenance of the penis, presence of morning, nighttime erections or with various stimuli, to determine if it is organic or psychogenic . In addition, the medical history is reviewed, to determine risk factors.

The physical examination through the exploration of the cardiovascular system, neurological examination, determination of endocrinopathies, hypogonadism, genital disorders or prosthetic pathology.

Finally, complementary examinations are carried out through laboratory tests such as lipid profile, glycemia, morning total testosterone, etc. (Campillos T, 2003). Psychotherapy is used for treatment, and drug therapy, within which there are those that are administered orally, those that are injected directly into the penis or those that are inserted into the urethra through the tip of the penis.

Oral medications include phosphodiesterase inhibitors, testosterone, dopamine and serotonin agonists, yohimbine hydrochloride and trazodone.

Injectable medications, which go directly into the penis are papaverine hydrochloride, phentolamine and alprostadil; which widen the blood vessels allowing the penis to fill with blood, however, these medications can cause unwanted side effects, which include a persistent erection (known as priapism) and scars.

A system for inserting an alprostadil granule into the urethra by means of a prefilled applicator to deposit the granule about an inch into the urethra. It is in the form of a muse and from 8 to 10 minutes later its administration begins the erection that can last from 30 to 60 minutes; however the most common side effects are pain in the penis, testicles and area between the penis and the rectum; sensation of heat or burning in the urethra; redness due to increased flow blood to the penis; and mild bleeding or urethral spots.

Phosphodiesterase inhibitor oral medications include sildenafil, vardenafil hydrochloride and tadalafil.

In March 1998, the Food and Drug Administration (FDA) approved in the United States sildenafil, the first medication to treat erectile dysfunction (Nkudic, 2009).

The Erection Firmness Scale was originally developed by Dr. Irwin Goldstein for the use of Viagra® clinical studies, with the objective of providing an additional evaluation of its effectiveness. Currently, four degrees of firmness are handled that have been integrated on a scale known as the Goldstein index. This scale differentiates the degrees of erection ranging from 1 to 4, provides a "quantitative" measure of the degree of erection firmness as well as the effectiveness of the treatment of patients with erectile dysfunction. The grades described in this scale are: Grade 1, where the size of the penis increases, but is not rigid, which prevents penetration; Grade 2, where the penis is stiff, but not enough for penetration; Grade 3, where the penis is firm enough for penetration, but not completely rigid; and, Grade 4, where the penis is completely firm and rigid.

Sildenafil is a selective inhibitor of isoenzyme phosphodiesterase type 5 (PDE5), one of the 7 phosphodiesterase isoenzymes that have been identified. The PDE5 isoenzyme (selectively inhibited by sildenafil) predominates in human cavernous bodies, its function is to selectively degrade the cGMP (cyclic guanosine monophosphate) of that tissue. This cGMP relaxes the smooth muscle of that structure, before and during intercourse in order to initiate and maintain the physiological erection of the penis by blood engorgement.

During normal sexual stimulation or excitation, in addition to the cholinergic parasympathetic component, the endothelium of the blood vessels of the corpora cavernosa releases nitric oxide that diffuses into the nearby smooth muscle to induce relaxation. In human cavernous bodies, the function of nitric oxide is to activate the enzyme guanylate cyclase. For its part, the enzyme guanylate cyclase acts by increasing the concentration of cGMP. In sum, in patients with ED, sildenafil selectively inhibits the PDE5 isoenzyme, protecting from the catabolism the cGMP produced by guanylate cyclase activated by nitric oxide that is released to sexual stimulation. Thus, cGMP will have high levels in the bodies Cavernous, which will make smooth muscles relax, engorgement and erection increased and prolonged for successful intercourse. In patients, the mechanism of sildenafil to produce an erection will only be possible if the process begins with sexual stimulation that releases enough nitric oxide, activates guanylate cylase and produces enough cGMP. Previously administered (1 hour) sildenafil will avoid degrading cGMP by inhibiting PDE5. It is administered orally, easily released and quickly absorbed on an empty stomach. It reaches maximum plasma concentrations in 30 to 120 minutes (average 60 min). Its intake with high fat foods reduces absorption by 29%. Its main metabolite circulates linked to plasma proteins in 96%. The volume of distribution of 105 L indicates tissue entry. It does not accumulate in single daily doses. The half-life of both is 4 to 5 hours. The duration of the effect (erection) reaches 4 hours, but decreased compared to the effect at 2 hours.

It is biotransformed by the cytochrome P450 (CYP450) of the hepatic microsomal system or fraction, especially CYP3A4 and CYP2C9 isozymes (Álvarez P, 1999).

In the state of the art, postphodiesterase inhibitors are commonly found for oral administration in the form of tablets, on the other hand, in the form of semi-solid, compositions are found in the form of an aqueous solution of sildenafil that is prepared in the form of solution, suspension, emulsion with a concentration of 1 to 200 mg / mL and pH between 2.5 and 5.0 mainly for injectable application (WO2005077374), a method and composition for the treatment of Erectile dysfunction consisting of administering an effective amount of sildenafil locally, the * composition is prepared in the form of a gel, ointment, cream or lotion (US6037346), among others.

OBJECT OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration in the form of semi-solid or liquid containing at least one selective phosphodiesterase enzyme inhibitor and / or its pharmaceutically acceptable salts, in combination with one more pharmaceutically acceptable excipients. The object of the present invention is to provide a composition that carries out the release of the active ingredient in a sustained manner allowing to maintain a therapeutic effect for a longer time than that obtained by oral administration in another pharmaceutical form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1. Plasma concentration graph (ng / mL) vs sampling time (hour.s) in loglO semilogarithmic scale after administration of the composition in the form of an oral gel and in the form of tablets to the volunteer number 1.

FIGURE 2. Graph of plasma concentration (ng / mL) vs sampling time (hours) in loglO semilogarithmic scale after administration of the composition in the form of an oral gel and in the form of tablets to the volunteer number 4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel oral pharmaceutical composition in the form of a liquid and / or semi-solid that contains a therapeutically effective amount of at least one selective phosphodiesterase enzyme inhibitor and / or its pharmaceutically acceptable salts, in combination with one or more solvents and / or co-solvents and / or one more pharmaceutically acceptable excipients.

For purposes of the present invention, the phosphodiesterase enzyme selective inhibitory agent is selected from zaprinast, sildenafil, vardenafil and tadafil, its pharmaceutically acceptable salts, derivatives, hydrates, prodrugs, polymorphs, amorphous and / or combinations thereof.

The therapeutically effective amount of the phosphodiesterase enzyme selective inhibitor and / or its pharmaceutically acceptable salts, useful for the purpose of the present invention is in a range of 2mg to 200mg or in a weight ratio to the total weight of the composition in a range of 0.002% p / p to 20% p / p-

The novel composition is characterized by having at least one solvent and / or co-solvent where at least a substantial part ⁴ of at least one selective phosphodiesterase enzyme inhibitor agent is dissolved or solubilized, said solvent and / or co-solvent can be organic, inorganic or combinations of both in a proportion such that the active ingredient is partially or totally dissolved. The function of the solvent and / or co-solvent, in addition to dissolving or solubilizing, is to serve as a vehicle for the phosphodiesterase enzyme selective inhibitor that optionally incorporates one or more pharmaceutically acceptable excipients.

The solvent and / or co-solvent useful for the present composition consists, in a non-limiting manner, of one or more excipients selected from the following group: glycerin, water, n-butanol, propylene glycol, 1,3-butandioi, oleic acid, linoleic acid , soybean oil, caprylic / capric monoglycerides, caprylic / capric diglycerides, caprylic / capric triglycerides, caprylic / capric monoglycerides of polyoxyethylene, caprylic / capric diglycerides of polyoxyethylene, capric / capric triglycerides of polyoxyl esters of polyoxyethylene of propylene glycol, castor oil. polyoxyethylene, polyoxyethylene glyceryl trioleate, ethyl butyrate, ethyl caprylate, ethyl oleate, ethylene glycol monomethyl ether, ethylene dimethyl ether glycol, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol butylphenyl ether, ethylene glycol ether, ethylene glycol ether dimethyl ether glycol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monobutyl ether, diethylene glycol dibutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol divinyl ether, triethylene glycol dimethyl ether, triethylene ethylene glycol monoethylene ether dimethyl ether glycol, polysorbates, glycol ethers, isopropyl alcohol, ethyl alcohol, polyglyceryl 3 palmitate, lecithin, glycerin stearate *, phospholipids, polyethylene glycol, behenyl alcohol, soy sterols, soy glycine, hydrogenated lecithin, hydrogenated alcohol , polyglyceryl-5 dioleate, polyglyceryl-5 laurate, pol glyceryl oleate 5, polyglyceryl-6 caprylate, oils, lysolecithin, N-methyl-2-pyrrolidone, 2-pyrrolidone, benzyl alcohol, glycerol, among others.

Optionally, one or more gelling agents may be added to the composition, which is selected in a non-limiting manner, of at least one compound of the following group: microcrystalline cellulose, alginates, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, xanthan gum, sodium carboxymethylcellulose, methylhydroxypropylcellulose, tragacanth gum, guar flour, gum arabic, starch, sodium carboxymethyl starch, gelatin, silicon dioxide, poly (acyl acryl acid, aluminum derivatives) Bentonite or combinations thereof.

The amount of at least one solvent agent and / or at least one cosolvent agent used for the present invention is contained in the composition in a weight ratio of 80% w / w to 99.998% w / w with respect to the total weight of the composition.

In addition, the present composition may also contain one or more pharmaceutically acceptable excipients, in a weight ratio with respect to the total weight of the composition in a range of 0.000% w / w to 15% w / w selected from preservatives, wetting agents, emulsifying agents, flavoring agents, antimicrobial agents, pH regulating agents, suspending agents, sweeteners, surface active agents, co-surfactants, fillers, among others.

The phosphodiesterase enzyme selective inhibitor, being partially or totally dissolved in the composition described in the present invention, is characterized in that it exhibits a behavior As for the release and effect other than expected, that is, upon being dissolved, a sudden absorption of the entire active substance in the organism is expected, achieving an immediate effect but with a rapid elimination in the blood levels of the active substance. However, as a result of the present development, in a surprising and unexpected way, a composition was obtained that even when the active principle is administered partially or totally dissolved in the composition, the release of said active principle is sustained achieving an immediate effect, and a prolonged effect caused by a gradual and sustained absorption, without the rapid elimination of the active ingredient, which significantly increases the time of the therapeutic effect.

The previous result was obtained from a pilot study to compare the bioavailability of a tablet-shaped composition with 100 mg of sildenafil and the novel product composition of the present invention in the form of an oral gel with a concentration of 100 mg / 5g of sildenafil. The initial studies were conducted with 8 male volunteers, tests were conducted on volunteers, sampling at 0, 0.166, 0.33, 0.5, 0.66, 0.83, 1, 1.33, 1.66, 2, 3 and 5 hours.

The quantitative analysis was performed by Ultra High Resolution Liquid Chromatography (UPLC) coupled to Tandem Mass Spectrometry. Finally, the following pharmacokinetic parameters were calculated for each of the compositions: Area Under the 0-t Curve (ABCo-t), Area Bajp the 0-Infinity Curve (ABC ₀ -inf), the maximum plasma concentration (C _max ), the time where the maximum plasma concentration is reached (t _max ), the elimination constant (K _e ), the elimination half-life (i 2), the average residence time (TMR) and the Area Under the Extrapolated Curve (ABC _Ext -i _n f)

Tables 1 and 2 show the results of the plasma concentration of the volunteers obtained after administering the gel-developed composition with 100mg / 5g of sildenafil.

Table 1. Plasma concentration of volunteers for the 100mg / 5g gel (t = 0 to 0.83 hrs)

NC, unquantified sample. Quantification Limit: 1 ng / mL Table 2. Plasma concentration of volunteers for the 100mg / g gel (t = 5 hrs)

NC, unquantified sample. Quantification Limit: 1 ng / mL

Tables 3 and 4 show the results of the plasma concentration of the volunteers obtained once the composition is administered in the form of 100 mg sildenafil tablets.

Table 3. Plasma concentration of volunteers for lOOmg tablets (t = 0 to 0.83 hrs)

NC, unquantified sample. Quantification Limit: i ng / mL Table 4. Plasma concentration of volunteers for lOOmg tablets (t = 5 hrs)

NC, sample not c antified. Quantification Limit: 1 ng / mL

In the above tables (1 to 4) it can be seen that as in the composition in the form of a sildenafil gel, the plasma concentration increases in a gradual way, therapeutically effective plasma concentrations remain such that the effect of the active substance is maintained throughout 5 hours trial. On the other hand, sildenafil tablets have a too rapid increase in plasma concentration, which means that the elimination of the active substance is carried out very quickly, limiting the time of the therapeutic effect of the active substance.

Through the use of the present invention, phase IV of the erection has been achieved, that is, a rigid erection commonly known as a Grade 4 erection where the penis is completely firm and rigid due to that the intracavernous pressure reaches the systolic pressure caused by the compression of the hamstring muscles at the base of the penis and the total closure of the arterial and venous flow.

In general, the plasma concentrations for the volunteers who participated in the comparative study between the compositions in the form of a tablet and in the form of an oral gel, showed the same behavior only in terms of increasing and decreasing concentrations at the different sampling times selected. .

When plotting the data for each of the volunteers, the results described above were observed, for example, in the case of volunteer 1, the graph of plasma concentration vs. Logio semilogarithmic sampling time (Figure 1), shows a gradual increase in plasma concentration, that is, the concentration of the active substance is not immediately raised, however, if the desired therapeutic effect is achieved, in the same graph, it is also observed that after 1.66 hours after administration of the composition, it is maintained above 100 ng / mL while the plasma concentration after administration of the composition in the form of sildenafil tablets, from 1 time of administration begins to reduce said plasma concentration by presenting values below those obtained with the gel-shaped composition at 5 hours.

In the case of the graph of plasma concentration vs. Logi ₀ semilogarithmic sampling time, prepared with sildenafil plasma concentration data for the case of volunteer 4 (Figure 2), a slow increase in plasma concentration levels is observed, however, at 0.33 hours after The oral gel composition has been administered, a concentration greater than 100 ng / mL is reached and said concentration is maintained until 5 hours after administration. On the other hand, the plasma sildenafil concentration after being administered orally, reaches 1000 ng / mL at 0.5 hours and begins to decrease to 100 ng / mL at 5 hours with a tendency to continue decreasing.

The following tables present the results of the evaluation of the pharmacokinetic parameters obtained for each of the compositions, in order to observe and evaluate the behavior in vivo. Table 5. Pharmacokinetic parameters per volunteer for the 100mg / 5g gel

C _max : _{maximum plasma} concentration (mg / mL); tmax: time of C „ _a« ; K _e : elimination constant (1 / h); tl / 2 half-life (h); ABC0-t; Area Under Curve 0 at the last sampling time (h * mg / mL) ABCO-inf: Area Under the Curve extrapolated to infinity (h * mg / mL);

TMR: average residence time (h)

Table 6. Pharmacokinetic parameters per volunteer for tablets with 100 mg sildenafil

tmax: Cmax time; Cmax: maximum plasma concentration (mg / mL); Ke: elimination constant (1 / h); tl / 2 half-life (h); ABC0-t; Area Under Curve 0 at the last sampling time (h * mg / mL); ABCO-inf: Area Under the Curve extrapolated to infinity (h * mg / mL); TMR: average residence time (h) » According to Tables 5 and 6, tmax and Cmax show that by using oral gel, the time to reach the maximum concentration of sildenafil in plasma is prolonged, on the other hand, said maximum concentration obtained with the oral gel It has ⁸ as a superior range 950,750 ng / mL, which is significantly lower compared to that obtained with sildenafil tablets which have a higher range of 1838,194 ng / mL. Surprisingly, said Cmax values that occur with the administration of oral ge.l diminish or eliminate the side effects that occur with other forms of oral administration.

In the case of the elimination constant (Ke), this expresses the percentage of drug removed every hour, by administering the oral gel, an average elimination constant of 0.312 is obtained while with the administration of oral tablets, a average elimination constant of 0.453. In addition, the half-life (ti _{/ 2} ) that is the time elapsed until the plasma concentration of the active substance is reduced by half, allows us to determine the period that the drug remains in the body and the time it will take to eliminated, in the case of oral gel administration, an average half-life of 2,742 is obtained, a longer time of 0.999, compared to the obtained by the administration of the tablets that was 1,744, that is, by means of the values of the K _e and the ti _{/ 2} it can be concluded that with the administration of the oral gel, the elimination of the sxldenafil from the plasma is carried out by a slower than compared to administration by oral tablets and therefore, the therapeutic effect is maintained for a longer period of time with the oral gel.

In pharmacokinetics, the area under the curve from zero to infinite time is frequently used. The area under the curve of the first moment is defined as the area of the product of the plasma concentration by time, from zero to infinity (ABC ₀ -inf) · The average residence time (TMR) is therefore the relationship between the area under the curve at the first moment and the area under the curve of the zero moment, to infinite time, in other words, the TMR can be defined as the average time for intact molecules to travel through the body and involves all kinetic processes, including "in vivo" release from the pharmaceutical form, absorption and all disposal processes.

According to the above, the average TMR of 4,522, obtained from the pharmacokinetic values of oral gel administration, indicates that by means of said administration the permanence of the active substance is greater by at least 40% compared to the administration of the tablets that has an average TMR of 2,938, which means that the release "in vivo" from the pharmaceutical form, absorption and all disposal processes are seen positively modified with the administration of the composition product of this invention since they allow the permanence of sildenafil for a longer period of time, achieving the therapeutic effect for longer times than that obtained with the administration of other forms of administration known in the state of The technique.

By means of the novel composition developed in the present invention, maximum plasma concentrations are reached in a longer time, that is, the release and absorption of sildenafil by oral gel administration is carried out in a sustained manner with a gradual absorption.

Additionally, as a result of the evaluation of the organoleptic characteristics of the novel composition in the form of an oral gel, it is shown that in a preponderant way the volunteers attribute good smell qualities, ease of ingestion, pleasant consistency, pleasant taste, sweet and / or fresh sensation in the mouth. A pharmaceutical composition described in the present invention can be prepared by different procedures known in the state of the art, for oral administration in the form of: gel, paste, suspension, gelatin, solution, emulsion, syrup, tinctures, microdoses, jelly, hard gelatin capsule with liquid content, soft gelatin capsule with liquid content, gum with liquid center and / or combinations thereof.

The preparation of the composition described in the present invention can be packaged for commercialization by way of example but not limited to: envelopes, bags, dosing bottle, aluminum containers, ampoule, syringes, pipettes, gum with liquid center, tubes, soft gelatin capsules, hard gelatin capsules and / or combinations thereof.

An additional feature of the present invention is the ease of portability of the medicament - for transport in a safe, discreet manner and with the advantage of not requiring water to be ingested as in the case of tablets.

The compositions used during the development of the invention are presented below as illustrative, but not limited to, examples: Example 1: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.

Example 2: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.

Example 3: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.

% W / w component

Sildenafil 2,844

Glycerin 14,216 Methylparaben 0.300

Xantana rubber 0.30Ό

Propylparaben 0.040

0.080 polyacrylic polymer

Sucralose 0.200

Mint flavor 0.120

Purified water 79,900

Citric Acid 2,000

Example 4: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.

% W / w component

Sildenafil 2,844

Glycerin 18,216

Methylparaben 0.200

Xantana rubber 5.400

Propylparaben 0.020

Sucralose 0.120 Mint flavor 0.200

Purified water 71,000

Citric Acid 2,000

Example 5: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of tadalafil.

As a final point to the description of the invention, the main advantages presented in a non-limiting way are the compositions developed:

- Stable composition in liquid and / or semi-solid form of a phosphodiesterase enzyme selective inhibitor.

- Composition with sustained release of the active substance. - Composition that generates a gradual and sustained absorption of the active substance.

- The elimination of the active substance is slower compared to other forms of oral administration, which allows greater residence of the active substance in the body.

- A grade 4 erection is obtained through the composition,

- The time of the therapeutic effect is longer than other pharmaceutical forms of oral administration.

- The sudden increase in plasma concentrations of the active substance is avoided, providing security to the composition.

- Portable composition and easy administration.

- Easily divisible composition for administration of lower doses according to the individual dosage.

- The described compositions have application for the control and / or treatment and / or prevention of diseases related to phosphodiesterase enzyme inhibition.

- Reduces or eliminates the side effects of the active principle.

Claims

CLAIMS Having described the invention, the content of the following claims is claimed as property:

1. A pharmaceutical composition in the form of a liquid and / or semi-solid for oral administration of modified release containing a therapeutically effective amount of at least one selective phosphodiesterase enzyme inhibitor and / or its pharmaceutically acceptable salts, in combination with one or more solvents and / or co-solvents and / or one more pharmaceutically acceptable excipients.

2. A pharmaceutical composition according to claim 1, wherein the phosphodiesterase enzyme selective inhibitor is selected from zaprinast, sildenafil, vardenafil and tadafil, its pharmaceutically acceptable salts, derivatives, hydrates, prodrugs, polymorphs, amorphous and / or combinations thereof.

3. A pharmaceutical composition according to claim 1, wherein the selective phosphodiesterase enzyme inhibitor is sildenafil, its pharmaceutically acceptable salts, derivatives, hydrates, prodrugs, polymorphs, amorphous and / or combinations thereof.

4. A pharmaceutical composition according to claims 1 to 3, wherein at least a substantial part of at least one phosphodiesterase enzyme selective inhibitor is dissolved or solubilized in one or more solvents and / or one or more co- solvents

5. A pharmaceutical composition according to claims 1 to 4, characterized in that at least one selective phosphodiesterase enzyme inhibitor is in a weight ratio of 0.002% w / w at 20% w / w relative to the total weight of the composition.

6. A pharmaceutical composition according to claim 1, characterized in that at least one solvent and / or at least one co-solvent are selected from the following group: glycerin, water, n-butanol, propylene glycol, 1,3-butanediol, acid oleic, linoleic acid, soybean oil, monoglycerides capril / capric,

diglycerides caprylic / capric, caprylic / capric triglycerides, caprylic / capric polyoxyethylene monoglycerides, polyoxyethylene capric / capric diglycerides, polyoxyethylene caprylic / capric triglycerides, propylene glycol fatty acid esters, propylene glycol laurate oil polyoxyethylene castor, glyceryl polyoxyethylene trioleate, ethyl butyrate, ethyl caprylate, ethyl oleate, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol ethylene glycol ether , ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol butylphenyl ether, ethylene glycol terpinyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, ethyl ether, ethyl ether, ethyl ether , diethylene glycol monoisobutyl ether, diethylene glycol divinyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether, triethylene glycol dimethyl ether, polysorbates, glycol ethers, isopropyl ethacrylic acid, ethyl acetate glycerin, phospholipids, polyethylene glycol, behenyl alcohol ico, soy sterols, soy glycine, hydrogenated lecithin, alcohols, polyglyceryl-10 laurate, polyglyceryl-5 dioleate, polyglyceri 1-5 laurate, polyglyceryl-5 oleate, polyglyceryl-6 caprylate, oils, lisolecithin, N-methyl-N pyrrolidone, 2-pyrrolidone, benzyl alcohol, glycerolformal, and / or combinations thereof.

7. A pharmaceutical composition according to claims 1 and 6, characterized in that at least one solvent and / or at least one co-solvent is in a weight ratio of 80% w / w 99.998% w / w with respect to total weight of the composition.

8. A pharmaceutical composition according to claims 1 to 7, characterized in that it additionally contains one or more pharmaceutically acceptable excipients.

9. A pharmaceutical composition according to claims 1 to 8, characterized in that it optionally contains one or more pharmaceutically acceptable excipients selected from gelling agents, one or more preservative agents, wetting agents, emulsifying agents, flavoring agents, antimicrobial agents, agents H regulators, suspending agents, sweeteners, surfactants, co-surfactants, fillers and / or combinations thereof.

10. A pharmaceutical composition according to claims 1 and 9, characterized in that it contains one or more pharmaceutically acceptable excipients in a proportion by weight of 0.0% w / w 15.0% w / w with respect to the total weight of the composition.

11. A pharmaceutical composition according to claim 9, characterized in that the gelling agent is selected from the following group: microcrystalline cellulose, alginates, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, xanthan gum, sodium carboxymethylcellulose, methylhydroxypropylcellulose, gum tragacanth, guar flour, gum Arabic, starch, sodium carboxymethyl starch, gelatin,. silicon dioxide, poly (acyl acid), derivatives of methacrylic acid, aluminum stearate, bentonite and / or their pharmaceutically acceptable salts and / or combinations thereof.

12. A pharmaceutical composition according to claim 1, characterized in that it is administered orally.

13. A pharmaceutical composition according to claims 1 and 12, characterized in that it is administered orally in the form of a gel, paste, suspension, gelatin, solution, emulsion, syrup, tinctures, microdoses, jelly, hard gelatin capsule containing liquid, soft gelatin capsule with liquid content, gum with liquid center and / or combinations thereof.

14. The use of a pharmaceutical composition according to claims 1 to 13, for the treatment of diseases related to the phosphodiesterase enzyme.

15. The use of a pharmaceutical composition according to claims 1 to 14, wherein the phosphodiesterase enzyme-related disease is selected from the following group: angina pectoris, hypertension, atherosclerosis, heart failure, pulmonary arterial hypertension functional grade II and III and / or sexual dysfunction.

16. The use of a pharmaceutical composition according to claims 1 to 15, for the treatment of sexual dysfunction.

17. The use of a pharmaceutical composition according to claim 16, wherein the sexual dysfunction may be male erectile dysfunction, hypoactive sexual desire syndrome, female anorgasmia syndrome, premature ejaculation syndrome, vaginismus syndrome, sexual avoidance syndrome and sexual distress disorder, delayed ejaculation, orgasmic insensitivity, dyspereunia, female anorgasmia and orgasmic insensitivity.

18. The use of a pharmaceutical composition according to claim 16, wherein the sexual dysfunction is male erectile dysfunction.