WO2014119985A2 - Pharmaceutical composition comprising a selective phosphodiesterase enzyme inhibitor in oral gel form - Google Patents
Pharmaceutical composition comprising a selective phosphodiesterase enzyme inhibitor in oral gel form Download PDFInfo
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- WO2014119985A2 WO2014119985A2 PCT/MX2014/000028 MX2014000028W WO2014119985A2 WO 2014119985 A2 WO2014119985 A2 WO 2014119985A2 MX 2014000028 W MX2014000028 W MX 2014000028W WO 2014119985 A2 WO2014119985 A2 WO 2014119985A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
Definitions
- 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.
- 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.
- 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 .
- 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 ( ⁇ lvarez 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.
- 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.
- PR radical prostatectomy
- 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).
- 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 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).
- AC acetylcholine
- ON nitric oxide
- CGRP vasoactive intestinal polypeptide
- PGE1 prostaglandin El
- 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.
- 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.
- 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 .
- the medical history is reviewed, to determine risk factors.
- 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.
- 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.
- 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.
- 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.
- cGMP cyclic guanosine monophosphate
- nitric oxide that diffuses into the nearby smooth muscle to induce relaxation.
- the function of nitric oxide is to activate the enzyme guanylate cyclase.
- the enzyme guanylate cyclase acts by increasing the concentration of cGMP.
- 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.
- cGMP will have high levels in the bodies Cavernous, which will make smooth muscles relax, engorgement and erection increased and prolonged for successful intercourse.
- 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.
- CYP450 cytochrome P450
- 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.
- 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.
- 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.
- 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.
- 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.
- excipients selected from the following group: glycerin, water, n-butanol, propylene glycol, 1,3-butandioi, oleic acid, linoleic acid , soybean 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, ethylene glycol ether dimethyl ether glycol, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol divinyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethylene ether dimethyl ether glycol
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. .
- C max maximum plasma concentration (mg / mL); tmax: time of C Cincinnati 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);
- 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) »
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Example 4 Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
- Example 4 Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
- Example 5 Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of tadalafil.
- composition with sustained release of the active substance.
- - Composition that generates a gradual and sustained absorption of the active substance.
- the time of the therapeutic effect is longer than other pharmaceutical forms of oral administration.
- compositions have application for the control and / or treatment and / or prevention of diseases related to phosphodiesterase enzyme inhibition.
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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
COMPOSICIÓN FARMACÉUTICA CON UN INHIBIDOR SELECTIVO DE LA PHARMACEUTICAL COMPOSITION WITH A SELECTIVE INHIBITOR OF THE
ENZIMA FOSFODIESTERASA EN FORMA DE GEL ORAL ENZYM PHOSPHODESTERASE IN THE FORM OF ORAL GEL
CAMPO DE LA INVENCION FIELD OF THE INVENTION
La presente invención se refiere a una novedosa composición semisólida estable para administración oral que comprende al menos un agente inhibidor selectivo de la enzima fosfodiesterasa y/o al menos un excipiente farmacéuticamente aceptable. La composición una vez administrada por via oral, mantiene una liberación sostenida, duplicando el tiempo de permanencia del ingrediente activo en el organismo y prolongando el efecto terapéutico del inhibidor selectivo de la enzima fosfodiesterasa . 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.
El uso de la composición semisólida es para la inhibición selectiva de la enzima fosfodiesterasa por ejemplo de manera no limitativa, para el control o tratamiento de disfunción eréctil, con un efecto terapéutico de hasta por 8 horas.
ANTECEDENTES 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
La sexualidad es el conjunto de atributos físicos, psicológicos, funcionales, sociales y culturales que identifican al propio sexo y su comportamiento sexual, estén relacionados o no con los órganos sexuales o la procreación. El ejercicio de la sexualidad es una de las expresiones más básicas y vitales de la especie humana. Evolucionó con el hombre, desde la brutalidad y el placer en épocas primitivas, hasta el erotismo más sofisticado del mundo contemporáneo; principalmente a partir del descubrimiento y uso masivo de los métodos para el control de la natalidad. 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.
De acuerdo a la Asociación Mexicana para la Salud Sexual A.C., las disfunciones sexuales son una serie de síndromes en los que los procesos eróticos de la respuesta sexual resultan no deseables para el individuo o para el grupo social y que se presentan en forma recurrente y persistente . Entre los determinantes de dichas disfunciones, se encuentran : la constitución biológica, desinformación, la naturaleza psicológica, la naturaleza del vínculo de pareja y el ambiente social y cultural, disfunciones de origen fisiológico, entre otros. 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.
Algunas de las disfunciones sexuales conocidas en la actualidad son: el síndrome de deseo sexual hipoactivo,
disfunción eréctil masculina, síndrome de anorgasmia femenina, síndrome de eyaculación precoz, síndrome de vaginismo, síndrome de evitación sexual y trastorno por angustia sexual (fobia sexual), eyaculación retardada, insensibilidad orgásmica, dispereunia, anorgasmia femenina, insensibilidad orgásmica, entre otros. 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.
La disfunción eréctil masculina se define como la incapacidad de un hombre para obtener una erección peneana como parte de un completo proceso multifacético de la función sexual masculina, quitando así al coito la condición sine qua non de la vida sexual y dando igual importancia a otros aspectos del comportamiento sexual masculino (Álvarez E, 2009). Se ha demostrado que la disfunción eréctil (DE) es una patología frecuente que afecta la calidad de vida, no solo del hombre que la padece, sino también de su pareja y por lo tanto de su entorno . 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.
En una revisión reciente de estudios epidemiológicos sobre la disfunción eréctil sugiere que aproximadamente del 5% al 20% de los hombres tienen disfunción eréctil de moderada a grave. La diferencia en la incidencia informada probablemente se deba a c diferencias en la metodología y a las edades y estado socioeconómico de las poblaciones de estudio .
La disfunción eréctil tiene factores de riesgo en común con la enfermedad cardiovascular, como la falta de ejercicio, la obesidad, el tabaquismo, la diabetes, la hipercolesterolemia y el síndrome metabólico. El riesgo de padecer disfunción eréctil se puede reducir modificando esos factores de riesgo, en especial con el ejercicio o la pérdida de peso.- Otro factor de riesgo es la prostatectomía radical (PR) en cualquiera de sus formas (abierta, laparoscópica o robótica) , debido al riesgo de lesión de los nervios cavernosos, mala oxigenación de los cuerpos cavernosos e insuficiencia vascular. Alrededor de 25-75% de los hombres que se someten a una PR experimentandisfunción eréctil postoperatoria. Los pacientes candidatos a proteactetomía radical con conservación de los nervios, al conservar los nervios cavernosos se puede garantizar la recuperación de la función eréctil después de la PR (Wespes E, 2009) . 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).
Para mantener una erección normal se necesita la integridad de los sistemas vascular, neurológico, endocrinológico y psicológico. Se denomina ciclo sexual masculino a las diferentes fases de la erección peneana inducida por estimulación sexual y consisten en: 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:
Fase I de flacidez: El tono simpático es predominante, hay flujo arterial y contracción de la musculatura
trabecular de los cuerpos cavernosos con escaso volumen sanguíneo en los sinusoides de los cuerpos cavernosos. 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.
Fase II de llene o tumescencia: en respuesta a una estimulación parasimpática aumenta el flujo sanguíneo por la dilatación arterial, disminuye la resistencia de los espacios sinusoidales por relajación. Al expandirse los sinusoides se produce comprensión de los flexos venosos intracavernosos y subalbugineos reteniendo sangre dentro de los cuerpos cavernosos provocando la expansión del pene y la erección completa. 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.
Fase III de erección completa: la presión de los cuerpos es levemente menor que la presión sistólica y el pene se encuentra totalmente expandido y el flujo sanguíneo de entrada y salida es escaso (aproximadamente 3-5 mL/min) . 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).
Fase IV de erección rígida: la presión intracavernosa puede alcanzar varias veces la presión sistólica debido a la compresión de los músculos isquiocavernosos en la base del pene y al cierre total del flujo arterial y venoso. Esta fase ocurre durante, el coito y la masturbación cuando la estimulación directa del pene genera el reflejo bulbo cavernoso. Si se interrumpe la estimulación o hay fatiga muscular, la presión intracavernosa cae y el pene vuelve a la fase de erección completa. 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.
Fase V Eyaculación: es inducida por contracciones rítmicas de los músculos isquiocavernosos y especialmente
bulbo cavernosos que propulcionan el semen por el lumen uretral . Phase V Ejaculation: is induced by rhythmic contractions of the ischiocavernosus muscles and especially Cavernous bulb that propel semen through the urethral lumen.
Fase VI de detumescencia : la vuelta del tono muscular después del orgasmo o el cese de la estimulación inducen la concentración arterial, la apertura de los circuitos venosos y se produce la detumescencia por escape progresivo de la sangre desde los cuerpos cavernosos. 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.
Las fases descritas explican por qué la erección es un fenómeno esencial vascular que depende del balance entre el aporte sanguíneo en donde la erección depende de un control central y de un control periférico, en el control central el órgano más importante es el cerebro: los estímulos sexuales son integrados en el hipotálamo y el mensaje es transmitido, al pene, vía médula espinal y centro sacro de la erección. 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.
La erección es continuamente inhibida por el tono basal simpático, los mensajes anti erección son mediados por la noradrenalina y estímulos simpáticos. Los mensajes pro erección son mediados por dopamina y descienden por cordones espinales y estimulan el parasimpático . Hay por lo tanto un constante equilibrio entre los factores pro y antierección y cuando ocurre una excitación sexual apropiada, aumenta la actividad parasimpática y disminuye la actividad simpática. El control periférico de la erección
depende del balance entre los factores neuronales y locales . 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.
Los elementos neuronales con acción contráctil son la noradrenalina y el neuropéptido y, que actúan sobre las células del músculo liso arterial y trabecular del cuerpo cavernoso. 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.
Los factores de acción relajante sobre el músculo liso son la acetilcolina (AC) , el óxido nítrico (ON) , liberado por acción de la AC, el polipéptido intestinal vasoactivo (PIV) y el CGRP (de su nombre en inglés: calcitonin gene related peptide) . Los factores locales de acción contráctil son la endotelina 1 y prostaglandina F2 alfa. Los de acción relajante son el ON y la prostaglandina El (PGE1) (Álvarez E, 2009) . 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).
En la función eréctil intervienen diversos factores Various factors are involved in erectile function
(físicos y psíquicos) por lo que se clasifica en: (physical and psychic) so it is classified as:
Orgánica: por lesiones vasculares, neurológicas , hormonales o locales. Organic: for vascular, neurological, hormonal or local lesions.
Psicógena: por inhibición central del mecanismo eréctil sin lesiones físicas. Psychogenic: by central inhibition of the erectile mechanism without physical injuries.
Mixta: cuando la presencia de una anomalía orgánica no implica que sea el único motivo, ni la exclusión de causas psicógenas concomitantes. Mixed: when the presence of an organic anomaly does not imply that it is the only reason, nor the exclusion of concomitant psychogenic causes.
Algunos factores de riesgo son: la edad, la diabetes, la enfermedad cardiovascular, tabaquismo, secundaria a
fármacos, secundaria al consumo de drogas, alteraciones endocrinas, anomalías del pene, insuficiencia renal crónica, insuficiencia hepática, patología neurológica, EPOC, trastornos afectivos, cirugía regional o traumatismo en esa zona, entre otros. 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.
Para realizar un diagnóstico de disfunción eréctil se realiza un test de índice internacional de disfunción eréctil que es simple, rápido, con buena sensibilidad y especificidad; permite clasificar la DE en leve, moderada y severa. Después se revisan los antecedentes del problema o historia sexual donde se establece fecha de comienzo, forma de instauración, se pregunta sobre la rigidez peneana, mantenimiento de ésta, presencia de erecciones matutinas, nocturnas o con diversos estímulos, para determinar si es orgánica o psicógena. Además, se revisa la historia médica, para determinar factores de riesgo. 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.
El examen físico por medio de la exploración del sistema cardiovascular, exploración neurológica, determinación de endocrinopatías , hipogonadismo, trastornos genitales o patología prostética. The physical examination through the exploration of the cardiovascular system, neurological examination, determination of endocrinopathies, hypogonadism, genital disorders or prosthetic pathology.
Por último se realizan las exploraciones complementarias por medio de la realización de pruebas de laboratorio como pueden ser perfil lipídico, glucemia, testosterona total matutina, etc. (Campillos T, 2003) .
Para el tratamiento se recurre a la psicoterapia, y a la terapia con medicamentos, dentro de la cual existen los que son administrados por vía oral, los que se inyectan directamente en el pene o los que se insertan en la uretra por la punta del pene. 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.
Dentro de los medicamentos orales se encuentran los inhibidores de la fosfodiesterasa, la testosterona, los agonistas de la dopamina y la serotonina, el clorhidrato de yohimbina y trazodona. Oral medications include phosphodiesterase inhibitors, testosterone, dopamine and serotonin agonists, yohimbine hydrochloride and trazodone.
Los medicamentos inyectables, los cuales van directamente en el pene son el clorhidrato de papaverina, fentolamina y alprostadil ; los cuales ensanchan los vasos sanguíneos permitiendo que el pene se llene de sangre, sin embargo, estos medicamentos pueden producir efectos secundarios no deseados, que incluyen una erección persistente (conocida como priapismo) y cicatrices. 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.
Un sistema para insertar un gránulo de alprostadil en la uretra por medio de un aplicador prellenado para depositar el gránulo alrededor de una pulgada dentro de la uretra. Se encuentra en forma de muse y de 8 a 10 minutos después su administración comienza la erección que puede durar de 30 a 60 minutos; sin embargo los efectos secundarios más comunes son dolor en el pene, testículos y área entre el pene y el recto; sensación de calor o ardor en la uretra; enrojecimiento debido al aumento del flujo
sanguíneo hacia el pene; y leve sangrado o manchas uretrales . 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.
Dentro de los medicamentos orales inhibidores de la fosfodiesterasa se encuentran el sildenafil, el clorhidrato de vardenafil y el tadalafil. Phosphodiesterase inhibitor oral medications include sildenafil, vardenafil hydrochloride and tadalafil.
En marzo de 1998, la Administración de Medicamentos y Alimentos (FDA) aprobó en Estados Unidos el sildenafil, el primer medicamento para tratar la disfunción eréctil (Nkudic, 2009) . In March 1998, the Food and Drug Administration (FDA) approved in the United States sildenafil, the first medication to treat erectile dysfunction (Nkudic, 2009).
La Escala de Firmeza de Erección fue desarrollada originalmente por el Dr. Irwin Goldstein para el uso de estudios clínicos de Viagra®, con el objetivo de proporcionar una evaluación adicional de su eficacia. En la actualidad, se manejan cuatro grados de firmeza que se han integrado en una escala conocida como índice de Goldstein. Dicha escala diferencia los grados de erección que van del 1 al 4, brinda una medida "cuantitativa" del grado de la firmeza de erección así como la eficacia del tratamiento de pacientes con disfunción eréctil. Los grados descritos en esta escala son: Grado 1, donde el tamaño del pene aumenta, pero no está rígido, lo que impide la penetración; Grado 2, donde el pene está rígido, pero no lo suficiente como para la penetración; Grado 3, donde el pene está lo suficientemente firme para la penetración, pero no
completamente rígido; y, Grado 4, donde el pene está completamente firme y rígido. 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.
El sildenafil es un inhibidor selectivo de la isoenzima fosfodiesterasa tipo 5 (PDE5) , una de las 7 isoenzimas de fosfodiesterasa que se han identificado. La isoenzima PDE5 (inhibida selectivamente por sildenafil) predomina en los cuerpos cavernosos humanos, su función es degradar selectivamente la GMPc (guanosina monofosfato cíclica) de ese tejido. Esta GMPc relaja el músculo liso de esa estructura, antes y durante el coito a fin que inicie y mantenga la erección fisiológica del pene por la ingurgitación sanguínea. 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.
Durante la estimulación o excitación sexual normal, además del componente parasimpático colinérgico, el endotelio de los vasos sanguíneos de los cuerpos cavernosos libera oxido nítrico que difunde hacia el músculo liso próximo para inducir su relajación. En los cuerpos cavernosos humanos, la función del oxido nítrico es activar la enzima guanilato ciclasa. Por su parte, la enzima guanilato ciclasa actúa incrementando la concentración de GMPc. En suma, en pacientes con DE, el sildenafil inhibe selectivamente la isoenzima PDE5, protegiendo del catabolismo la GMPc producida por guanilato ciclasa activada por el oxido nítrico que se libera al estímulo sexual. Así, GMPc tendrá niveles altos en los cuerpos
cavernosos, que hará que los músculos lisos se relajen, se produzca ingurgitación y erección incrementada y prolongada para un coito exitoso. En los pacientes, el mecanismo de sildenafil para producir erección sólo será posible si el proceso se inicia con estimulo sexual que libere suficiente oxido nítrico, que active guanilato cilasa y produzca suficiente GMPc. Administrado previamente (1 hora) sildenafil evitará se degrade GMPc al inhibir PDE5. Se administra por vía oral, se libera fácilmente y se absorbe rápidamente en ayunas. Alcanza concentraciones plasmáticas máximas en 30 a 120 minutos (promedio 60 min) . Su ingesta con alimentos de alto contenido graso reduce la absorción en 29%. Su principal metabolito circula ligado a proteínas plasmáticas en 96%. El volumen de distribución de 105 L indica ingreso tisular. No se acumula en dosis únicas diarias. La vida media de ambos es de 4 a 5 horas. La duración del efecto (erección) llega a 4 horas, pero disminuida comparada con el efecto a las 2 horas. 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.
Es biotransformado por el citocromo P450 (CYP450) del sistema o fracción microsomal hepático, en especial isoenzimas CYP3A4 y CYP2C9 (Álvarez P, 1999) . It is biotransformed by the cytochrome P450 (CYP450) of the hepatic microsomal system or fraction, especially CYP3A4 and CYP2C9 isozymes (Álvarez P, 1999).
En el estado de la técnica, los inhibidores de posfodiesterasa se encuentran comúnmente para su administración oral en forma de comprimidos, por otra parte, en forma de semisólido, se encuentran composiciones
en forma de solución acuosa de sildenafil que se prepara en forma de solución, suspensión, emulsión con una concentración de 1 a 200 mg/mL y pH entre 2.5 y 5.0 principalmente para aplicación inyectable (WO2005077374 ) , un método y composición para el tratamiento de disfunción eréctil que consiste en administrar localmente una cantidad eficaz de sildenafil, la* composición se prepara en forma de gel, ungüento, crema o loción (US6037346), entre otras.
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.
OBJETO DE LA INVENCIÓN OBJECT OF THE INVENTION
La presente invención se refiere a una composición farmacéuticapara administración oral en forma de semisólido o liquido que contiene al menos un agente inhibidor selectivo de la enzima fosfodiesterasa y/o sus sales farmacéuticamente aceptables, en combinación con uno más excipientes farmacéuticamente aceptables. El objeto de la presente invención, es aportar una composición que lleve a cabo la liberación del ingrediente activo en forma sostenida permitiendo mantener un efecto terapéutico por mayor tiempo que el obtenido por administración oral en otra forma farmacéutica.
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.
BREVE DESCRIPCIÓN DE LOS DIBUJOS BRIEF DESCRIPTION OF THE DRAWINGS
FIGURA 1. Gráfica de concentración plasmática (ng/mL) vs tiempo de muestreo (hora.s) en escala semilogaritmica loglO después de la administración de la composición en forma de gel oral y en forma de comprimidos al voluntario número 1. 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.
FIGURA 2. Gráfica de concentración plasmática (ng/mL) vs tiempo de muestreo (horas) en escala semilogaritmica loglO después de la administración de la composición en forma de gel oral y en forma de comprimidos al voluntario número 4.
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.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
La presente invención se refiere a una novedosa composición farmacéutica oral en forma deliquido y/o semisólido que contieneuna cantidad efectiva terapéuticamente de al menos un agente inhibidor selectivo de la enzima fosfodiesterasa y/o sus sales farmacéuticamente aceptables, en combinación con uno o más solventes y/o co-solventes y/o uno más excipientes farmacéuticamente aceptables. 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.
Para efectos de la presente invención el agente inhibidor selectivo de la enzima fosfodiesterasa, es seleccionado de zaprinast, sildenafil, vardenafil y tadafil, sus sales farmacéuticamente aceptables, derivados , hidratos , profármacos, polimorfos, amorfos y/o combinaciones de los mismos. 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.
La cantidad efeGtiva terapéuticamente del agente inhibidor selectivo de la enzima fosfodiesterasa y/o sus sales farmacéuticamente aceptables, útil para el propósito de la presente invención se encuentra en un rango de 2mg a 200 mg o en una proporción en peso con respecto al peso total de la composición en un rango de 0.002%p/p al 20% p/p- 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-
La novedosa composición se caracteriza por contar con al menos un solvente y/o co-solvente en donde por lo menos
una parte sustancial 4de al menos unagente inhibidor selectivo de la enzima fosfodiesterasa se encuentra disuelta o solubilizada, dicho solvente y/o co-solvente puede ser orgánico, inorgánico o combinaciones de ambos en una proporción tal que el ingrediente activo se encuentre parcial o totalmente disuelto. La función del solvente y/o co-solvente, además de disolver o solubilizar, es la de servir como vehículo para el agente inhibidor selectivo de la enzima fosfodiesterasa que de manera opcional se le incorporan uno o más excipientes farmacéuticamente aceptables . 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.
El solvente y/o co-solvente útil para la presente composición consiste de manera no limitativa, en uno o más excipientes seleccionados del siguiente grupo: glicerina, agua, n-butanol, propilenglicol , 1 , 3-butandioi , ácido oleico, ácido linoleico, aceite de soya, monoglicéridos caprílico/cáprico, diglicéridos caprí lico/cáprico, triglicéridos caprílico/cáprico, monoglicéridos caprílico/cáprico de polioxietileno, diglicéridos caprílico/cáprico de polioxietileno, triglicéridos caprílico/cáprico de polioxietileno, esteres de ácido graso de propilénglicol , laurato de propilenglicol, aceite de ricino. de polioxietileno, trioleato de gliceríl polioxietileno, butirato de etilo, caprilato de etilo, oleato de etilo, etilén glicol monometil éter, etilén
glicol dimetil éter, etilen glicol monoetil éter, etilen glicol dietil éter, etilen glicol monobutil éter, etilen glicol dibutil éter, etilen glicol monofenil éter, etilen glicol monobencil éter, etilen glicol butilfenil éter, etilen glicol terpinil éter , dietilén glicol monometil éter, dietilen glicol dimetil éter, dietilén glicol monoetil éter, dietilen glicol dietil éter, dietilén glicol monobutil éter, dietilen glicol dibutil éter, dietilén glicol monoisobutil éter, dietilen glicol divinil éter , trietilén glicol dimetil éter, trietilén glicol monoetil éter, trietilén glicol monobutil éter , trietilén glicol dimetil éter, polisorbatos , glicol éteres, alcohol isopropilico, alcohol etílico, poligliceril 3 palmitato, lecitina, estearato * de glicerina, fosfolípidos, polietilenglicol, alcohol behenílico, esteróles de soya, glicina de soya, lecitina hidrogenada, alcoholes, poligliceril-10 laurato, poligliceril-5 dioleato, poliglíceril-5 laurato, polígliceril-5 oleato, poligliceril-6 caprilato, aceites, lisolecitina, N-metil-2- pirrolidona, 2-pirrolidona, alcohol bencílico, glicerolformal, entre otros. 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.
De manera opcional se puede adicionar a la composición uno o más agentes gelificantes el cual se selecciona de manera no limitativa, de al menos un compuesto del siguiente grupo: celulosa microcristalina, alginatos,
metilcelulosa, hidroxietilcelulosa , hidroxipropilcelulosa, goma xantana, carboximetilcelulosa sódica, metilhidroxipropilcelulosa, goma de tragacanto, harina guar, goma arábiga, almidón, carboximetilalmidón sódico, gelatina, dióxido de silicio, poli (ácido acilico) , derivados del ácido metacrilico, estearato de aluminio, bentonita o combinaciones de los mismos. 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.
La cantidad de al menos un agente solvente y/o al menos un agente cosolvente que se emplea para la presente invención se encuentra contenido en la composición en una proporción en peso del 80% p/p a 99.998% p/p con respecto al peso total de la composición. 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.
Además, la presente composición también puede conteneruno o más excipientes farmacéuticamente aceptables, en una proporción en peso con respecto al peso total de la composición en un rango de 0.000%p/p al 15% p/p seleccionados de agentes conservadores, agentes humectantes, agentes emulsificantes , agentes saborizantes , agentes antimicrobianos, agentes reguladores de pH, agentes para suspensiones, edulcolorantes , agentes tensoactivos, agentes cotensoactivos , agentes de relleno, entre otros. 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.
El agente inhibidor selectivo de la enzima fosfodiesterasa, al encontrarse parcial o totalmente disuelto en la composición descrita en la presente invención se caracteriza porque presenta un comportamiento
en cuanto a la liberación y efecto diferente al esperado, es decir, al encontrarse disuelto, se espera una absorción súbita de todo el principio activo en el organismo, logrando un efecto inmediato pero con una eliminación rápida en los niveles sanguíneos del principio activo. Sin embargo, resultado del presente desarrollo, de manera sorprendente y no esperada, se obtuvo una composición que aún cuando el principio activo se administra parcial o totalmente disuelto en la composición, la liberación de dicho principio activo es de forma sostenida logrando un efecto inmediato, y un efecto prolongado causado por una absorción paulatina y sostenida, sin la eliminación rápida del principio activo con lo cual se incrementa significativamente el tiempo del efecto terapéutico. 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.
El resultado anterior, fue obtenido de un estudio piloto para comparar la biodisponibilidad de una composición en forma de tableta con 100 mg de sildenafil y la novedosacomposición producto de la presente invención en forma de gel oral con una concentración de 100 mg/5g de sildenafil. Los estudios iniciales se realizaron con 8 voluntarios del sexo masculino se realizaron pruebas en voluntarios, realizando muestreo a las 0, 0.166, 0.33, 0.5, 0.66, 0.83, 1, 1.33, 1.66, 2, 3 y 5 horas. 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.
El análisis cuantitativo, se realizó mediante Cromatografía de Líquidos de Ultra Alta Resolución (UPLC)
acoplada a Espectrometría de Masas en Tándem. Finalmente se calcularon para cada una de las composiciones, los siguientes parámetros farmacocinéticos : Área Bajo la Curva de 0-t (ABCo-t) , Área Bajp la Curva de 0-infinito (ABC0-inf) , la concentración plasmática máxima (Cmax) , el tiempo donde se alcanza la Concentración plasmática máxima (tmax) , la constante de eliminación (Ke) , la vidamedia de eliminación ( i 2) , el tiempo medio de residencia (TMR) y el Área Bajo la Curva Extrapolada (ABCExt-inf) · 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)
En las Tablas 1 y 2 se presentan los resultados de concentración plasmática de los voluntarios obtenidos una vez administrada la composición desarrollada en forma de gel con 100mg/5g de sildenafil. 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.
Tabla 1. Concentración plasmática de voluntarios para el gel de 100mg/5g (t=0 a 0.83 hrs) Table 1. Plasma concentration of volunteers for the 100mg / 5g gel (t = 0 to 0.83 hrs)
NC, muestra no cuantificada . Limite de Cuantificación : 1 ng/mL
Tabla 2. Concentración plasmática de voluntarios para el gel de 100mg/g (t=l a 5 hrs) NC, unquantified sample. Quantification Limit: 1 ng / mL Table 2. Plasma concentration of volunteers for the 100mg / g gel (t = 5 hrs)
NC, muestra no cuantificada . Limite de Cuantificación : 1 ng/mL NC, unquantified sample. Quantification Limit: 1 ng / mL
En las Tablas 3 y 4 se presentan los resultados de concentración plasmática de los voluntarios obtenidos una vez administrada la composición en forma de comprimidos de sildenafil de 100 mg. 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.
Tabla 3. Concentración plasmática de voluntarios para loscomprimidos de lOOmg (t=0 a 0.83 hrs) Table 3. Plasma concentration of volunteers for lOOmg tablets (t = 0 to 0.83 hrs)
NC, muestra no cuantificada . Limite de Cuantificación: i ng/mL
Tabla 4. Concentración plasmática de voluntarios para los comprimidos de lOOmg (t=l a 5 hrs) NC, unquantified sample. Quantification Limit: i ng / mL Table 4. Plasma concentration of volunteers for lOOmg tablets (t = 5 hrs)
NC, muestra no c antificada . Limite de Cuantificación: 1 ng/mL NC, sample not c antified. Quantification Limit: 1 ng / mL
En las tablas anteriores (1 a 4) se puede apreciar como en la composición en forma de gel de sildenafil, la concentración plasmática se incrementa de una forma paulatina permaneciendo concentraciones plasmáticas terapéuticamente efectivas tales que el efecto del principio activo se mantiene a lo largo de las 5 horas de prueba. Por otro lado, los comprimidos de sildenafil, presentan un incremento demasiado rápido en la concentración plasmática con lo cual la eliminación del principio activo se lleva a cabo muy rápido, limitando el tiempo del efecto terapéutico del principio activo. 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.
Mediante el uso de la presente invención, se ha conseguido alcanzar la fase IV de la erección, es decir, una erección rígida comúnmente conocida como erección Grado 4 donde el pene está completamente firme y rígido debido a
que la presión intracavernosa alcanza la presión sistólica causado por la compresión de los músculos isquiocavernosos en la base del pene y al cierre total del flujo arterial y venoso . 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.
De manera general, las concentraciones plasmáticas para los voluntarios que participaron en el estudio comparativo entre las composición en forma de comprimido y en forma de gel oral, mostraron el mismo comportamiento solamente en cuanto al incremento y disminución de concentraciones a los diferentes tiempos de muestreo seleccionados . 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. .
Al graficar los datos para cada uno de los voluntarios se observaron los resultados descritos anteriormente, por ejemplo, en el caso del voluntario 1, la gráfica de concentración plasmática vs . tiempo de muestreo en escala semilogaritmica logio (Figura 1), muestra un incremento gradual en la concentración plasmática, es decir, no se eleva de manera inmediata la concentración del principio activo, sin embargo, si se logra obtener el efecto terapéutico deseado, en la misma gráfica, se observa además como después de las 1.66 horas de administrada la composición, se mantiene por arriba de los 100 ng/mL mientras que la concentración plasmática después de la administración de la composición en forma de comprimidos de sildenafil, a partir de 1 hora de su administración empieza
a disminuir dicha concentración plasmática presentando valores por debajo de los obtenidos con la composición en forma de gel a las 5 horas. 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.
En el caso déla gráfica de concentración plasmática vs . tiempo de muestreo en escala semilogaritmica logi0, elaborada con los datos de concentración plasmática de sildenafil para el caso del voluntario 4 (Figura 2), se observa un incremento lento en los niveles de concentración plasmática, sin embargo, a las 0.33 horas de haber sido administradas la composición en forma de gel oral, se alcanza una concentración mayor a 100 ng/mL y dicha concentración se mantiene hasta las 5 horas de administrado. Por otro lado, la concentración plasmática de sildenafil después de administrarse via oral, alcanza los 1000 ng/mL a las 0.5 horas y empieza a disminuir hasta los 100 ng/mL a las 5 horas con una tendencia a seguir disminuyendo . 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.
En las siguientes tablas se presentan los resultados de la evaluación de los parámetros farmacocinét icos obtenidos para cada una de las composiciones, a fin de observar y evaluar el comportamiento in vivo.
Tabla 5. Parámetros farmacocinéticos por voluntario para el gel de 100mg/5g 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
Cmax: concentraciónplasmáticamáxima (mg/mL) ; tmax: tiempo de C„a«; Ke: constante de eliminación (1/h); tl/2 vida media (h) ; ABC0-t; Área Bajo la Curva 0 al último tiempo de muestreo (h*mg/mL) ABCO-inf: Área Bajo la Curva extrapolada al infinito (h*mg/mL) ;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: tiempo medio de residencia (h) TMR: average residence time (h)
Tabla 6. Parámetros farmacocinéticos por voluntario para los comprimidos con 100 mg de sildenafil Table 6. Pharmacokinetic parameters per volunteer for tablets with 100 mg sildenafil
tmax: tiempo de Cmax; Cmax: concentraciónplasmáticamáxima (mg/mL); Ke : constante de eliminación (1/h); tl/2 vida media (h) ; ABC0-t; Área Bajo la Curva 0 al último tiempo de muestreo (h*mg/mL) ; ABCO-inf: Área Bajo la Curva extrapolada al infinito (h*mg/mL) ; TMR: tiempo medio de residencia (h)»
De acuerdo a las tablas 5 y 6, el tmax y Cmax muestra que mediante el uso de gel oral, se prolonga el tiempo para alcanzar la concentración máxima de sildenafil en plasma, por otra parte, dicha concentración máxima que se obtiene con el gel oral presenta8 como rango superior 950.750 ng/mL, el cual es menor significativamente en comparación al obtenido con los comprimidos de sildenafil los cuales presentan un rango superior de 1838.194 ng/mL. Sorprendentemente dichos valores de Cmax que se presentan con la administración del ge.l oral, diminuyen o eliminan los efectos secundarios que se presentan con otras formas de administración oral. 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.
En el caso de la constante de eliminación (Ke) , esta expresa el porcentaje de fármaco eliminado cada hora, mediante la administración del gel oral, se obtiene una constante de eliminación promedio de 0.312 mientras que con la administración de comprimidos orales, se obtiene una constante de eliminación promedio de 0.453. Además, el tiempo de vida media (ti/2) que es el tiempo transcurrido hasta que la concentración plasmática del principio activo se reduce a la mitad, nos permite determinar el periodo que permanece el fármaco en el organismo y el tiempo en que tardará en eliminarse, para el caso de la administración del gel oral, se obtiene un tiempo de vida media promedio de 2.742, un tiempo mayor por 0.999, comparado con el
obtenido por la administración de los comprimidos que fue de 1.744, es decir, mediante los valores de la Ke y el ti/2 se puede concluir que con la administración del gel oral, la eliminación del sxldenafil del plasma se lleva a cabo de una manera más lenta que en comparación con la administración por comprimidos orales y por lo tanto, el efecto terapéutico se mantiene durante un mayor periodo de tiempo con el gel oral. 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.
En farmacocinética se emplea frecuentemente el área bajo la curva desde tiempo cero a infinito. El área bajo la curva del primer momento se define como el área del producto de la concentración plasmática por el tiempo, desde cero hasta infinito (ABC0-inf) · El tiempo medio de residencia (TMR) es pues, la relación entre el área bajo la curva en el primer momento y el área bajo la curva del momento cero, hasta tiempo infinito, en otras palabras, el TMR puededefinirse como el tiempo medio para que las moléculas intactas transiten a través del cuerpo e involucra todos los procesos cinéticos, incluyendo la liberación "in vivo" desde la forma farmacéutica, la absorción y todos los procesos de disposición. 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.
De acuerdo a lo anterior, el TMR promedio de 4.522, obtenido de los valores farmacocinéticos de la administración del gel oral indica que mediante dicha forma de administración la permanencia del principio activo es
mayor en al menos el 40% en comparación con la administración de los comprimidos que presenta un TMR promedio de 2.938, con lo cual se infiere que la liberación "in vivo" desde la forma farmacéutica, la absorción y todos los procesos de disposición se ven modificados de manera positiva con la administración de la composición producto de esta invención ya que permiten la permanencia del sildenafil por un mayor periodo de tiempo, consiguiendo el efecto terapéutico por tiempos mayores al obtenido con la administración de otras formas de administración conocidas en el estado de la técnica. 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.
Mediante la novedosa composición desarrollada en la presente invención, se alcanzan concentraciones plasmáticas máximas en mayor tiempo, es decir, la liberación y absorción de sildenafil mediante la administración en gel oral se lleva a cabo de manera sostenida con una absorción de forma paulatina. 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.
De manera adicional, resultado de la evaluación de las características organolépticas de la novedosa composición en forma de gel oral, se muestra que de manera preponderante los voluntarios le atribuyen buenas cualidades de olor, facilidad para ingerir, consistencia agradable, sabor agradable, dulce y/o fresca sensación en la boca.
Una composición farmacéutica descrita en la presente invención se puede preparar por diferentes procedimientos conocidos en el estado de la técnica, para su administración por vía oral en forma de: gel, pasta, suspensión, gelatina, solución, emulsión, jarabe, tinturas, microdosis, jalea, cápsula de gelatina dura con contenido liquido, cápsula de gelatina blanda con contenido liquido, chicle con centro liquido y/o combinaciones de las mismas. 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.
La preparación de la composición descrita en la presente invención, se puede empacar para su comercialización a manera de ejemplo pero no de manera limitativa en: sobres, bolsas, frasco dosificador, envases de aluminio, ampolleta, jeringas, pipetas, chicles con centro liquido, tubos, cápsulas de gelatina blanda, cápsulas de gelatina dura y/o combinaciones de los mismos. 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.
Una característica adicional de la presente invención es la facilidad de portabilidad del medicamento- para su transporte de manera segura, discreta y con la ventaja de no requerir agua para ingerirse como en el caso de los comprimidos . 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.
A continuación se presentan a manera de ejemplos ilustrativos, más no limitativos, las composiciones utilizadas durante el desarrollo de la invención:
Ejemplo 1: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5gde sildenafil. 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.
Ejemplo 2: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5g de sildenafil. Example 2: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
Ejemplo 3: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5g de sildenafil. Example 3: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
Componente % p/p % W / w component
Sildenafil 2.844 Sildenafil 2,844
Glicerina 14.216
Metilparabeno 0.300Glycerin 14,216 Methylparaben 0.300
Goma Xantana 0.30Ό Xantana rubber 0.30Ό
Propilparabeno 0.040 Propylparaben 0.040
Polímero poliacrílico 0.080 0.080 polyacrylic polymer
Sucralosa 0.200 Sucralose 0.200
Sabor menta 0.120 Mint flavor 0.120
Agua purificada 79.900 Purified water 79,900
Ácido cítrico 2.000 Citric Acid 2,000
Ejemplo 4: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5g de sildenafil. Example 4: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
Ejemplo 4: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5g de sildenafil. Example 4: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of sildenafil.
Componente % p/p % W / w component
Sildenafil 2.844 Sildenafil 2,844
Glicerina 18.216 Glycerin 18,216
Metilparabeno 0.200 Methylparaben 0.200
Goma Xantana 5.400 Xantana rubber 5.400
Propilparabeno 0.020 Propylparaben 0.020
Sucralosa 0.120
Sabor menta 0.200Sucralose 0.120 Mint flavor 0.200
Agua purificada 71.000 Purified water 71,000
Ácido cítrico 2.000 Citric Acid 2,000
Ejemplo 5: Composición farmacéutica en forma de gel para administración oral con una concentración de 100 mg/5g de tadalafil. Example 5: Pharmaceutical composition in gel form for oral administration with a concentration of 100 mg / 5g of tadalafil.
Como punto final a la descripción de la invención se presentan a continuación las principales ventajas que de manera no limitativa presenta las composiciones desarrolladas : As a final point to the description of the invention, the main advantages presented in a non-limiting way are the compositions developed:
- Composición estable en forma líquida y/o semisólida de un agente inhibidor selectivo de la enzima fosfodiesterasa . - Stable composition in liquid and / or semi-solid form of a phosphodiesterase enzyme selective inhibitor.
- Composición con liberación sostenida del principio activo .
- Composición que genera una absorción paulatina y sostenida del principio activo. - Composition with sustained release of the active substance. - Composition that generates a gradual and sustained absorption of the active substance.
- La eliminación del principio activo es más lenta en comparación con otras formas de administración oral, lo que permite mayor residencia del principio activo en el organismo. - 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.
- Mediante la composición se obtiene una erección grado 4. , - A grade 4 erection is obtained through the composition,
- El tiempo del efecto terapéutico es mayor al de otras formas farmacéuticas de administración oral. - The time of the therapeutic effect is longer than other pharmaceutical forms of oral administration.
- Se evita el incremento súbito de las concentraciones plasmáticas del principio activo, aportando seguridad a la composición. - The sudden increase in plasma concentrations of the active substance is avoided, providing security to the composition.
- Composición portable y de fácil administración. - Portable composition and easy administration.
- Composición fácilmente divisible para administración de dosis menores de acuerdo a la posologia individual. - Easily divisible composition for administration of lower doses according to the individual dosage.
- Las composiciones descritas tiene aplicación para el control y/o tratamiento y/o prevención de enfermedades relacionadas con la inhibición de la enzima fosfodiesterasa . - The described compositions have application for the control and / or treatment and / or prevention of diseases related to phosphodiesterase enzyme inhibition.
- Disminuye o elimina los efectos secundarios del pricipio activo.
- Reduces or eliminates the side effects of the active principle.
Claims
1. Una composición farmacéuticaen forma de liquido y/o semisólido para administración oral de liberación modificadaque contiene una cantidad efectiva terapéuticamente de al menos un agente inhibidor selectivo de la enzima fosfodiesterasa y/o sus sales farmacéuticamente aceptables, en combinación con uno o más solventes y/o co-solventes y/o uno más excipientes farmacéuticamente aceptables. 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. Una composición farmacéutica de conformidad con la reivindicación 1, donde el agente inhibidor selectivo de la enzima fosfodiesterasa se selecciona de zaprinast, sildenafil, vardenafil y tadafil, sus sales farmacéuticamente aceptables, derivados, hidratos, profármacos, polimorfos, amorfos y/o combinaciones de los mismos. 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. Una composición farmacéutica de conformidad con la reivindicación 1, olonde el agente inhibidor selectivo de la enzima fosfodiesterasa es sildenafil, sus sales farmacéuticamente aceptables, derivados, hidratos, profármacos, polimorfos, amorfos y/o combinaciones de los mismos.
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. Una composición farmacéutica de conformidad con las reivindicaciones 1 a 3, donde por lo menos una parte sustancial de al menos un agente inhibidor selectivo de la enzima fosfodiesterasa se encuentra disuelta o solubilizada en uno o más solventes y/o uno o más co- solventes . 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. Una composición farmacéutica de conformidad con las reivindicaciones 1 a 4, caracterizada porque al menos un agente inhibidor selectivo de la enzima fosfodiesterasa se encuentra en una proporción en peso de 0.002% p/p al 20% p/p con respecto al peso total de la composición. 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. Una composición farmacéutica de conformidad con la reivindicación 1, caracterizado porque al menos un solvente y/o al menos un co-solvente son seleccionados del siguiente grupo: glicerina, agua, n-butanol, propilenglicol, 1 , 3-butandiol , ácido oleico, ácido linoleico, aceite de soya, monoglicéridoscaprílico/cáprico, 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,
diglicéridoscaprílico/cáprico, triglicéridos caprílico/cáprico, monoglicéridos caprílico/cáprico de polioxietileno, diglicéridoscaprílico/cáprico de polioxietileno , triglicéridos caprílico/cáprico de polioxietileno, ésteres de ácido graso de propilenglicol, laurato de propilenglicol, aceite de
ricino de polioxietileno, trioleato de gliceril polioxietileno, butirato de etilo, caprilato de etilo, oleato de etilo, etilen glicol monometil éter, etilen glicol dimetil éter, etilen glicol monoetil éter, etilen glicol dietil éter, etilen glicol monobutil éter, etilen glicol dibutil éter, etilen glicol monofenil éter, etilen glicol monobencil éter, etilen glicol butilfenil éter, etilen glicol terpinil éter, dietilen glicol monometil éter, dietilén glicol dimetil éter, dietilén glicol monoetil éter, dietilen glicol dietil éter, dietilén glicol monobutil éter, dietilén glicol dibutil éter, dietilen glicol monoisobutil éter, dietilen glicol divinil éter, trietilén glicol dimetil éter, trietilén glicol monoetil éter, trietilén glicol monobutil éter, trietilén glicol dimetil éter, polisorbatos , glicol éteres, alcohol isopropilico, alcohol etílico, poligliceril 3 paflmitato, lecitina, estearato de glicerina, fosfolípidos , polietilenglicol, alcohol behenilico, esteróles de soya, glicina de soya, lecitina hidrogenada, alcoholes, poligliceril-10 laurato, poligliceril-5 dioleato, poliglicerí1-5 laurato, poligliceril-5 oleato, poligliceril-6 caprilato, aceites, lisolecitina, N-metil-2-
pirrolidona, 2-pirrolidona, alcohol bencílico, glicerolformal , y/o combinaciones de los mismos. 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. Una composición farmacéutica de conformidad con las reivindicaciones 1 y 6, caracterizada porque al menos un solvente y/o al menos un co-solvente se encuentra en una proporción en peso del 80% p/p a 99.998% p/p con respecto al peso total de la composición. 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. Una composición farmacéutica de conformidad con las reivindicaciones 1 a 7, caracterizado porque contiene de manera adicional uno o más excipientes farmacéuticamente aceptables. 8. A pharmaceutical composition according to claims 1 to 7, characterized in that it additionally contains one or more pharmaceutically acceptable excipients.
9. Una composición farmacéutica de conformidad con las reivindicaciones 1 a 8, caracterizado porque contiene de manera opcional uno o más excipientes farmacéuticamente aceptables seleccionados de agentes gelificantes, uno o más agentes conservadores, agentes humectantes, agentes emulsificantes , agentes saborizantes , agentes antimicrobianos, agentes reguladores de H, agentes para suspensiones, edulcolorantes , agentes tensoactivos , agentes cotensoactivos , agentes de relleno y/o combinaciones de los mismos. 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. Una composición farmacéutica de conformidad con las reivindicaciones 1 y 9, caracterizada porque contiene uno o más excipientes farmacéuticamente aceptables en
una proporción en peso del 0.0% p/p a 15.0% p/p con respecto al peso total de la composición. 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. Una composición farmacéutica de conformidad con la reivindicación 9, caracterizada porque el agente gelificante se selecciona del siguiente grupo: celulosa microcristalina, alginatos, metilcelulosa , hidroxietilcelulosa, hidroxipropilcelulosa, goma xantana, carboximetilcelulosa sódica, metilhidroxipropilcelulosa , goma de tragacanto, harina guar, goma arábiga, almidón, carboximetilalmidón sódico, gelatina, . dióxido de silicio, poli (ácido acilico) , derivados del ácido metacrilico, estearato de aluminio, bentonita y/o sus sales farmacéuticamente aceptables y/o combinaciones de los mismos. 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. Una composición farmacéutica de conformidad con la reivindicación 1, caracterizada porque se administra por via oral. 12. A pharmaceutical composition according to claim 1, characterized in that it is administered orally.
13. Una composición farmacéutica de conformidad con las reivindicaciones 1 y 12, caracterizada porque se administra por via oral en forma de gel, pasta, suspensión, gelatina, solución, emulsión, jarabe, tinturas, microdosis, jalea, cápsula de gelatina dura con contenido liquido, cápsula de gelatina blanda con contenido liquido, chicle con centro liquido y/o combinaciones de las mismas.
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. El uso de una composición farmacéutica de conformidad con las reivindicaciones 1 a 13, para el tratamiento de enfermedades relacionadas con la enzima fosfodiesterasa . 14. The use of a pharmaceutical composition according to claims 1 to 13, for the treatment of diseases related to the phosphodiesterase enzyme.
15. El uso de una composición farmacéutica de conformidad con las reivindicaciones 1 a 14, donde la enfermedad relacionada con la enzima fosfodiesterasa se selecciona del siguiente grupo: angina de pecho, hipertensión, aterosclerosis , falla cardiaca, hipertensión arterial pulmonar grado funcional II y III y/o disfunción sexual. 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. El uso de una composición farmacéutica de conformidad con las reivindicaciones 1 a 15, para el tratamiento de una disfunción sexual. 16. The use of a pharmaceutical composition according to claims 1 to 15, for the treatment of sexual dysfunction.
17. El uso de una composición farmacéutica de conformidad con la reivindicación 16, donde la disfunción sexual puede ser disfunción eréctil masculina, síndrome de deseo sexual hipoactivo, síndrome de anorgasmia femenina, síndrome de eyaculacion precoz, síndrome de vaginismo, síndrome de evitación sexual y trastorno por angustia sexual, eyaculacion retardada, insensibilidad orgásmica, dispereunia, anorgasmia femenina e insensibilidad orgásmica.
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. El uso de una composición farmacéutica de conformidad con la reivindicación 16, donde la disfunción sexual es disfunción eréctil masculina.
18. The use of a pharmaceutical composition according to claim 16, wherein the sexual dysfunction is male erectile dysfunction.
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MX2013001279A MX2013001279A (en) | 2013-01-31 | 2013-01-31 | Pharmaceutical composition with a selective enzyme phosphodiesterase inhibitor in an oral gel form. |
MXMX/A/2013/001279 | 2013-01-31 |
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CN112587476A (en) * | 2020-12-23 | 2021-04-02 | 无锡市妇幼保健院 | Sildenafil gel new formulation suitable for neonatal arterial hypertension and preparation method thereof |
CN113577079A (en) * | 2021-07-28 | 2021-11-02 | 山东裕欣药业有限公司 | Preparation method and composition of phosphodiesterase inhibitor |
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ES2584248B1 (en) * | 2015-03-24 | 2017-04-19 | Farmalider, S.A. | Pharmaceutical composition of sildenafil citrate in suspension form for oral use |
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