WO2014119985A2 - Composition pharmaceutique présentant un inhibiteur sélectif de l'enzyme phosphodiestérase sous forme de gel oral - Google Patents

Composition pharmaceutique présentant un inhibiteur sélectif de l'enzyme phosphodiestérase sous forme de gel oral Download PDF

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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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pharmaceutical composition
ether
composition according
ethylene glycol
pharmaceutically acceptable
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WO2014119985A3 (fr
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Miguel Ángel GARCIA PÉREZ
Gabriel MARCELÍN JIMÉNEZ
Concepción Albina VÁZQUEZ FLORES
Ricardo David ÁVILA CEDILLO
Alionka Citlalli P. ANGELES MORENO
Octavio CARO RODRÍGUEZ
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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
    • 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
    • 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
    • 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
    • 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
    • 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

La présente invention concerne une nouvelle composition semi-solide stable pour l'administration orale qui comprend au moins un agent inhibiteur sélectif de l'enzyme phosphodiestérase et/ou au moins un excipient pharmaceutiquement acceptable. La composition, une fois administrée par voie orale, conserve une libération soutenue, dupliquant le temps de permanence de l'ingrédient actif dans l'organisme et prolongeant l'effet thérapeutique de l'inhibiteur sélectif de l'enzyme phosphodiestérase. La composition semi-solide est destinée à être utilisée pour l'inhibition sélective de l'enzyme phosphodiestérase par exemple de manière non limitative, pour le contrôle ou le traitement de la dysfonction érectile, présentant un effet thérapeutique pouvant aller jusqu'à 8 heures.
PCT/MX2014/000028 2013-01-31 2014-01-28 Composition pharmaceutique présentant un inhibiteur sélectif de l'enzyme phosphodiestérase sous forme de gel oral Ceased WO2014119985A2 (fr)

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MX2013001279A MX2013001279A (es) 2013-01-31 2013-01-31 Composicion farmaceutica con un inhibidor selectivo de la enzima fosfodiesterasa en forma de gel oral.
MXMX/A/2013/001279 2013-01-31

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WO2014119985A2 true WO2014119985A2 (fr) 2014-08-07
WO2014119985A3 WO2014119985A3 (fr) 2014-11-27

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2649834C1 (ru) * 2016-07-06 2018-04-04 Фармалидер С.А. Фармацевтическая композиция силденафила цитрата в форме суспензии для перорального применения
CN112587476A (zh) * 2020-12-23 2021-04-02 无锡市妇幼保健院 一种适用于新生儿动脉高压的西地那非啫喱新剂型及其制备方法
CN113577079A (zh) * 2021-07-28 2021-11-02 山东裕欣药业有限公司 一种磷酸二酯酶抑制剂的制备方法及组合物
US20230091358A1 (en) * 2017-09-22 2023-03-23 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
WO2024215214A1 (fr) * 2023-04-08 2024-10-17 Sativa-Med Spółka Akcyjna Composition liquide d'inhibiteurs de phosphodiestérase de type 5 (pde-5), son procédé de préparation et son utilisation pour le traitement des dysfonctionnements érectiles

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ES2584248B1 (es) * 2015-03-24 2017-04-19 Farmalider, S.A. Composición farmacéutica de citrato de sildenafilo en forma de suspensión para uso oral

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AU2001232344A1 (en) * 2000-02-21 2001-08-27 Fujisawa Pharmaceutical Co. Ltd. Liquid preparation with improved absorbability
JP5686978B2 (ja) * 2009-03-18 2015-03-18 第一三共ヘルスケア株式会社 シルデナフィルクエン酸塩含有内服液剤及びその液剤含有容器
DE102009033396A1 (de) * 2009-07-16 2011-01-20 Ratiopharm Gmbh Wässrige Lösung und gelatinierte Zusammensetzung umfassend einen Phosphodiesterase-5-Inhibitor sowie diesbezügliche Verfahren und Verwendung
CN102204917B (zh) * 2011-03-30 2013-10-09 天津红日药业股份有限公司 一种含有法舒地尔与西地那非的药物组合物及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
RU2649834C1 (ru) * 2016-07-06 2018-04-04 Фармалидер С.А. Фармацевтическая композиция силденафила цитрата в форме суспензии для перорального применения
US20230091358A1 (en) * 2017-09-22 2023-03-23 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
CN112587476A (zh) * 2020-12-23 2021-04-02 无锡市妇幼保健院 一种适用于新生儿动脉高压的西地那非啫喱新剂型及其制备方法
CN112587476B (zh) * 2020-12-23 2022-09-27 无锡市妇幼保健院 一种适用于新生儿动脉高压的西地那非啫喱新剂型及其制备方法
CN113577079A (zh) * 2021-07-28 2021-11-02 山东裕欣药业有限公司 一种磷酸二酯酶抑制剂的制备方法及组合物
CN113577079B (zh) * 2021-07-28 2022-08-23 山东裕欣药业有限公司 一种磷酸二酯酶抑制剂的制备方法及组合物
WO2024215214A1 (fr) * 2023-04-08 2024-10-17 Sativa-Med Spółka Akcyjna Composition liquide d'inhibiteurs de phosphodiestérase de type 5 (pde-5), son procédé de préparation et son utilisation pour le traitement des dysfonctionnements érectiles

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