MX2007002167A - Pulmonary delivery of inhibitors of phosphodiesterase type 5 - Google Patents

Abstract

Provided herein are compositions of 1) diketopiperazine salts PDE5 inhibitors and 2) DKP microparticles having a PDE5 inhibitors thereon, as well as methods for the pulmonary delivery of these compositions for the treatment of pulmonary hypertension and sexual dysfunction(s).

Description

PULMONARY SUPPLY OF FOSFO INHIBITORS OF THIS TYPE 5 RATE RELATED APPLICATION This application claims priority according to 35 U.S.C. §119 (e) of US Provisional Patent Application No. 60 / 603,764, filed on August 23, 2004. Field of the Invention The present invention relates generally to the treatment of pulmonary hypertension and sexual dysfunction, including dysfunction erectile and female sexual dysfunction. In particular, the present invention relates to diketopiperazine salts of phosphodiesterase type 5 inhibitors. Likewise, the present invention relates to the pulmonary administration of phosphodiesterase type 5 inhibitors, particularly substituted pyrimidinones, such as pyrazolopyrimidinones, sildenafil and vardenafil, using microparticle compositions comprising diketopiperazine or substituted polymers. BACKGROUND OF THE INVENTION Sildenafil, a phosphodiesterase inhibitor of pyrazolopyrimidinone type 5 (PDE5), is a widely prescribed drug with FDA approval for the treatment of erectile dysfunction (US Patent No. 6,469,012, entitled "Pyrazolopyrimidines for the treatment of impotence. "). It has also been applied to female sexual dysfunction of a variety of etiologies (see for example: Dasgupta et al., J. Urol. 171: 1189-93, 2004; Laan et al., J. Womens Health Gend., Based Med. 11: 357 -365, 2002, Berman and Associates, J. Sex Marital Ther 27: 411-420, 2001, Vemulapalli and Kurowski, Life Sci. 67: 23-29, 2000, Sher and Fisch, Hum. Reprod. 15: 806- 809, 2000; Nurnberg and associates, Psychiatr.Serv. 50: 1076-1078, 1999; Shen et al., J. Reprod. Med. 44: 535-542, 1999). Sildenafil and other PDE5 inhibitors have also been shown to be useful in the treatment of pulmonary hypertension (see for example: Leuchte et al., Chest. 125: 580-6, 2004; Bonnell et al., Ann. Thorac. Surg. 77: 238- 42, 2004, Travadi and Patole, Pediatr Pulmonol 36: 529-35, 2003, Michelakis and associates, Circulation 108: 2066-9, 2003, Bhatia and associates, Mayo Clin. Proc. 78: 1207-13, 2003). . More recently, sildenafil received approval from the FDA for the treatment of pulmonary arterial hypertension (PAH). Other drugs with related chemical structures, mechanisms of action and clinical indications include vardenafil and tadalafil. A point of user dissatisfaction with said drugs has been the duration and variability of the time necessary for the drug to have an effect. As marketed through their respective manufactures, these drugs are available as tablets administered orally. Therefore, the drug enters the bloodstream through the digestive tract. This may require one or several hours depending in part on food consumption. Likewise, these tablets administered orally may be exposed to drug-drug interactions, food-drug interactions and / or may be poorly absorbed by the gastrointestinal tract. In an attempt to overcome these problems, pharmacists have made chewable tablets and gums from crushed tablets to facilitate the absorption of the drug through the sublingual and buccal routes, even through these routes the drugs may require at least 15 20 minutes to take effect. In the early 70s, it was discovered that certain medicines can be administered as dry powder directly to the lungs by inhalation through the mouth or inspiration through the nose. This process allows the medicine to be derived from the digestive system, and in certain cases, it may allow smaller doses to be used to achieve the same results as ingested or orally injected medicines. In some cases, the process provides a delivery technique that reduces the side effects associated with these drugs and reduces interactions with other prescribed drugs, as well as provides a faster absorption of drug medication and / or uptake.

Accordingly, there is a need for a rapid-action pulmonary delivery system for the treatment of pulmonary hypertension and sexual dysfunction. Brief Description of the Invention The present invention provides compositions and methods for pulmonary delivery of phosphodiesterase type 5 (PDE5) inhibitors to treat pulmonary hypertension and sexual dysfunction. Compositions according to the present invention include diketopiperazine (DKP) salts of PDE5 inhibitors and DKP microparticles associated with PDE5 inhibitors. The embodiments of the present invention provide forms of treatment of sexual dysfunction including erectile dysfunction and female sexual dysfunction. The present invention also provides compositions that include compositions of diketopiperazine salts of PDE5 inhibitors, including but not limited to, substituted pyrimidinones and pyrazolopyrimidinones such as sildenafil, vardenafil, tadafinil and analogs thereof. In one embodiment of the present invention, diketopiperazine has the general structure: Formula 1 wherein the ring atoms E- and E2 are either O or N and at least one of Ri and R2 contain a carboxyl group. In another embodiment of the present invention, both Ri and R2 contain a carboxyl group. One embodiment of the present invention provides a diketopiperazine salt wherein diketopiperazine is selected from the group consisting of 2,5-diketo-3,6-di (4-phenylaminobutyl) piperazine, 2,5-diketo-3,6- d, (4-sucinylaminobutyl) piperazine, 2,5-diketo-3,6-di (4-glutarylaminobutyl) piperazine, and 2,5-diketo-3,6-d, (4-malelylaminobutyl) piperazine. One embodiment of the present invention includes a diketopiperazine salt of a PDE5 inhibitor wherein the ratio of the PDE5 inhibitor to the diketopiperazine salt is about 1: 1 or about 2: 1. In another embodiment of the present invention, the diketopiperazine salt is formulated as a dry microparticle. Another embodiment of the present invention includes a microparticle composition for the delivery of a PDE5 inhibitor comprising diketopiperazine microparticles, wherein the microparticles are soluble in a defined first pH and soluble in a defined second pH, and a PDE5 inhibitor or a salt pharmaceutically! acceptable of it. The PDE5 inhibitors of the present invention can be selected from the group consisting of sildenafil citrate, vardenafil hydrochloride and tadalafil. In one embodiment of the present invention, the microparticle composition is formed by precipitation, either by freezing or cooling, of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof in the diketopiperazine microparticles. In one embodiment of the present invention, the microparticle composition is formed by spray-dried diketopiperazine microparticles suspended in a solution of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. In another embodiment of the present invention, the pharmaceutically acceptable salt is a diketopiperazine salt. In one embodiment of the present invention, the microparticle composition is formed by precipitation of a solution comprising a diketopiperazine and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention provides a microparticle composition for delivery of a PDE5 inhibitor to the pulmonary system, wherein the composition comprises diketopiperazine microparticles having a diameter of between about 0.5 microns and about 10 microns, and which releases the PDE5 inhibitor incorporated or a pharmaceutically acceptable salt thereof at a pH of about 6.0 or greater.

In another embodiment of the present invention, the microparticle composition is formulated for oral administration. Another embodiment of the present invention provides a method for treating sexual dysfunction, wherein the method comprises supplying to the pulmonary system of a patient in need of treatment for sexual dysfunction, diketopiperazine microparticles comprising a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. Sexual dysfunction is erectile dysfunction or female sexual dysfunction. Female sexual dysfunction is selected from the group consisting of sexual dysfunction induced by antidepressants, sexual dysfunction secondary to multiple sclerosis, anorgasmia, low stimulation, delayed orgasm, decreased vaginal congestion, dyspareunia and infertility-induced sexual dysfunction. One embodiment of the present invention provides a method for treating pulmonary hypertension, wherein the method comprises delivering to the pulmonary system of a patient in need of treatment for pulmonary hypertension, diketopiperazine microparticles comprising a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. . Pulmonary hypertension is selected from the group consisting of primary pulmonary hypertension (PPH), acute pulmonary hypertension, pulmonary arterial hypertension (PAH), hypertension associated with pregnancy such as preeclampsia, and persistent pulmonary hypertension of the newborn (PPHN).

A method for oral delivery of a diketopiperazine formulation that is rapidly absorbed is also provided. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates an isometric view of a suitable exemplary inhaler for delivering the compositions of the present invention to the pulmonary system. Figure 2 illustrates the chemical structure of sildenafil citrate. Figure 3 illustrates the chemical structure of vardenafil hydrochloride. Figure 4 illustrates the chemical structure of the sildenafil analogue UK 343-664. Figure 5 illustrates the chemical structure of the sildenafil analogue UK 347-334. Figure 6 illustrates the chemical structure of tadalafil. Detailed Description of the Invention The present invention includes compositions of 1) diketopiperazine salts (DKP) or inhibitors of phosphodiesterase type 5 (PDE5), and 2) DKP microparticles having a PDE5 inhibitor associated therewith, as well as methods for delivery of these compositions for the treatment of pulmonary hypertension and sexual dysfunction (s). Pyrazolopyrimidjnones, such as sildenafil, vardenafil, UK 343-664 and UK 347-334 (see figures 2, 3, 4 and 5, respectively and table 1) are inhibitors of cyclic guanosine monophosphate-specific phosphodiesterase type 5 (PDE5). of enzymes (cGMP). Cyclic GMP is involved in the physiological regulation of smooth muscle relaxation. Nitric oxide (NO) activates enzyme guanylate cyclase, which forms cGMP which in turn leads to smooth muscle relaxation, vasodilation and increased blood flow. PDE5 converts cGMP to GMP, thereby counteracting the vasodilation carried out by cGMP; The inhibition of PDE5 increases vasodilation that facilitates the erection of the penis in men and congestion of the endometrial and vaginal tissues in women. Similarly, vasodilation can reduce hypertension.

Table 1 Other substituted pyrimidinone PDE5 inhibitors, such as tadalafil (Figure 6 and Table 1), can be effective for prolonged periods of time, attenuating the imperative for a rapid generation of effectiveness for the treatment of sexual dysfunction. However, the rapid generation of effectiveness can still offer a measure of flexibility and convenience for the user. Said rapid generation may also be important for the application of the treatment of pulmonary hypertension, particularly of acute forms. These PDE5 inhibitors have usually been administered orally. The oral administration route is associated with a slower absorption to the optimum desired, which results in a delayed effectiveness. The administration of PDE5 inhibitors through the lungs facilitates improved and rapid absorption through the large surface area produced by the lungs. In one embodiment of the present invention, the compositions are provided from DKP salts of PDE5 inhibitors. In another embodiment of the present invention, DKP microparticles having PDE5 inhibitors associated therewith are provided. As used in the present invention, the term "diketopiperazine" or "DKP", include diketopiperazines and salts, derivatives, analogs and modifications thereof, which are within the scope of general formula 1, wherein the ring atoms E- and E2 at positions 1 and 4 are either O or N and at least some of the side chains R and R2 located at positions 3 and 6, respectively, contain a carboxylic acid (carboxylate) group. Compounds according to formula 1 include, without limitation, diketopiperazines, dicetomorpholines and diketodioxanes and their substitution analogs. For exemplary purposes of the preferred embodiment, diketopiperazines and their derivatives will be described in greater detail; however, it will be understood that this is not the exception of other heterocyclic compounds based on formula 1.

Formula 1 Diketopiperazines, in addition to making aerodynamically suitable microparticles, also facilitate transport through cell layers, further accelerating absorption in the circulation. Diketopiperazines can be formed into particles that incorporate a drug or particles in which a drug can be adsorbed. The combination of a drug and a diketopiperazine can start improved drug stability. These particles can be administered by various routes of administration. In the form of dry powders, these particles can be delivered by inhalation to specific areas of the respiratory system, depending on the size of the particle. In addition, the particles can be made small enough for incorporation into an intravenous suspension dosage form. Oral administration is also possible with the particles incorporated in a suspension, tablets or capsules. Diketopiperazines can also facilitate the absorption of an associated drug. In another embodiment of the present invention, DKP is a derivative of 3,6-di (4-aminobutyl) -2,5-diketopiperazine, which can be formed by (thermal) condensation of the amino acid plant. Exemplary derivatives include 3,6-di (succinyl-4-aminobutyl) -, 3,6-di (maleyl-4-aminobutyl) -, 3,6-di (glutaryl-4-aminobutyl) -, 3,6 -di (malonyl-4-aminobutyl) -, 3,6-di (oxalyl-4-aminobutyl) -, and 3,6-di (fumaryl-4-aminobutyl) -2,5-diketopiperazine (hereinafter referred to as diketopiperazine) fumaryl or FDKP). The use of DKPs for drug delivery is known in the art (see for example, U.S. Patent Nos. 5,352,461 entitled "Self-assembling Dicetopiperazine Drug Delivery System"; 5,503,852 entitled "Method for Developing a Delivery System. of Dicetopiperazine Drug Self-assembly "; 6,071,497 entitled" Microparticles for Delivery to Lungs Comprising Dicetopiperazine "and 6,331,318 entitled" Delivery System of Dicetopiperazine Substituted with Carbon ", each of which is incorporated in its entirety to this invention as reference for all its teachings with respect to diketopiperazines and drug delivery transmitted by diketopiperazines). The use of DKP salts is described in the pending US Patent Application No. ?? / ???, ??? filed on August 23, 2005 and entitled "Dicetopiperazine Salts for Supply of Drugs and Related Methods" and known to all through US Provisional Patent Application No. 60 / 603,761, which is incorporated herein in its entirety invention as reference. The supply of pulmonary drugs using microparticles DKP, is described in US Patent No. 6,428,771 entitled "Method for Delivery of Drugs to the System", which is incorporated in its entirety to the present invention as a reference. As used in the present invention, the term "microparticles" includes microcapsules that have an outer shell composed of either a diketopiperazine alone or a combination of a diketopiperazine and one or more drugs. It also includes microspheres containing drugs dispersed throughout the sphere; particles of irregular shape; and particles in which the drug is coated on the surface (s) of the particle or fills in the voids therein. To combine the PDE5 inhibitors with a DKP, several alternatives are available. In one embodiment of the present invention, a DKP salt of a PDE5 inhibitor is produced. In a non-limiting example, the; Sildenafil is normally sold as a citrate salt. An anionic DKP, such as FDKP, can be replaced by citrate 'to make the FDKP salt of sildenafil. The FDKP salt of sildenafil can be prepared by dissolving both sildenafil and FDKP in a suitable solvent in the proper ratio. For example, the removal of solvent by evaporation, lyophilization or spray drying, can provide the isolated salt in the form of an oil or a dry powder. Similarly, salts incorporating other PDE5 inhibitors (eg, tadalafil, vardenafil, and the like) or other substituted DKPs can also be made. In another embodiment of the present invention, microparticles that combine a DKP and a PDE5 inhibitor, or a salt thereof, are prepared by spray drying a solution of the PDE5 inhibitor, or salt thereof, and DKP or by drying by Spray a solution of the PDE5 inhibitor or a salt thereof, where the DKP microparticles are suspended. These solutions can also be lyophilized. Depending in part on the concentration of the solution, a suitable dry powder can be obtained directly (see for example, US Patent No. 6,440,463 entitled "Methods for Fine Powder Formation", which is incorporated in its entirety to the present invention. as reference). Alternatively, the solid obtained can be micronized to obtain particles of a suitable size. For pulmonary administration, particles less than about 10μ, preferably less than about 5μ and more preferably from about 1μ to about 3μ are desirable.

In one embodiment, PDE5 inhibitors or salts thereof, are associated with microparticles by dissolving a DKP with acid R groups in bicarbonate or other basic solution, adding the active agent in solution or suspension, and subsequently precipitating the microparticle by addition of acid, such as 1 M citric acid. In another embodiment, the PDE5 inhibitors or salts thereof, are associated with microparticles by dissolving a DKP with basic R groups in an acidic solution, such as 1 M citric acid, by adding the active agent in solution or suspension, and subsequently precipitating the microparticle adding bicarbonate or another basic solution. In yet another embodiment, the PDE5 inhibitors or salts thereof, are associated with microparticles by dissolving a DKP with both acidic and basic R groups in an acidic or basic solution, adding the active agent in solution or suspension to be encapsulated. , later precipitating the microparticle neutralizing the solution. The microparticles; they can be stored in a dry state and suspended for administration to a patient. In a first embodiment, the reconstituted microparticles maintain their stability in an acid medium and dissociate as the medium reaches a physiological pH within the range of between 6 and 14. In a second embodiment, the suspended microparticles maintain their stability in a basic medium and they dissociate at a pH between 0 and 6. In a third embodiment, the reconstituted microparticles maintain their stability in an acidic or basic medium and dissociate as the medium reaches a physiological pH within the pH range of between 6 and 8. impurities are usually eliminated when the microparticles are precipitated. However, impurities can also be removed by washing the particles to dissolve the impurities. A preferred wash solution is water or aqueous buffer. Solvents in addition to water can also be used to wash the microspheres or precipitate the DKPs, in order to remove impurities that are not soluble in water. Any solvent in which neither the PDE5 inhibitor or salt thereof nor the DKP is soluble is suitable. Examples include acetic acid, ethanol and toluene. In an alternative embodiment, the DKP microparticles are prepared and provided in a suspension, usually an aqueous suspension, to which a solution of the PDE5 inhibitors, or salts thereof, is subsequently added. The suspension is subsequently lyophilized or freeze-dried to produce DKP microparticles having a PDE5 inhibitor coating. Pulmonary delivery can be achieved very effectively using dry powders comprising the microparticles of the present invention, and can lead to rapid absorption into the circulation (bloodstream).

Once a dry powder is obtained it can be administered using a variety of dry powder inhalers commercially available or otherwise known in the art. Particularly suitable inhalation systems are described in US Patent Applications Nos. 09 / 621,092 and 10 / 655,153, both entitled "Unit Dose Capsules and Dry Powder Inhaler", which are incorporated in their entirety to the present invention. as reference. The drug powder inhaler claimed in the pending patent applications referenced above is illustrated in Figure 1. Figure 1 shows an embodiment of a dry powder inhaler 10 suitable for delivering the compositions described in the present invention to the pulmonary system . In conceptual broad terms, an inhaler housing 15 includes an inlet section 20, a mixing section 30 and a nozzle part 40. In the preferred embodiment, this inhaler housing 15 is approximately 93 mm in length, 38 mm in height and 22 mm thick. ' The other parts illustrated and described in the present invention are of proportional size. The mouthpiece 40 can be turned from a position stored within the housing 15 to a cartridge installation position in which the mouthpiece 40 is oriented 90 degrees towards the housing dimension. When the lid 352 closes, the mouth piece can be further rotated in an operating position in which the mouthpiece is located 180 degrees from the position of the dimension along the housing. The buccal piece 40 is stored inside the inhaler 15, a sliding dirt protection cover 16 slidably slidable and stored in the housing can slide upwards to protect the mouthpiece 40 and the entrance of the inhalation passage of the inhaler. The housing 15 can be formed of a polycarbonate plastic that is radiation-proof for the rapid sterilization of the inhaler in mass production, as well as the use of hospital-clinic. A cartridge containing a powder formulation of A composition of the present invention is inserted into the mixing chamber 30, for pulmonary delivery of the composition. The diketopiperazine salts of PDE5 inhibitors or particles having PDE5 inhibitors associated therewith, are suitable for oral administration, for example, in the form of tablets, pills, capsules or lozenges. These microparticles, depending on the chemical nature and size, will be either absorbed in, or passed through the epithelial lining of the gastrointestinal tract within the bloodstream or lymphatic system. These may contain any of the following ingredients or compounds of a similar nature: a linker such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel ™, or corn starch; a lubricant such as magnesium stearate or Sterotes ™; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to the material of the above type, a liquid carrier. In addition, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, shellac or other enteric agents. In another embodiment of the present invention, there is provided a method of treating sexual dysfunction, wherein the method comprises delivery to the pulmonary system of a patient in need of sexual dysfunction treatment, a DKP salt of a PDE5 inhibitor or DKP microparticles comprising a PDE5 inhibitor or a salt thereof. To treat a patient with sexual dysfunction, the patient simply inhales the convention of the present invention before erectile function is desired at the time of sexual intercourse in a sufficient pharmacologically active amount to achieve vasodilation. Physicians and pharmacologists skilled in the art have knowledge in the crushing of doses to obtain an amount sufficient to achieve the desired clinical end point. A pharmacologically sufficient amount of drug is a dose that achieves the desirable clinical endpoint, but which has no undesirable side effects at a level that could result in the completion of treatment. Typical doses for the pulmonary drug delivery of the present invention may be from about 0.1 to about 100 mg, depending on the particular drug being used. Preferably, the dose delivered to the alveolar surface is within the range of from about 0.5 to about 50 mg. Although conventional oral PDE5 inhibitor formulations do not produce effective systemic concentrations of the drug until several hours after administration, an oral formulation that provides rapid action generation as an alternative for pulmonary delivery is therefore desirable. A fast acting formulation can be prepared by the use of an agent, such as a DKP that facilitates rapid absorption of the drug after oral administration. Therefore, an oral dosage form containing, for example, a combination of FDKP and sildenafil, either in the form of a salt or a physical mixture, can provide rapid generation of the action of the drug. There is sexual dysfunction in many forms and can be classified into two classes, male sexual dysfunction and female sexual dysfunction. The most common form of male sexual dysfunction is erectile dysfunction. Female sexual dysfunction can be due to a variety of causes, including but not limited to, sexual dysfunction induced by antidepressants, sexual dysfunction secondary to multiple sclerosis, anorgasmia, low arousal, delayed orgasm, decreased vaginal congestion, dyspareunia or sexual dysfunction induced by infertility In one embodiment of the present invention, there is provided a method for treating pulmonary hypertension, wherein the method comprises delivering to the pulmonary system of a patient in need of pulmonary hypertension treatment, a DKP salt of a PDE5 inhibitor or DKP microparticles comprising a PDE5 inhibitor or a salt thereof. For the treatment of pulmonary hypertension, the patient can take a dose of 0.5 to 50 mg one to six times a day. The ability to administer a therapeutically active drug directly to the inner surface of the lung is particularly important for the pathology of pulmonary hypertension. As compared to systemic administration, pulmonary administration can provide significant improvement and efficiency in the treatment of this life-threatening condition. Pulmonary hypertension is a rare condition of the I blood vessels of the lung, where the pressure in the pulmonary artery I (the blood vessel that is driven from the heart to the lungs) | It rises above normal levels and can become a risk to life. Symptoms of pulmonary hypertension include shortening of breathing with minimal exertion, fatigue, chest pain, dizziness, and fainting spells. When pulmonary hypertension occurs in the absence of a known cause, it is referred to as primary pulmonary hypertension (PPH). This term should not be constructed as meaning that comq has only one name is a single disease. There are likewise many known causes of PPH. PPH is extremely rare, occurring in approximately two people per million in the population per year. Secondary pulmonary hypertension (HPS) means that the cause is known. Common causes of HPS include respiratory ailments, emphysema and bronchitis. Other less frequent causes are inflammatory diseases or vascular collagen diseases, such as scleroderma, CREST syndrome, systemic lupus erythematosus (SLE). Congenital heart failures cause extra blood drips through the lungs such as ventricular and atrial septal defects, thromboembolism: chronic lung disease (old blood clots in the pulmonary artery), HIV infection, liver disease and diet drugs type fenfluramine and dexfenfluramine, and are also causes of pulmonary hypertension. Many forms of | Pulmonary hypertension are suitable for treatment with the compositions of the present invention, including but not limited to, primary pulmonary hypertension (PPH), acute pulmonary hypertension, pulmonary arterial hypertension (PAH), hypertension associated with pregnancy such as preeclampsia and persistent pulmonary hypertension of newborns (PPHN). EXAMPLES Example 1 Preparation of Sildenafil FDKP Salt - Method 1 13 grams of FDKP (28.73 mmol, 1 equiv.) Were placed in a 250 mL 3-necked round bottom flask equipped with a reflux condenser, magnetic stir bar, and thermometer. The reaction is run under a nitrogen atmosphere. Water (150 mL) and sildenafil (13.6 g, 1 equiv.) Were added to the bottle in sequence. The resulting yellow solution was heated to a temperature of 50 ° C and held for 2 hours. The solution was filtered with heat to remove any insoluble material. The water in the sample was removed by rotary evaporation. The recovered solids were dried in a vacuum oven (50 ° C, 76: 2 cm (30 inches) of mercury) overnight. Subsequently, the salt was tested with respect to moisture content! (Karl Fischer) and sodium content (elemental analysis and grinding). The production of the salt is usually from about 90% to about 95% by weight. Example 2 Preparation of Sildenafil FDKP Salt - Method 2 13 grams of FDKP (28.73 mmol, 1 equiv.) And ethanol (150 mL) were placed in a 250 mL 3-neck round bottom flask equipped with a reflux condenser, magnetic stirring bar and thermometer. The reaction is run under a nitrogen atmosphere. The pulp was heated to a temperature of 50 ° C. Sildenafil (13.6 g, 1 equiv.) Was added in one portion. The resulting paste was maintained at a temperature of 50 ° C for 2 hours. The contents of the reaction were cooled to room temperature (from 20 ° C to 30 ° C) and the solids were isolated by vacuum filtration. The recovered salt was washed with ethanol (300 mL) and acetone (150 mL) and dried in a vacuum oven (50 ° C, 76.2 cm (30 inches) of mercury) overnight. No additional purification was required. Subsequently, the salt was tested with respect to moisture content (Karl Fischer) and sodium content (elemental analysis and grinding). The production of the salt is usually from 90% to 95% by weight. Example 3 Preparation of FDKP Microparticles Associated with Sildenafil Sildenafil is associated with 2, 5-diketo-3,6-di (4-phenylaminobutyl) piperazine (FDKP) in microparticles adding 1.6 grams of sildenafil to 320 mL of a 0.5% solution of sodium lauryl sulfate in 0.1 M sodium bicarbonate. To this suspension were added 4 grams of 2,5-diketo-3,6-di (4-phenylaminobutyl) piperazine. The final suspension was placed under a sonicator probe and sonicated for a period of one minute while adding 320 mL of 0.1 M citric acid.

The suspension was sonicated for an additional five minutes at room temperature, at which time the precipitation of the microparticles was completed. The particles were isolated by centrifugation at 10,000 rpm for ten minutes, and the sample was lyophilized at room temperature overnight. The production was determined after drying. The size of the FDKP microparticles containing PFE5 was determined by electron scanning microscopy (SEM), visible light microscopy with image analysis, laser light scanning, laser diffraction and i Coulter counter techniques. Unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as molecular weight, reaction conditions, etc., used in the present specification and in the claims, shall be understood as being modified in all cases for the term "approximately". Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired properties that may be obtained through the present invention. Finally, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter must be constructed at least in light of the number of significant digits reported and applying ordinary rounding techniques. Although the numerical ranges and parameters that establish the scope of the present invention are approximations, the numerical values established in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors that necessarily result from the standard deviation found in their respective test measures. The terms "a", "a", "the", "the" and similar references used within the context of the present invention (especially within the context of the following claims), will be constructed to cover both the singular and the plural, unless expressly indicated in the present invention or clearly contradicted in context. The mention of ranges of values in the present invention is intended to serve merely as a method to refer individually to each value separately that is within this range. Unless otherwise indicated in the present invention, each individual value is incorporated in the specification as if it were mentioned individually. All of the methods described herein can be carried out in any suitable order unless otherwise indicated or clearly contradicted in context. The use of any and all examples, or example language (for example, "such as") provided in the present invention, is intended to merely illuminate the present invention and not contain limitation for the scope thereof in a manner contrary to that claimed . The language in the present specification should not be constructed as indicating any unclaimed element essential for the practice of it. The groups of alternative elements or embodiments of the present invention described herein will not be construed as limitations. Each element of the group can be referred to and claimed individually or in any combination of other elements of the group or other elements found here. It is anticipated that one or more elements of a group may be included, or removed from a group for reasons of convenience and / or patents. When such inclusion or deletion occurs, the present specification is considered to contain the group as modified, which meets the written description of all Markush groups used in the appended claims. Preferred embodiments of the present invention are described, including the best mode known to the inventors to carry out the same. Of course, variations of said preferred embodiments will be appreciated by those skilled in the art at the time of reading the above description. The inventor expects those skilled in the art to employ such variations as appropriate, and the inventors claim that the present invention is carried out in a manner different from that specifically described herein. Accordingly, the present invention includes all modifications and equivalents of subject matter mentioned in the claims appended thereto, as permitted by applicable law. In addition, any combination of the elements described above in all possible variations thereof is comprised in the present invention, unless otherwise indicated or clearly contradicted in context. In addition, numerous references to patents and printed publications have been made throughout the specification. Each of the aforementioned references and printed publications are incorporated in their entirety individually to the present invention as a reference. Finally, it will be understood that the embodiments of the present invention described herein are illustrative of the principles thereof. Other modifications that may be employed are within the scope of the present invention. Therefore, by way of example, and not limitation, the alternative configurations of the present invention may be used in accordance with the teachings shown herein. Accordingly, the present invention is not limited to what is shown and accurately described therein.

Claims (30)

1. R E I V I N D I C C O N S 1. A composition comprising a diketopiperazine salt of a phosphodiesterase type 5 (PDE5) inhibitor.
2. 2. The composition as described in claim 1, characterized in that the PDE5 inhibitor is a substituted pyrimidinone.
3. 3. The composition as described in the claim 2, characterized in that the substituted pyrimidinone selected from the group consisting of sildenafil, vardenafil, tadalafil and analogues thereof.
4. 4. The composition as described in claim 1, characterized in that the PDE5 inhibitor is a pyrazolopyrimidinone.
5. 5. The composition as described in claim 4, characterized in that the pyrazolopyrimidinone is selected from the group consisting of sildenafil, vardenafil and analogues thereof.
6. 6. The composition as described in claim 1, characterized in that diketopiperazine has the general structure: Formula 1 wherein the ring atoms E-i and E2 are either O or N and at least one of Ri and R2 containing a carboxyl group.
7. 7. The composition as described in claim 6, characterized in that both R1 and R2 contain a carboxyl group.
8. 8. The composition as described in claim 6, characterized in that the diketopiperazine is selected from the group consisting of 2,5-diketo-3,6-di (4-phenylaminobutyl) piperazine, 2,5-diketo-3. , 6-di (4-sucinylaminobutyl) piperazine, 2,5-diketo-3,6-di (4-glutarylaminobutyl) piperazine, and 2,5-diketo-3,6-di (4-malelylaminobutyl) piperazine.
9. 9. The composition as described in claim 1, characterized in that the ratio of PDE5 inhibitor to diketopiperazine is about 1: 1.
10. 10. The composition as described in claim 1, characterized in that the ratio of PDE5 inhibitor to diketopiperazine is about 2: 1.
11. The composition as described in claim 1, characterized in that the diketopiperazine salt is formulated in the form of a dry microparticle.
12. 12. A microparticle composition for the delivery of a PDE5 inhibitor comprising: diketopiperazine microparticles, wherein the microparticles are insoluble at the first defined pH and soluble at the second defined pH; and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. |
13. 13. A microparticle composition as described in claim 12, characterized in that wherein the PDE5 inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of sildenafil citrate, vardenafil hydrochloride and tadalafil.
14. 14. A microparticle composition as described in claim 12, characterized in that the microparticle is formed by precipitation of an inhibitor. PDE5 or a pharmaceutically acceptable salt thereof in i diketopiperazine microparticles.
15. 15. A microparticle composition as described in claim 14, characterized in that the precipitation is initiated by freezing or cooling.
16. 16. A microparticle composition as described in claim 12, characterized in that the microparticle is formed by spray-dried i-di-capivazine microparticles suspended in a solution of a PDE5 inhibitor or a pharmaceutically acceptable salt thereof. !
17. 17. A microparticle composition as described in claim 12, characterized in that the pharmaceutically acceptable salt is a diketopiperazine salt.
18. 18. A microparticle composition as described in claim 12, characterized in that the! The microparticle is formed by precipitation of a solution i comprising a diketopiperazine and a PDE5 inhibitor or a pharmaceutically acceptable salt thereof.
19. 19. A microparticle composition as described in claim 12, characterized in that the diketopiperazine microparticles are formulated for delivery to the pulmonary system.
20. 20. A microparticle composition as described in claim 12, characterized in that the dicetópiperazine microparticles have a diameter of between 0.5 microns and 10 microns | and wherein the release of the incorporated PDE5 inhibitor or a pharmaceutically acceptable salt thereof is at a pH of 6.0 or greater.
21. 21. A microparticle composition as described in claim 12, characterized in that the diketopiperazine microparticles are formulated for oral administration. 1
22. 22. The use of a diketopiperazine-phosphodiesterase type 5 inhibitor composition in the manufacture of a medicament for delivery to the pulmonary system.
23. 23. The medicamjento as described in claim 22, characterized in that the composition of diketopiperazine-phosphodiesterase type 5 is a salt of I III diketopiperazine of a phosphodiesterase type 5 inhibitor.
24. The medicament as described in claim 22, characterized in that the composition of diketopiperazine phosphodiesterase type 5 is a microparticle of diketopiperazine associated with a phosphodiesterase type 5 inhibitor, or a salt of the same.
25. 25. The medicament as described in claim 22, characterized in that the diketopiperazine-phosphodiesterase type 5 inhibitor composition is useful in the treatment of sexual dysfunction.
26. 26. The drug tao as described in claim 25, characterized in that the sexual dysfunction is erectile dysfunction.
27. 27. The medicament as described in claim 25, characterized in that the sexual dysfunction is female sexual dysfunction.
28. 28. The medicament as described in claim 27, characterized in that female sexual dysfunction is selected from the group consisting of sexual dysfunction induced by antidepressants, sexual dysfunction secondary to multiple sclerosis,: anorgasmia, low arousal, delayed orgasm, congestion decreased vaginal function, dyspareunia and sexual dysfunction induced by infertility.
29. 29. The medicament as described in claim 22, characterized in that the diketopiperazine composition of phosphodiesterase type 5 inhibitor is useful for the treatment of pulmonary hypertension.
30. 30. The medicament as described in claim 29, characterized in that the pulmonary hypertension is selected from the group consisting of primary pulmonary hypertension, acute pulmonary hypertension, pulmonary arterial hypertension, hypertension; associated with pregnancy such as preeclampsia, and persistent pulmonary hyperintending of newborns. SUMMARY i Compositions are provided of 1) diketopiperazine salt inhibitors PDE5 and 2) DKP microparticles having PDE5 inhibitors therein, as well as methods for pulmonary delivery of these compositions for the treatment of pulmonary hypertension and dysfunction (s). sexual.