Methods and compositions comprising desmopressin in combination with a 5-alpha reductase inhibitor.

(54) Title: METHODS AND COMPOSITIONS THAT INCLUDE DESMOPRESSIN IN COMBINATION WITH AN INHIBITOR OF 5-ALPHA REDUCTASE.

(54) Title: METHODS AND COMPOSITIONS COMPRISING DESMOPRESSIN IN COMBINATION WITH A 5-ALPHA REDUCTASE INHIBITOR.

(57) Summary

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reductase inhibitor. The methods and compositions are useful in the treatment of nocturia and other urinary frequency disorders.

(57) Abstract

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reducíase inhibitor. The melhods and composilions are useful in íhe treaímení of nocturia and other urinary frequency disorders.

METHODS AND COMPOSITIONS INVOLVING DESMOPRESSIN IN COMBINATION WITH A 5-ALPHA REDUCTASE INHIBITOR

FIELD OF THE INVENTION

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reductase inhibitor. The methods and compositions are useful in the treatment of nocturia and other urinary frequency disorders.

BACKGROUND OF THE INVENTION

Nocturia and other urinary frequency disorders affect a considerable part of the human population. Patients with nocturia experience sleep disruption due to the need to get up at night to urinate. Patients with overactive bladder often experience urge incontinence, urgency to urinate, and increased urinary frequency. Overactive bladder can be caused by uncontrolled contractions of the smooth muscle fiber branches that form the muscular lining of the urinary bladder (the detrusor muscle) during the filling phase of the bladder and is more prevalent in older adults.

Compositions and methods for treating nocturia and other urinary disorders have been described. For example, US Patents No. 7,579,321; 7,799,761 and 8,143,225 describe pharmaceutical compositions and methods using a low dosage of desmopressin. United States patent application publication US 2009/0042970 describes the treatment of nocturia and other urinary frequency disorders using, for example, transdermal administration of desmopressin. Also, US patent application publication US 2012/0015880 describes the treatment of nocturia and other urinary frequency disorders using, for example, intranasal administration of desmopressin.

One of the challenges of treating nocturia and other urinary frequency disorders using desmopressin is achieving a therapeutic but non-toxic concentration of desmopressin in the blood plasma. Administration of too large a dose of desmopressin can have serious side effects, such as hyponatraemia that can lead to seizures or death of the patient. Therefore, there is a need for compositions and methods with better safety profiles and / or better efficacy, using a lower dose of desmopressin. The present invention addresses this need and provides other related advantages.

BRIEF DESCRIPTION OF THE INVENTION

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reductase inhibitor. This combination therapy provides benefits to human subjects, especially adult males, suffering from associated disorders or with the presence of unwanted urination from the subject's bladder or frequent urgency to urinate. These people may suffer from overproduction of urine, inadequate urine concentration, low urine osmolarity, excessive frequency of urination (eg. g., excessive frequency of urination associated with central hydruric diabetes), primary nocturnal enuresis, nocturia, overactive bladder syndrome (OAB), urgency and urinary frequency during waking hours, incontinence, or unwanted production of urine that generates urine leakage during rest or due to physical exertion or tension. Desmopressin and the 5-alpha reductase inhibitor are administered to the subject so that they both exert physiological activity for a period of time in overlap. Examples of 5-alpha reductase inhibitors include, for example, dutasteride, epristeride, finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505, and pharmaceutically acceptable salts thereof. In certain embodiments, the method optionally also comprises administering an alpha-adrenergic receptor antagonist.

Accordingly, one aspect of the invention provides a method of inhibiting urgency in a human subject for a range of about two hours to no more than about seven hours. The method comprises administering to a human subject in need thereof an effective amount of desmopressin and a 5-alpha reductase inhibitor so that they both exert physiological activity for a period of time in overlap. The desmopressin and / or 5-alpha reductase inhibitor dosage and / or the dosage regimen can be adjusted so that the method inhibits urination in a human subject for a range of from about 4 hours to about 7 hours. Desmopressin is administered at a dosage such that the subject does not experience hypernatremia, a harmful condition in which the sodium concentration in the subject's plasma is too low, e.g. eg, below about 135 mmol / L. Hyponatremia is avoided as long as the maximum dose of desmopressin in the blood is less than 10 pg / ml, preferably less than 5 pg / ml, and more preferably less than 5 pg / ml, e.g. eg, 2 or 3 pg / ml. Severe hyponatremia can lead to electrolyte abnormalities that can lead to cardiac arrhythmias, heart attacks, seizures, and / or strokes. In certain embodiments, the method optionally further comprises administering an alpha-adrenergic receptor antagonist such that, for example, desmopressin, the 5-alpha reductase inhibitor, and the alpha-adrenergic receptor each exert physiological activity for a period of overlapping time.

The 5α-reductase inhibitors are a group of drugs with antiandrogenic activity that are used in the treatment of benign prosthetic hyperplasia. These drugs decrease the levels of available 5α-reductase and thus reduce the products of its enzymatic reaction, including those that convert testosterone to the more potent dihydrotestosterone and act on progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone.

Another aspect of the invention provides a method of inducing an antidiuretic effect in a human subject. The method comprises administering to a human subject in need thereof an effective amount of desmopressin and a 5-alpha reductase inhibitor so that they both exert physiological activity for a period of time in overlap.

Another aspect of the invention provides a pharmaceutical composition comprising desmopressin, a 5-alpha reductase inhibitor, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition is formulated for transmucosal administration, e.g. eg, buccal or nasal administration to a human subject. In other embodiments, the composition is formulated as a transdermal or intradermal patch. In other embodiments, the 5-alpha reductase inhibitor is ingested orally, while desmopressin is ingested intramucosa, e.g. eg, sublingual or intranasal.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a graph of blood desmopressin concentration and variable flow rate versus time illustrating a 7 hour activity of a device and method.

Figure 2 is a graph of blood desmopressin concentration and constant flow rate versus time illustrating a 7 hour activity of a device and method, according to an alternate embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides methods and compositions for use of desmopressin in combination with a 5-alpha reductase inhibitor. This combination therapy provides benefits to subjects suffering from associated disorders or the presence of unwanted urination of the subject's bladder or frequent urgency to urinate. These subjects may suffer from overproduction of urine, inadequate urine concentration, low urine osmolarity, excessive frequency of urination (eg. g., excessive frequency of urination associated with central hydruric diabetes), primary nocturnal enuresis, nocturia, urgency and urinary frequency during waking hours, overactive bladder syndromes (OAB), incontinence or unwanted production of urine that generates loss of urinate during rest or due to physical exertion or tension. Desmopressin and the 5-alpha reductase inhibitor are administered to the subject so that they both exert physiological activity for a period of time in overlap. The inhibitor can be administered at doses below those used in clinical practice for the treatment of BPH. In certain embodiments, the method optionally also comprises administering an alpha-adrenergic receptor antagonist.

Various aspects of the invention are indicated in sections below. However, the aspects of the invention described in a particular section should not be limited to any particular section.

Definitions

To facilitate understanding of the present invention, various terms and phrases are defined below.

The terms a, an and the, as used herein, mean one or more and include the plural, unless the context does not permit.

As used herein, the term "effective amount" refers to the amount of a compound (eg, a compound of the present invention) sufficient to elicit beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treat" includes any effect, e.g. eg, abatement, reduction, modulation, enhancement or elimination, resulting in amelioration of the condition, disease, disorder and the like of a symptom of these.

As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with an inert or active carrier, which makes the composition especially suitable for in vivo or ex vivo therapeutic use.

As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (eg, acid or base) of a compound of the present invention that, upon administration to a subject, can yield a compound. of the present invention or an active metabolite or residue thereof. As those skilled in the art know, the salts of the compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, acids. ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, and the like. Other acids, such as oxalics, may be employed, although not pharmaceutically acceptable per se, in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal hydroxides (eg, sodium), alkaline earth metals (eg, magnesium) hydroxides, ammonia, and compounds of the formula NW₄⁺, where W is Ci-₄, and the like.

Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hydrochloride, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate, hydrochloric acid sulfate lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na⁺, NH4⁺ and NW4⁺ (where W is a Ci-₄) and the like.

For therapeutic use, the salts of the compounds of the present invention are contemplated as pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable can also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound.

The terms subject and patient are used interchangeably and refer to human beings, especially adult male humans.

Throughout the description, when compositions and kits are described as inclusive, carriers, or composed of specific components or when the processes and methods are described as carriers, inclusive, or composed of specific steps, it is contemplated that there are further compositions and kits of the present invention. consisting essentially of, or consisting of, the components mentioned and that there are processes and methods according to the present invention which consist essentially of or consist of the mentioned processing steps.

I. Therapeutic methods

The invention provides therapeutic methods that use desmopressin in combination with a 5-alpha reductase inhibitor. This combination therapy is beneficial to subjects with associated disorders or frequent unwanted urges to urinate. As described above, these subjects may suffer from overproduction of urine, inadequate urine concentration, low urine osmolarity, OAB, excessive frequency of urination (eg. g., excessive frequency of urination associated with central hydruric diabetes), primary nocturnal enuresis, nocturia, urgency and urinary frequency during waking hours, incontinence or unwanted production of urine that causes loss of urine during rest or due to exertion physical or tension. Desmopressin and the 5-alpha reductase inhibitor are administered to the subject so that they both exert physiological activity for a period of time in overlap. Desirably, the administration of desmopressin and the 5-alpha reductase inhibitor produces a synergistic effect. Examples of benefits of such a synergistic effect include improved reduction in a subject's urge to urinate and / or reduction in the amount of desmopressin necessary to achieve a therapeutic effect. Also, the administration of smaller amounts of the 5-alpha reductase inhibitor relative to the doses that are used clinically to treat BPH means that the side effects of these drugs are reduced. In certain embodiments, the method optionally also comprises administering an alpha-adrenergic receptor antagonist.

One aspect of the invention provides a method of inhibiting urination urgency in a human subject for a range of about two hours to no more than about eight hours. The method comprises administering to a human subject in need thereof an effective amount of desmopressin and a 5-alpha reductase inhibitor so that they both exert physiological activity for a period of time in overlap. The desmopressin and / or 5-alpha reductase inhibitor dosage and / or the dosage regimen can be adjusted so that the method inhibits urination in a human subject for specified intervals. For example, in certain embodiments, the method inhibits urination in a human subject for a range of from about 4 hours to about 6 hours (or 7 hours). Various modalities of the method are described (p. (e.g., dosage and route of administration of desmopressin, the 5-alpha reductase inhibitor, the target patient population, and examples of benefits of combination therapy) in the sections that follow. Also, in certain embodiments, the method optionally further comprises administering an alpha-adrenergic receptor antagonist such that, for example, desmopressin, the 5-alpha reductase inhibitor, and the alpha-adrenergic receptor each exert physiological activity for a period of overlapping time.

Another aspect of the invention provides a method of inducing an antidiuretic effect in a human subject. The method comprises administering to a human subject, e.g. For example, an adult male, who needs an effective amount of desmopressin and a 5-alpha reductase inhibitor for both to exert physiological activity for a period of time in overlap. The method can also be characterized according to the interval during which the antidiuretic effect is provided. For example, in certain modalities, an antidiuretic effect is achieved for a range of about two hours to no more than about seven to eight hours. In certain other modalities, the antidiuretic effect is achieved over a range of about four hours to about six hours. Various modalities of the method are described (p. (g., dosage and route of administration of desmopressin, dosage and route of administration of the 5-alpha reductase inhibitor, target patient population and examples of benefits of combination therapy) in the sections below. Also, in certain embodiments, the method optionally also comprises administering an alpha-adrenergic receptor antagonist.

Desmopressin

The term desmopressin refers to l-desamino-8-D-arginine vasopressin and includes the free base form and pharmaceutically acceptable salts and hydrates thereof. An example of a salt form is an acetate salt. Desmopressin, l-desamino-8-D-arginine vasopressin monoacetate, is also known as DDAVP and is described, for example, in US Patent No. 3,497,491 and is commercially available as a prescription medication that is marketed, for example, under the names DesmoMelt, Stimate, MINIRIN® and DESMOSPRAY®. Desmopressin as an active pharmaceutical ingredient is also commercially available for formulation into new compositions and drug dosage forms. The dosage of desmopressin that is administered to a human subject can be selected based on the weight of the subject and the desired duration for which a therapeutic effect is desired. The dosage can be characterized according to the concentration of desmopressin that is achieved in the blood plasma.

Accordingly, the therapeutic methods described herein can be characterized according to the concentration of desmopressin that is achieved in the blood plasma. In certain embodiments, administration achieves a blood plasma concentration of desmopressin in the human subject that does not exceed 15 pg / mL. In certain embodiments, administration achieves a blood plasma concentration of desmopressin in the human subject that does not exceed 10 pg / mL. In certain other embodiments, administration achieves a blood plasma concentration of desmopressin in the human subject ranging from about 0.2 pg / mL to about 5 pg / mL. In still other modalities, administration achieves a concentration of desmopressin in blood plasma in the human subject ranging from about 0.5 pg / mL to about 2.5 pg / mL. In still other modalities, administration achieves a blood plasma concentration of desmopressin in the human subject ranging from about 0.5 pg / mL to about 1.5 pg / mL. Generally, the amount of desmopressin that reaches the bloodstream from the administration of a given specific dosage form should not exceed 2 ng / kg of body weight and can be as low as 0.5 ng / kg, 1.0 ng / kg or 1.5 ng / kg.

Desmopressin can be administered using traditional routes of administration. For example, in certain modalities, desmopressin is administered transdermally, intradermally, transmucosally, or even possibly orally, although the variability in bioavailability of oral doses is so great that it is difficult or impossible to reproductively achieve concentrations in very low blood evenly. In certain other embodiments, desmopressin is administered transdermally, intradermally, or transmucosally. In still other embodiments, desmopressin is administered transdermally. In still other embodiments, desmopressin is administered intranasally.

When desmopressin is administered transdermally or intradermally, the method can be characterized according to the rate at which desmopressin passes through the skin of a human subject. For example, in certain embodiments, desmopressin is administered at a first flow rate sufficient to rapidly achieve a desired blood plasma concentration of desmopressin, e.g. eg, less than five, preferably less than 2 pg / ml and then at a second lower flow rate sufficient to maintain the first concentration obtained in the blood plasma for a desired interval, e.g. eg six hours. In certain embodiments, the method is also characterized by a flow range, such as when desmopressin is administered at a flow rate ranging from about 5 ng / hour to about 35 ng / hour. In still other embodiments, desmopressin is administered at a flow rate ranging from about 5 ng / hour to about 35 ng / hour. In still other embodiments, desmopressin is administered at a flow rate ranging from about 5 ng / hour to about 15 ng / hour.

Various devices and methods for administering desmopressin have been previously described and are contemplated for use in the present invention. See, for example, US Patent Application Publication Nos. 2009/0042970 and US 2012/0015880, each of which is incorporated herein by this reference. A device that can be used to administer desmopressin has a reservoir that contains a solution of desmopressin in a pharmaceutically acceptable carrier. An interface member for application to the skin of a patient, such as a permeable pad for attachment to the skin, or one or a series of microneedles, is in fluid communication with the reservoir. The devices comprise various means for delivering a desmopressin solution from the reservoir to the interface member and downstream intradermally or transdermally into the blood of a patient. The flow rate of desmopressin is controlled by adjusting the concentration of desmopressin in the reservoir, in combination with controlling the rate of flow of the solution from the reservoir, the rate of flow of the solution to the interface member, the rate of flow of the solution from the interface member into the patient's body or by exploiting some combination of these control points. In either case, the flow rate is controlled to be sufficient to establish a concentration of desmopressin in the patient's blood immediately above the activation threshold of the water channel, e.g. eg, in the range of 0.1 to about 2.5 pg / ml, advantageously not more than 1, 1.5, 2 or 2.5 pg / ml. The flow rate in any case is insufficient to induce a desmopressin concentration in the patient's blood to a level greater than about 10 pg / ml. The flow rate can be between about 5, 10, 15, 20, 25 or 30 to 35 ng / hr (i.e. 5000, 10,000, 15,000, 20,000, 25,000 or 30,000 to 35,000 pg / hr), advantageously around 10-20 ng / h or 20-35 ng / hr, most advantageously around 5-15 ng / hr, to establish the desired blood concentration for a reasonable predetermined time before the patient or device turns off the desmopressin flow.

The dosage of desmopressin and / or the duration of a therapeutic concentration of desmopressin in blood plasma necessary to achieve a therapeutic effect is preferably less when desmopressin is used in conjunction with a 5-alpha reductase inhibitor than when desmopressin alone is administered, and reduces urgency to urination compared to when the 5-alpha reductase inhibitor is given alone. For example, in certain modalities, the 5-alpha reductase inhibitor can reduce urination urgency for a period of time after which the concentration of desmopressin in the blood plasma falls below the threshold necessary to achieve antidiuresis (activation of channels of water in the kidneys). As another example, the physiological effect of the 5-alpha reductase inhibitor in combination with less urine in the bladder during the induced antidiuresis interval has the effect of decreasing the urgency of urination of the patient.

The desmopressin flow rate can preferably be set so that, with the desired blood concentration and the known desmopressin clearance rate (half-life of about 1.5 to 2.0 hours), the patient achieves the low but above threshold blood concentration. desired in a reasonable time, p. ex. less than about an hour (and usually as soon as possible) and is maintained in a low dose range just above the trigger threshold (roughly within the 0.5 to 1.5 pg / mL range) for a desired period of time (eg, two hours for an exercise or 4-6 hours or 5-8 hours for the treatment of nocturia). Termination of flow with automatic or manually actuated mechanisms embedded in the device or by removing the device from contact with the skin causes normal drug clearance mechanisms from the patient's body to rapidly reduce the low concentration to an even lower concentration, for example. below the trigger threshold.

The interface member of the device may comprise a membrane permeable to the desmopressin solution that defines a contact surface with the skin of the patient. The desmopressin solution permeable surface allows delivery of the desmopressin from the reservoir and through or to the skin of the patient. For greater bioavailability and precision of delivery, intradermal delivery is preferred. Intradermal delivery allows direct delivery to a vascularized compartment that produces rapid absorption into the systemic circulation and correspondingly rapid activation / deactivation effects. Although transdermal delivery is contemplated, its use is more subject to variable bioavailability due to the horny layer that functions as a physical barrier for the drug reaching the epidermis and the creation of a drug reservoir in the epidermis.

Accordingly, transdermal delivery methods and devices can benefit from techniques that reduce the effectiveness of the horny layer as a barrier to drug entry. These include, for example, mechanical methods of removing parts of the horny layer prior to applying a desmopressin transdermal delivery device. The skin can also be microperforated to introduce microducts or microcracks into the horny layer to enhance subsequent transdermal delivery, e.g. eg, by one or more microneedles as described below.

The permeability of the horny layer can also be enhanced by treatment with a chemical permeability enhancer, such as dimethylsulfoxide, decylmethylsulfoxide, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzethyl ammonium chloride, , lecithin (refer, for example, to US Patent No. 4,783,450, the disclosure of which is incorporated herein by this reference), l- / hdodecylazacycloheptan-2-one (refer, for example, to U.S. Patents No. 3,989,816; 4,316,893; 4,405,616 and 4,557,934, the descriptions of which are incorporated herein by this reference), ethanol, propanol, octanol, benzyl alcohol, lauric acid, oleic acid, valeric acid, isopropyl myristate, isopropyl palmitate, methylpropionate, ethyl oleate, propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, polyethylene glycol monolaurate, urea, hydroxide (refer, for example, to US Patent No. 6,558,695, the disclosure of which is incorporated herein by this reference), dimethylacetamide, dimethylformamide, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine, triethanolamine, salicylic acid, citric acid, succinic acid, and permeability enhancing peptides ( refer, for example, to US Patent No. 5,534,496, the disclosure of which is incorporated herein by this reference).

An effective means of delivering desmopressin from the reservoir to the skin is intradermal administration, via an interface member comprising one or more microneedles that penetrate the horny layer of the patient and allow fluid communication between the reservoir and the epidermis or the direct contact with the surfaces or cavities in desmopressin coated or including microneedles. The extent and size of the microneedles are adequate to penetrate the horny layer, but small enough to produce little or no sensation to the patient. For example, suitable extensions are around 0.3 to 1.5 mm, advantageously between around 0.8 and 1.1 mm. An example of a single needle device is provided in US Patent No. 6,939,324, the disclosure of which is incorporated herein by this reference.

Multiple microneedles may be desired, e.g. eg, in series, if a larger surface area for delivery or a more flexible patch is desired. Each of the microneedles has a channel that transports fluid from the reservoir to the end of the needle or the microneedles may otherwise allow delivery of fluid from the reservoir, e.g. eg with porous or perforated walls. Alternatively, the microneedles may be coated with a desmopressin preparation or include a desmopressin film or matrix in the cavities or in the material structure of a microneedle itself, to provide a desmopressin burst upon application in a manner of help to quickly reach the activation concentration threshold, optionally with a desmopressin solution passed through the needles to help achieve or maintain the desired concentration.

The use of dissolvable microneedles is also contemplated and their use avoids, in some cases, the pain and / or irritation caused by metal needles or sharp items. US Patent No. 7,182,747, for example, describes solid solution perforators that can be adapted for use in the inventions described herein. Unlike conventional hollow needle technologies, these microneedles are manufactured from a solid matrix of dissolvable or biodegradable material that optionally carries one or more of the selected drugs and is formed in one or more piercers.

Another device for delivering desmopressin is a patch that is applied by the user before sleeping or before some other interval of activity in which the patient wishes to interrupt urine production. The patch may include an active solution flow control mechanism, e.g. e.g. with a user-selectable timer function, so that the user can select the length of time to suppress normal urine output, i.e., in the case of sleep, roughly equivalent to the desired sleep time or less to this, although this mechanism is not necessary. The patient removes the patch from its wrapper, sets the delivery time if necessary, and applies the patch to an area of ​​the skin. Desmopressin delivery begins at the levels and rates described herein and urine output is suppressed for the desired time. When the flow controller is turned off, the patch is removed, or the desmopressin reservoir runs out, normal urine output quickly returns. In a preferred simple version of the device, the amount of desmopressin in the reservoir and its designed flow rate by depletion of the reservoir sets the delivery time, e.g. For example, five to seven hours, with the end of the flow corresponds simply to the exhaustion of the patch supply. Thus, the patient can sleep without possibly having to wake up repeatedly during sleep hours or perform other activity without worrying about involuntary urination.

With reference to the drawings, the operation of examples of devices will be described.

Figure 1 illustrates the operation of an exemplary embodiment of the invention in the treatment of a patient for whom it is desired to deactivate the production of urine, e.g. eg, treat nocturia. A device according to the invention that delivers a low dose / low variable flow of desmopressin to a patient is attached to the patient's skin, the patient urinates, and the device is activated at 10:00 PM. Figure 1 shows illustrative blood desmopressin concentrations and flow rates for this patient at various times after device application or activation. At one hour (11:00 PM), the desmopressin flow rate peaked at around 20 ng / h and increased the desmopressin concentration in the patient's blood to more than about 1.0 pg / ml, that is, by above the concentration sufficient to activate the water channels in the kidneys and to induce an antidiuretic effect (illustrated here as at a blood concentration of about 0.8 pg / ml). At 2 hours (midnight), the flow rate decreases slightly but remains in the range of 20 ng / h and the concentration of desmopressin in the blood increases to about 1.5 pg / ml. These values ​​decrease slowly but are relatively constant for the next 2.5 to 3 hours. After about 5 hours (3:00 AM), the flow rate decreased to a level where the activation concentration of desmopressin cannot be maintained. As the flow rate continues to decrease, the desmopressin concentration in the blood falls below the activation level of the water channel and urine production begins (in this case around 3:45 AM). At 5:00 AM, the blood concentration is below about 0.5 pg / ml and the flow rate dropped to zero. At 6:00 AM, the patient is awake and feels a normal urgency to urinate due to the production of urine during approximately the last hour and a half of sleep. During sleep there is a sustained antidiuretic interval, little or no urine production and there is no urgency to urinate to disturb or interrupt sleep. The flow rate of desmopressin and the concentration of desmopressin in the blood may depend more or less on the dosage of the 5-alpha reductase inhibitor that is administered to the patient. It is noted that the desmopressin and the 5-alpha reductase inhibitor can be administered to the patient in separate formulations or the desmopressin and the 5-alpha reductase inhibitor can be mixed to form a single formulation that is administered to the patient.

Figure 2 illustrates another example embodiment of the invention for treating a patient to deactivate urine production, e.g. eg, treating nocturia. A device according to the invention is attached which delivers a constant flow of a low dosage of desmopressin to the skin of the patient. The device is activated (if necessary) and the patient urinates at 10:00 PM. Figure 2 shows examples of illustrative concentrations of desmopressin in blood resulting from a flow of about 10 ng / h during about five hours of infusion from 10:00 PM to 3:00 AM relative to a threshold concentration. of the antidiuretic effect of desmopressin in the blood. In less than about an hour from the start of flow, the concentration of desmopressin in the blood exceeds the threshold level and begins to produce an antidiuretic effect. The blood concentration approaches a more or less stable range in less than about two to three hours (between about 1.0 and 1.5 pg / ml) that is maintained for the remainder of the five hours of flow until 3:00 A.M. At this point the flow stops (eg, rest or exhaustion). The desmopressin concentration in the blood then decreases due to clearance mechanisms according to the elimination half-life of the drug and falls below the threshold approximately two hours later (5:00 AM). At 7:00 AM the patient produced urine and wakes up to urinate. The flow rate of desmopressin and the concentration of desmopressin in the blood may depend more or less on the dosage of the 5-alpha reductase inhibitor that is administered to the patient.

The following examples are provided for illustrative purposes only. The activation concentration will of course vary between individuals, as will the blood volume. The important principle in the operation of the device is that the entire antidiuretic effect can be controlled safely, since the diuretic action is maintained by sustaining a low concentration of desmopressin by a continuous low influx of the drug and a disruption of the influx allows the body to quickly clear the drug and restore normal urine output. This means that the patch device enhances the safety of desmopressin administration with little or no risk of developing water intoxication when used as directed.

In accordance with the invention, the 5-alpha reductase inhibitor may be present in admixture with desmopressin in the patch devices described above or in the intranasal dosage form described below, but is preferably supplied as a daily oral dose and it is active and present in blood plasma for as long as desmopressin is present.

An example of a device for intranasal administration of desmopressin is a safety dispenser to induce an antidiuretic effect in a target patient population while reducing the risk that a member of the population may develop hyponatremia. The dispenser comprises a reservoir with a composition comprising a desmopressin preparation and a nasal membrane penetration enhancer in an amount sufficient to constitute multiple doses of drug. The reservoir is connected to an outlet and has a pump, preferably a disposable pump and preferably one that can be operated manually, such as a dispenser driven by a squeeze bottle or a piston pump placed in a glass bottle. The pump allows multiple metered doses to be serially dispensed from the reservoir through the outlet as an aerosol into one or both nostrils of a patient to deliver a dose of a uniform size to an intranasal mucosa or other surface.

Each aerosol comprises multiple droplets, preferably with an average volume distribution ranging from 20 pm for DIO to about 300 pm for D90. This means that about 10% of the droplets have a diameter less than about 20 pm and 90% have a diameter less than 300 pm. Each aerosol dose has a desmopressin weight and concentration that preferably comprises between 0.5 ng of desmopressin per kilogram of the patient's body weight and 75 ng of desmopressin per kilogram of the patient's body weight. The aerosol is characterized by a desmopressin bioavailability greater than about 5%, that is, between about 5% and 25% of the active ingredient in the composition actually enters the patient's bloodstream and contributes to the effect of the drug and the rest is degrades, typically by digestion. Generally, the greater the bioavailability of an aerosol, the less desmopressin per aerosol that needs to be delivered to the nasal cavity and vice versa. The goal is to achieve a maximum concentration (C_max) of desmopressin in more consistent target blood in members of the patient population.

The combination of properties of the aerosol dispenser and the composition it contains allows the respective aerosol doses to be effective in restricting the concentration of desmopressin produced in the bloodstream of patients, based on kilograms, to a relatively narrow range and thus achieving a limited and relatively uniform duration of antidiuresis time. In other words, the respective successive aerosol doses establish in a patient a C_mRelatively consistent desmopressin ax by drug transport across intranasal mucous membranes. The amount of drug that is delivered into the bloodstream for repeated doses from the same dispenser to the same person should preferably differ no more than 100% and more preferably less than 50%. The coefficient of variation of the dispenser is similar to the coefficient of variation of the C_mto_x producing serial subcutaneous doses of desmopressin designed to achieve the same goal. Preferably, the respective successive doses of aerosol are sufficient to establish in a patient a C_mto_X of desmopressin, by intransal delivery, with a coefficient of variation of about 50%, more preferably about 25% of the coefficient of variation of C_max which produces a subcutaneous dose of desmopressin designed to achieve the same C_mto_Xtarget.

The value of the C_mto_X The objective may vary, depending on the duration of the antidiuretic interval for which the dispensed composition is designed to induce and the dosage of 5-alpha reductase inhibitor. For example, a product designed for a 7-8 hour interval of suppression of urine output could be designed to deliver a C_ril¿_x not to exceed 15 +/- 3 pg / ml. Thus, by way of illustration, a 7 hour product could have a bioavailability of 10% and a desmopressin loading per aerosol of 0.75 pg or 750 ng. This would mean that around 75 ng of drug would reach the patient's bloodstream and that a 70 kg (~ 155 Ib) adult would receive a dose into their bloodstream of around 1.0 ng / kg and achieve a C_max lower target to around 5 pg / ml. Another modality of the same product could have a bioavailability of 8% and a desmopressin loading per aerosol of 2.0 pg or 2000 ng, which would deliver about 160 ng of drug to the patient's bloodstream as an effective dose of 160 ng / 75 kg. or just over 2 ng / kg and the C_m¿_x lower target to about 10 pg / ml. Another product example can be designed for a 3-4 hour urine break and could provide a C_max not to exceed about 3 pg / ml.

Alternatively, a single dispenser that supplies e.g. For example, 200 ng or 500 ng per spray, when used according to the package insert or doctor's instructions, could be used to achieve, for example, different durations of antidiuresis in the same person or the same duration of antidiuresis in adults of different weights, simply varying the amount of aerosols delivered per administration event. Typically, about 20 minutes to one hour after administration of the pharmaceutical composition of the present invention, the average urine output per minute in a treated individual decreases to less than about 4 ml / minute, preferably less than about 1 ml / min and held in this low range for a desired period of time, such as 180 minutes, 240 minutes, 300 minutes, 360 minutes, or 420 minutes. Around twenty minutes after administration, the mean urine osmolarity is greater than around 300 mOsmol / kg and is maintained at a high concentration for a period of up to 180 minutes, 240 minutes, 300 minutes, 360 minutes or 420 minutes.

An important property of intranasal administration is that it uniformly delivers a maximal blood concentration per aerosol within a relatively narrow dose range and time, and thus accidental delivery of a higher dose that produces a high dose is avoided or minimized. longer-than-expected antidiuretic effect and the possibility of inducing hyponatraemia. Uniform delivery, as the phrase is used herein, should be construed as repeatable within a range similar to the range seen when very low doses of desmopressin are administered by subcutaneous injection or perhaps slightly higher. Such uniformity is generally more easily achieved by exploiting formulations with higher bioavailability and, consequently, a bioavailability of at least 5%, preferably at least 10%, more preferably at least 15% and preferably even higher is preferred. The highest bioavailability is achieved by exploiting formulation technology, especially the use of permeation enhancers, as well as by chemical modification of the aerosol composition as described herein.

In one embodiment, the dispenser may further comprise means for blocking the delivery of a second desmopressin aerosol or a series of aerosols above a certain dose, e.g. eg, above about a dose sufficient to produce a blood concentration greater than about 10 to 12 pg / ml, for a predetermined time interval after dispensing a first dose. This can be achieved passively as a consequence of the design of the aerosol mechanism as set forth, for example, in US Patent No. 7,335,186, the disclosure of which is incorporated herein by this reference. Alternatively, an active, battery powered, mechanical spring or compressed gas timer can be included in the dispenser, along with mechanisms known per se designed to prevent a second delivery until a predetermined interval elapses, e.g. eg ', 8 hours or some between 6 and 24 hours. Such a mechanism can discourage abuse of the product and further minimize the chances that a patient may self-induce antidiuresis unintentionally or inadvertently for too long.

Examples of penetration enhancers for use in the formulation are Hsieh enhancers (refer to US 5,023,252) commercially available from CPEX Pharmaceuticals (formerly Bentley) of Exeter, New Hampshire. Within the class of Hsieh enhancers useful in articles of manufacture, those described in US 7,112,561 and US 7,112,561 are preferred, and the most currently preferred are described in US 7,244,703, as cyclopentanedecanolide, commercially known as CPE-215. Many other enhancers can be used.

In some embodiments, the invention provides uses for the security dispenser to induce an antidiuretic effect. The desmopressin dispenser and formulation may comprise any of the properties described herein. For example, in one embodiment, the C_max of desmopressin is directly proportional to the amount of desmopressin administered nasally in a C_rriáx which ranges from around 0.5 pg / ml to around 10.0 pg / ml. The value of the C_max The objective may vary, depending on the duration of the antidiuretic interval for which the dispensed composition is designed to induce and the dosage of 5-alpha reductase inhibitor. For example, the use of a safety dispenser described herein can produce antidiuresis for less than about 8 hours, less than about 6 hours, for between about 2 and 4 hours, or between about 4 and 7 hours. Another example of using a product can be designed to supply a C_mmax in a patient of no more than about 15 pg / ml, 10 pg / ml, 7 pg / ml, or 3 pg / ml.

5-alpha reductase inhibitors

The 5-alpha reductase inhibitors are a class of medicinal agents that inhibit the activity of 5-alpha reductase. Examples of 5-alpha reductase inhibitors include, for example, dutasteride, epristeride, finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505, and pharmaceutically acceptable salts thereof. A brief description of possibly suitable 5-alpha reductase inhibitors follows.

Dutasteride

Dutasteride has the chemical name (5α, 17β) - / ν- {2,5 bis (trifluoromethyl) phenyl} -3-oxo4-azaandrost-l-ene-17-carboxamide and is marketed as a soft gelatin capsule with the name commercial AVODART®. A pharmaceutically acceptable salt of dutasteride can be used. Dutastaride can be administered by routes known in the art, such as oral administration. The amount of dutasteride or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 0.1 mg to about 5 mg per day. In certain modalities, dutasteride is administered (eg. g., orally) at a daily dosage ranging from about 0.1 to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 3 mg to about 4 mg, or about 4 mg to about 5 mg. In certain other embodiments, dutasteride is administered (eg, orally) at a daily dosage ranging from or about 0.3 mg to about 0.7 mg. The currently preferred dose for an adult male is less than the recommended dose for the treatment of BPH, namely, less than about 0.5 mg / day, e.g. eg 0.1 to 0.3 or 0.4 mg / day.

Epristerida

Epristeride has the chemical name 17p - (/ V-tert-butylcarboxamido) androsta3,5-diene-3-carboxylic acid. A pharmaceutically acceptable salt of epristeride can be used. The amount of epristeride or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 1 mg to about 500 mg. In certain modalities, epristeride is given at a daily dosage ranging from about 0.1 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about 5 mg, about 5 mg and about. about 10mg, about 1mg to about 50mg, about 50mg to about 100mg, about 100mg to about 150mg, about 150mg to about 200mg, about 200mg to about 250 mg, around 250mg to around 300mg, around 300mg to around 350mg, around 350mg to around 400mg, around 400mg to around 450mg, or around 450mg to around 500mg .

Finasteride

Finasteride has the chemical name / V- (1, l-dimethylethyl) -3-oxo- (5a, 17p) -4-azaandrostl-ene-17-carboxamide and is marketed as a tablet under the trade name PROPECIA®. A pharmaceutically acceptable salt of finasteride can be used. Finasteride can be administered by routes known in the art, such as oral administration. The amount of finasteride or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 0.2 mg to about 20 mg per day. In certain modalities, finasteride is administered (eg. g., orally) at a daily dosage ranging from about 0.2 mg to about 0.5 mg, about 0.5 mg to about 1 mg, about 1 mg to about 2 mg, about 2 mg to about from 3mg, about 3mg to about 5mg. In certain other embodiments, finasteride is administered (eg, orally) at a daily dosage ranging from or about 1 mg to about 5 mg. The currently preferred dose of finasteride for an adult male in combination with desmopressin is less than the recommended dose for the treatment of BPH, namely less than about 5 mg / day, e.g. eg, about 1 to 3 or 4 mg / day. Less than 1.0 mg / day to mute works well and avoids most adverse side effects.

AS-601811

AS-601811 has the chemical name 4,8-dimethyl-2,3,5,6-tetrahydro-lHbenzo [c] quinolizin-3-one. A pharmaceutically acceptable salt of AS-601811 can be used. The amount of AS-601811 or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 1 mg to about 500 mg. In certain embodiments, AS-601811 is administered at a daily dosage ranging from about 1mg to about 50mg, about 50mg to about 100mg, about 100mg to about 150mg, about 150mg at around 200mg, around 200mg to around 250mg, around 250mg to around 300mg, around 300mg to around 350mg, around 350mg to around 400mg, around 400mg to about 450 mg, or around 450mg to around 500mg.

Izonsterida

Izonsteride has the chemical name (4aR, 10bR) -8 - ((4-ethyl-2-benzothiazolyl) thio) l, 4,4a, 5,6,10b-hexahydro-4,10b-dimethylbenzo [f] quinolin-3 - (2H) -one. A pharmaceutically acceptable salt of izonsteride can be used. The amount of izonsteride or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 1 mg to about 500 mg. In certain embodiments, izonsteride is administered at a daily dosage ranging from about 1 to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200mg, around 200mg to around 250mg, around 250mg to around 300mg, around 300mg to around 350mg, around 350mg to around 400mg, around 400mg to around 450 mg, or around 450mg to around 500mg.

Turosteride

Turosteride has the chemical name 1,3-diisopropyl-1 - ((4-methyl-3-oxo-4-aza-5 alphaandrostan-17beta-yl) carbonyl) urea. A pharmaceutically acceptable salt of turosteride can be used. The amount of turosteride or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 1 mg to about 500 mg. In certain modalities, turosteride is given at a daily dosage ranging from about 1 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200mg, around 200mg to around 250mg, around 250mg to around 300mg, around 300mg to around 350mg, around 350mg to around 400mg, around 400mg to around 450 mg, or around 450mg to around 500mg.

FK143

FK143 has the chemical name 4- [3- [3- [bis (4-isobutylphenyl) methylamino] benzoyl] -l // - ndol-l-yl] butyric acid. A pharmaceutically acceptable salt of FK143 can be used. The amount of FK143 or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 1 mg to about 500 mg. In certain embodiments, FK143 is administered at a daily dosage ranging from about 1 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200mg, around 200mg to around 250mg, around 250mg to around 300mg, around 300mg to around 350mg, around 350mg to around 400mg, around 400mg to around 450 mg, or around 450mg to around 500mg.

TF-505

TF-505 has the chemical name (-) - (S) -4- [l- [4- [l- (4isobutylphenyl) butoxy] benzoyl] indolizin-3-yl] butyric acid. A pharmaceutically acceptable salt of TF-505 can be used. TF-505 can be administered by routes known in the art, such as oral administration. The amount of TF-505 or pharmaceutically acceptable salts thereof that is administered to the patient can range, for example, from about 10 mg to 100 mg per day. In certain modalities, TF-505 is administered (eg. g., orally) at a daily dosage ranging from about 1 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40mg, around 40mg to around 50mg, around 50mg to around 60mg, around 60mg to around 70mg, around 70mg to around 80mg, around 80 to around 90mg, or around 90mg to around 100mg, In certain other embodiments, TF505 is administered (eg, orally) at a daily dosage ranging from about 25 mg to about 50 mg.

It is noted that more than one 5-alpha reductase inhibitor can be administered to a subject. For example, in certain embodiments, dutasteride and a pharmaceutically acceptable salt of tamsulosin (eg, tamsulosin hydrochloride) are administered to the subject. Capsules containing dutasteride and tamsulosin hydrochloride are commercially available under the brand name JALYN®.

Also, it is noted that the 5-alpha reductase inhibitor can be administered by traditional routes of administration known in the art. Some routes of administration may be preferred for a particular therapeutic agent, such as when the particular route of administration reduces first-pass metabolism or improves bioavailability. In certain embodiments, the 5-alpha reductase inhibitor is administered orally, transdermally, intradermally, or by transmucosal administration alone or in conjunction with desmopressin. In still other embodiments, the 5-alpha reductase inhibitor is administered orally.

A preferred daily dose range of a 5-alpha reductase inhibitor is a lower daily dosage amount than that used for monotherapy to treat BPH. In certain modalities, combination therapy using desmopressin and 5-alpha reductase inhibitor uses a daily dose amount of 5-alpha reductase inhibitor that is around 40% to around 50%, around 50% to around 60 %, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 75% to about 90% of the daily dose used as monotherapy to treat BPH.

The method can also be characterized according to the period of time between the start of desmopressin administration and the administration of the 5-alpha reductase inhibitor. In certain embodiments, the first administration of desmopressin may coincide with the administration of the 5-alpha reductase inhibitor. Alternatively, the initiation of desmopressin administration may be earlier or later than the initiation of the 5-alpha reductase inhibitor administration. In certain embodiments, the 5-alpha reductase inhibitor is administered within 1 hour of the start of desmopressin administration. In certain modalities, the 5-alpha reductase inhibitor is administered within 0.5 hours, 1 hour, 1.5 hours, or 2 hours after the start of desmopressin administration. In certain modalities, the 5-alpha reductase inhibitor is given in the morning (eg. g., at a daily dosage sufficient to provide a therapeutic benefit at least for the period of time that desmopressin is administered).

Alpha-adrenergic receptor antagonists

Alpha-adrenergic receptor antagonists are a class of medicinal alpha-adrenergic receptor antagonists. Alpha-adrenergic receptor antagonists are sometimes referred to as alpha blockers. Examples of alpha-adrenergic receptor antagonists include alfuzosin, doxazosin, idazoxan, prazosin, silodosin, tamsulosin, terazosin, tolazolin, yohimbine, and pharmaceutically acceptable salts thereof. A brief description of these possibly suitable alpha-adrenergic receptor antagonists follows.

Alfuzosin

Alfuzosin has the chemical name AA [3 - [(4-amino-6,7-dimethoxy-2quinazolinyl) methylamine] propyl] tetrahydro-2-furancarboxamide. A pharmaceutically acceptable salt of alfuzosin can be used. For example, alfuzosin hydrochloride salt is marketed under the brand name UROXATRAL® in tablet form. Alfuzosin can be administered by routes known in the art, such as oral administration. The amount of alfuzosin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 1 mg to about 100 mg per day. In certain modalities, alfuzosin is administered (e.g. g., orally) at a daily dosage ranging from about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 20 mg, about 20 mg to about 30mg, around 30mg to around 40mg, around 40mg to around 50mg, around 50mg and around 60mg, around 60mg to around 70mg, around 70mg to around 80 mg, about 80 mg to about 90 mg, or around 90 mg and around 100 mg, In certain other modalities, alfuzosin is administered (eg, orally) at a daily dosage ranging from around 7.5 mg to around 12.5 mg, around 9 mg to about 11 mg, or about 9.5 mg to about 10.5 mg.

Doxazosin

Doxazosin has the chemical name l- (4-amino-6,7-dimethoxy-2-quinazolinil) -4 - [(2,3dihydro-l, 4-benzodioxin-2-yl) carbonyl] piperazine. A pharmaceutically acceptable salt of doxazosin (eg, doxazosin hydrochloride or doxazosin mesylate) can be used. For example, doxazosin mesylate salt is marketed under the brand name CARDURA® in tablet form. Doxazosin can be administered by routes known in the art, such as oral administration. The amount of doxazosin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.1 mg to about 50 mg per day. In certain modalities, doxazosin is administered (eg. g., orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about from 2.0 mg, around 2.0 mg to around 2.5 mg, around 2.5 mg to around 3.0 mg, around 3.0 mg to around 3.5 mg, around 3.5 mg to around 4.0 mg, around 4.0 mg to around from 4.5 mg, about 4.5 mg to about 5.0 mg, around 5.0mg to around 5.5mg, around 5.5mg to around 6.0mg, around 6.0mg to around 6.5mg, around 6.5mg to around 7.0mg, around 7.0mg to around 7.5mg, around 7.5mg to around 8.0mg, around 8.0mg to around 9.0mg, around 9.0mg to around 10mg, around 10mg to around 12mg, around 12mg to around 14mg, about 14 mg to about 16 mg, about 16mg to about 18mg, about 18mg to about 20mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 35mg, around 35mg to around 40mg, around 40mg to around 45mg, or around 45mg to around 50mg.

Idazoxan

Idazoxan has the chemical name 2- (2,3-dihydro-1,4-benzodioxin-2-yl) -4,5-dihydrol / T-imidazoL A pharmaceutically acceptable salt of idazoxan (e.g. hydrochloride of idazoxan). Idazoxan can be administered by routes known in the art, such as oral administration. The amount of idazoxan or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.1 mg to about 100 mg per day. In certain modalities, idazoxan is administered (eg. g., orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about from 2.0 mg, around 2.0 mg to around 2.5 mg, around 2.5 mg to around 3.0 mg, around 3.0 mg to around 3.5 mg, around 3.5 mg to around 4.0 mg, around 4.0 mg to around from 4.5 mg, about 4.5 mg to about 5.0 mg, about 5.0mg to about 6.0mg to about 7.0mg, about 7.0mg to about 8.0mg, about 8.0mg to about 9.0mg, about 9.0mg to about 10mg, about 10mg to about 15mg, about 15mg to about 20mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 35mg, about 35mg to about 40mg, about 40mg to about 45mg, around 45mg to around 50mg, around 50mg to around 60mg, around 60mg to around 70mg, around 70mg to around 80mg, around 80mg to around 90mg, or around 90mg to around 100mg.

Prazosina

Prazosin has the chemical name l- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4- (2furanylcarbonyl) piperazine. A pharmaceutically acceptable salt of prazosin can be used. For example, prazosin hydrochloride salt is marketed under the brand name MINIPRESS® in capsule form. Prozasin can be administered by routes known in the art, such as oral administration. The amount of prozasin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.1 mg to about 100 mg per day. In certain modalities, prozasin is administered (e.g. g., orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about from 2.0 mg, around 2.0 mg to around 2.5 mg, around 2.5 mg to around 3.0 mg, around 3.0 mg to around 4.0 mg, around 4.0 mg to around 5.0 mg, around 5.0 mg to around from 7.0 mg, about 7.0 mg to about 9.0 mg, about 9.0mg to about 15mg, about 15mg to about 20mg, about 20mg to about 25mg, about 25mg to about 35mg, about 35mg to about 45mg, around 45 m to around 60 mg, around 60 mg to around 70 mg, around 70 mg to around 80 mg, around 80 mg to around 90 mg, or around 90 mg to around 100 mg.

Silodosin

Silodosin has the chemical name 2,3-dihydro-l- (3-hydroxypropyl) -5 - [(2 /?) - 2 - [[2- [2 (2,2,2-trifluoroethoxy) phenoxy] ethyl ] amino] propyl] -1 / Vindole-7-carboxamide and is marketed under the brand name RAPAFLO® in capsule form. A pharmaceutically acceptable salt of silodosin (eg, silodosin hydrochloride) can be used. Silodosin can be administered by routes known in the art, such as by oral administration. The amount of silodosin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.1 mg to about 50 mg per day. In certain modalities, silodosin is administered (eg. g., orally) at a daily dosage ranging from about 0.1 mg to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mg to about 2.0 mg, about 2.0 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mg to about 5.0 mg, about 5.0 mg to about 6.0 mg, about 6.0 mg to about 7.0 mg, about 7.0 mg to about 8.0 mg, about 8.0 mg to 10 mg, about 10mg to about 15mg, about 15mg to about 20mg, about 20mg to about 25mg, about 25mg to about 35mg, about 35mg to about 45mg, around 45mg to around 50mg. In certain modalities, silodosin is administered (eg, orally) at a daily dosage ranging from about 2.0 mg to about 6.0 mg, about 3.0 mg to about 5.0 mg, about 3.5 mg to about of 4.5 mg. In still other certain modalities, silodosin is administered (eg, orally) at a daily dosage ranging from about 6.0 mg to about 10 mg, about 7.0 mg to about 9.0 mg, or about 7.5 mg to about 8.5 mg.

Tamsulosin

Tamsulosin has the chemical name 5 - [(2 /?) - 2 - [[2- (2-ethoxyphenoxy) ethyl] amino] propyl] 2-methoxybenzenesulfonamide. A pharmaceutically acceptable salt of tamsulosin can be used. For example, tamsulosin hydrochloride salt is marketed under the brand name FLOMAX® in capsule form. Tamsulosin can be administered by routes known in the art, such as oral administration. The amount of tamsulosin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.05 mg to about 10 mg per day. In certain modalities, tamsulosin is administered (eg. g., orally) at a daily dosage ranging from around 0.05 to around 0.10 mg, around 0.30 mg, around 0.50 mg, around 0.70 mg, around 0.10 mga around 0.30 mga around 0.50 mga about 0.70mg to about 0.20mg, about 0.40mg, about 0.60mg, about 0.80mg, about 0.20mg to about 0.40mg to about 0.60mg to about 0.80mg to about 0.90mg, about 0.90mg to about 1.0mg, about 1.0mg to about 1.5mg, about 1.5mg to about 2.0mg, about 2.0mg to about 2.5mg, about 2.5mg to about 3.0mg, around 3.0mg to around 4.0mg, around 4.0mg to around 5.0mg, around 5.0mg to around 6.0mg, around 6.0mg to around 8.0mg, around 8.0mg to around 10mg. In certain modalities, tamsulosin is administered (eg. g., orally) at a daily dosage ranging from about 0.20 mg to about 0.60 mg, about 0.30 mg to about 0.50 mg, about 0.35 mg to about 0.45 mg. In still other certain modalities, tamsulosin is administered (eg, orally) at a daily dosage ranging from about 0.60 mg to about 1.0 mg, about 0.70 mg to about 0.90 mg, or about 0.75 mg. mg to about 0.85 mg.

Terazosin

Terazosin has the chemical name l- (4-amino-6,7-dimethoxy-2-quinazolinyl) -4 [(tetrahydro-2-furanyl) carbonyl] piperazine. A pharmaceutically acceptable salt of terazosin (eg, terazosin hydrochloride or terazosin mesylate) can be used. For example, terazosin hydrochloride salt is marketed under the brand name HYTRIN® in capsule form. Terazosin can be administered by routes known in the art, such as oral administration. The amount of terazosin or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 0.1 mg to about 50 mg per day. In certain modalities, terazosin is administered (eg. g., orally) at a daily dosage ranging from about 0.1 to about 0.5 mg, about 0.5 mg to about 1.0 mg, about 1.0 mg to about 1.5 mg, about 1.5 mg to about 2.0 mg, around 2.0 mg to around 2.5 mg, around 2.5 mg to around 3.0 mg, around 3.0 mg to around 3.5 mg, around 3.5 mg to around 4.0 mg, around 4.0 mg to around 4.5mg, about 4.5mg to about 5.0mg, around 5.0mg to around 6.0mg, around 6.0mg to around 7.0mg, around 7.0mg to around 8.0mg, around 8.0mg to around 9.0mg, around 9.0mg to around 10mg, around 10mg to around 15mg, around 15mg to around 20mg, around 20mg to around 30mg, around 30mg to around 40mg, or around 40mg to around 50mg . In certain modalities, terazosin is administered (eg. g., orally) at a daily dosage ranging from about 0.5 mg to about 1.5 mg, about 0.8 mg to about 1.2 mg, about 0.9 mg to about 1.1 mg. In still other certain modalities, terazosin is administered (eg, orally) at a daily dosage ranging from about 1.5 mg to about 2.5 mg, about 1.8 mg to about 2.2 mg, or about 1.9 mg to about 2.1 mg.

Tolazoline

Tolazoline has the chemical name 4,5-dihydro-2- (phenylmethyl) -lZi^í-¡Midazole. A pharmaceutically acceptable salt of tolazoline can be used (eg._z tolazoline hydrochloride). Tolazolin can be administered by routes known in the art, such as intravenous injection. The amount of tolazoline or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 1 mg / kg of body weight to about 100 mg / kg of body weight per 24 hour period. In certain modalities, tolazoline is administered (eg. g., intravenously) at a total daily dosage ranging from about 1 mg / kg of body weight to about 2 mg / kg of body weight, about 2 mg / kg of body weight to about 3 mg / kg of body weight, about 3 mg / kg of body weight to about 5 mg / kg of body weight, about 5 mg / kg of body weight to about 7 mg / kg of body weight, about 7 mg / kg of body weight to about 9 mg / kg of body weight, about 9 mg / kg of body weight to about 10 mg / kg of body weight, about 10 mg / kg of body weight to about 20 mg / kg of body weight, about 20 mg / kg of body weight to about 30 mg / kg of body weight, about 30 mg / kg of body weight to about 40 mg / kg of body weight, about 40 mg / kg of body weight to about 60 mg / kg of body weight, about 60 mg / kg of body weight to about 80 mg / kg of body weight, or about 80 mg / kg of body weight to about 100 mg / kg of body weight.

Yohimbine

Yohimbine has the chemical name (16α, 17σ) -17hydroxyyohimban-16-carboxylic acid methyl ester. A pharmaceutically acceptable salt of yohimbine (eg, yohimbine hydrochloride) can be used. Yohimbine can be administered by routes known in the art, such as oral administration. The amount of yohimbine or a pharmaceutically acceptable salt thereof that is administered to the patient can range, for example, from about 1 mg to about 50 mg per day. In certain modalities, yohimbine is administered (eg. g., orally) at a daily dosage ranging from about 1.0 mg to about 2.0 mg, about 2.0 mg to about 3.0 mg, about 3.0 mg to about 4.0 mg, about 4.0 mg to about 5.0mg, about 5.0mg to about 6.0mg, about 6.0mg to about 7.0mg, about 7.0mg to about 8.0mg, about 8.0mg to about 9.0mg, about 9.0mg to about 10 mg, about 10 mg to about 15 mg, about 15mg to about 20mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 35mg, about 35mg to about 40mg, around 40mg to around 45mg, or around 45mg to around 50mg.

Other examples of alpha-adrenergic receptor antagonists include, for example, amosulalol, arotinolol, dapiprazole, ergoloid mesylates, fenspiride, indoramine, labetalol, naphtopidil, nicergoline, phenoxybenzamine, phentolamine, typical and atypical antipsychotics of these pharmaceutically acceptable, atipamezole, and these salts.

It is noted that the alpha-adrenergic receptor antagonist can be administered by traditional routes of administration known in the art. Some routes of administration may be preferred for a particular therapeutic agent, such as when the particular route of administration reduces first-pass metabolism or improves bioavailability. In certain embodiments, the alpha-adrenergic receptor antagonist is administered orally, transdermally, intradermally, or by transmucosal administration alone or in conjunction with desmopressin. In still other embodiments, the alpha-adrenergic receptor antagonist is administered orally.

The method can also be characterized according to the period of time between the start of the administration of desmopressin and the administration of the alpha-adrenergic receptor antagonist. In certain embodiments, the first administration of desmopressin may coincide with the administration of the alpha-adrenergic receptor antagonist. Alternatively, the initiation of desmopressin administration may be earlier or later than the initiation of the alpha-adrenergic receptor antagonist administration. In certain embodiments, the alpha-adrenergic receptor antagonist is administered within 1 hour of the start of desmopressin administration. In certain embodiments, the alpha adrenergic receptor antagonist is administered within 0.5 hours, 1 hour, 1.5 hours, or 2 hours after the start of desmopressin administration.

Patient populations

Methods of providing therapeutic benefit to human subjects, preferably adult males, suffering from associated disorders or exhibiting unwanted urination are contemplated. Examples of disorders include nocturia, incontinence, enuresis, and hydruric diabetes. In certain modalities, the human subject suffers from nocturia.

Restoration of urine output

The methods can also be characterized by the length of time required for the subject to return to normal urine output after completion of the administration of desmopressin and the 5-alpha reductase inhibitor. It is important for the subject to resume normal urine production on a daily basis to maintain an adequate fluid balance and to be able to excrete waste through urination. Accordingly, in certain embodiments, the method is also characterized in that urine output in the human subject is restored within less than about two hours after completion of desmopressin administration. In certain other embodiments, the method is also characterized in that urine output in the human subject is restored in less than about an hour after completion of desmopressin administration.

Examples of benefits of combination therapy

Methods and compositions are contemplated to provide various benefits. A contemplated benefit is the better efficacy in inhibiting urgency in a human subject when desmopressin is administered with a 5-alpha reductase inhibitor, compared to the efficacy seen when desmopressin is administered alone. In certain modalities, the improvement can be 5%, 10%, 20%, 30%, 50%, 75%, 100% or greater in the inhibition of urination in a human subject when desmopressin is administered with an inhibitor. of 5-alpha reductase compared to the efficacy seen when desmopressin is administered alone.

Another contemplated benefit is a reduction in side effects associated with the administration of desmopressin. In certain modalities, the reduction in side effects can be 5%, 10%, 20%, 30%, 50%, 75%, 100% or greater in side effects in a human subject when desmopressin is administered with an inhibitor. of 5-alpha reductase compared to the side effects seen when desmopressin is administered alone at a dosage necessary to achieve a similar therapeutic effect.

Administration of desmopressin and a 5-alpha reductase inhibitor can produce a synergistic effect, e.g. eg, a synergistic improvement in the efficacy of urgency inhibition in a human subject. In certain modalities, the synergistic improvement in efficacy is at least 5%, 10%, 15%, 20%, 25%, 30% or greater compared to the additive improvement in efficacy associated with the administration of desmopressin and a 5-alpha reductase inhibitor together.

II. Pharmaceutical Compositions and Dosage Considerations

Another aspect of the invention provides a pharmaceutical composition comprising one or more therapeutic agents described herein and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be specially formulated for administration in liquid or solid form, including those adapted for the following: (1) oral administration, for example, potions (aqueous or non-aqueous solutions or suspensions), tablets (e.g. g., those aimed at oral, sublingual and / or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection, for example, as a sterile solution or suspension or a sustained release formulation; (3) topical application, for example, as a cream, ointment, or controlled-release patch or spray that is applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream, or foam; (5) sublingually; (6) eyepiece; (7) transdermal or (8) nasal. A further description of examples of excipients and formulations designed for a particular route of administration follows.

In certain embodiments, the invention provides a pharmaceutical composition comprising desmopressin, a 5-alpha reductase inhibitor, and a pharmaceutically acceptable carrier. The 5-alpha reductase inhibitor can be, for example, dutasteride, epristeride, finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505 or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition is formulated for nasal administration to a human subject.

The phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (eg, lubricant, magnesium in talc, calcium stearate, or zinc or steric acid) or a solvent encapsulation material involved in the transfer or transport of the target compound from one organ or part of the body to another organ or part of the body. Each carrier must be acceptable in the sense that it is compatible with the other ingredients in the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffers; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other compatible non-toxic substances used in pharmaceutical formulations.

Wetting, emulsifying, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives, and antioxidants, may also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces a therapeutic effect.

Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules or as a solution or suspension in a liquid. aqueous or non-aqueous, as an oil-in-water or water-in-oil liquid emulsion, as an elixir or syrup, or as lozenges (using an inert base, as gelatin and glycerin or sucrose and acacia) and / or as mouthwashes and the like, each with a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a bolus, electuary, or paste.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, lozenges, powders, granules, lozenges, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or phosphate. dicalcium and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate, (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate and nonionic surfactants, (8 ) absorbents, such as bentonite clay and kaolin; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures of these; (10) coloring agents; and (11) controlled release agents, such as crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Similar solid compositions can also be employed as fillers in hard and soft gelatin-filled capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Tablets can be prepared using a binder (eg, gelatin or hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrator (eg, cross-linked sodium starch glycolate or sodium carboxymethylcellulose), surface active agent or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents that are commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. of ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed oil, peanut, corn, germ, olive, castor and sesame), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and sorbitan fatty acid esters and mixtures of these.

In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitan and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth and mixtures of these.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied to obtain an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound of the present invention that is used, or the salt thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the compound. particular use, speed and extent of absorption, duration of treatment, other drugs, compounds and / or materials employed in combination with the particular compound used, the age, sex, weight, general health and prior medical history of the patient being treated, and similar factors known in the medical art.

A physician skilled in the art can easily determine and indicate the effective amount of the pharmaceutical composition required. For example, the physician could start the doses of the compounds of the invention that are used in the pharmaceutical composition at levels lower than those necessary to achieve the desired therapeutic effect and progressively increase the dosage until the desired effect is achieved.

III, Medical Kits

Another aspect of the invention provides a kit for inhibiting urgency in a human subject or inducing an antidiuretic effect in a human subject. The kit comprises (i) instructions for use (ii) desmopressin and (iii) a 5-alpha reductase inhibitor, present as a mixture or separately and, if separated, administered differently, e.g. eg, orally for the inhibitor and transmucosally or via an epithelial patch for desmopressin.

The preceding description describes multiple aspects and modalities of the invention, including therapeutic methods, pharmaceutical compositions, and medical kits. The patent application specifically contemplates all combinations and changes of aspects and modalities.

Aspects of the present description can also be described as follows:

one. A method of inhibiting urgency in an adult human subject for a range of from about two hours to no more than about eight hours, comprising administering to an adult human subject in need thereof a low and effective dose amount of desmopressin and a 5-alpha reductase inhibitor such that both exert physiological activity for a period of time in overlap.

2. The method of 1, wherein the method inhibits urination in a human subject for a range of from about four hours to about seven hours.

3. Method 1, in which an antidiuretic effect is achieved for a range of about two hours to no more than about six hours.

Four. Method 1, in which an antidiuretic effect is achieved for a range of about four hours to no more than about seven hours.

5. The method of any of 1 to 4, wherein the administration achieves a concentration of desmopressin in the subject's blood plasma that does not exceed 15 pg / mL.

6. The method of any of 1 to 4, wherein administration achieves a concentration of desmopressin in the subject's blood plasma that does not exceed 10 pg / mL.

7. The method of any of 1 to 4, wherein administration achieves a concentration of desmopressin in the subject's blood plasma that ranges from about

0.5 pg / mL and around 5 pg / mL.

8. The method of any 1 to 4, in which the administration achieves a concentration of desmopressin in the blood plasma in the human subject that ranges from about 0.5 pg / mL to about 2.5 pg / mL.

9. The method of any of 1 to 8, wherein the desmopressin is administered transdermally, intradermally, or transmucosally through the oral or nasal mucosa.

10. The method of any of 1 to 8, wherein the desmopressin is administered transdermally or intradermally.

eleven. The method of any of 1 to 8, in which desmopressin is administered intranasally.

12. The method of any of 1 to 8, in which desmopressin is administered sublingually through the oral mucosa.

13. The method of 10, in which the desmopressin is administered at a flow rate ranging from about 5 ng / hour to about 35 ng / hour.

14. Method 10, in which desmopressin is administered at a flow rate ranging from about 5 ng / hour to about 15 ng / hour.

fifteen. The method of any of 1 to 14, wherein the 5-alpha reductase inhibitor is dutasteride, epristeride, finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505, or a pharmaceutically acceptable salt thereof.

16. The method of any of 1 to 14, wherein the 5-alpha reductase inhibitor is dutasteride.

17. The method of any of 1 to 14, wherein the 5-alpha reductase inhibitor is finasteride.

18. The method of any of 1 to 14, wherein the 5-alpha reductase inhibitor is a mixture of dutasteride and tamsulosin hydrochloride.

19. The method of any of 1 to 18, wherein the 5-alpha reductase inhibitor is administered orally, transdermally, intradermally, or through the nasal or oral mucosa.

twenty. The method of any of 1 to 18, wherein the 5-alpha reductase inhibitor is administered orally.

twenty-one. The method of any of 1 to 20, wherein the 5-alpha reductase inhibitor is administered up to 1 hour before or after the start of desmopressin administration.

22. The method of any of 1 to 21, wherein the subject suffers from nocturia, incontinence, enuresis, or hydruric diabetes.

2. 3. The method of any of 1 to 21, in which the subject suffers from nocturia.

24. The method of any of 1 to 23, wherein urine output in the human subject is restored in less than about two hours after completion of desmopressin administration.

25. The method of 1 comprising administering a 5-alpha reductase inhibitor to the subject daily for a period of at least one month and administering desmopressin before the subject goes to bed.

26. The method of 1 which comprises administering to the subject a 5-alpha reductase inhibitor at a dose level lower than its lowest recommended on-label dose of the drug for the treatment of BPH and administering desmopressin before the subject goes to bed.

27. The method of 1 which comprises administering to the subject as a mixture before going to bed desmopressin and a 5-alpha reductase inhibitor at a dose level lower than the lowest drug dose recommended on the label of said inhibitor for the treatment of BPH.

28. The method of any of 1 to 27, further comprising administering an alpha-adrenergic receptor antagonist.

29. The method of 28, in which the alpha-adrenergic receptor antagonist is alfuzosin, amosulalol, arotinolol, dapiprazole, doxazosin, ergoloid mesylates, fenspiride, idazoxan, indoramine, labetalol, naphtopidil, nicergoline, prazosin, silodosin, theine tamsulosine, torazosin , yohimbine, phenoxybenzamine, phentolamine, atipamezole or a pharmaceutically acceptable salt thereof.

30. The method of any of 1 to 29, wherein the subject is an adult male human subject.

31. A pharmaceutical composition comprising desmopressin, a 5-alpha reductase inhibitor, and a pharmaceutically acceptable carrier.

32. The pharmaceutical composition of 31, wherein the pharmaceutical composition is formulated for intranasal or sublingual administration to a human subject.

33. The pharmaceutical composition of 31 or 32, wherein the 5-alpha reductase inhibitor is dutasteride, epristeride, finasteride, izonsteride, turosteride, AS-601811, FK143, TF-505 or a pharmaceutically acceptable salt thereof.

• EXAMPLES

The invention now described in general terms will be more readily understood by reference to the following examples, which are included merely to illustrate certain aspects and embodiments of the present invention and are not intended to limit the invention.

EXAMPLE 1

A clinical study was conducted to evaluate the impact of the administration of desmopressin in combination with a 5-alpha reductase inhibitor alone or together with an alpha-adrenergic receptor antagonist to reduce the presence of nocturnal urination in the patient. The experimental procedures and results are described below. The results show that the administration of desmopressin in combination with a 5-alpha reductase inhibitor alone or together with an alpha-adrenergic receptor antagonist produces a higher percentage of patients who experience a reduction in the presence of nocturnal urination, compared to the administration of desmopressin alone, the 5-alpha reductase inhibitor alone, or the 5-alpha reductase inhibitor together with an alpha-adrenergic receptor antagonist.

Part I - Experimental procedures

The patients in the clinical study met the following criteria: (a) men or women at least 50 years of age who had experienced an average of at least two nocturnal urinations per night for a period of at least six months, and (b) who do not have any congestive heart failure, hydruric diabetes , kidney failure, liver failure, incontinence, disease requiring systemic steroids, neoplasia in the previous 5 years, sleep apnea, nephrotic syndrome, unexplained pelvic mass, Neurological urinary bladder dysfunction, having had urinary bladder surgery or radiotherapy, or are pregnant or breastfeeding.

The patients received as a nasal spray (i) a dosage of 1.5 g of desmopressin or (ii) placebo. Desmopressin nasal spray (or placebo) was administered every day immediately before bedtime for a period of twelve weeks. In addition, patients previously diagnosed with benign prostatic hyperplasia (BPH) and who had received a 5-alpha reductase inhibitor alone or together with an alpha adrenergic receptor antagonist for the treatment of BPH continued to receive the 5-alpha reductase inhibitor alone or together. with the alpha-adrenergic receptor antagonist at the same dosage and frequency that was used prior to enrollment in the study. All patients in this study who received a 5-alpha reductase inhibitor alone or together with an alpha-adrenergic receptor antagonist for the treatment of their BPH had received the 5-alpha reductase inhibitor alone or together with the alpha receptor antagonist. -adrenergic for at least 2 months prior to enrollment in the study and had an average of at least two nocturnal urinations per night prior to enrollment in this study. The desmopressin nasal spray was made by combining aliquots of an Emulsion Stock Solution and a Buffer Solution as described below.

Emulsion Stock Solution:

To produce an emulsion stock solution, the following ingredients were added in parts by weight to a container equipped with a stir bar and mixed for 15 minutes at 60 to 65 ° C: (i) 180 parts of aqueous solution of sorbitan monolaureate ( Span-20) (12 mg / mL); (ii) 30 parts of aqueous Polysorbate 20 (Tween-20) solution (2 mg / mL); (iii) 400 parts of cottonseed oil aqueous emulsion (26.6 mg / mL); (iv) 600 parts of aqueous emulsion of cyclopentanedecanolide (CPE-215) (40 mg / mL); and (v) water to produce 1,500 total grams of batch size. After mixing, the preparation was homogenized using high speed mixing at 6500 RPM + for 20 to 25 minutes to produce a fine emulsion. This solution was placed in an autoclave to ensure sterility.

Buffer solution:

To produce a citric acid stock buffer solution, the following ingredients were added in parts by weight to a container equipped with a stir bar and mixed for 5 minutes at 60 to 65 ° C: (i) 6200 parts of water, (¡i ) 16 parts of anhydrous citric acid aqueous solution (1.85 mg / mL); (iii) 76 parts of aqueous solution of sodium citrate dihydrate (8.9 mg / mL); (iv) 104 parts of aqueous Polysorbate 20 (Tween-20) solution (12 mg / mL); and (v) water to produce 8,500 total grams of batch size.

Desmopressin Stock Solution:

To produce a desmopressin stock solution, 0.111 parts of desmopressin acetate trihydrate was added to a sufficient stock buffer to produce 100.0 mL of solution and stirred until all of the desmopressin dissolved to produce a stock solution with a concentration of 100 pg desmopressin / mL. From this stock solution, a 30 pg / mL solution was prepared by dilution.

Desmopressin Nasal Spray:

To produce desmopressin nasal spray, 30 pg / mL aliquots were filtered to remove any bacterial contamination and diluted with an equal volume of emulsion stock solution to produce preservative-free, aseptic dosage forms with 15 pg / mL desmopressin. , pH 5.5, and with 2% cyclopentanedecanolide. These were bottled in sterile pumped aerosol bottles with Pfeiffer APF pump aerosols delivering 100 pL per metered aerosol (ie 1.5 pg desmopressin (ie 1500 ng desmopressin) per aerosol). The liquid does not contain detectable microorganisms.

The patients recorded the presence of nocturnal urination during the study period. Patients were indicated as "responding" if after receiving treatment there was a reduction in the average number of nocturnal voids during the treatment period. Patients who did not experience a reduction in the average number of nocturnal voids during the treatment period were indicated as 'no response'.

Part II - Results

The results of the clinical study are shown in Tables 1 through 4 below. Table 1 shows the results of the administration of desmopressin or a placebo to patients with BPH who received a 5-alpha reductase inhibitor alone or in conjunction with an alpha-adrenergic receptor antagonist. The absolute response rate of BPH patients treated with desmopressin in combination with a 5-alpha reductase inhibitor alone or together with an alpha adrenergic receptor antagonist was 57%, compared to 17% for the placebo group (ie i.e. without desmopressin). This is a 40% difference.

TABLE 1

Patients with BPH who received combination therapy of desmopressin or only a 5-alpha reductase inhibitor alone or together with an alpha adrenergic receptor antagonist

<td rowspan="2">Second (or Third) Component of Combination Therapy</td><td colspan="2">Responding Patients</td><td colspan="2">Nonresponsive Patients</td>

<td>Number of Patients Receiving Desmopressin (n = 14)</td><td>Number of Patients Receiving Placebo (n = 12)</td><td>Number of Patients Receiving Desmopressin (n = 14)</td><td>Number of Patients Receiving Placebo (n = 12)</td>

<td>5-alpha reductase inhibitor</td><td> 3</td><td> 1*</td><td> 4</td><td> 5</td>

<td>antagonist of alpha receptor adrenergic and 5-alpha reductase inhibitor</td><td> 5</td><td> 1</td><td> 2</td><td> 5</td>

<td>Total Number of Patients</td><td> 8</td><td> 2</td><td> 6</td><td> 10</td>

<td>Total percentage</td><td> 57 % (8/14)</td><td> 17 % (2/12)</td><td> 43 % (6/14)</td><td> 83 % (10/12)</td>

* A patient was taking a 5 alpha reductase inhibitor and an anticholinergic agent.

Table 2 shows the results of the administration of desmopressin or a placebo to patients diagnosed with BPH, but who did not receive a 5-alpha reductase inhibitor alone or in conjunction with an alpha-adrenergic receptor antagonist. The absolute response rate of BPH patients receiving desmopressin (i.e. no alpha adrenergic receptor antagonist or 5-alpha reductase inhibitor) was 43%, compared with 29% for the placebo group (i.e. none of desmopressin, an alpha-adrenergic receptor antagonist or 5-alpha reductase inhibitor). This is a difference of 14%.

TABLE 2

BPH patients receiving desmopressin or placebo

<td rowspan="2">Second (Or Third) Component Of Combination Therapy</td><td colspan="2">Responding Patients</td><td colspan="2">Nonresponsive Patients</td>

<td>Number of Patients Receiving Desmopressin (n = 42)</td><td>Number of Patients Receiving Placebo (n = 56)</td><td>Number of Patients Receiving Desmopressin (n = 42)</td><td>Number of Patients Receiving Placebo (n = 56)</td>

<td>none</td><td> 18</td><td> 16</td><td> 24</td><td> 40</td>

<td>Total percentage</td><td> 43 %</td><td> 29 %</td><td> 57 %</td><td> 71 %</td>

Table 3 shows the results of the administration of desmopressin or a placebo to male patients without BPH and therefore who did not receive a 5-alpha reductase inhibitor alone or in conjunction with an alpha-adrenergic receptor antagonist. The absolute response rate of male patients without BPH who received desmopressin was 53%, compared with 35% for the placebo group (ie, without desmopressin). This is a difference of 18%.

TABLE 3 Male patients without BPH who received desmopressin or placebo

<td rowspan="2">Second (or Third) Component of Combination Therapy</td><td colspan="2">Responding Patients</td><td colspan="2">Nonresponsive Patients</td>

<td>Number of Patients Receiving Desmopressin (n = 34)</td><td>Number of Patients Receiving Placebo (n = 23)</td><td>Number of Patients Receiving Desmopressin (n = 34)</td><td>Number of Patients Receiving Placebo (n = 23)</td>

<td>none</td><td> 18</td><td> 8</td><td> 16</td><td> 15</td>

<td>Total Percentage</td><td> 53%</td><td> 35 %</td><td> 47%</td><td> 65 %</td>

In summary, patients who received the combination therapy (i.e., desmopressin in combination with a 5-alpha reductase inhibitor alone or together with an alpha-adrenergic receptor antagonist) had a higher absolute response rate and a relative response rate. greater than patients who received placebo, compared with the response rates observed for (i) BPH patients who received only desmopressin and (ii) male patients without BPH who received only desmopressin. This is illustrated in Table 4 below.

TABLE 4 Data Analysis

<td>Patient Population</td><td>Absolute Response Rate for Patients who They received Desmopressin</td><td>Difference in Response Rate of Responders Between Desmopressin-Treated Patients and Those Receiving Placebo</td>

<td>Responders suffering from BPH who received a 5-alpha reductase inhibitor alone or in conjunction with an alpha-adrenergic receptor antagonist</td><td> 57%</td><td> 40%</td>

<td>Responders suffering from BPH who did not receive a 5-alpha reductase inhibitor or alpha adrenergic receptor antagonist</td><td> 43 %</td><td> 14%</td>

<td>Male responders not diagnosed with BPH and not receiving a 5-alpha reductase inhibitor or alpha-adrenergic receptor antagonist</td><td> 53 %</td><td> 18 %</td>

Incorporation by reference

The full disclosure of all patent documents and scientific articles mentioned herein is incorporated by this reference for all purposes.

Equivalents

The invention can be presented in other specific forms without departing from its spirit or essential characteristics. Therefore, the foregoing embodiments will be considered to be illustrative in all respects and do not limit the invention described herein. Therefore, the scope of the invention is indicated by the appended claims and not by the preceding description, and all encompassed changes in the meaning and spectrum of equivalence of the claims are intended to be encompassed by the claims.