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US20160317542A1 - Pde5 inhibitor powder formulations and methods relating thereto - Google Patents

Pde5 inhibitor powder formulations and methods relating thereto Download PDF

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Publication number
US20160317542A1
US20160317542A1 US15/102,957 US201415102957A US2016317542A1 US 20160317542 A1 US20160317542 A1 US 20160317542A1 US 201415102957 A US201415102957 A US 201415102957A US 2016317542 A1 US2016317542 A1 US 2016317542A1
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Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
composition
vardenafil
powder
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Inventor
Zhen Xu
Hugh Smyth
Aileen Gibbons
Revati Shreeniwas
Pravin Soni
Dan Deaton
James Hannon
Stephen Lermer
Robert Curtis
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Respira Therapeutics Inc
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Respira Therapeutics Inc
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Assigned to Respira Therapeutics, Inc. reassignment Respira Therapeutics, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LERMER, Stephen, SHREENIWAS, Revati, SMYTH, HUGH, DEATON, DAN, GIBBONS, Aileen, CURTIS, ROBERT, HANNON, JAMES, SONI, PRAVIN, XU, ZHEN
Publication of US20160317542A1 publication Critical patent/US20160317542A1/en
Assigned to Respira Therapeutics, Inc. reassignment Respira Therapeutics, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DONOVAN, MARTIN J.
Assigned to Respira Therapeutics, Inc. reassignment Respira Therapeutics, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DONOVAN, MARTIN J.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0005—Details of inhalators; Constructional features thereof with means for agitating the medicament
    • A61M15/0006—Details of inhalators; Constructional features thereof with means for agitating the medicament using rotating means
    • A61M15/0008—Details of inhalators; Constructional features thereof with means for agitating the medicament using rotating means rotating by airflow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to powder formulations of PDE5 inhibitors and methods relating thereto.
  • Phosphodiesterase type 5 inhibitors block the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis.
  • PDE5 inhibitors block the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis.
  • These drugs including vardenafil (LevitraTM), sildenafil (ViagraTM), and tadalafil (CialisTM), are administered orally for the treatment of erectile dysfunction and were the first effective oral treatment available for the condition.
  • PDE5 inhibitors have also been studied for other clinical use as well, including cardiovascular and heart diseases. For example, because PDE5 is also present in the arterial wall smooth muscle within the lungs, PDE5 inhibitors have also been explored for lung diseases such as pulmonary hypertension and cystic fibrosis. Pulmonary arterial hypertension, a disease characterized by sustained elevations of pulmonary artery pressure, which leads to an increased incidence of failure of the right ventricle of the heart, which in turn can result in the blood vessels in the lungs become overloaded with fluid. Two oral PDE5 inhibitors, sildenafil (RevatioTM) and tadalafil (AdcircaTM), are approved for the treatment of pulmonary arterial hypertension.
  • RevatioTM sildenafil
  • AdcircaTM tadalafil
  • PDE5 inhibitors have been found to have activity as both a corrector and potentiator of CFTR protein abnormalities in animal models of cystic fibrosis disease. (Lubamba et al., Am. J. Respir. Crit. Care Med. (2008) 177:506-515, Lubamba et al., J. Cystic Fibrosis (2012) 11:266-273). Sildenafil has also been studied as a potential anti-inflammatory treatment for cystic fibrosis. Oral PDE5 inhibitors have also been reported to have anti-remodeling properties and to improve cardiac inotropism, independent of afterload changes, with a good safety profile. (Giannetta et al., BMC Medicine (2014) 12:185).
  • a powder pharmaceutical composition comprising a) at least about 2% by weight of a PDE5 inhibitor or a pharmaceutically acceptable salt or ester thereof relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier.
  • a method of aerosolizing a powder pharmaceutical composition comprising a) at least 2% by weight of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier, the method comprising: providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • a method of treating a disease in a subject in need thereof comprising administering to the subject via a pulmonary route an effective amount of a powder pharmaceutical composition comprising a) at least about 2% of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, by weight relative to the total weight of the overall pharmaceutical composition dose, and b) at least one pharmaceutically acceptable carrier.
  • FIG. 1 illustrates a 1 H NMR spectrometry spectrum for VarHCl.3H 2 O (top) and Var(HCl) 2 .xH 2 O (bottom) according to certain aspects.
  • FIG. 2 illustrates a 13 C NMR spectrometry spectrum for Var(HCl) 2 .xH 2 O (top) and VarHCl.3H 2 O (bottom) according to certain aspects.
  • FIG. 3 illustrates the results of pH titration analysis for Var(HCl) 2 , VarHCl, and VarBase according to some aspects.
  • FIGS. 4A-4F illustrates the results of instrinsic stability testing of VarHCl.3H 2 O as assessed by a HPLC high performance liquid chromatography (HPLC) according to certain aspects.
  • FIG. 4A shows a HPLC trace for VarHCl.3H 2 O as obtained from the manufacturer.
  • FIG. 4B and FIG. 4C show HPLC traces for VarHCl.3H 2 O following acid degradation in 1N HCl at r.t. for 48 hr and in 1N HCl at 60° C. for 4 hr, respectively.
  • FIG. 4D and FIG. 4E show HPLC traces for VarHCl.3H 2 O following basic degradation in 1N NaOH at r.t. for 48 hr and in 1N NaOH at 60° C. for 4 hr, respectively.
  • FIG. 4F shows an HPLC trace for VarHCl.3H 2 O following oxidative degradation in 6% H 2 O 2 at r.t. for 48 hr.
  • FIGS. 5A-5D illustrate the results of VarHCl.3H 2 O-lactose (1:1) formulation blend stability at different temperatures and humidities as assessed by HPLC according to some aspects.
  • FIG. 5A shows a HPLC trace of the formulation stored pouched at 25° C. and 60% relative humidity (RH).
  • FIG. 5B shows a HPLC trace of the formulation stored pouched at 40° C. and 75% RH.
  • FIG. 5C shows a HPLC trace of the formulation stored open to ambient environment at 40° C. and 75% RH.
  • FIG. 5D shows a HPLC trace of the formulation prior to storage (control).
  • FIGS. 6A-6C illustrates the particle size distribution of micronized Var(HCl) 2 .xH 2 O, VarBase, and VarHCl.xH 2 O, respectively, according to certain aspects.
  • FIGS. 7A-7C provide scanning electron microscopy (SEM) images of micronized Var(HCl) 2 .xH 2 O, VarBase, and VarHCl.xH 2 O, respectively, according to certain aspects.
  • FIGS. 8A-8C illustrate the results of differential scanning calorimetry (DSC) analysis to assess the thermal properties of micronized vardenafil compounds according to certain aspects.
  • FIG. 8A shows the DSC thermogram for Var(HCl) 2 .xH 2 O.
  • FIG. 8B shows the DSC thermogram for VarBase.
  • FIG. 8C shows the DSC thermogram for VarHCl.xH 2 O.
  • FIGS. 9A-9D illustrate dynamic vapor sorption (DVS) analysis of micronized vardenafil compounds to assess moisture sorption and desorption behavior according to certain aspects.
  • FIGS. 9A and 9B show the DVS isotherm plot for micronized Var(HCl) 2 .xH 2 O and micronized VarBase, respectively.
  • DVS isotherm plots for micronized VarHCl.xH 2 O are shown in FIG. 9C and FIG. 9D , with the Y axis reflecting either percent change in mass or the stoichiometric water sorption and desorption profiles (ratio of H 2 O vapor absorbed to dry VarHCl (mol/mol)).
  • FIG. 10 illustrates thermogravimetric analysis (TGA) of micronized Var(HCl) 2 .xH 2 O to assess mass loss according to certain aspects.
  • FIGS. 11A-11C illustrate results of x-ray powder diffraction (XRPD) analysis assessing crystalline forms of vardenafil formulations after micronization.
  • FIGS. 10A, 10B, and 10C show the diffractograms for micronized Var(HCl) 2 .xH 2 O, micronized VarBase, and micronized VarHCl.xH 2 O, respectively.
  • FIG. 12 illustrates an exemplary conditions for preparation of a 5% Var(HCl) 2 .xH 2 O and lactose blend formulation.
  • Components were hand blended and then mixed in a shaker-mixer at 22 rpm-, 49 rpm, and 99 rpm for 5 min, 10 min, 15 min, and 20 min. Extend of blend uniformity was assessed by the coefficient of variation (% CV) sampling.
  • FIG. 13 is a block diagram of a method of aerosolizing a powder pharmaceutical composition according to some aspects.
  • FIG. 14A shows a cross-section of an exemplary tubular body having an inlet and a dispersion chamber according to some aspects.
  • FIG. 14B shows a bead position with a chamber of the tubular body of FIG. 14A according to some aspects.
  • FIGS. 15A-15B illustrates the aerosol performance of a range of high dose Var(HCl) 2 .xH 2 O-lactose blend formulations according to some aspects.
  • FIG. 15A shows a strong correlation of emitted dose (ED (%) and API concentration (% w/w) of 20%, 40%, 60%, and 80% API blend formulations. The amount of powder deposition in the inhaler device was also assessed and well-correlated with API concentration as shown in FIG. 15B .
  • FIG. 16 is a block diagram of a method of treating a disease in a mammal in need thereof with a powder pharmaceutical composition according to some aspects.
  • formulation and “composition” are used interchangeably and refer to a mixture of at least one compound, element, or molecule. In some aspects the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with one or more carrier or other excipients.
  • therapeutic agent active agent
  • active pharmaceutical ingredient active pharmaceutical ingredient
  • API pharmaceutically active agent
  • drug drug
  • the compound of Formula I is chemically identified as 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-imidazo[5,1-i][1,2,4]triazin-4-one, also known as vardenafil.
  • the compounds include the chemical forms as set forth in Formulas (2), (3), and (4) above, including vardenafil base (VarBase), salts (mono and bis), such as hydrogen chloride salts, and hydrates (mono, di-, tri-hyrdates), as well as different polymorphs.
  • treating refers to providing an appropriate dose of a therapeutic agent to a subject suffering from an ailment.
  • condition refers to a disease state for which the compounds, compositions and methods of the present disclosure are being used to treat.
  • subject refers to a mammal that may benefit from the administration of a drug composition or method of this invention.
  • subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rabbits, rats, mice and aquatic mammals.
  • a subject is a human.
  • an “effective amount” or a “therapeutically effective amount” of a drug refers to a non-toxic, but sufficient amount of the drug, to achieve therapeutic results in treating a condition for which the drug is known to be effective. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an “effective amount” or a “therapeutically effective amount” may be dependent in some instances on such biological factors. Further, while the achievement of therapeutic effects may be measured by a physician or other qualified medical personnel using evaluations known in the art, it is recognized that individual variation and response to treatments may make the achievement of therapeutic effects a somewhat subjective decision. The determination of an effective amount is well within the ordinary skill in the art of pharmaceutical sciences and medicine. See, for example, Meiner and Tonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographs in Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein by reference.
  • pharmaceutically acceptable carrier As used herein, “pharmaceutically acceptable carrier,” “carrier,” and “excipient” may be used interchangeably, and refer to any inert and pharmaceutically acceptable material that has substantially no biological activity, and makes up a substantial part of the formulation.
  • administering refers to the manner in which an active agent is presented to a subject. Administration can be accomplished by various art-known routes such as oral, parenteral, transdermal, inhalation, implantation, etc.
  • pulmonary administration represents any method of administration in which an active agent can be administered through the pulmonary route by inhaling an aerosolized liquid or powder form (nasally or orally).
  • aerosolized liquid or powder forms are traditionally intended to substantially release and or deliver the active agent to the mucosal membrane and epithelium of the lungs.
  • the active agent is in powder form.
  • nominal dose refers to the total amount or mass of active agent packaged or partitioned for administration to a subject.
  • nominal dose is the total amount of active agent that is enclosed in a capsule for use with an inhaler.
  • fine particle fraction or “fine particle fraction from the emitted dose” (% FPF(ED)) refers to the mass of active agent having an aerodynamic diameter below about about 5 ⁇ m as a percentage of an emitted dose mass. Typically, the cutoff size is less than or equal to an aerodynamic diameter of about 5 ⁇ m but, depending on the experimental conditions, can be around 6.4 ⁇ m. The FPF is often used to evaluate the efficiency of aerosol deaggregation.
  • respirable fraction is the mass of an active agent that is below a certain aerodynamic cutoff size as a percentage of a nominal dose mass. Also known as the fine particle fraction from the total dose (FPF(TD)). Fine particle fraction may also be calculated as a percentage of the emitted dose (FPF(ED)).
  • the respirable fraction represents the proportion of powder aerosol that can enter the deep respiratory tract.
  • the RF cutoff size is an aerodynamic diameter of less than about 10 ⁇ m, preferably less than about 7 ⁇ m, and most preferably less than or about 5 ⁇ m. For example, depending on the experimental conditions, the cutoff size RF can be around 6.4 ⁇ m.
  • the respirable fraction may be determined using an inertial sampling device.
  • the aerodynamic diameter (D ae ) is a spherical equivalent diameter and derives from the equivalence between the inhaled particle and a sphere of unit density ( ⁇ o ) undergoing sedimentation at the same rate as per the following formula:
  • D v is the volume-equivalent diameter
  • ⁇ is the particle density
  • ⁇ is the shape factor.
  • the aerodynamic behavior depends on particle geometry, density and volume diameter: a small spherical particle with a high density will behave aerodynamically as a bigger particle, being poorly transported in the lower airways.
  • the D ae can be improved reducing the volume diameter and the density or increasing the shape factor of the particles, by means of different processes.
  • MMAD mass median aerodynamic diameter
  • compositions of PDE5 inhibitors and pharmaceutically acceptable salts and esters thereof include at least about 2% by weight of active agent and at least one pharmaceutically acceptable carrier.
  • a powder pharmaceutical composition comprising a) at least about 2% by weight of a PDE5 inhibitor or a pharmaceutically acceptable salt or ester thereof relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier.
  • the PDE5 inhibitor may be at least one of vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, or a pharmaceutically acceptable salt or ester thereof.
  • the composition may include at least about 2% to about 20% by weight of the PDE5 inhibitor.
  • the composition may include at least about 2% to about 20% by weight of vardenafil or a pharmaceutically acceptable salt or ester thereof.
  • the at least one pharmaceutically acceptable carrier may include lactose, mannitol, trehalose, or starch.
  • the at least one pharmaceutically acceptable carrier may include at least one of a mono-, di- or poly-saccharide, or their derivatives, calcium stearate, magnesium stearate, leucine or its derivatives, lecithin, human serum albumin, polylysine, polyarginine, or other force control agents, or combinations thereof.
  • the PDE5 inhibitor or a pharmaceutically acceptable salt or ester may be micronized.
  • the composition may be packaged to have a nominal load of about 3 mg to 30 mg. In one aspect, the composition may be packaged to have a nominal dose of at least about 0.25 mg. In one aspect, the composition may be packaged to have a delivered dose of at least about 0.075 mg.
  • a method of aerosolizing a powder pharmaceutical composition comprising a) at least 2% by weight of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier, the method comprising: providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • the powder pharmaceutical composition may have one or more of the properties recited in the previous paragraph.
  • the composition may have a mass median aerodynamic diameter of between 0.5 ⁇ m and 5 ⁇ m upon aerosolization.
  • the composition may have a fine particle fraction of at least about 20% upon aerosolization.
  • the composition may have an emitted dose of at least about 40% upon aerosolization.
  • the powdered medicament may be stored within a storage compartment (of the inhaler), and wherein the powder pharmaceutical composition is transferred from the storage compartment, through the inlet and into the dispersion chamber.
  • the inlet may be in fluid communication with an initial chamber, and wherein the powder pharmaceutical composition is received into the initial chamber prior to passing through the inlet and into the dispersion chamber.
  • a method of treating a disease in a subject in need thereof comprising administering to the subject via a pulmonary route an effective amount of a powder pharmaceutical composition comprising a) at least about 2% of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, by weight relative to the total weight of the overall pharmaceutical composition dose, and b) at least one pharmaceutically acceptable carrier.
  • the disease may be a lung disease or a heart disease.
  • the lung disease may be pulmonary arterial hypertension or cystic fibrosis.
  • the heart disease may be congestive heart failure.
  • the powder pharmaceutical composition may have one or more of the properties recited in the previous paragraphs.
  • the powder pharmaceutical composition may be administered as an aerosol.
  • the powder pharmaceutical composition may be administered using a dry powder inhaler or a metered dose inhaler.
  • the powder pharmaceutical composition may be administered by providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • a delivered dose of about 0.25 mg to about 20 mg may be delivered to the subject upon aerosolization.
  • the active agent of the pharmaceutical composition may a PDE5 inhibitor.
  • PDE5 inhibitors include, but are not limited to, vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, zaprinast, or any of their pharmaceutically acceptable salts, esters, or derivatives.
  • the active agent may be vardenafil, in all of its suitable forms, which has the formula (I):
  • the compound of Formula (I) is chemically identified as 2-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-1H-imidazo[5,1-i][1,2,4]triazin-4-one.
  • Two polymorphic structures have been known for the free base of vardenafil described by Formula (I) (Form I described in WO/1999/024433 and Form II described in U.S. Pat. No. 7,977,478).
  • Vardenafil can further form salts, which are described by general chemical Formula (II), wherein HA stands for any acid (as described in WO/2013/075680).
  • vardenafil The majority of solid forms of vardenafil are the respective hydrochlorides and their hydrates (as described in U.S. Pat. Nos. 6,362,178 and 7,977,478; Haning et al., Bioorg. Med. Chem. Lett. 12 (2002) 865-868), which are described by general Formula (III).
  • the hydrochloride trihydrate (as described in U.S. Pat. Nos. 6,362,178 and 8,273,876, WO/2002/050076) described by chemical Formula (IV), is the form of vardenafil that has been used for preparing oral dosage forms (WO/2010/130393, WO/2008/151811, WO/2005/110420, WO/2004/006894).
  • the active agent may be vardenafil as shown in Formula (I) (also referred to herein as VarBase), sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, as well as pharmaceutically acceptable, pharmacologically active derivatives thereof, or compounds significantly related thereto, including without limitation, salts, pharmaceutically acceptable salts, N-oxides, prodrugs, active metabolites, isomers, fragments, solvates, including hydrates, polymorphs, pseudopolymorphs, esters, etc.
  • Formula (I) also referred to herein as VarBase
  • sildenafil sildenafil
  • tadalafil tadalafil
  • avanafil benzamidenafil
  • lodenafil lodenafil
  • mirodenafil mirodenafil
  • udenafil udena
  • the term “active agent” includes all pharmaceutically acceptable forms of vardenafil or the other PDE5 inhibitors described herein.
  • the active agent can be in an isomeric mixture.
  • the active agent can be in a solvated form such as a hydrate. Any form of the active agent is suitable for use in the compositions of the present invention, such as, for example, a pharmaceutically acceptable salt of the active agent, a free acid of the active agent, or a mixture thereof.
  • the term “active agent” may include all pharmaceutically acceptable salts, derivatives, esters, and analogs of vardenafil or the other PDE5 inhibitors listed herein, as well as combinations thereof.
  • the active agent may be a vardenafil compound having the chemical forms as set forth in Formulas (I), (II), (III), or (IV) above.
  • the pharmaceutically acceptable salts of vardenafil may include, without limitation, hydrogen chloride salt forms thereof and the like.
  • the mono-hydrogen chloride may be represented by Formulas (II) or (IV).
  • Formula (II) When unhydrated, the mono-hydrogen chloride form may be represented by Formula (II), also referred to herein as VarHCl.
  • Formula (IV) also referred to herein as VarHCl.3H 2 O.
  • Formula (III) When partially hydrated, it is represented by Formula (III), also referred to herein as VarHCl.xH 2 O, where “x” represents undetermined amount of bound water between 0-3.
  • the di-hydrogen chloride form of vardenafil can be represented by Formulas (II) or (III).
  • Formula (II) When unhydrated, the di-hydrogen chloride form may be represented by Formula (II), also referred to herein as Var(HCl) 2 .
  • Formula (III) When hydrated, this form is represented by Formula (III), which is referred to herein as Var(HCl) 2 .xH 2 O, as this form is unstable and readily loses water molecules.
  • active agent may be present in different crystal forms.
  • the different crystalline forms of the same compound can have an impact on one or more physical properties, such as stability, solubility, melting point, bulk density, flow properties, bioavailability, etc.
  • vardenafil base as shown in Formula (I) has two polymorphic forms.
  • the solid powder forms of active agent may be characterized by one or more of several techniques including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), x-ray powder diffraction (XRPD), and Karl Fischer (KF) titration, and pH titration.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVD dynamic vapor sorption
  • XRPD x-ray powder diffraction
  • Karl Fischer Karl Fischer
  • a subset of a diffraction pattern, spectrum, or plot may be used to characterize an active agent provided that subset distinguishes the active agent from the other forms.
  • one or more X-ray powder diffraction pattern alone may be used to characterize an active agent.
  • one or more DVS or DSC plots alone may be used to characterize an active agent.
  • one or more pH titration analyses may be used to characterize an active agent.
  • one or more NMR spectra alone may be used to characterize an active agent. Such characterizations are done by comparing the XRPD, DSC, DVS, TGA, NMR data amongst the forms to determine characteristic peaks.
  • one or more X-ray diffraction peak characterizes an active agent
  • combining multiple techniques for analysis of an active agent forms can be advantageous to confirm chemical identity of the active agent.
  • HPLC analysis combined with Karl Fischer titration can identify the chemical forms of vardenafil as Var(HCl) 2 .xH 2 O and not VarHCl.xH 2 O.
  • elemental analysis of carbon, hydrogen, and nitrogen can identify different chemical forms of vardenafil based on their molecular formulas.
  • VarBase and vardenafil HCl salts (VarSalts) and hydrates the following equations may be used:
  • NMR analysis may be performed to identify chemical shifts characteristic of different vardenafil forms.
  • the NMR analysis may be either 1 H NMR analysis or 13 C NMR analysis as shown in FIG. 1 and FIG. 2 .
  • d 6 -DMSO can be used as a solvent.
  • VarHCl.3H 2 O can be identified by a methyl peak shifted to 2.472 ppm and triplet (doublet+singlet) around 8 ppm as shown in FIG.
  • Var(HCl) 2 .xH 2 O can be identified by a methyl peak shifted to 2.604 ppm and a quintet (triplet+doublet) around 8 ppm as shown in FIG. 1 .
  • active agents may be characterized and distinguished using DSC as shown in FIGS. 8A-8C .
  • Var(HCl) 2 .xH 2 O may be characterized by a onset of glass transition at about 50° C. that ended at about 110° C., a small endothermic peak at about 140° C., and two large endothermic peaks at 222° C. and 294° C.
  • VarBase may be identified by a heat of fusion temperature of 190° C., with an onset temperature of about 177° C. when the scanning rate was set at 10° C./min, and degradation peaks when the temperature is raised above 250° C.
  • the melting temperature of the vardenafil forms as determined by DSC may identify different forms of VarBase.
  • Var(HCl) 2 .xH 2 O may be identified by a large endothermic peak at 107° C., and onset temperature of about 50-60° C., and a heat of fusion temperature of about 199° C.
  • active agents may be characterized and distinguished using DVS as shown in FIGS. 9A-9D , TGA as shown in FIG. 10 , and XRPD as shown in FIGS. 11A-11C .
  • the disclosed dry powder compositions can additionally include a carrier/excipient.
  • Dry powder compositions may contain a powder mix for inhalation of the active ingredient and a suitable powder base (a carrier, a diluent, and/or an excipient substance) such as mono-, di or poly-saccharides (for example, lactose, mannitol, trehalose, or starch).
  • a suitable powder base a carrier, a diluent, and/or an excipient substance
  • the carrier may form from about 1% to about 95% by weight of the formulation.
  • the powder base may act as a carrier, a diluent that aids in dispensing the active agent, and a fluidizing agent to assist dispersion of the active agent.
  • lactose may be a suitable powder base for use with PDE5 inhibitor dry powder compositions.
  • lactose is a suitable carrier for vardenafil formulations for pulmonary administration because it does not react with vardenafil as shown, for example, in FIGS. 5A-5D for VarHCl.3H 2 O.
  • vardenafil-lactose blends are chemically stable even though lactose is a reducing sugar that could react via a Maillard chemical reaction with the amines in vardenafil.
  • the lactose may be, for example, alpha-lactose monohydrate, anhydrous alpha-lactose, anhydrous beta-lactose, or a blend thereof (for example, 70-80% anhydrous beta-lactose and 20-30% anhydrous alpha-lactose).
  • lactose (or other powder base) may be sieved, milled, micronized, or some combination thereof.
  • the lactose may comprise a fine lactose fraction.
  • the fine lactose fraction is defined as the fraction of lactose having a particle size of less than 7 ⁇ m, such as less than 6 ⁇ m, for example less than 5 ⁇ m.
  • the particle size of the fine lactose fraction may be less than 4.5 ⁇ m.
  • the fine lactose fraction if present, may comprise 2% to 50% by weight of the total lactose component, such as 5% to 10% by weight fine lactose, for example 4.5% by weight fine lactose.
  • lactose of different size fractions may be combined in a dry powder composition.
  • the particle size of the carrier will be much greater than that of the active agent.
  • the lactose (or other powder base) may have average diameter of between about 2 ⁇ m to about 250 ⁇ m, more preferably about 5 ⁇ m to about 150 ⁇ m, or more preferably about 60 ⁇ m to about 90 ⁇ m. These sizes can be determined by laser diffraction obtaining an equivalent volume diameter, or by other sizing methods such as sieving.
  • the disclosed dry powder compositions may also include, in addition to the active ingredient and carrier, a further excipient (a ternary agent) such as a mono-, di or poly-saccharides and their derivatives, calcium stearate or magnesium stearate, leucine and its derivatives, lecithin, human serum albumin, polylysine, polyarginine, and other force control agents.
  • a further excipient such as a mono-, di or poly-saccharides and their derivatives, calcium stearate or magnesium stearate, leucine and its derivatives, lecithin, human serum albumin, polylysine, polyarginine, and other force control agents.
  • a further excipient such as a mono-, di or poly-saccharides and their derivatives, calcium stearate or magnesium stearate, leucine and its derivatives, lecithin, human serum albumin, polylysine, polyarginine, and other force control agents.
  • magnesium stearate may
  • the dry powder composition contains pure active agent, without any carriers or excipients.
  • compositions may take the form of dry powders suitable for pulmonary administration via inhalation.
  • Dry powder dosage forms of PDE5 inhibitors (such vardenafil, sildenafil, tadalafil, avanafil, benzamidenafil, lodenafil, mirodenafil, udenafil, or zaprinast, or pharmaceutically acceptable salts or esters thereof) and a pharmaceutically acceptable carrier as described herein offer advantages over other traditional formulations for oral administration (such as tablets, capsules, and liquids administered by swallowing).
  • administration by inhalation of the dry powder formulation overcomes the dosing limitations of oral administrations because higher concentrations of the active agent can be delivered to the site of action (lungs) without the side effects seen with systemic administration.
  • administration by inhalation may even allow the use of these agents in patients who are unable to tolerate these drugs because of hypotension, drug interactions in the liver or other systemic adverse effects, including systemic toxicities associated with chronic daily use, which arise with traditional dosage forms for oral administration.
  • dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity (nominal dose) of therapeutic agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers. Methods for preparing such dosage forms are known or will be apparent to those skilled in the art.
  • the dosage form to be administered will, in any event, contain a quantity of the therapeutic agent in a therapeutically effective amount for relief of the condition being treated when administered in accordance with the teachings of this disclosure.
  • the disclosed compositions may comprise from about 2% to about 100%. In some instances, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% by weight of the active agent may be used (in whatever chosen form). In some cases, the compositions comprise about 5% to about 50%, or about 2% to about 20% by weight of the active agent. One skilled in the art understands that the foregoing percentages will vary depending upon the particular source of active agent utilized, the amount of active agent desired in the final formulation, and the aerosol performance of the final formulation.
  • the compositions may comprise at least about 2% by weight of the active agent, such as, for example, at least about 2% to about 20% by weight of the active agent.
  • the concentration of the active agent may be 5% to 20% in dry compositions with an acceptable carrier for pulmonary administration (such as lactose).
  • the concentration of active agent may be greater than 20%.
  • the active agent concentration may be anywhere from 20% to 100% active agent.
  • the composition may 100% pure active agent, or nearly 100% pure active agent as shown, for example, in Table 5. In certain instances, for example as shown in FIG.
  • the emitted dose of a composition upon aerosolization may decrease as the concentration of active agent increases. In some cases, this may be due to deposition of the active agent onto the inhaler device used for aerosolization as shown, for example in FIG. 15B . However, this may vary based on the configuration of the inhaler device used for aerosolization.
  • the dry powder formulation may exhibit long term stability. In some instances, this is in contrast to vardenafil in aqueous solutions, which may be more prone to acidic, basic, or oxidative degradation as shown in FIGS. 4A-4F .
  • the dry powder compositions may be stored to reduce the possibility of either dehydration or exposure to moisture in the air.
  • the compositions may also be stable when stored at room temperature.
  • the composition may be stable at room temperature for at least 1 month, or at least 3 months, or at least 6 months as shown in FIGS. 5A-5D .
  • the composition may be stable at room temperature for about 1 year or about two years.
  • the dry powder composition contain primarily pure active agent.
  • the dry powder composition may contain at least 50%, such as, for example, at least 90%, pharmaceutically acceptable carrier/excipient.
  • the excipient may include lactose.
  • the disclosed dry powder compositions are generally aerosolizable for the purposes of administration as a dry powder dispersion.
  • Suitable devices for aerosolization include dry powder inhaler and metered dose inhalers. Such devices function to emit a dispersion of the formulation contained within the device.
  • the characteristics of the emitted dispersion, particularly the aerosol performance of the composition, are properties that relate in part to the dry powder composition.
  • any suitable methods can be used to mix the formulation comprising the active agent as described, for example, in Remington: The Science and Practice of Pharmacy, 25 th Edition.
  • the active agent and carrier are combined, mixed and the mixture may be directly packaged for aerosolization (such as in a capsule).
  • the active agent and carrier are combined and mixed using the method of geometric dilution as generally known in the art.
  • a method of producing a powder pharmaceutical composition comprising the active agent, by contacting at least about 2% of the active agent by weight relative to the total weight of the overall pharmaceutical composition with at least one pharmaceutically acceptable carrier.
  • the active agent may be a PDE5 inhibitor, such as vardenafil, or a pharmaceutically acceptable salt, ester, or solvate thereof as described herein. In some instances, the active agent may be at least about 2% by weight of the composition, or some other amount as described above.
  • Active ingredients for administration by inhalation generally have a controlled particle size.
  • the optimum particle size for inhalation into the bronchial system is usually 1-10 ⁇ m, preferably 1-5 ⁇ m. Particles having a size above 20 ⁇ m are generally too large when inhaled to reach the small airways.
  • the compound as produced may be size reduced by conventional means, such as by micronization. Micronization of the active agent or of all formulation components can be performed using any suitable commercially available apparatus such as those described in Remington: The Science and Practice of Pharmacy, 25 th Edition. For example, micronization may be performed by air jet micronization, spiral milling, controlled precipitation, high-pressure homogenization, spray drying, or cryo-milling.
  • the desired fraction may be separated out by air classification or sieving.
  • the active agent particles will be crystalline.
  • the active agent alone can be micronized prior to mixing.
  • vardenafil compounds may be micronized within the respirable range.
  • the D v50 of the micronized particles may be between about 1 ⁇ m and about 2 ⁇ m with a span of about 0.25 to about 1.6.
  • mixing is performed by agitating the components of the dry powder formulations to produce a mixture having a uniform concentration of active agent.
  • the components may be combined and then mixed such as by a low shear or high shear blender and/or agitated at high speed using a mechanical mixer.
  • the components may be mixed at an agitation speed of about 20 rpm, about 50 rpm, or about 100 rpm.
  • the components are mixed at an agitation speed of about 99-100 rpm.
  • the components should be mixed for a sufficient time to ensure uniformity of the blend.
  • the components may be mixed for at least 5 min, 10 min, 15 min, or 20 min.
  • blend uniformity of the mixture may be assessed and, if necessary, the mixture may be agitated for an additional period of time until the desired blend uniformity is achieved.
  • Blend uniformity may be assessed as the coefficient of variability for samples assessed throughout the mixture.
  • the dry powder composition after mixing has a coefficient of variation of no more than about 5% or, in some instances, no more than about 10%.
  • a 5% blend of Var(HCl) 2 .xH 2 O and lactose had a blend uniformity (% coefficient of variation) less than about 5% when mixed for about 5-20 min at about 100 rpm.
  • a relaxation or de-energizing step may be performed to allow the powder blend to discharge built up electrostatic charges from handling.
  • This step may involve incubation at a certain temperature from room temperature to near 50° C. for a predetermined time from 1 day to 30 days, or exposure to a controlled humidity air source for a controlled time period, or some other method of charge dissipation commonly known.
  • an ionizing source that produces approximately equal amounts of positive and negative ions may be used to dissipate charge.
  • the dry powder composition may be packaged into individual doses suitable for administration via inhalation.
  • the formulation may be transferred into individual doses using a dosing system that is commonly used to fill capsules, blister cavities, reservoirs, and containers. Following filling of the doses, the powder is ready for dosing from an inhaler device.
  • the formulation may be packaged in a blister dose containment system.
  • capsule material may include a gelatin or HPMC (hydroxypropylmethylcellulose) capsule dose containment system.
  • the capsules may each contain one dose, or multiple capsules can be used to contain the equivalent of one dose.
  • Examples of commercial dry powder inhaler products where the powder is stored in capsules include the FORADIL® Aerolizer®, the SPIRIVA® HandiHaler®, and the VENTOLIN® Rotahaler (GSK).
  • the formulation may be packaged in individual blisters, where one blister may contain one dose.
  • Examples of commercial dry powder inhaler products where the powder is stored in blister dose containment systems include the FLOVENT® Diskus®, SEREVENT® Diskus®, and the ADVAIR® Diskus®.
  • the formulation may be packaged into a reservoir, where a particular reservoir may contain sufficient powder for multiple doses.
  • the composition may be packaged to have a nominal load of about 3 mg to 30 mg. Based on the aerosol performance properties and concentration of the active agent in the dry powder composition, the composition may be packaged to have a delivered dose of at least about 0.1 mg to about 20 mg, or at least about 0.25 mg to about 20 mg, or at least about 0.5 mg to about 10 mg, or at least about 0.1 mg, about 0.25 mg, 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg.
  • the composition may be packaged to have a delivered dose of about 0.25 mg to 20 mg, including delivered doses in the range of about 0.25 mg to about 5 mg, about 0.25 mg to about 2 mg, about 0.25 mg to about 3 mg, about 0.25 mg to about 4 mg, about 1 mg to about 5 mg, about 2 mg to about 8 mg, about 2 mg to about 12 mg, and about 5 mg to about 15 mg.
  • compositions disclosed herein are useful in therapeutic applications, such as for treating pulmonary hypertension, cystic fibrosis, and congestive heart failure.
  • the compositions of the present invention provide the rapid and predictable delivery of an active agent in the lungs that should increase the bioavailability of the active agent, overcoming the limitations of oral dosing and reducing risk of drug interactions and systemic side effects.
  • the delivery of the therapeutic agent optimizes absorption within the lungs.
  • the therapeutic agent can reach the site of action locally in the lung, or in systemic circulation, in a substantially shorter period of time and at a substantially higher local lung concentration than with traditional oral (for example, tablet) administration.
  • administration of the dry powder composition via the pulmonary route may permit higher concentrations of active agent to be administered than with oral administration.
  • the dry powder compositions disclosed herein offer advantages over compositions for oral administration.
  • vardenafil exhibits a good balance between lipophilicity (relatively low) and solubility (relatively high), which is desirable for a dry powder formulation for pulmonary delivery to facilitate cellular uptake, lung residence time, and metabolism within the airways.
  • An advantage of inhaled compositions over oral dosage forms may be the short time until effects are observed. The short onset of action can be important for many diseases.
  • Another advantage of dry powder formulations for inhalation is avoiding metabolism in the liver and side effects associated therewith at high concentrations of active agent.
  • compositions disclosed herein are preferably carried out via any of the accepted modes of pulmonary administration, particularly oral dry powder inhalation.
  • the composition may be administered through the mouth or through the nasal passages.
  • Suitable devices for administration of the dry powder composition include dry powder inhalers and metered dose inhalers.
  • FIG. 13 is a block diagram illustrating methods for aerosolizing such dry powder compositions according to certain aspects.
  • a powder pharmaceutical composition comprising a) at least 2% by weight of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, relative to the total weight of the overall pharmaceutical composition, and b) at least one pharmaceutically acceptable carrier may be provided.
  • Step 1302 illustrates that an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber may be provided. Steps 1301 and 1302 may be performed in any order or simultaneously.
  • step 1303 air flow is induced through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • the powdered medicament may be stored within a storage compartment (of the inhaler), and wherein the powder pharmaceutical composition is transferred from the storage compartment, through the inlet and into the dispersion chamber.
  • the inlet may be in fluid communication with an initial chamber, and wherein the powder pharmaceutical composition is received into the initial chamber prior to passing through the inlet and into the dispersion chamber.
  • a patient may prime an aerosolization device by puncturing the container holding the formulation (such as a capsule or blister) that is contained within a powder reservoir, or the patient may transfer drug from the powder reservoir into the inhalation portion of the device, and then inhale.
  • Inhalation by a patient draws the powder through the inhaler device where powder entrainment results in dilation, fluidization, and at least the partial de-agglomerating of powder aggregates and micro aggregates and then dispersion of the API powder aerosol (in other words, aerosolization).
  • This approach may be useful for effectively dispersing both pure drug-powder formulations where there are no carrier particles are present and traditional binary or ternary carrier-based formulations.
  • Exemplary devices for use in administering the dry powder composition include dry powder inhalers and metered dose inhalers such as, but not limited to Twisthaler® (Merck), Diskus® (GSK), Handihaler® (BI), Aerolizer®, Turbuhaler® (AstraZeneca), Flexhaler® (Astrazeneca), Neohaler® (Breezhaler®) (Novartis), Easyhaler® (Orion), Novolizer® (Meda Pharma), Rotahaler® (GSK), and others.
  • difference devices will have different performance characteristics based on the device resistance, deaggregation mechanisms, adhesion of drug to the internal flow channels, ability of the patient to coordinate and inhale, among other factors.
  • the dry powder compositions may be administered using a dry powder inhaler or a metered dose inhaler that comprises a dry powder deaggregator, also referred to as a powder dispersion mechanism.
  • a dry powder inhaler or a metered dose inhaler that comprises a dry powder deaggregator
  • exemplary powder dispersion mechanisms are described in U.S. Patent Publication Nos. 2013/0340754 and 2013/0340747, which are incorporated herein by reference in their entirety.
  • such powder dispersion mechanisms may comprise of a bead positioned within a chamber that is arranged and configured to induce a sudden, rapid, or otherwise abrupt expansion of a flow stream upon entering the chamber.
  • the chamber may be coupled to any form or type of dose containment system or source that supplies powdered active agent into the chamber. Referring now to FIG.
  • a cross-section of an example tubular body 100 having an inlet 102 and a dispersion chamber 104 is shown according to the principles of the present disclosure.
  • a fluid (air) flow path of the inlet 102 is defined by a first internal diameter 106
  • a fluid (air) flow path of the chamber 104 is defined by a second internal diameter 108 .
  • at least one of the first internal diameter 106 and the second internal diameter 108 may vary in dimension as defined with respect to a longitudinal axis L of the tubular body 100 .
  • these configurable dimensions may be defined such as to provide for a draft angle for injection molding.
  • a bead 302 may be positioned within the chamber 104 of the tubular body 100 of FIG. 14A .
  • the bead 302 may be approximately spherical, at least on the macroscale, and oscillate in a manner similar to that described in U.S. Pat. No. 8,651,104, which is herein incorporated by reference in its entirety.
  • a relationship between the diameter 304 of the bead 302 , the first internal diameter 106 of the inlet 102 , and the second internal diameter 108 of the chamber 104 may be as described in U.S. Patent Publication Nos. 2013/0340754 and 2013/0340747, which are incorporated herein by reference in their entirety.
  • the powder dispersion mechanism may be coupled to a dry powder inhaler or metered dose inhaler such as a commercially available device.
  • the dispersion mechanism (dispersion chamber) may be adapted to receive an aerosolized powdered active agent from an inlet channel such as described, for example, in U.S. Patent Publication Nos. 2013/0340754, which is incorporated herein by reference in its entirety.
  • the powder dispersion mechanism (dry powder deaggregator) may be adapted to receive at least a portion of the aerosolized powdered active agent from the first chamber of the inhaler.
  • the powder dispersion mechanism may include a dispersion chamber that may hold an actuator that is movable within the dispersion chamber along a longitudinal axis.
  • the dry powder inhaler may include an outlet channel through which air and powdered active agent exit the inhaler to be delivered to a subject.
  • a geometry of the inhaler may be such that a flow profile is generated within the dispersion chamber that causes the actuator to oscillate along the longitudinal axis, enabling the oscillating actuator to effectively disperse powdered medicament received in the dispersion chamber for delivery to the patient through the outlet channel.
  • the powder dispersion mechanism may have an inlet diameter of about 2.72 mm and an oscillation chamber length and diameter of about 10 mm and about 5.89 mm, respectively.
  • the powder dispersion mechanism may include a bead having a diameter of 4 mm in the chamber.
  • the bead may have a density of about 0.9 mg/mm 3 .
  • the bead may be made of polypropylene or a similar material.
  • the powder dispersion mechanism can be coupled with a commercial inhaler or other component to form a delivery system for aerosolization of the dry powder compositions.
  • the delivery system may work at effectively at different airflow rates and pressure drops within the range of normal physiological inhalation for a subject such as, for example, about 40 to about 60 L/min and about 2 to about 4 kPa.
  • a dry powder inhaler system may be used to aerosolize and administer the dry powder formulation.
  • the dry powder inhaler system may include a receptacle containing an amount of powdered active agent.
  • the dry powder inhaler system may include an inlet channel that is adapted to receive air and powdered active agent from the receptacle.
  • the dry powder inhaler system may include a first chamber that is adapted to receive air and powdered active agent from the inlet channel. A volume of the first chamber may be greater than volume of the inlet channel.
  • the dry powder inhaler system may include a dispersion chamber that is adapted to receive air and powdered medicament from the first chamber.
  • the dispersion chamber may hold an actuator that is movable within the dispersion chamber along a longitudinal axis.
  • the dry powder inhaler system may include an outlet channel through which air and powdered active agent exit the dispersion chamber to be delivered to a patient.
  • a geometry of the system may be such that a flow profile is generated within the system that causes the actuator to oscillate along the longitudinal axis, enabling the oscillating actuator to effectively disperse powdered medicament received in the dispersion chamber for delivery to the patient through the outlet channel.
  • a method for aerosolizing a powdered medicament may include providing an inhaler comprising a first chamber, and a dispersion chamber, the dispersion chamber containing an actuator that is movable within the dispersion chamber along a longitudinal axis, and an outlet channel.
  • the method may include inducing air flow through the outlet channel to cause air and powdered medicament to enter into the first chamber through the inlet channel into the dispersion chamber, and to cause the actuator to oscillate within the dispersion chamber to effectively disperse powdered medicament passing through the first chamber and the dispersion chamber to be entrained by the air and delivered to the patient through the outlet channel.
  • the emitted dose” (ED (%)) of a formulation refers to the mass of an active agent that is emitted from a dry powder inhaler aerosolization device as a percentage of a nominal dose mass. Powder formulations that exhibit better powder flow properties often result in higher ED (%).
  • ED (%) emitted dose
  • RF (%) respirable fraction
  • Fine particle fraction is the mass of active agent having an aerodynamic diameter below about about 5 ⁇ m as a percentage of an emitted dose mass.
  • the % FPF(ED) may be the percentage of an active agent of a formulation having an aerodynamic diameter at or below about 5 ⁇ m.
  • the respirable fraction represents the proportion of powder aerosol active agent that can enter the deep respiratory tract.
  • Another parameter is mass median aerodynamic diameter (MMAD).
  • the MMAD is the median of the distribution of airborne particle mass with respect to the aerodynamic diameter. Airflow conditions are generally selected to span the range of physiological inhalation capabilities of a subject.
  • the pressure drop for an inhalation may be in the range of about 0.5 kPa to about 8 kPa, more typically within the range of about 1 kPa to about 4 kPa, and including airflow rates of about 5 L/min to about 120 L/min, more typically in the range of about 15 L/min to about 100 L/min.
  • the dry powder composition may have an emitted dose of at least about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% upon aerosolization.
  • pure active agent compositions may have an emitted dose of at least about 65% for VarBase, at least about 25% for Var(HCl) 2 .xH 2 O, at least about 70% for Var(HCl) 2 .xH 2 O (rehydrated), and at least about 40% for VarHCl.xH 2 O.
  • the active agent may be micronized.
  • nominal dose may not impact emitted dose of pure active agent compositions.
  • dry powder compositions of vardenafil compounds plus a carrier, such as lactose may have emitted doses that are, on average, somewhat higher than the pure active agent compositions.
  • a 5% Var(HCl) 2 .xH 2 O composition may have an emitted dose of at least about 75% regardless of whether the nominal load used for aerosolization was 10 mg or 20 mg as shown in Table 6.
  • 5% and 20% Var(HCl) 2 .xH 2 O compositions may have an emitted dose of at least about 80% as shown in Table 7.
  • 5% and 20% VarBase and VarHCl.xH 2 O compositions may have emitted doses of at least about 70% as shown in Table 8.
  • the dry powder composition may have a fine particle fraction of at least about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% upon aerosolization.
  • composition of pure active agent may have a fine particle fraction of at least about 20% as shown in Table 5.
  • pure active agent compositions may have an emitted dose of at least about 35-60% for VarBase, at least about 85-90% for Var(HCl) 2 .xH 2 O, at least about 60-65% for Var(HCl) 2 .xH 2 O (rehydrated), and at least about 65-70% for VarHCl.xH 2 O.
  • a composition of a vardenafil compound and a carrier may have a fine particle fraction of at least about 40-50% as shown in Tables 6-8.
  • a 5% Var(HCl) 2 .xH 2 O composition may have a fine particle fraction of at least about 65-70% regardless of whether the nominal load used for aerosolization was 10 mg or 20 mg as shown in Table 6.
  • 5% and 20% Var(HCl) 2 .xH 2 O compositions may have a fine particle fraction of at least about 65-80% as shown in Table 7.
  • increasing the concentration of active agent (such as Var(HCl) 2 xH 2 O) in the composition may increase the fine particle fraction upon aerosolization.
  • 5% and 20% VarBase and VarHCl.xH 2 O compositions may have a fine particle fractions of at least about 40-70% as shown in Table 8.
  • increasing the active agent such as VarBase and VarHCl.xH 2 O
  • increasing the active agent may increase the fine particle fraction upon aerosolization.
  • VarHCl.xH 2 O has a slightly higher respirable fraction upon aerosolization than VarBase.
  • the dry powder composition may have a respirable fraction of at least about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 55%, about 60%, about 65%, or about 70%, upon aerosolization.
  • pure active agent compositions may have a respirable fraction of at least about 25% or 45% for VarBase depending on nominal dose (10 mg vs 3 mg), at least about 20% for Var(HCl) 2 .xH 2 O (regardless of nominal dose, 10 mg vs 3 mg), at least about 45% for Var(HCl) 2 .xH 2 O (rehydrated), and at least about 30% for VarHCl.xH 2 O.
  • the active agent may be micronized.
  • a 5% Var(HCl) 2 .xH 2 O composition may have a respirable fraction of at least about 50% regardless of whether the nominal load used for aerosolization was 10 mg or 20 mg as shown in Table 6.
  • 5% and 20% Var(HCl) 2 .xH 2 O compositions may have a respirable fraction of at least about 50-60% as shown in Table 7.
  • increasing the concentration of the active agent may diminish the respirable fraction of the composition (such as VarHCl.xH 2 O) upon aerosolization.
  • 5% and 20% VarBase and VarHCl.xH 2 O compositions may have respirable fractions of at least about 25-50% as shown in Table 8.
  • increasing the concentration of the active agent such as VarBase and VarHCl.xH 2 O
  • the MMAD of the composition is less than about 10 ⁇ m, less than about 5 ⁇ m, or less than about 3 ⁇ m, upon aerosolization.
  • the compositions may have a mass median aerodynamic diameter (MMAD) of between about 0.5 ⁇ m and about 8 ⁇ m, such as, for example, between about 1 ⁇ m and about 2 ⁇ m, between about 1 ⁇ m and about 3 ⁇ m, between about 0.5 ⁇ m and about 4 ⁇ m, or between about 0.5 ⁇ m and about 5 ⁇ m, or other ranges therein.
  • MMAD mass median aerodynamic diameter
  • the composition may have a relatively small MMAD of about 0.7 to about 1.5 ⁇ m, including about 0.7 ⁇ m to about 1.5 ⁇ m, about 0.8 ⁇ m to about 0.85 ⁇ m, about 0.8 ⁇ m to about 0.95 ⁇ m, and about 0.9 ⁇ m to about 1.2 ⁇ m.
  • the dry composition formulations may have similar aerosolization properties at both high and low airflow rates. This may reduce variability in dosing (due to inhalation variability). For example, as shown in Table 9, a 5% Var(HCl) 2 .xH 2 O composition has similar emitted dose and respirable fraction upon aerosolization at both 2 kPa and 4 kPa airflow using a dry powder inhaler.
  • the dry powder composition Upon inhalation, some portion of the dry powder composition, particularly the active agent, is emitted from a delivery system, such as an inhaler, upon aerosolization of the dry powder composition.
  • a delivery system such as an inhaler
  • the term delivered dose refers to the percentage mass emitted dose (ED (%)) as a function of the nominal dose mass in the delivery system.
  • the composition may have a delivered dose of about 0.25 mg to 20 mg, including delivered doses in the range of about 0.25 mg to about 5 mg, about 0.25 mg to about 2 mg, about 0.25 mg to about 3 mg, about 0.25 mg to about 4 mg, about 1 mg to about 5 mg, about 2 mg to about 8 mg, about 2 mg to about 12 mg, and about 5 mg to about 15 mg.
  • the composition upon aerosolization, may have a delivered dose of at least about 0.1 mg to about 20 mg, or at least about 0.25 mg to about 20 mg, or at least about 0.5 mg to about 10 mg, or at least about 0.1 mg, about 0.25 mg, 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg.
  • the dry powder composition is formulated and packaged to have substantial delivered (emitted) dose uniformity.
  • the uniformity of the emitted dose reflects the safety, quality, and efficacy of the dry powder compositions.
  • the composition may have a delivered dose uniformity of about 75% to about 125% target dose over 2-60 inhalations.
  • the percent recovery is a way to check the mass balance before and after dose delivery by capturing and measuring the amount of drug discharged from an inhaler to verify accuracy of analysis.
  • the total mass of drug collected in all of the components divided by the total number of minimum recommended doses discharged is not less than 75% and not more than 125% of the average minimum recommended dose determined during testing for delivered-dose uniformity. See USP ⁇ 601>.
  • the percent recovery of the dry powder formulation is at least about 95% or at least about 100%, for example, as shown in Table 5 and Table 8, for various dry compositions with different active agents and concentrations and nominal loads.
  • compositions disclosed herein have particular utility in the area of human and veterinary therapeutics.
  • a method of treating a disease in a mammal in need thereof comprising administering to the mammal via a pulmonary route an effective amount of a powder pharmaceutical composition comprising a) at least about 2% of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, by weight relative to the total weight of the overall pharmaceutical composition dose, and b) at least one pharmaceutically acceptable carrier.
  • the dry powder formulations and methods described herein provide improved methods of treating certain diseases that are currently treated only with oral formulations that are swallowed.
  • the disease may be a lung disease such as pulmonary hypertension or cystic fibrosis.
  • the lung disease may be pulmonary arterial hypertension.
  • the disease may be a heart disease.
  • the heart disease may be congestive heart failure/disease.
  • Pulmonary hypertension includes, but is not limited to, pulmonary arterial hypertension, primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, pulmonary artery hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenic pulmonary arteriopathy and pulmonary hypertension associated with or related to, left ventricular dysfunction, mitral valvular disease, constrictive pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive disease, collagen vascular disease, congenital heart disease, congenital heart disease, pulmonary venus hypertension, chronic obstructive pulmonary disease, interstitial lung disease, lung fibro
  • Cystic fibrosis is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. There are more than 1,800 The F508del mutation, results in a “trafficking” defect, in which the CFTR protein does not reach the cell surface in sufficient quantities. The absence of working CFTR proteins results in poor flow of salt and water into and out of cells in a number of organs, which results in a thick, sticky mucus that builds up and blocks the airways of in the lungs, causing chronic lung infections, inflammation and progressive lung damage. While cystic fibrosis is caused by mutations in the CTFR gene, cGMP has a key role in the cell and regulates many aspects of proper CFTR functioning.
  • cGMP is metabolized by the PDE5 enzyme.
  • PDE5 inhibitors may maintain and control levels of cGMP, which, in turn, may modulate CFTR and improve CTFR function.
  • PDE5 inhibitors have also been shown to exhibit anti-inflammatory and anti-pseudomonal activity in preclinical models. (Poschet et al. 2007 Lung Cell. Molec. Physiol. 293(3):L712-L719)
  • oral sildenafil, a PDE5i has reduced biomarkers of lung inflammation in clinical trials in adult CF patients with F508del mutation. (Taylor-Cousar et al., Abstract A94, Therapeutic & Diagnostic Adv. Cystic Fibrosis 2013, p. A2066.)
  • PDE5 expression appears to be increased in a number of myocardial disease states, including chronic myopathies involving myocyte or ventricular hypertrophy.
  • PDE5 inhibitors increase cGMP, which inhibits phosphodiesterase-3 and thereby increases cyclic adenosine monophosphate. (cAMP).
  • cAMP cyclic adenosine monophosphate
  • PDE5 inhibitors were found to improve hemodynamic and clinical parameters in patients with congestive heart disease in a number of small trials (Schwartz).
  • the delivery of dry powder formulations of PDE5 inhibitors may be more efficient that oral dose formulations by creating a high local lung concentration of the active agent, potentially yielding a quicker onset of action with likely comparable or enhanced efficacy with fewer side effects.
  • Local delivery of PDE5i directly into the lung may circumvent poor oral bioavailability and provide even greater selectivity of effect by delivering high local lung concentrations with lower total dose exposure with the potential for greater efficacy.
  • Administration of dry powder formulations via inhalation are also advantageous because the route of administration allows avoidance of extensive first pass hepatic metabolism and drug-drug interaction with CYP3A inducers/inhibitors.
  • Many drugs used to treat lung diseases can be metabolized using this enzyme system and, therefore, are susceptible to interactions or contraindications.
  • Inhalation delivery may avoid the severity of these interactions because avoidance of first pass metabolism, while the lower administered dose (but higher lung tissue dose) may minimize the potential for interactions
  • Inhalation delivery may also avoid adverse side effects associated with orally administered PDE5 inhibitor formulations, such as hypotension, hearing or visual improvement, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, rhinitis, diarrhea, myalgia, pyrexia, gastritis, sinusitis, paraesthesia.
  • V/Q ventilation/perfusion
  • COPD chronic obstructive pulmonary disease
  • a dry powder PDE5 inhibitor formulation with low oral and throat deposition and swallowing may better target the active agent to the ventilated areas of the lung, controlling the pulmonary hypertension while avoiding increasing V/Q mismatch and hypoxia.
  • administration of PDE5 inhibitors via a pulmonary route may be useful for treating subjects who are unable to tolerate clinically useful doses of oral formulations because of hypotension, drug interactions or other systemic adverse effects.
  • lower doses of dry powder formulations may be administered to a subject.
  • similar doses of the dry powder formulations as used for oral doses for swallowing may be administered to a subject, wherein, because the drug is administered directly to the target site, there may be a reduction in systemic drug levels using a dry powder inhaler formulation. This may lead to a reduction of systemic toxicities associated with chronic daily use (headache, lowered blood pressure, cardiovascular effects anterior ischemic optic neuropathy, priapism, vaso-occlusive crises.
  • PDE5 inhibitors dissolve in the digestive tract and are absorbed into the blood stream. Upon reaching the pulmonary circulation, the PDE5 compound diffuses across the vascular endothelium into the surrounding smooth muscle cells, where it inhibits the PDE5 enzyme present in the intracellular fluid of the muscle cells, resulting in a dilatory effect on the pulmonary arteries and arterioles.
  • inhaled powder formulation of PDE5 inhibitors are expected to take a more direct route after deposition in the lumen of pulmonary airways, diffusing across the airway walls into the vascular smooth muscle cells where it acts on the PDE5 enzyme and may result in a dilatory effect on the pulmonary arteries and arterioles.
  • the target area of the lung for powder delivery is the deep lung where the pulmonary vasculature has smooth muscle cells upon which the active agent can exert its pharmacological effects.
  • effective delivery to this area of the lung may require smaller aerodynamic particle size ranges (typically greater than 1 micron on average, for example, between 1-5 microns MMAD, or between about 1-3 microns MMAD) for the aerosolized active agent.
  • the target tissue is the airway epithelial (such as the ciliated airways), particularly those affected by defective CFTR protein.
  • effective delivery to this area of the lung may require aerodynamic particle size ranges of between about 1 to about 5 microns in aerodynamic diameter, about 2 to about 6 microns. or about 2 to about 7 microns.
  • the dry powder formulations provided in this disclosure have an MMAD in the appropriate size range for delivery to the deeper parts of the lung.
  • pulmonary delivery with higher aerosolization efficiencies may allow less mouth and throat deposition upon aerosolization and inhalation by a subject.
  • reducing swallowing by achieving efficient aerosolization may reduce the incidence of systemic effects.
  • a delivered dose of about 0.25 mg to about 20 mg may be delivered to the subject upon aerosolization.
  • typical doses for treatment of pulmonary hypertension will be about 0.5 mg to about 20 mg of active agent, depending on patient disease category, disease stage, and other health aspects of the subjects such as, for example, medication, patient age, etc.
  • the inhaled dose required to attain efficacy in a human subject with pulmonary hypertension delivered via a high efficiency inhaler device may be about 1/10th to 1/20th the oral dose, or 0.25 mg to 0.5 mg, possibly 0.1 mg to 3 mg of active agent delivered to the deep lung.
  • typical doses for treatment of cystic fibrosis will be about 0.5 mg to about 30 mg of active agent, depending on patient genetic factors (such as type of CTFR mutation), disease stage, and other health aspects of the subjects such as, for example, medication, patient age, etc.
  • typical doses for treatment of myocardial diseases will be about 0.5 mg to about 20 mg of active agent, depending on patient disease category, disease stage, and other health aspects of the subjects such as, for example, medication, patient age, etc.
  • FIG. 16 is a block diagram illustrating methods of treating a disease in a mammal in need thereof according to some aspects.
  • a subject with a disease in need of treatment is provided.
  • the disease may be a lung disease or a heart disease.
  • the lung disease may be pulmonary hypertension or cystic fibrosis.
  • the heart disease may be congestive heart failure.
  • the method further includes administering to the subject via a pulmonary route an effective amount of a powder pharmaceutical composition comprising a) at least about 2% of a PDE5 inhibitor, or a pharmaceutically acceptable salt or ester thereof, by weight relative to the total weight of the overall pharmaceutical composition dose, and b) at least one pharmaceutically acceptable carrier.
  • the powder pharmaceutical composition may be administered as an aerosol.
  • the powder pharmaceutical composition may be administered using a dry powder inhaler or a metered dose inhaler.
  • the powder pharmaceutical composition may be administered by providing an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • an inhaler comprising a dispersion chamber having an inlet and an outlet, the dispersion chamber containing an actuator that is movable reciprocatable along a longitudinal axis of the dispersion chamber; and inducing air flow through the outlet channel to cause air and the powder pharmaceutical composition to enter into the dispersion chamber from the inlet, and to cause the actuator to oscillate within the dispersion chamber to assist in dispersing the powder pharmaceutical composition from the outlet for delivery to a subject through the outlet.
  • VarHCl and Var(HCl) 2 can be difficult to differentiate from each other by each individual analytical method such as high performance liquid chromatography (HPLC), ultraviolet spectrophotometer (UV), mass spectroscopy (MS), Infra-red (IR), elemental analysis (CHN) and chloride ion analysis.
  • HPLC high performance liquid chromatography
  • UV ultraviolet spectrophotometer
  • MS mass spectroscopy
  • IR Infra-red
  • CHN elemental analysis
  • chloride ion analysis chloride ion analysis.
  • the molecular weight of Var(HCl) 2 .xH 2 O (579.55 g/mol) and VarHCl.3H 2 O (579.12 g/mol) are nearly identical. As such, differentiating between these molecules by any individual mass related analytical techniques reliably may not be possible.
  • Var(HCl) 2 .xH 2 O vardenafil dihydrochloride hydrate
  • VarHCl.3H 2 O vardenafil hydrochloride trihydrate
  • Testing methods were developed to ensure the ability to identify and differentiate the chemical identity of vardenafil forms for use in preparation of formulations. As described further below, the methods are: HPLC quantification coupled with Karl Fischer (KF) titration (Section A), elemental analysis (C, H, N) coupled with KF (Section B), NMR ( 1 H and 13 C) (Section C), and pH titration assessment (Section D). For example, as shown below, these methods were used to differentiate Var(HCl) 2 .xH 2 O and VarHCl.xH 2 O.
  • HPLC columns can be used to separate vardenafil compounds (active pharmaceutical ingredients; APIs) based on their polarity, this is not how HPLC was used to characterize the vardenafil compounds.
  • the principle of this method is that the HPLC area under the curve (AUC) for the vardenafil portion of VarHCl and Var(HCl) 2 are the same as VarBase (488.61 g/mol) when the same mass of compounds are compared.
  • VarBase 488.61 g/mol
  • HPLC analysis was performed using an Agilent 1260 Infinity series module HPLC system with appropriate columns and buffers (acidic aqueous and acidic organic mobile phases). The column temperature was maintained at 40° C. and the detection was monitored at a wavelength of 215 nm.
  • VarBase and a vardenafil salt hydrate were purchased and analyzed using the above-described method. The results are shown in Table 2. Based on the dry weight and AUC, the amount of vardenafil in the salt is 87.2% of that in VarBase. This is consistent with the percent API of Var(HCl) 2 , which is calculated to have a percent API of 87.1% as shown in Table 1 above. Thus, although the VarSalt was claimed to VarHCl.3H 2 O, this analysis shows that the compound was actually Var(HCl) 2 .xH 2 O.
  • Elemental analysis can determine the mass fraction of carbon, hydrogen, nitrogen and other heteroatoms (generally referred to as CHNX).
  • CHNX The most common elemental analysis accomplished by combustion analysis is for carbon, hydrogen, nitrogen, which is referred to herein as CHN analysis.
  • Commercial VarSalt was purchased for this analysis.
  • the amount of water in the vardenafil compound was also accurately determined by KF titration before the CHN analysis was performed to ensure accuracy.
  • the elemental analysis showed a % C value of 45.88, a % H value of 5.92 and a % N value of 13.87, within an error margin of ⁇ 0.3%.
  • the water content was measured using a coulometric KF titrator, and the result was 6.92%.
  • the VarSalt appeared to have approximately 2 HCl molecules and 2 water molecules, indicating that the VarSalt was likely Var(HCl) 2 .2H 2 O (or possibly a mixture of dihydrate and trihydrate forms).
  • VarHCl.3H 2 O and Var(HCl) 2 .xH 2 O have generally been deemed as indistinguishable using NMR.
  • U.S. Pat. No. 6,362,178 describes that the chemical shift for VarHCl.3H 2 O (Example 20) and Var(HCl) 2 .xH 2 O (Example 337) are identical by 1 H NMR, as set forth below.
  • De-shielding causes a methyl group shift from 2.472 to 2.604.
  • two of the three protons in the benzene ring of vardenafil showed a triplet (doublet+singlet) for VarHCl.3H 2 O, while the same protons showed a quintet (triplet+doublet) for Var(HCl) 2 xH 2 O.
  • Var(HCl) 2 , VarHCl, and VarBase are by means of pH titration analysis.
  • the experiment was performed at ambient condition (22.5° C. and 31% RH).
  • One gram of Var(HCl) 2 .xH 2 O was dissolved in 15 mL pure H 2 O in a beaker.
  • NaOH solution (10%) was added in 20 ⁇ L stepwise increments while the solution was stirred vigorously.
  • the pH and temperature was recorded 20 sec after each addition of NaOH solution.
  • the results of this analysis are shown in FIG. 3 .
  • the intrinsic stability of vardenifil compounds can be assessed to aid in identification of suitable conditions for preparation of pharmaceutically acceptable formulations. Characterization of the degradation pathways for vardenafil compounds provides information useful to the development of pharmaceutically acceptable formulations for long term storage. Described below are exemplary experiments relating to characterization of VarHCl.3H 2 O.
  • VarHCl.3H 2 O, HPLC grade water, 36.5% HCl, NaOH pellets, 6% H 2 O 2 were all purchased. 1N HCl and 1N NaOH were prepared in house.
  • VarHCl.3H 2 O HPLC grade water, 36.5% HCl, NaOH pellets, 6% H 2 O 2 were all purchased, and 1N HCl and 1N NaOH were prepared in house.
  • Intrinsic stability testing was performed according to International Conference on Harmonization (ICH) Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003, Rev. 2). Briefly, the compound was tested for acid hydrolysis (1N HCl) and base hydrolysis (1N NaOH) at r.t. for 48 hr and at 60° C. for 4 hr. Oxidation assessment (6% H 2 O 2 ) was performed at r.t. for 48 hr. The stability of VarHCl.3H 2 O in solution was assessed using HPLC analysis as described above in Example 1, Section A.
  • VarHCl.3H 2 O demonstrated degradation in acidic, basic, and oxidative conditions per ICH Guidance.
  • the extent of degradation was significant in basic and oxidative conditions, which is understandable because the sulfonamide group in VarHCl.3H 2 O is susceptible to hydrolysis, particularly in basic condition.
  • the tertiary amine group may easily form amine oxide in oxidative condition and the amine oxide may undergo further degradation via a host of chemical reactions.
  • These observations differ from literature reports on the degradation of VarHCl.3H 2 O (Rao et al, Chromatographia 2008, 68, 829-835, showing less extensive degradation in basic conditions).
  • VarBase could also be oxidized more easily when the free tertiary amine is presented in the molecule.
  • Var(HCl) 2 .xH 2 O and VarBase were purchased, and VarHCl.3H 2 O was prepared in house using Var(HCl) 2 .xH 2 O. Conversion of Var(HCl) 2 .xH 2 O to VarHCl.3H 2 O was performed by the pH titration described above in Example 1, Section D. Var(HCl) 2 .xH 2 O was used in micronized form (prepared using a commercial dry jet-miller) as described in Example 4. VarBase and VarHCl.3H 2 O were not micronized. Respitose® ML006 (“ML006”) (DMV-Fonterra Excipients), an inhalation grade lactose, was also purchased.
  • ML006 Respitose® ML006
  • Blending ratios were selected based on powder surface area to ensure sufficient contact between API and excipient.
  • the following blends were made: Var(HCl) 2 .xH 2 O: ML006 (1:9), VarBase: ML006 (1:1) and VarHCl.3H 2 O: ML006 (1:1).
  • Blends were prepared by geometric dilution preblending by hand, followed by mixing using a commercially available laboratory shaker-mixer. Where enclosed, blends were pouched using foil to prevent moisture ingress into the powder mixture.
  • Samples were (1) pouched and stored at 25° C. and 60% relative humidity (RH), (2) pouched and stored at 40° C. and 75% RH, and (3) unpouched (exposed to ambient environment) at 40° C. and 75% RH. Samples were assessed for degradation by HPLC, as described above. Analysis was completed for the following time points: Var(HCl) 2 .xH 2 O blend at six month, VarBase blend at three months, and VarHCl.3H 2 O blend at one month.
  • FIG. 5A 25/60 pouched
  • FIG. 5B 40/75 pouched
  • FIG. 5C 40/75 open
  • FIG. 5D VarHCl.3H 2 O control
  • Particle size of a dry powder aerosol formulation for administration by inhalation is closely linked to the deposition profile in the airways. Thus, a narrow size distribution allows better targeting of the aerosol.
  • the median respirable particle size range is 0.5 to 5 microns, and more preferably 1-2 microns.
  • Var(HCl) 2 .xH 2 O, VarBase, and VarHCl.3H 2 O were purchased and then micronized using a commercial dry jet-miller. The jet milling was achieved using typical jet milling conditions and a single milling process. As shown in Example 5, micronization leads to partial dehydration of VarHCl.3H 2 O. As such, following micronization and absent rehydration, the compound is designated as VarHCl.xH 2 O.
  • D v0.1 , D v0.5 and D v0.9 are 10%, 50% and 90% of the volume size distributed below the respective values.
  • FIG. 6A Var(HCl) 2 .xH 2 O
  • FIG. 6B VarBase
  • FIG. 6C VarHCl.xH 2 O
  • All three APIs were easily micronized into respirable size range.
  • the particle size distributions were surprisingly narrow with spans less than 1.6 (VarHCl.xH 2 O—0.99, Var(HCl) 2 .xH 2 O—0.27, VarBase—1.557).
  • vardenafil compounds can be micronized to achieve a desirable median respirable particle size range with a narrow size distribution.
  • dry powder formulations of vardenafil may be particularly suited for aerosol administration via inhalation.
  • FIG. 7A Scanning electron microscopy (SEM) imaging of the micronized APIs are shown in FIG. 7A (Var(HCl) 2 .xH 2 O), FIG. 7B (VarBase), and FIG. 7C (VarHCl.xH 2 O).
  • the powder was placed on the SEM stub and sputter coated with Pd—Au.
  • Particle size distribution shown in SEM matches the laser diffraction data.
  • the particles form aggregates which are typical for micronized powders via jet-milling.
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic vapor sorption
  • XRPD x-ray powder diffraction
  • Thermal properties were assessed using a Q2000 Modulated DSC (TA Instrument, New Castle, Del.). Method: scanning rate 10° C./min from 0-350° C.; heating; equilibrate at 0° C. for 4 min; modulation ⁇ 0.796° C./min.
  • TGA was performed on micronized Var(HCl) 2 .xH 2 O to assess weight loss on heating. Active agent mass was monitored as it was exposed to a temperature program in a controlled atmosphere. Experimental parameters: scanning rate at 10° C./min, and temperature ranges from 40-280° C.
  • Var(HCl) 2 .xH 2 O DSC of micronized Var(HCl) 2 .xH 2 O is shown in FIG. 8A .
  • Var(HCl) 2 .xH 2 O exhibited an onset of glass transition T g ⁇ 50° C. that ended at ⁇ 110° C. This suggests that the high energy jet-milling process introduced amorphous content in the powder.
  • a small endothermic peak was observed at ⁇ 140° C. that overlapped with the glass transition. This indicates that some trihydrate form was present and underwent partial water loss.
  • Two large endothermic peaks were also observed at 222° C. and at 294° C. The former was the heat of fusion T m . The nature of the latter is still under investigation.
  • the result is similar to the DSC of Var(HCl) 2 .3H 2 O shown in U.S. Pat. No. 7,977,478 ( FIG. 15 ) but covered a larger temperature range.
  • DVS of micronized Var(HCl) 2 .xH 2 O is shown in FIG. 9A .
  • a critical relative humidity was shown at 70% in sorption and 40% in desorption.
  • the first may be a glass transition from amorphous to crystalline, and the second may reflect the formation of trihydrate.
  • the desorption phase indicated that the trihydrate form is only stable in a short humidity range of 50% RH-80% RH. It is possible that, when RH is below 40% RH, loss of bound water may occur.
  • Another desorption inflection point occurred around 20% RH. This suggests that Var(HCl) 2 .xH 2 O is unstable in normal ambient condition and tends to lose bound water. A large hysteresis loop was observed due to the hydration of Var(HCl) 2 .
  • TGA of micronized Var(HCl) 2 .xH 2 O is shown in FIG. 10 .
  • Var(HCl) 2 .xH 2 O started to continuously lose water above 40° C. There was a transition at around 220° C. to 240° C. This could be the melting phase when the TGA result was combined with DSC thermogram. Another two transitions (inflection points) occurred around 80° C. and 130° C. The water loss upon heating profile is comparable to that described in U.S. Pat. No. 7,977,478 ( FIG. 16 ).
  • FIG. 11A XRPD of micronized Var(HCl) 2 .xH 2 O is shown in FIG. 11A .
  • the peaks of the micronized Var(HCl) 2 xH 2 O preparation were compared to those illustrated in that reference, which indicates that the Var(HCl) 2 xH 2 O preparation is likely a monohydrate and dihydrate mixture.
  • VarBase DSC of micronized VarBase is shown in FIG. 8B .
  • the onset temperature was at ⁇ 177° C. when DSC scanning rate was set at 10° C./min.
  • the temperature increased above 250° C. decomposition peaks were observed.
  • VarBase has two polymorphic forms: Form I and Form II.
  • T m the Form I polymorph.
  • the Form I polymorph had previously been characterized by XRPD (WO/2011/079935). The XRPD analysis of the VarBase preparation confirmed that it is the Form I polymorph.
  • VarBase preparation sorption and desorption phases are much simpler as compared to Var(HCl)2 and VarHCl and their hydration forms, likely because VarBase cannot form hydrates and, thus, cannot for pseudopolymorphs. No obvious hysteresis loop was observed indicating that no hydration occurred. Some minor phase change was observed. This may be due to a small amount of amorphous content in the preparation caused by mechanical stress during jet-milling.
  • XRPD of micronized VarBase is shown in FIG. 11B .
  • the comparison of 2 ⁇ values and % intensity with the crystalline Form I and Form II of VarBase revealed that the VarBase preparation is mainly crystalline Form I.
  • the 2 ⁇ values of the major intensity peaks are: 9.8, 11.2, 12.4, 14.2, 15.3, 16.2, 17.1, 18.0, 20.1, 21.6, 23.2, 24.6, 27.3 degree. This result is in good agreement with DSC result.
  • VarHCl.3H 2 O is thermodynamically stable. However, under certain conditions (such as micronization), partial dehydration can occur. This is illustrated in the results described below.
  • VarHCl.xH 2 O DSC of micronized VarHCl.xH 2 O is shown in FIG. 8C .
  • VarHCl.xH 2 O had a large endothermic peak at 107° C. showing the loss of bound water.
  • the onset temperature was about 50 ⁇ 60° C. This indicates that VarHCl.xH 2 O could be susceptible to elevated temperature above 50 ⁇ 60° C.
  • the heat of fusion T m was 199.2° C. Above the heat of fusion temperature, the material quickly underwent decomposition. This is the first reporting of DSC analysis of micronized VarHCl.xH 2 O.
  • VarHCl sorption phase there were two inflection points.
  • RH relative humidity
  • VarHCl is highly hygroscopic.
  • RH 5-40% a steady but slower water sorption occurred at increasing RH.
  • the sorption phase reached a plateau between 60-80% RH when the water content of the molecule reached the stoichiometric trihydrate form.
  • VarHCl.3H 2 O could maintain its integrity (not reaching deliquescence) up to 80% RH.
  • the quick water uptake at RH as low as 5% and preferential formation of monohydrate is presumably caused by different H-bond associations among the three water molecules that can bind to VarHCl.
  • the first water molecule can preferentially form H-bonding with the acidic proton and the carbonyl group of vardenafil. This six-membered ring structure could result in stabilized H-bonding that the following H 2 O molecules may not have. See Scheme 1 below.
  • XRPD of micronized VarHCl.xH 2 O is shown in FIG. 11C .
  • the corresponding 2 ⁇ values of the major intensity peaks are: 5.1, 8.2, 10.3, 10.9, 15.4, 16.4, 17.3, 19.9, 20.2, 20.8, 22.4, 23.0, 24.5, 25.1, 26.1, 27.0, 27.9, 29.1 degree.
  • the 20 values of the intensity peaks for the micronized VarHCl.xH 2 O were compared to previously reported values from the XRPD analysis of VarHCl.3H 2 O (see, for example, U.S. Pat. No. 8,273,876). This comparison indicated that the micronized compound may lose some crystallinity due to the jet-milling process as the peaks are not as sharp (possibly due to loss of peak intensity due to the creation of amorphous content).
  • lactose was a suitable excipient for vardenafil compound formulations
  • several lactose blends were prepared with various vardenafil compounds described in the previous examples. Mixing conditions were assessed to identify satisfactory blends.
  • the vardenafil compounds used were: Var(HCl) 2 .xH 2 O, VarBase, micronized VarHCl.xH 2 O, and micronized VarHCl.3H 2 O (rehydrated).
  • Formulations were prepared using two different lactose carriers, a sieved grade of alpha-monohydrate lactose with an average particle size of about 50 ⁇ m (LAC1) and a fine particle lactose having a particle size distribution D v50 below about 5 ⁇ m (LAC2).
  • the micronized APIs and LAC1 were passed through a 250 ⁇ m sieve.
  • the API powders were then accurately weighed according to the API concentration using a micro balance.
  • the pre-blend (1-5 g) was achieved by geometric dilution of API powder into LAC1. Trituration and gentle stirring with a spatula allowed for a good initial blending condition.
  • the mixtures were then blended with a Turbula® T2C Shaker-Mixer. UV analysis was performed. The API was detected by UV spectrophotometry.
  • FIG. 12 An exemplary blending example using 5% Var(HCl) 2 .xH 2 O and LAC1 is shown in FIG. 12 .
  • Blending at high speed (99 rpm) gave the best blending uniformity.
  • the % CV results were consistently within the range of 5% in 5-20 min.
  • blending at slow and medium speeds showed a pattern of mixing and de-mixing that is not suitable to reproducibly obtain a homogenous mixture.
  • Blending at high speed for 20 min generally resulted in an overall good blending uniformity for all API formulations. If UV analysis indicated that % CV was greater than 5% in any instances, formulations were mixed for an additional 10-20 min high speed to reduce the % CV to less than 5%.
  • the aerodynamic size distribution of API can be assessed by collecting the deposited API mass and the ED %, RF %, FPF % and MMAD ( ⁇ m) can be calculated from the API deposition pattern.
  • the emitted dose fraction (ED (%); Eq. 4) is determined as the percentage powder mass emitted from the initial dosing chamber/capsule relative to the total dose in capsules (nominal dose) (TD).
  • Emitted dose (ED) includes the sum of the API mass left on inhaler device and deposited on the device stages.
  • Fine particle fraction (FPF (%); Eq. 5) is expressed as a percentage of fine particle dose (FPD) below a certain aerodynamic cutoff size to ED.
  • Respirable fraction (RF (%); Eq. 6) is defined as the percentage of FPD to total dose (TD).
  • Formulation aerosol performance tests were carried out using a powder deaggregator modified from that described in U.S. Patent Publication Nos. 2013/0340754 and 2013/0340747 combined with an off-the-shelf RS01 dry powder inhaler capsule piercing mechanism (Plastiape, IT) feeding method.
  • the blends were packaged into size 3 HPMC capsules. Nominal dose amounts of 3 mg were prepared for each formulation; 10 mg nominal doses were also prepared for pure drug VarBase and Var(HCl) 2 .xH 2 O formulations.
  • MMAD mass median aerodynamic diameter
  • Micronized pure drug formulations (100% API, no excipient) were found to generally have an emitted dose (ED) fraction in the range of 24-82% and an RF fraction in the range of 21-46%, as shown in Table 5. This was mainly due to poor powder flow with the delivery system described in Section A. However, the FPF(ED) was generally quite high, except for the 10 mg VarBase formulation.
  • the micronized Var(HCl) 2 .xH 2 O resulted in the highest FPF(ED), followed by the VarHCl.xH 2 O formulation, the VarHCl.3H 2 O formulation, and the 3 mg VarBase formulation, each of which was well over 50%. Higher dose did not increase the aerosol performance but did negatively impact FPF(ED) for the VarBase formulation.
  • the 5-20% concentration range may result in about 80% ED for the Var(HCl) 2 .xH 2 O-LAC1 formulations when used with this delivery system at an airflow of 4 kPa.
  • higher concentration formulations may be used with a different device capsule piercing mechanism that disperses the drug along the axis of the air flow and not toward the device internal walls like the capsule piercing mechanism used in these experiments. In such cases, it can be expected that less loss of drug to the internal surfaces will be achieved.
  • Having aerosol performance of a formulation be independent of airflow conditions is preferable because there is greater reproducibility in administration where airflow rate may be variable (for example, based on the user).
  • the NGI device was used to assess the aerosol performance of the 20% Var(HCl) 2 .xH2O+LAC1 formulation as described above in Example 7, Section A except at an airflow pressure of 4 kPa and 2 kPa (corresponding to about 60 and about 40 L/min airflow rate, respectively).
  • the ED, RF, and FPF(ED) were decreased slightly at 2 kPa as compared to 4 kPa.
  • the effective aerodynamic cutoff diameter (D a50 ) for each impactor stage of the NGI device is different at different flow rates.
  • the impactor stage cutoff is 4.41 ⁇ m (stage 2 and below).
  • the impactor stage cutoff is 3.32 ⁇ m (stage 3 and below).
  • the RF and FPF(ED) could be slightly underestimated at an airflow rate of 2 kPa.
  • the aerosol performance at 2 kPa did not appear to cause a substantial change in aerosol performance when compared at 4 kPa.

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US20250332171A1 (en) 2025-10-30
US20220143034A1 (en) 2022-05-12
US20240156827A1 (en) 2024-05-16
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US20220016126A1 (en) 2022-01-20

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