Patent Application
20210315915
The present invention relates to non-aqueous, inhalable pharmaceutical compositions of ribavirin, methods of producing the same, and the use of such compositions in the treatment of virally associated respiratory infections, and associated diseases and conditions.
Acute exacerbations of chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis are major causes of morbidity and mortality. Kurai, et al., “Virus-Induced exacerbations in asthma and COPD”, Front. Microbiol., 4: 293 (2013). A growing body of clinical observations are consistent with a causal relationship between viral infection (human rhinovirus (HRV)/influenza virus/respiratory syncytial virus (RSV)/human metapneumovirus (hMPV)/adenovirus/parainfluenza virus (PIV)) and a significant percentage of exacerbations (i.e., 20-60%). See id. Additionally, virally induced airway damage is increasingly thought to prime secondary bacterial infections, which themselves account for 25-40% of exacerbations. Typically, the disease course of viral induced exacerbations is an initial upper respiratory tract (URT) infection followed by progression to the lower respiratory tract (LRT) over 4-6 days. Viral replication in the LRT is then sustained in COPD patients relative to otherwise healthy individuals (i.e., up to 21 days relative to <5 days).
These observations suggest that the preemptive administration of an antiviral agent to the LRT at the onset of URT symptoms could be a sound intervention strategy. The ideal antiviral agent would have broad spectrum activity to address the diversity of viral pathogens capable of inducing exacerbations. It is likely that intervention as early as possible will improve outcomes. Thus, there is an ongoing need for an inhaled antiviral to be available to COPD patients with a frequent exacerbation phenotype, to provide a rapid start of therapy upon URT symptoms.
Ribavirin is a marketed broad-spectrum antiviral compound. In the United States, ribavirin containing dosage forms include oral tablets (e.g., sold under the COPEGUS® brand name), oral capsules (e.g., REBETOL®, RIBASPHE®), oral solutions (FDA tentative approval), as an injectable solution (in combination with Pegainterferin Alfa-2 under the brand name PEGINTERFERON®, and PEGINTRON/REBETOL COMBO PACK®), as well as in the form of an inhaled solution (VIRAZOLE®). The approved therapeutic indications for the oral capsule, tablet, solution and injectable form products collectively include treatment of Chronic Hepatitis C (CHC) when prescribed in combination with (pegylated and nonpegylated) interferon alfa-2b, and the treatment of Chronic Hepatitis B (CHB). In the nebulized inhaled form, ribavirin has been approved for the treatment of severe respiratory syncytial virus (RSV) infections.
One drawback to ribavirin is that some patients taking ribavirin may experience significant drops in red blood cell count, and develop associated anemia. Further, ribavirin may also produce testicular lesions in rodents, and is considered teratogenic and/or produces embryocidal effects in certain animal species which have been studied.
The FDA approved labeling, for example, with Rebotol® (ribavirin in combination with Peglntron™), indicates that ribavirin has a multiple-dose half-life of 12-days, and it may persist in nonplasma compartments for as long as 6 months. Because of this, Rebetol® therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Great care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking Rebetol® therapy.
As an inhaled formulation, ribavirin is available in the United States as a nebulized solution, and is sold under the brand name Virazole®. Virazole® is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to RSV. The indicated administration for Virazole® takes place over a very long period of time and under very specific conditions. Virazole® is administered as an aqueous solution and is given in a hospital setting with a special nebulizer attached to an oxygen tent, a face mask, or a ventilator. According to label dosage and administration instructions, the recommended treatment regimen is 20 mg/mL Virazole® as the starting solution in the drug reservoir of the Valeant Small Particle Aerosol Generator SPAG-2 unit, with continuous aerosol administration for 12-18 hours per day for 3 to 7 days. With the recommended drug concentration of 20 mg/mL, the average aerosol concentration for a 12 hour delivery period would be 190 micrograms/liter of air.
The administration of Virazole® in non-mechanically ventilated infants, involves delivering Virazole® to an infant oxygen hood from the SPAG-2 aerosol generator. Administration by face mask or oxygen tent may be necessary if a hood cannot be employed. Further, because the volume and condensation area are larger in a tent, the setting may alter delivery dynamics of the drug.
The recommended dose and administration schedule for infants who require mechanical ventilation is the same as for those who do not. Either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2. In either case, it is recommended that patients should have their endotracheal tubes suctioned every 1-2 hours, and their pulmonary pressures monitored frequently (every 2-4 hours). For both pressure and volume ventilators, heated wire connective tubing and bacteria filters in series in the expiratory limb of the system (which must be changed frequently, i.e., every 4 hours) must be used to minimize the risk of Virazole® precipitation in the system and the subsequent risk of ventilator dysfunction.
As can be appreciated, the aerosolization of ribavirin in a tent or as a facemask may pose risks to anyone in proximity to the patient being treated, including medical staff and family members of the patient, who may breathe or otherwise be exposed to ribavirin in the air and many of whom will be of child bearing age. Thus, a major limitation of ribavirin use in RSV infected infants is the labeled indication for nebulized administration that results in high doses (6 grams/day), long (12-18 hours) dose administration, and high patient-to-patient variability. In addition, aerosolized ribavirin has been reported to cause moderate and long term bronchospasms, aggravating the clinical evolution of the disease. See Ventura, F., et al., “Is the use of ribavirin aerosols in respiratory syncytial virus infections justified? Clinical and economic evaluation” Arch Pediatr. February; 5(2):123-31 (1998). The prescribing information for Virazole® warns of pulmonary deterioration in COPD and asthma patients, and minor abnormalities in pulmonary function in healthy volunteers. Additional data is provided in the Virazole® NDA. Thus treatment can cause bronchospasm in COPD patients, which is believed to be linked to the mass of hypotonic particles being inhaled from an aqueous formulation. See, Walsh, B. et al., “Characterization of Ribavirin Aerosol With Small Particle Aerosol Generator and Vibrating Mesh Micropump Aerosol Technologies” Respir Care 2016, 61, 577-585.
Recent advances in inhaled drug delivery technology provide an opportunity to improve the efficiency of ribavirin administration and exploit its broad spectrum antiviral activity. Alternatives to aqueous nebulized formulations include metered dose inhalers, which deliver active pharmaceutical ingredients as a solution or suspension via a pressurized liquid propellant; and dry powder formulations, such as milled sized-reduced active pharmaceutical particles, spray dried inhalable dry powders, etc.
Such inhaled preparations have been discussed in the art. For example, descriptions of inhaled formulations, which are alternatives to nebulized solutions, include WO 2009/095681 and WO 2009/143011. Despite such disclosures, ribavirin has not been marketed in the United States in such alternative forms. Thus, there is a need to improve upon the formulation options available.
It is a goal of the present invention to provide an inhalable form of ribavirin which addresses one or more of these such shortcomings, and which allows the efficient delivery of ribavirin to and throughout the pulmonary system, with sufficient drug loading in a formulation to permit reduced drug delivery times when compared to a nebulized formulation, while reducing the release of the compound into the general environment, thus reducing the risk of exposure to those in proximity to the patient being treated with the compound, and avoid adverse reactions, e.g., bronchospasm.
The present invention, in one aspect, provides a pharmaceutical composition comprising fabricated particles comprising ribavirin and optionally one or more excipients, which are described herein. In certain embodiments, the fabricated particles have a mass median aerodynamic diameter (MMAD) ranging from about 0.5 μm to about 6 μm. In certain aspects, the ribavirin is in a substantially crystalline form.
In a further aspect of the invention, the fabricated particles are formed by molding the ribavirin and optional excipient in mold cavities. In some embodiments, after the molding process, the fabricated particles have a substantially uniform shape, and are non-spherical. For example, the fabricated particles may comprise two substantially parallel surfaces, with in some instances, such parallel surfaces having substantially equal linear dimensions. The bulk density of the pharmaceutical compositions of the present invention are generally less than about 3.0 g/cm3, for example less than 2.5 g/cm3, less than 2.0 g/cm3, less than 1.5 g/cm3, and less than 1.0 g/cm3.
A further aspect of the invention provides fabricated particles wherein the excipient comprises a carbohydrate, an amino acid, a polypeptide, a synthetic polymer, a natural polymer, or mixtures thereof.
A further aspect of the invention provides fabricated particles where each particle has a substantially similar volume and substantially similar three-dimensional shape, which, in part, contribute to the percent or quantity of particles that reach the lung. In some embodiments in rat models, in vivo lung Cmax values are at least 5 times higher, and greater than 10 times higher, than micronized drug with the same drug dose. In other embodiments, in vivo lung Cmax values are at least 10, 15, 20, or 25 times higher than particles made through micronization with the same drug dose.
The respiratory tract may be thought of as containing nose, mouth, thoracic, bronchiolar, and alveolar compartments. Each compartment had two sub-compartments, the epithelial lining fluid (mucus) and the epithelial cells. Dissolved ribavirin concentration levels in the bronchiolar epithelial lining fluid (BELF) may be an useful indication of a ribavirin formulation ability achieving a Cmax capable of preventing or reducing viral replication in the epithelial cells thus reduce the frequency and severity of acute exacerbations triggered by viruses such as Respiratory Syncytial virus (RSV), human rhinovirus (HRV), MERS, SARS, influenza virus, parainfluenza, human metapneumovirus, adenovirus, coronavirus, and/or picornavirus.
Sampling of BELF allows dissolved RBV Cmax to be determined. The dissolved RBV present in bronchiolar epithelial lining fluid may be determined from analysis of a retrieved BELF lavage. For example, lavage may be performed within 60 minutes after delivery of the inhaled composition by inhalation, under sedation or local anesthesia, using saline which is flushed and retrieved (e.g. 4×50 mL washes) from the bronchiolar compartment. Cmax of dissolved RBV in the BELF prior to lavage may be determined/derived from the measured total ribavirin quantity in the retrieved lavage fluid (whose RBV total contains both the previously dissolved and undissolved BELF amounts) by physiologically based pharmacokinetic modelling (PBPK).
Thus, a still further aspect of the invention relates to a powder ribavirin composition which achieves a determined Cmax of dissolved ribavirin in bronchial epithelial lung fluid from 10 μM to 10mM, such as in on embodiment 100 μM to 1mM, in another 10 μM to 1mM, in a further 10 μM to 500 μM, in a still further 50 μM to 500 μM, and still further 50 μM to 100 μM.
In some embodiments, the shape factor of the particles includes a solid wafer shaped “pollen” particle with two substantially planar, substantially parallel surfaces comprising a substantial majority of the surface area of the particle. In some embodiments, the particle shape includes a cylindrical solid volume.
The invention also relates to dose containment of the fabricated particles, and to inhaler devices for delivery of the pharmaceutical composition.
These and other objects and features of the invention will become more fully apparent when the following detailed description is read in conjunction with the accompanying figures and examples,
Abbreviations:
ΔHm: melting enthalpy
μM: microMolar
mM: milliMolar
Amb: ambient
DSC: differential scanning calorimetry
PC: polycarbonate
PES: polyethersulfone
PTFE: polytetrafluoroethylene
PVDF: polyvinylidene fluoride
PVOH: polyvinyl alcohol
RBV: ribavirin
RH: relative humidity
Tm: melting temperature
WFI: water for injection
XRPD: X-Ray Powder Diffraction
The present inventions now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the inventions are illustrated. Indeed, these inventions may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.
The following terms, as used herein, have the meanings indicated: “Amino acid” refers to α-amino acids such as glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, trytophan, serine, threonine, cysteine, tyrosine, asparagine, glutamic acid, lysine, arginine, histidine, norleucine, and modified forms thereof.
“Amorphous” means disordered arrangements of molecules without a distinguishable crystal lattice.
“AUC” or “the area under the curve” is the area under the curve in a plot of concentration of drug in a given fluid, e.g., blood, plasma, lung homogenate or bronchiolar epithelial lining fluid, against time.
“BID” means 2 times a day.
“Bulk Density” refers to the ratio of the mass of an untapped powder sample to its volume including the contribution of the interparticulate void volume. Hence, the bulk density depends on both the density of powder particles and the spatial arrangement of particles in the powder bed. The bulk density is expressed in grams per milliliter (g/mL) although the international unit is kilogram per cubic meter (1 g/mL=1000 kg/m3). It may also be expressed in grams per cubic centimeter (g/cm3).
“Cmax” means the maximum (or peak) concentration of a drug in a given fluid (e.g., plasma) that is achieved in a specified compartment or test area of the body after the drug has been administrated and prior to the administration of a second dose.
“Crystals” possess different arrangements and/or conformations of the molecules in a crystal lattice.
“Dry powder” refers to a powder composition that typically contains less than about 20% moisture, preferably less than 10% moisture, more preferably contains less than about 5% moisture, and most preferably contains less than about 3% moisture, depending upon the particular formulation.
“Dry powder inhaler” or “DPI” means a device containing one or more doses of the pharmaceutical composition of the present invention in dry powder form, a mechanism for exposing a dose of the dry powder into an air flow, and an outlet, in the form of a mouthpiece, through which a user may inhale the pharmaceutical composition.
“ELF” means “epithelial lining fluid” (i.e., lung mucus).
“Emitted Dose” or “ED” provides an indication of the delivery of a drug formulation from a suitable inhaler device after a firing or dispersion event. More specifically, for dry powder formulations, the ED is a measure of the percentage of powder which is drawn out of a unit dose package and which exits the mouthpiece of an inhaler device. The ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose, i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally-measured parameter, and can be determined using the method of USP Section 601 Aerosols, Metered-Dose Inhalers and Dry Powder Inhalers, Delivered Dose Uniformity, Sampling the Delivered Dose from Dry Powder Inhalers, United States
Pharmacopeia convention, Rockville, Md., 13th Revision, 222-225, 2007. This method utilizes an in vitro device set up to mimic patient dosing.
“Fabricated particle” means an intentionally molded particle formed of an active pharmaceutical ingredient and optionally further comprising one or more excipients.
“Fine particle fraction” or “FPF” is the mass of drug entering the respiratory tract during inhalation that is contained in aerosol particles between two chosen aerodynamic diameters. Inhaled fine particle fraction is the ratio of inhaled fine particle mass to mass of drug inhaled as aerosol.
“Fine Particle Mass” or “FPM” when referring to a Next Generation Impactor (NGI) is the sum of stages 3, 4 & 5 at 60 L/min that incorporates the 0.94-4.46 μm range.
“IAD”=“immediately after dosing”,
“Leucine”, whether present as a single amino acid or as an amino acid component of a peptide, refers to the amino acid leucine, which may be a racemic mixture or in either its D- or L-form.
“Lung”, in reference to a sample, refers to whole lung homogenate and epithelial lining fluid.
“Mass median aerodynamic diameter” or “MMAD” is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, in air, as the particle. The aerodynamic diameter encompasses particle shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by cascade impaction, unless otherwise indicated.
“Metered dose inhaler” or “MDI” means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap. MDI system includes a suitable channeling device. Suitable channeling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
“Next Generation Impactor (NGI)” is a cascade impactor for classifying aerosol particles into size fractions, containing seven impaction stages plus a final micro-orifice collector, which is commercially available, for example, from MSP Corporation, Minn., USA. The impactor is described, for example in U.S. Pat. 6,453,758, 6,543,301, and 6,595,368; UK Patent GB2351155, GB2371001, and GB2371247.
“Non-spherical” refers to a shape, which is other than a sphere or spheroid.
“Pharmaceutically acceptable carrier/diluent” refers to materials that may optionally be included in the compositions of the invention, and taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. Pharmaceutically acceptable carrier/diluent may include one or more materials, which improve the chemical or physical stability of the composition.
“Pharmacologically effective amount” or “physiologically effective amount of a bioactive agent” is the amount of an active agent present in an aerosolizable composition as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action (e.g., the lungs) of a subject to be treated to give an anticipated physiological response when such composition is administered to the lungs. The precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e., the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein.
“Polymorphic forms” or “Polymorph” means different crystalline forms as well as solvates and hydrates.
“Polypeptide(s)” refers to multiple bonded amino acids, which may include dimers or trimers of bonded amino acids or even longer chains of bonded amino acids. For example, in some embodiments, for di-leucyl containing trimers, the third amino acid component of the trimer is one of the following leucine (leu), valine (val), isoleucine (isoleu), tryptophan (try) alanine (ala), methionine (met), phenylalanine (phe), tyrosine (tyr), histidine (his), or proline (pro).
“Ribavirin” means, 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide or 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboxamide, and has the following structural formula:
Ribavirin has been designated as CAS Number 36791-04-5. Its empirical formula (Hill Notation) is C8H12N4O5, and it has a molecular weight of 244.20 g/mole. Ribavirin is identified as MDL number MFCD00058564 and is commercially available from Sigma-Aldrich, as compound no. R9644. Ribavirin synthesis is described in Witkowski J.T., et al., Design, synthesis, and broad spectrum antiviral activity of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides. J. Med. Chem. 1972 Nov; 15(11):1150-1154.
“Solvates” means crystal forms containing either stoichiometric or nonstoichiometric amounts of solvents. If the incorporated solvent is water, it is referred to as a “hydrate”.
“Tapped Density” means bulk density of a powder (or granular solid) after consolidation/compression prescribed in terms of “tapping” the container of powder a measured number of times, usually from a predetermined height. The method of “tapping” is best described as “lifting and dropping”. Tapping in this context is not to be confused with tamping, sideways hitting or vibration.
“TID” means three times a day, and “QID” means 4 times a day.
“Tmax” means the time after administration of a drug when the maximum concentration is reached in a particular fluid, e.g., blood, plasma, ELF, or lung.
As described herein, applicants have invented a novel pharmaceutical composition comprising a plurality of solid-phase fabricated particles comprising ribavirin and optionally one or more excipients.
Generally, the particles of the present invention are fabricated through the PRINT® Technology (Liquidia Technologies, Inc., Morrisville, N.C., USA). In particular, the PRINT® (Particle Replication In Non-Wetting Templates) particles are made by molding the materials intended to make up the particles in mold cavities. The molds can be polymer-based molds and the mold cavities can be configured to have desired shapes and dimensions. Uniquely, as the particles are formed in the cavities of the mold, the particles are highly uniform with respect to shape, size and composition. The methods and materials for fabricating the particles of the present invention are further described and disclosed in the following issued patents and co-pending patent applications, each of which are incorporated herein by reference in their entirety: U.S. Pat. Nos. 8,944,804, 8,465,775; 8,263,129; 8,158,728; 8,128,393; 7,976,759; 8,444,907; and U.S. Pat. Application Publications Nos. 2013-0249138; US 2012-0114554; and US 2009-0250588, and Rolland J., et al. “Direct Fabrication and Harvesting of Monodisperse, Shape-Specific Nanobiomaterials” J. Am. Chem. Soc. 2005, 127, 10096-10100; each of which are incorporated herein by reference in their entirety.
The fabricated particles are generally non-spherical, having an engineered shape corresponding to a mold in which the particles are formed. The fabricated particles are therefore substantially uniform in shape, substantially equal size, or substantially uniform in shape and substantially equal size. The uniformity is advantageously monodisperse in comparison with other milled, or spray dried materials which will possess a variety of aerodynamically sized and shaped particles.
A further attribute of the fabricated particles of the invention is that in their physical structure, they may be generally homogeneously solid throughout. Thus, they lack hollow cavities or large porous structures which may be created in droplet creation and liquid phase evaporative processes, for example spray drying. This homogeneity allows for densification of the materials within the particles, which may provide such benefits such as compositional rigor, increased drug loading per fabricated particle, and the like.
In one or more embodiments of this aspect of the invention, the fabricated particles may be substantially non-porous.
Molding potentially allows the fabricated particles to be formed in a wide variety of shapes, including but not limited to: those having two substantially parallel surfaces; two substantially parallel surfaces with each substantially parallel surface having substantially equal linear dimensions; two substantially parallel surfaces and one or more substantially non-parallel surfaces. Other shapes include those with one or more angle, edge, arc, vertex, and/or point, and any combination thereof. Other shapes when viewed in 2-dimensions, in a particular orientation, may include triangles, trapezoids, rectangles, arrows, quadrilaterals, polygons, circles, and the like. In 3-dimensions, the shapes may include cones, cubes, cuboidals, prisms, pyramids, polyhedrons, and cylinders, whether right, truncated, frustum, or oblique.
In some embodiments, the shape may comprise when viewed from a top-plan view, a multi-spoked particle, where a plurality of the spokes radiate generally in a single plane from a central point, each spoke forming an arm. For example, see
The “pollen”-shaped particles depicted in
In some embodiments, the fabricated particles are substantially cylindrical shaped. Cylindrical shaped particles are depicted in
Thus, the fabricated particles comprise, in cross section, two substantially parallel surfaces (sides), wherein thickness of the particles (between the parallel surfaces (sides)) is about 5.0 μm or less, such as 4.5 μm, 4.0 μm, 3.5 μm, 3.0 μm, 2.5 μm, 2.0 μm, 1.5 μm, 1.0 μm, 0.75 μm, 0.5 μm to approximately 0.25 μm. In some embodiments, fabricated particles of the invention include those having a shape which, when observed in side-view, has a width which is greater than the height of the particle, the height of the shape being defined between the top surface and the bottom surface of the particle, the top and bottom surfaces being substantially parallel to each other, and wherein thickness of the particles between the top and bottom surfaces is less than or equal to about 6 μm, such as less than or equal to about, independently, 4.5 μm, 4.0 μm, 3.5 μm, 3.0 μm, 2.5 μm, 2.0 μm, 1.5 μm, 1.0 μm, 0.75 μm, 0.5 μm or 0.25 μm. In some embodiments, the height of the particle is about 2 μm or less. In some embodiments, the height of the particle is less than 1 μm, such as, between about 0.25 μm and about 0.75 μm.
In other embodiments, fabricated particles of the invention include those having a shape which, when observed in side-view, has a height which is greater than the width of the particle, the height of the shape being defined between the top surface and the bottom surface of the particle, the top and bottom surfaces being substantially parallel to each other, and wherein thickness of the particles between the top and bottom surfaces is less than or equal to about 6 μm, such as less than or equal to about, independently, 4.5 μm, 4.0 μm, 3.5 μm, 3.0 μm, 2.5 μm, 2.0 μm, 1.5 μm, 1.0 μm, 0.75 μm, 0.5 μm or 0.25 μm. In some embodiments, the height of the particle is about 2 μm or less. In some embodiments, the height of the particle is approximately 1 μm, such as, between about 0.90 μm and about 1.1 μm.
As will be appreciated, aerosolized particles deposit in the lung dependent upon aerodynamic factors, as well as on other factors such as density, air flow velocity and directionality, among others. Aerodynamically, the fabricated particles of the present invention are designed to be less than about 7 μm, but larger than about 0.5 μm in size. Thus, they are designed to deposit in the central and/or peripheral airways. Thus, fabricated particles may be molded to have an aerodynamic size, independently, of less than 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.
The pharmaceutical compositions of the present invention are intended for delivery to the lung and will possess a mass median aerodynamic diameter (MMAD) of less than about 7 μm, for example, from about 6 μm to about 0.5 μm. Thus, compositions of such fabricated particles may have a MMAD of less than, independently, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.
In some embodiments, each of the fabricated particles of the composition comprises an amount of ribavirin ranging from about 0.04 picograms to about 4.5 picograms, such as, from about 0.40 picograms to about 0.45 picograms.
The percentage of ribavirin present in the fabricated particles is dependent on a number of factors, such as the amount of ribavirin which is desired to be administered, the given volume of the composition which is required to be delivered, and the particle composition. However, in one or more embodiments of the invention, the percentage loading of ribavirin ranging from about 1% w/w to greater than 99% w/w of the fabricated particles. Representative of this are fabricated particles comprising a percentage loading of ribavirin 5% w/w to about 99.5% w/w; 10% w/w to about 99.5% w/w; from about 10% w/w to about 55% w/w; from about 20% w/w to about 50% w/w; or a range of from about 30% w/w to about 40% w/w.
Thus, in various embodiments of the invention, the percentage loading of ribavirin in the fabricated particles is greater than about 1.0% w/w, such as greater than 5.0% w/w, such as greater than about 10%, 15%, 20%, 25% 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99% w/w fabricated particles.
In certain embodiments, the percentage loading of ribavirin in the fabricated particles is greater than or equal to 95% w/w. In certain embodiments, the percentage loading of ribavirin in the fabricated particles is greater than or equal to 97% w/w. In certain other embodiments, the percentage loading of ribavirin in the fabricated particles is greater than or equal to 99% w/w.
Thus, the range of ribavirin to excipient in the present invention may be from about 1% to 99.5% ribavirin, to from 99% to 0.5% excipient.
In one or more embodiments of the invention, the ribavirin in the fabricated particles is amorphous or substantially amorphous. In other embodiments of the invention, the ribavirin in the fabricated particles is crystalline or substantially crystalline.
Ribavirin is known to have two polymorphic crystalline forms. See Prusiner, P., et al., “The crystal and molecular structures of two polymorphic crystalline forms of virazole (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide). A new synthetic broad spectrum antiviral agent”, Acta Cryst. (1976), B32, 419-426. Crystalline ribavirin is a white powder freely soluble in water and slightly soluble in ethanol (96%). It has a specific optical rotation between −33.0° and −37.0° (dried basis 10 mg/ml, t=20° C.), pH 4.0-6.5. Ribavirin may exist in two polymorphic crystalline forms, II and I that are distinguishable by their melting range. One form crystallized from aqueous ethanol, Form II which is thermodynamically stable at room temperature, melts at about 166˜168° C. (thermostable Form II), while the other form (Form I) crystallized from ethanol, is metastable at room temperature, and has a melting range of 174˜176° C. In embodiments, crystalline Form II is preferred.
In one embodiment, the present invention incorporates a percentage of Form II ribavirin within the particles plus, optionally, one or more excipients described herein, or alternatively, 90% or greater, 95% or greater, 96%, 97%, 98%, 99%, or 100% of the entire particle is made of Form II ribavirin. In certain embodiments, the particles are 99% Form II ribavirin with the remaining 1% of the particle comprising polyvinyl alcohol (PVOH). In other embodiments, the particles are 100% Form II ribavirin.
In another embodiment, the present invention incorporates a percentage of Form I ribavirin within the particles plus one or more excipients described herein, or io alternatively, 90% or greater, 95% or greater, 96%, 97%, 98%, 99%, or 100% of the entire particle is made of Form I ribavirin. In certain embodiments, the particles are 99% Form I ribavirin with the remaining 1% of the particle comprising polyvinyl alcohol (PVOH). In other embodiments, the particles are 100% Form I ribavirin.
The fabricated particles of the present invention may also comprise varying mixtures (or ratios) of crystalline Form I ribavirin, crystalline Form II ribavirin, and/or amorphous ribavirin and optionally also comprise one or more excipients described herein or may be substantially free of any excipients. For example, the fabricated particles of the present invention in one embodiment may substantially comprise Form II ribavirin, wherein less than 10%, less than 5%, or less than 1% of the ribavirin is Form I and/or amorphous ribavirin.
A material may exist in different crystalline forms, each being a polymorph. A material may exist in a single crystalline form, or may have two, three, four, or more polymorphs. Although polymorphs have the same chemical composition, polymorphs potentially have different physical and/or chemical properties. For example, the polymorphs may have different physical and/or chemical properties. Polymorphs may have different solubility, dissolution rates, physical stability, chemical stability, melting points, colors, density, flow characteristics, safety, efficacy, and/or bioavailability. Additionally, polymorphs may convert from one form to another during manufacturing and/or storage, for example from the metastable form to the thermostable form. This form conversion may or may not be desirable. Consequently, polymorphs impact pharmaceutical CMC (Chemistry, Manufacturing, and Controls) and regulatory requirements. Therefore, there is a desire to produce a specific polymorph form or forms.
There are various techniques available to achieve and control polymorph formation and growth. While some are described herein, it will be readily recognized to those skilled in the art that alternatives to those discussed are available, and are considered within the scope of the present invention. Some non-limiting examples include use of a saturated or supersaturated solution and temperature control. A saturated or supersaturated solution may provide multiple points of nucleation leading to crystal formation. Crystals formed may or may not be the desired polymorph. If a specific polymorph is desired, use of crystal seeds (seeding) with the desired polymorph form will encourage the formation of crystals having the desired form. If a less desirable polymorph is formed, the crystals may be further treated to convert the undesirable polymorph to the desired polymorph.
When producing particles within molds, such as in PRINT® Technology, it may be useful and in some instances important to have crystals (seeds) present in some or each mold cavity or within communication with the mold cavities to initiate the crystallization process in the cavities. In some embodiments, the mold cavities are left in communication with each other through the use of a flash layer of the substance to be molded interconnecting the cavities. In alternative embodiments seeds are transferred to the mold cavities when the stock solution used to prepare the particles is dispensed into the mold. The stock solution may be filtered using a filter having a pore size sufficiently large to allow the passage of crystals of the active agent (i.e. such as a drug like Ribavirin). Alternatively, the stock solution may be used for fabrication of particles without filtering. In further embodiments, the stock solution is filtered before addition of the active agent, then utilized in PRINT® Technology molding processes, described herein, before the active agent fully dissolves such that crystals of the active agent remain in the stock solution introduced into the PRINT® Technology molding process.
Temperature may be varied during the crystallization process. The temperature may be varied during the formation of crystals or after the crystals are formed. For example, the temperature may be cycled, involve a specific temperature exposure schedule, or comprise exposure of the material for a specified temperature range for a specified time interval. Additional conditions during temperature control may also be critical to polymorph formation. For example, during or after crystallization, crystals may annealed when stored under specific temperature and relative humidity conditions for specific time duration.
Annealing may be employed to promote crystalline form formation and growth. Annealing may be conducted in an annealing chamber. Annealing chamber conditions can be highly influential on the time to crystallize. Annealing chamber conditions may also impact particle surface quality. Dependent on annealing conditions selected, a potential may exist for the formation of polycrystalline domains in the particles. Polycrystalline domains may lead to fracture which in turn impacts surface quality and therefore aerosolization performance.
Differential scanning calorimetry (DSC) has shown useful in understanding the presence of crystalline forms. Regarding ribavirin, DSC has been useful in understanding the level of Form I and/or Form II in manufactured materials. The ratio of enthalpies for the melting endotherms of Form I and Form II (ΔHm, Form I/ΔHm, Form II) is an indication of the form purity for a particular sample. Utilizing PRINT® Technology, samples comprising ΔHm, Form I/ΔHm, Form II less than 5% have been produced. In preferred embodiments, ΔHm, Form I/ΔHm, Form II is less than 1%.
Compositions of particles of the present invention may be characterized in terms of bulk density. The bulk density of the pharmaceutical compositions of the present invention are generally less than about 3.0 g/cm3, for example less than 2.5 g/cm3, less than or equal to 2.0 g/cm3, less than 1.5 g/cm3, and less than 1.0 g/cm3.
Ribavirin containing particles of the present invention may also comprise one or more excipients. Suitable excipients of the fabricated particles may include one or more carbohydrate, amino acid/polypeptide, natural polymers, or synthetic polymers, alone, or in any combination. With certain embodiments, the carbohydrate excipients may include for example:
In some embodiments, the disaccharide is lactose or trehalose or a combination of lactose and trehalose. In some embodiments, the disaccharide is trehalose.
In some embodiments, the polysaccharide is dextran having a molecular weight between about 1,000 g/mole and 20,000 g/mole. One particular polysaccharide is dextran having a molecular weight of about 6,000 g/mole.
Non-limiting examples, of amino acid/polypeptide components which are suitable for use in the present invention include, but are not limited to, alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. In certain embodiments, the amino acids are hydrophobic amino acids, such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine and proline. One suitable amino acid is the amino acid leucine. Leucine, when used in the formulations described herein includes D-leucine, L-leucine, and mixtures thereof, including racemic leucine.
Polypeptides including dimers, trimers, tetramers, and pentamers composed of hydrophobic amino acid components such as those described above are also suitable for use. Examples include di-leucine, di-valine, di-isoleucine, di-tryptophan, di-alanine, and the like; trileucine, trivaline, triisoleucine, tritryptophan etc.; mixed di- and tri-peptides, such as leucine-valine, isoleucine-leucine, tryptophan-alanine, leucine-tryptophan, etc., and leucine-valine-leucine, valine-isoleucine-tryptophan, alanine-leucine-valine, and the like and homo-tetramers or pentamers such as tetra-alanine and penta-alanine. In one embodiment, the polypeptide is trileucine.
Synthetic polymers include, but are not limited to, polyvinyl alcohol (PVOH), polyethylene, polyester, polyethylene terephthalate, polypropylene, low-density polyethylene and high-density polyethylene. In some embodiments the synthetic polymer is PVOH with a molecular weight between about 6,000 g/mole and 30,000 g/mole and has a percent hydrolysis of between about 75 and 90%. A preferred synthetic polymer is PVOH with a molecular weight of about 6,000 g/mole and a percent hydrolysis of 78%. A preferred synthetic polymer is PVOH with a viscosity of 4.8-5.8 mPa·sec (4% aqueous solution at 20° C.) and a degree of hydrolysis of 86.5-89.0%.
Natural polymers include, but are not limited to, collagen, chitosan, gelatin, starch, chitin, pectin, DNA, cellulose and proteins.
The amounts of the various excipients will be dependent of the amount of ribavirin present, as well as the particular excipients used.
As will be described below, in various embodiments of the invention the fabricated particles comprise ribavirin and excipients, e.g., an amino acid and a carbohydrate, representative examples including but not limited to: trileucine and trehalose; or a polysaccharide and/or a synthetic polymer, e.g., dextran and/or PVOH.
In one or more embodiments, the excipient is selected from a group consisting of trehalose, trileucine, dextran, and lactose, alone or in any combination.
In one or more embodiments, the excipient is lactose. In such embodiments the percentage of lactose is between 40 and 80 percent of the particles, e.g. 65 percent.
In one or more still further embodiments, the excipient includes or is trehalose. For example, in such embodiments, the percentage of trehalose in such particles is between 40 and 80 percent, e.g., 65 percent.
In still further embodiments, the excipient includes or is trileucine. In certain such embodiments, the percentage of trileucine is between about 5 and about 20 percent, e.g., 15 percent.
In one or more embodiments, the excipient is PVOH. For example, in such embodiments, the percentage of PVOH in such particles is between about 0 and about 5 percent, e.g. 1 percent.
In certain embodiments, in this aspect of the invention, the percentage of ribavirin is between 25 and 100 percent of the particles, e.g., 95-99 percent.
In one or more particular embodiments, the particles comprise ribavirin, trehalose and trileucine. In one or more of such embodiments, the composition comprises about 55 percent trehalose and about 10 percent trileucine by weight based on solid materials. In one or more embodiments, the excipient is PVOH. In other particular embodiments, the particles comprise ribavirin and PVOH. In one or more of such embodiments, the composition comprises about 95 percent ribavirin and about 5 percent PVOH or about 96 percent ribavirin and about 4 percent PVOH or about 97 percent ribavirin and about 3 percent PVOH or about 98 percent ribavirin and about 2 percent PVOH or about 99 percent ribavirin and about 1 percent PVOH by weight based on solid materials.
Exemplary compositional ranges are contained in the tables below.
Generally, the particles of the present invention are fabricated through PRINT® Technology (Liquidia Technologies, Inc.). In particular, PRINT® Technology uses the following steps: stock solution preparation, particle fabrication, optional annealing, and harvesting. After harvesting, the particles may be packaged and labeled.
The methods and materials for fabricating the particles of the present invention are further described and disclosed in the following issued patents and co-pending patent applications, each of which are incorporated herein by reference in their entirety: U.S. Pat. Nos. 8,944,804; 8,465,775; 8,263,129; 8,158,728; 8,128,393; 7,976,759; 8,444,907; and U.S. Pat. Application Publications Nos. 2013-0249138; and US 2012-0114554.
Particles of various shape/size configurations can be molded using stock solutions. PRINT® molds used to fabricate these particles are described in the references incorporated herein.
In one approach to this process, the fabricated particles are produced by a process comprising:
In another approach to this process, the fabricated particles are produced by a process comprising:
In certain embodiments, the fabricated particles containing ribavirin according to the present invention may be formed by a process comprising:
In other embodiments, the fabricated particles containing ribavirin according to the present invention may be formed by a process comprising:
In certain embodiments, the fabricated particles containing ribavirin according to the present invention may be formed by a process comprising:
In certain further embodiments, the fabricated particles containing ribavirin according to the present invention may be formed by a process comprising:
In certain embodiments, the fabricated particles containing from 1% to 100% of ribavirin according to the present invention may be formed by a process comprising:
In certain other embodiments, the fabricated particles containing from 1% to 100% of ribavirin according to the present invention may be formed by a process comprising:
In other embodiments, the crystalline particles containing from about 95% to 100%, of ribavirin according to the present invention may be formed by a process comprising:
In still other embodiments, the crystalline particles containing from about 95% to 100%, of ribavirin according to the present invention may be formed by a process comprising:
In certain embodiments, the temperature of the nip ranges from about 20° C. to about 300° C. In other embodiments, the pressure of the roller ranges from about 5 psi to about 80 psi. In still other embodiments, speed of the roller is greater than 0 ft/min and ranges up to about 25 ft/min.
In some embodiments, crystalline particle fabrication may be achieved as follows:
As shown in 1008 of
As shown in 100C, the delivery sheet is then overlaid with an interleaf layer 105 and together the delivery sheet, interleaf layer and mold are rolled. The roll is then held under annealing conditions, whereby the material of the thin film now in the mold cavities 103B and flash layer 106 transforms from predominately amorphous composition to the crystalline polymorph form of the seeded API material. After annealing, the mold is separated from the delivery sheet as shown in 100D, thereby leaving particles 103C that mimic the size and shape of the mold cavity and comprise the single polymorph form of API that was incompletely dissolved in the aqueous solution attached to the delivery sheet 104. As shown in 100E, the particles may then be removed from the harvest sheet producing independent, free-standing particles 103D. In preferred embodiments, flash layer 106 is sufficiently thin (i.e. 10 nm to 50 nm) such that upon mold 102 separation from delivery sheet 104 and particle 103C removal from delivery sheet 104 (alternatively called harvest sheet at this stage in the process) flash layer 106 is disrupted and does not interconnect or bind the particles from being free-standing independent particles 103D.
In some embodiments the wetting agent comprises between about 5% and 0.5% of the aqueous solution. In other embodiments, the wetting agent comprises about 1% of the aqueous solution. In a preferred embodiment the wetting agent is PVOH and comprises about 1% of the aqueous solution.
In some embodiments the mold comprises a cavity having a shape corresponding to a cylinder. In some embodiments the cylindrical shape of the mold cavity comprise a diameter of about 1 micrometer and a height of about 1 micrometer. In a preferred embodiment, the diameter of the cylindrical mold cavity is about 0.9 micrometers and the height of the cylindrical mold cavity is about 1 micrometer. According to a particular embodiment of the invention, each of the fabricated particles has a substantially cylindrical shape being between about 0.9 micrometers and 3 micrometers in diameter and between about 1 micrometer and 3 micrometers in height, thus giving the particle an aspect ratio of width to length of between about 0.9:3 and about 3:1.
In some embodiments the interleaf layer provides exposure of the annealing conditions to, or more directly or evenly to, the cavities in the mold to facilitate crystallization in the mold cavities. In some embodiments, the interleaf layer comprises mesh with between about 60% to 70% open area defined by holes between about 0.05 inch by 0.05 inch to about 0.15 inch by 0.18 inch and a thickness of between about 0.019 inch and about 0.035 inch. In a preferred embodiment, the interleaf layer comprises a mesh with about 65% open area defined by holes approximately 0.054 inch by 0.080 inch and a thickness of approximately 0.019 inch.
In some embodiments, the annealing conditions are between about 20 degrees to 60 degrees Celsius and 40-60 percent relative humidity. In other embodiments, the annealing conditions are between about 25 degrees to 40 degrees Celsius and 40-50 percent relative humidity. In more preferred embodiments, the annealing conditions are about 30 degrees Celsius (+/−2 degrees) and 48% relative humidity (+/−5%).
According to a particular embodiment where the particle composition is about 99% ribavirin and 1% PVOH; the mold cavities are cylinders about 0.9 micrometers in diameter and about 1 micrometer in depth; and the interleaf layer defines a mesh with about 65% open area defined by holes approximately 0.054 inch×0.080 inch and a thickness of approximately 0.019 inch, the annealing conditions are about 30 degrees Celsius (+/−2 degrees) and 48 relative humidity (+/−5%) for at least 14 days. Under such conditions the particles resulting in the mold cavities are about 99% ribavirin of which is about 99% crystalline polymorph form II.
In other embodiments, the particles are fabricated in 1.5 micrometer by 1.5 micrometer cylindrical PRINT® molds. According to such embodiments, a PVOH stock solution is made according to Example 1C having about 0.1 wt % PVOH and between about 10.0 to 11.5 wt % ribavirin. In a more particular embodiment, a stock solution was made according to Example 1C with 0.1075 wt % PVOH and 10.75 wt % ribavirin. Promptly following addition of the ribavirin to the PVOH solution, a thin film is cast on a PET web to a thickness of between about 750 nanometers to about 950 nanometers. The thin film is then mated with the PRINT® mold and the ribavirin solution in the mold cavities is allowed to anneal at 30 (+/−2) degrees C., 48% (+/−5%) relative humidity for about 2 weeks, also as described herein and in Example 1C and
In further embodiments the particles are fabricated in 3 micrometer by 3 micrometer cylindrical PRINT® molds. According to such embodiments, a PVOH stock solution is made according to Example 1C having about 0.1 wt % PVOH and between about 10.0 to 15 wt % ribavirin. In a more particular embodiment, a stock solution was made according to Example 1C with 0.13 wt % PVOH and 13 wt % ribavirin. Promptly following addition of the ribavirin to the PVOH solution, a thin film is cast on a PET web to a thickness of between about 950 nanometers to about 1350 nanometers. The thin film is then mated with the PRINT® mold and the ribavirin solution in the mold cavities is allowed to anneal at 30 degrees C. (+/−2), 48% relative humidity (+/−5%) for about 2 weeks, also as described herein and in Example 1C and
In certain embodiments of the present invention, fabrication conditions are important to the resulting polymorph form control in the particles. In a particular embodiment, as shown in
Importantly, Steps B-C of
In another embodiment, it is important that Steps B-F of
According to an embodiment of the present invention, Step G occurs in at least 14 days.
According to an embodiment of the present invention, precise shape controlled particles mimicking the shape and size of PRINT® mold cavities comprised of greater than 95% ribavirin, of which is greater than 95% polymorph Form II, are formed through an amorphous solid to crystalline solid crystallization process in less than 15 days. According to more preferred embodiments of the present invention, precise shape controlled particles mimicking the shape and size of PRINT® mold cavities comprised of greater than 97% ribavirin, of which is greater than 99% polymorph Form II, are formed through an amorphous solid to crystalline solid crystallization process in less than 15 days. According to more preferred embodiments of the present invention, precise shape controlled particles mimicking the shape and size of PRINT® mold cavities comprised of greater than 99% ribavirin, of which is greater than 99% polymorph Form II, are formed through an amorphous solid to crystalline solid crystallization process in less than 15 days. In embodiments, the amorphous solid to crystalline solid crystallization process does not include a liquid transition.
The present invention provides method of fabricating a plurality of particles having substantially uniform size and shape and being comprised of greater than 95% ribavirin, of which is greater than 95% polymorph form II, in less than 15 days. More preferably, the present invention provides method of fabricating a plurality of particles having substantially uniform size and shape and being comprised of greater than 95% ribavirin, of which is greater than 99% polymorph form II, in less than 15 days. More preferably, the present invention provides method of fabricating a plurality of particles having substantially uniform size and shape and being comprised of greater than 98% ribavirin, of which is greater than 99% polymorph form II, in less than 15 days.
According to an embodiment of the present invention, a method is provided for retaining crystalline polymorph form of a composition while reducing particulate size by greater than 5 times. According to another embodiment of the present invention, a method is provided for retaining crystalline polymorph form of a composition while reducing particulate size by greater than 15 times. According to an embodiment of the present invention, a method is provided for retaining crystalline polymorph form of a composition while transferring the physical form factor of the composition from random shape and sized particulates to uniform particles with a reduced particulate size of greater than 5 times. According to an embodiment of the present invention, a method is provided for retaining crystalline polymorph form of a composition while transferring the physical form factor of the composition from random shape and sized particulates to uniform particles with a reduced particulate size of greater than 15 times.
The fabricated particles described herein may be metered as individual doses, and delivered in a number of ways. Additional aspects of the invention relate to dosage forms and inhalers for delivering metered quantities of the compositions of the present invention. In such aspects, the composition of the present invention is in the form of a dry powder composition deliverable from a dry powder inhaler or as a pressurized liquid propellant suspension formulation delivered from a pressurized metered dose inhaler.
Thus, in one or more embodiments, the invention is directed to a dosage form adapted for administration to a patient by inhalation as a dry powder.
The pharmaceutical composition of the present invention may be contained within a dose container containing a single dose of the pharmaceutical composition. In one or more embodiments, the dose container may be a capsule, for example, the capsule may comprise hydroxypropyl methylcellulose, gelatin or plastic, or the like.
In a still further aspect of the present invention, the invention relates to a dry powdered inhaler which contains one or more pre-metered doses of the compositions of the present invention. The containers may be rupturable, peelable or otherwise openable one-at-a-time and the doses of the dry powder composition may be administered by inhalation on a mouthpiece of the inhalation device, as known in the art.
Thus, compositions of the present invention may be presented in capsules or cartridges (one dose per capsule/cartridge) which are then loaded into an inhalation device, typically by the patient on demand. The device has means to rupture, pierce or otherwise open the capsule so that the dose is able to be entrained into the patient's lung when they inhale at the device mouthpiece. As marketed examples of such devices there may be mentioned ROTAHALER™ of GlaxoSmithKline (described for example in US 4,353,365), the HANDIHALER™ of Boehringer Ingelheim. or the BREEZHALER™ of Novartis, and MONODOSE™ of Plastiape S.p.a. (Osnago (Lecco), Italy).
Multi-dose dry powder forms containing the pharmaceutical composition described herein may take a number of different forms. For instance, the multi-dose may comprise a series of sealed blisters with the composition sealingly contained in a blister pocket, and may be arranged as a disk-shape or an elongated strip. Representative inhalation devices which use such multi-dose forms include devices such as the DISKHALER™, DISKUS™ and ELLIPTA™ inhalers marketed by GlaxoSmithKline. DISKHALER™ is described for example in U.S. Pat. No. 4,627,432 and U.S. Pat. No. 4,811,731. The DISKUS™ inhalation device is, for example, described in U.S. Pat. No. 5,873,360 (GB 2242134A). The ELLIPTA inhaler is described for example in U.S. Pat. No. 8,511,304, U.S. Pat. No. 8,161,968, and U.S. Pat. No. 8,746,242.
Alternatively, compositions of the present invention may be administered via a dry powder reservoir based, meter-in-device dry powder inhaler, wherein the composition of the present invention is provided as a bulk in a reservoir of the inhaler. The inhaler includes a metering mechanism for metering an individual dose of the composition from the reservoir, which is exposed to an inhalation channel, where the metered dose is able to be inhaled by a patient inhaling at a mouthpiece of the device. Exemplary marketed devices of this type are the TURBUHALER™ of AstraZeneca, TWISTHALER™ of Merck and CLICKHALER™ of Innovata.
In addition to delivery from passive devices, compositions of the present invention may be delivered from active devices, which utilize energy not derived from the patient's inspiratory effort to deliver and deagglomerate the dose of the composition.
The dry powder pharmaceutical composition may be delivered solely in the form of the fabricated particles of ribavirin and excipient.
Alternatively, the fabricated particles may be admixed with a pharmaceutically acceptable carrier/diluent, such as lactose or mannitol, with or without further excipients materials, such as lubricants, amino acids, polypeptides, or other excipients noted to have beneficial properties in such pharmaceutically acceptable carrier/diluent formulations, which combined form a finely divided powder.
In one or more embodiments of the present invention, the dry powder compositions of the invention have a moisture content below about 10% by weight water, such as a moisture content of about 9% or below; such as about 9, 8, 7, 6, 5, 4, 3, 2, or 1% or below by weight water. In one or more embodiments of the invention, the dry powder composition has a moisture content below about 1% by weight water.
It is also considered within the scope of the present invention that the pharmaceutical composition described herein may be formulated in a suitable liquid pressurized liquid propellant, for use in a metered dose inhaler (MDI).
Thus, a further aspect of the invention is an inhaler, as well as a liquid propellant formulation for use therein. Such inhalers may be in the form of a metered dose inhaler (MDI) generally comprising a canister (e.g., an aluminium canister) closed with a valve io (e.g. a metering valve) and fitted to an actuator, provided with a mouthpiece, and filled with a liquid pressurized liquid propellant formulation containing the pharmaceutical compositions as described herein. Examples of suitable devices include metered dose inhalers, such as the Evohaler® (GSK), Modulite® (Chiesi), SkyeFine™ and SkyeDry™ (SkyeP harma).
When formulated for metered dose inhalers, the compositions in accordance with the present invention are formulated as a suspension in a pressurized liquid propellant. In one or more embodiments of the present invention, while the propellant used in the MDI may be CFC-11, and/or CFC-12, it is possible that the propellant be an ozone friendly, non-CFC propellant, such as 1,1,1,2-tetrafluoroethane (HFC 134a), 1,1,1,2,3,3,3-heptafluoro-n-propane (HFC-227), HCFC-22 (difluororchloromethane), or HFA-152 (difluoroethane and isobutene), either alone or in any combination.
Such formulations may be composed solely of propellant and the fabricated particles described herein, or alternatively may also include one or more surfactant materials, such as polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, propoxylated polyethylene glycol, polyoxyethylene lauryl ether, oleic acid, lecithin or an oligolactic acid derivative e.g. as described in WO94/21229 and WO98/34596, for suspending the composition therein, and may also include agents for solubilising (co-solvents may include, e.g. ethanol), wetting and emulsifying components of the formulation, and/or for lubricating the valve components of the MDI, to improve solubility, or to improve taste.
In one or more embodiments of the invention, the metallic internal surface of the can is coated with a fluoropolymer, more preferably blended with a non-fluoropolymer. In another embodiment of the invention the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a further embodiment of the invention the whole of the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES).
The metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).
In various embodiments, the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Pat. Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Pat. Nos. 6,360,739 and 6,431,168.
The stability of the suspension aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction, employing a cascade impactor, for example the Next Generation Impactor (NGI), or by the “twin impinger” analytical process. As used herein reference to the “twin impinger” assay means “Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A” as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the “respirable fraction” of the aerosol formulations to be calculated. One method used to calculate the “respirable fraction” is by reference to “fine particle fraction” which is the amount of active ingredient collected in the lower impingement chamber per actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above. In the context of his application, the NGI is used unless otherwise indicated.
MDI canisters generally comprise a container capable of withstanding the vapor pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminum or an alloy thereof which may optionally be anodized, lacquer-coated and/or plastic-coated (for example incorporated herein by reference WO96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers), which container is closed with a metering valve. The cap may be secured onto the can via ultrasonic welding, screw fitting or crimping. MDIs taught herein may be prepared by methods of the art (e.g. see Byron, above and WO96/32099). Preferably the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.
There is thus provided as a further aspect of the invention a pharmaceutical aerosol formulation comprising an amount of the fabricated particles as previously described and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
According to another aspect of the invention, there is provided a pharmaceutical aerosol formulation wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof.
The formulations of the invention may be buffered by the addition of suitable buffering agents.
In a further embodiment, the invention is directed to a dosage form adapted for administration to a patient by inhalation via a metered dose inhaler.
The high solubility and low lipophilicity of ribavirin are both favorable characteristics in terms of lung delivery of the fabricated particles of the present invention. In some embodiments, the clinical dosing regimen of the compositions of the present invention is io 1-100 mg QD, or 1-50 mg BID, or in some embodiments, 30 mg BID, in other embodiments, 60 mg BID.
The aerosol formulations of the present invention are preferably arranged so that each metered dose, either in dry powder or in a given “puff” from a MDI, contains from 1 mg to 100 mg, or from 3 mg to 75 mg, or from about 5 mg to 50 mg of ribavirin, or from 7.5 mg to 30 mg ribavirin. Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. In certain embodiments, the overall daily dose of ribavirin with an aerosol will be within the range from 100 μg to 50 mg, preferably from 750 μg to 3500 μg. The overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.
In the case of suspension aerosol formulations, the particle size of the fabricated particles of ribavirin should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 μm, desirably less than 20 μm, and in particular in the range of from 1 to 10 μm, such as from 1 to 5 μm, more preferably from 2 to 3 μm.
Ratios of material to material using in the compositions described are to be understood to be weight:weight measures, e.g. RBV:Trehalose: Trileucine (35:55:10) is on w:w:w basis.
In one instance, a ribavirin dose administered to a subject, using a ribavirin composition of RBV: Trehalose: Trileucine (35:55:10), could be 30 mg given BID. This ribavirin dose could be delivered to the subject with a single unit inhaler provided with 4 capsules using a suitable inhaler, such as a Monodose™ or a Rotahaler™. The device design may be optimized to achieve desired product delivery characteristics, for example by reducing the air inlet dimensions to increase velocity, etc. . . . Each capsule would contain 7.5 mg ribavirin and the subject will perform 2 inhalations per capsule.
In another instance, a ribavirin dose administered to a subject using a ribavirin composition of RBV, and could be given 60 mg given BID. This ribavirin dose could be delivered to the subject with a suitable single unit inhaler, such as a Monodose™, provided with two (2) capsule(s). Each capsule would contain 30 mg ribavirin and the subject will perform 1 inhalations per capsule. In one embodiment, the RBV composition would comprise from 95-99.9% w:w of crystalline polymorph Form II RBV (e.g. about RBV:PVOH (95-99.9%: 5-0.1%), e.g. RBV:PVOH (99:1).
The invention is now described in relation to a number of non-limiting examples:
Prepare an aqueous particle precursor solution according to the following table. Weigh Water for Injection (WFI) into an appropriate sized vessel. Sequentially, with stirring, add PVOH, dextran, and ribavirin. After at least 45 minutes of stirring visually verify that components have dissolved. Once components have dissolved, sterile filter using a 0.22 micron filter. Store at 4° C. until use.
Based on solids, the particle precursor contains the components and amounts detailed in Table 6 below.
Following separation of the mold film and web film, the particles are removed from the mold cavities and remain on the web until removed from the web and collected as a powder.
In the current Example, a 1 μm “pollen” shape was utilized, wherein the 1 μm is the maximum overall lateral dimension of the particle in top-plan view and the particle is between 0.55 μm and 0.60 μm in thickness.
Prepare an aqueous particle precursor solution according to the following Table 7. Weigh WFI into an appropriate sized vessel. Sequentially, with stirring, add 10% HCl and trileucine. Stir overnight at ambient temperature to dissolve the trileucine. With stirring, add trehalose dihydrate and ribavirin. After at least 30 minutes of stirring visually verify that components have dissolved. Once components have dissolved, sterile filter using a 0.22 micron filter. Store at 4° C. until use.
Based on solids, the particle precursor contains the components and amounts detailed in Table 8 below.
Following separation of the mold film and web film, the particles are removed from the mold cavities and remain on the web until removed from the web and collected as a powder.
In the current Example, a 1 μm “pollen” shape was utilized, wherein the 1 μm is the maximum overall lateral dimension of the particle in top-plan view and the particle is between 0.55 μm and 0.60 μm in thickness.
Particles containing ribavirin and PVOH were fabricated using the components in Table 9 below using the following methods.
Based on solids, the particle stock solution contained the components and amounts detailed in Table 10 below.
The 99:1 w/w ribavirin:PVOH (RBV:PVOH) material is made of discreet cylindrical shaped particles as depicted by electron microscopy (
Next Generation Impaction Characterization: Ribavirin/Trehalose/Trileucine Particles
The 35:55:10 w/w ribavirin:trehalose:trileucine (RBV:T:T) material is made of discreet pollen shaped particles as depicted by electron microscopy (
Table 11 depicts Aerosol Parameters for Ribavirin/Trehalose/Trileucine Particles (35:55:10 ribavirin:trehalose:trileucine (1 μm pollen)).
The NGI data in Table 11 was generated using a flow rate of 95 L/min with a 2.5 sec actuation for a 4 L induction volume. NGI stage cut points were as follows in Table 12:
RBV:Trileucine:Trehalose particles showed good maintenance of particle morphology following storage for 1 month under all conditions. Additionally, all chemical, physical, and aerodynamic properties were found to be intact following 1 month storage under nitrogen or dry conditions and the particles showed no crystallization.
1PRINT ® particle −1 μm × 0.9 μm cylinder
2PRINT ® particle −1 μm pollen
3Large amounts of powder on filter of cascade impactor (<0.25 μm) for pollen shaped particles; second value shows MMAD/GSD with filter value excluded for information.
4Dose-normalized Cmax and AUC, and actual doses were gravimetrically measured, except where double brackets border, i.e., [[ ]], indicating analytically determined values. Fold changes in lung dose-normalized Cmax are also calculated accordingly.
5Duplicate measurements.
Data from Table 14 are represented in
Table 15 depicts the toxicokinetics of ribavirin in the Wistar Han rat following snout-only inhalation of ribavirin during a single dose pharmacokinetic study. Briefly, ribavirin concentration analysis were rat plasma and lung homogenate (supernatant) samples analyzed for ribavirin using an analytical method based on protein precipitation followed by HPLC-MS/MS analysis. The lower limit of quantification (LLQ) was 20 ng/mL using a 25 μL aliquot of rat plasma or lung homogenate with a higher limit of quantification (HLQ) of 20000 ng/mL. Plasma samples were analyzed against a plasma calibration line. Lung homogenate (supernatant) samples were analyzed against a lung homogenate (supernatant) calibration line.
Table 16 depicts plasma concentrations of ribavirin at each time point following io snout-only inhalation administration of PRINT® crystalline ribavirin at an estimated inhaled dose of 1.72 mg/kg to male rats.
a Times are from the start of the 15 minute inhalation period.
Table 17 depicts plasma concentrations of ribavirin at each time point following snout-only inhalation administration of PRINT® ribavirin with lactose at an estimated inhaled dose of 3.89 mg/kg to male rats.
a Times are from the start of the 15 minute inhalation period.
Table 18 depicts lung concentrations at each time point following snout-only inhalation administration of PRINT® crystalline ribavirin at an estimated inhaled dose of 1.72 mg/kg to male rats.
a Times are from the start of the 15 minute inhalation period.
Table 19 depicts lung concentrations at each time point following snout-only inhalation administration of PRINT® ribavirin with lactose at an estimated inhaled dose io of 3.89 mg/kg to male rats.
a Times are from the start of the 15 minute inhalation period.
Table 20 depicts the 1 month in vial stability of RBV:PVOH (97:3) (crystalline) when stored under various conditions.
Table 21 depicts the 2 month in vial stability of crystalline RBV (97:3 RBV:PVOH) when stored under various conditions.
Table 22 depicts the NGI data for bulk samples of crystalline RBV (RBV:PVOH (97:3)) at 6 months stored in a closed vial with −20° C. room air, in a closed vial with 25° C./60% air, in an open vial continuously exposed 25° C./60% RH air and in a closed vial with 40° C. air.
Table 23 depicts the NGI data for crystalline RBV (RBV:PVOH (99:1)) at 2 months stored in a closed vial with -20° C. room air, in a closed vial with 25° C./60% air, in an open vial continuously exposed 25° C./60% RH air and in a closed vial with 40° C. air.
Ribavirin:PVOH (97:3) and Ribavirin:Trehalose/Trileucine (35:65) formulations.
Two polymorphic forms of RBV have been identified, with the Form II polymorph being more stable. Polymorphic forms of RBV may be identified by X-Ray Powder Diffraction (XRPD). The XRPD plot for RBV polymorphic Form I.is depicted in
12.0*
16.7*
19.7*
18.3*
23.6*
26.6*
23.0*
25.4*
Thus the most representative peaks for characterizing RBV polymorphic Form I are at about 16.7, 19.7, 23.6 and 26.6 degrees Theta, whereas the most representative peaks for characterizing RBV polymorphic Form II are at about 12.0, 18.3, 23.0 and 25.4 degrees Theta.
Solid state stability data of the Ribavirin:PVOH (99:1) 0.9×1.0μm Crystalline PRINT particles is depicted in
Aerodynamic Particle Size Distribution (APSD) has all been generated by Next Generation Impaction (NGI) equipment utilizing no preseparator and a Throat fitted with rubber integrated mouthpieces. Single capsule APSD determinations of 30.3 mg nominal capsule fill weight using the Monodose RS01 device at a flow rate of 60 litres per minute (L/min) has been provided.
Stability data has been provided in
All data is expressed as % Label Claim (%LC) to show the relative distributions in each stage or summary group.
The 30.3 mg nominal fill weight is equivalent to 30mg RBV for capsules filled with 99:1 RBV:PVOH formulation. Emitted Dose has been taken from NGI Totals (Sum of stages Throat, Stages 1-7, MOC, External Filter).
Data has been provided in
The data expressed in
As will be appreciated, the implication of this loading advantage is that the volume of material required to deliver a dose of RBV with the crystalline formulation is approximately 1/3 of that required with the amorphous form. A single capsule of crystalline RBV in a 99% RBV formulation is the equivalent of approximately 3 capsules of the amorphous formulation.
To investigate the effect of RBV when administered as a spray dried formulation, a study was conducted on 6 groups of 3 male rats/group that received a single 15 minute exposure via nose only inhalation of a spray dried particle containing 35% w/w Ribavirin, 55% trehalose and 10% (w/w) leucine. The nominal inhaled dose was 2mg/kg, and the actual inhaled dose: 2.036mg/kg/day. The particle size is indicated in Table 29.
In the study, a group of animals was killed immediately after the end of the exposure period and subsequently at 0.5, 1, 2, 6 and 24 hours after the end of the exposure period. From these animals, plasma and lung samples were collected for determination of RBV concentration. Spray dried particles containing 35% w/w Ribavirin with 55% w/w trehalose and 10% (w/w) leucine were prepared.
A target inhaled dose of 2 mg/kg ribavirin (single dose) was selected for each group as this represented an approximate rat equivalent dose of a possible human total dose of 20 mg (assuming a human body weight of 60 Kg and scaling factors of 6 [rat] and 37 [humans] when converting from mg/kg to mg/m2). The inhalation exposure system consisted of snout only, flow through ADG inhalation exposure chambers. The animals were restrained in polycarbonate restraint tubes which were attached to the chambers. Aerosols were generated into the top section of the inhalation chamber using a capsule based aerosol generator (CBAG). The diluent air connection located at the top of the exposure chamber remained open throughout the exposure period to balance airflow and maintain the chamber at near ambient pressure. The atmosphere in the chamber was extracted to ensure a flow of aerosol through the chamber.
The results, shown in Table 30, indicate that it is possible to generate aerosols of ribavirin using spray dried particles containing 35% w/w Ribavirin with 55% w/w trehalose. Ribavirin was quantified in plasma and lung samples.
Table 29 details the Particle Size Distribution Results for Spray dried RBV particles RBV:Trehalose:Leucine (35:55:10% w/w) Particle Compositions
1Dose-normalized Cmax and AUC0-t. Dose delivered: 2.036 mg/kg (measured by analytical method).
Studies in inhalation Pharmacokinetic (PK) rat lung models, represented by e.g., Tables 14 and 30, show that RBV PRINT particles achieve a greater than 8× increase in dose-normalized lung Cmax, and a greater than 11× increase in dose-normalized lung AUC0-t when compared with data generated with Spray dried RBV particles (SDD).
As will be appreciated by the above, the present invention provides advantages in ribavirin therapy. As a dry powder, these RBV containing compositions, whether presented as an amorphous or crystalline solid, potentially avoid the problems of bronchospasm associated with nebulized aqueous formulations, especially in COPD patients. Current clinical data in human healthy volunteers suggest the dry-powder formulation containing 35% ribavirin in 55% trehalose and 10% trileucine does not cause abnormalities in pulmonary function in these subjects. Bronchospasm is explained by the Walsh, Respi Care (2016) article mentioned previously, which suggests the mechanism of bronchospasm is irritation caused by the hypotonic solution, and in which the authors suggest replacing the sterile water for dilution of the active with saline. Because the compositions of fabricated particles of the present invention are not a hypotonic solution, this may provide patients with a clinical benefit of avoiding this unfavorable reaction.
Further benefit of the particle compositions of the present invention include their ability to deliver a required dosage in a more concentrated manner. The required dosage can be delivered in a shorter time span when compared to nebulized formulations (Virasol®). As a powder inhaled from an inhaler is directly introduced to a patient's lungs in one to a few inhalation cycles, treatment time is reduced to seconds rather than many minutes to hours, largely avoiding the environmental exposure caregivers experience with dilute, nebulized formulations, an advantage with teratogenic compounds such as ribavirin.
While both crystalline and amorphous forms of templated particles of RBV described herein offer advantages over the available nebulized forms, the crystalline templated RBV particles of the present invention, which may be loaded with greater than 90% crystalline RBV, offers loading advantages over the amorphous RBV PRINT formulations described herein. This reduction in the volume of inhaled powder to deliver a desired dose of ribavirin promotes convenience and compliance in effective treatment, while potentially reducing pulmonary irritation. These and many other advantages will be appreciated by those of skill in the art based upon the description provided herein.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2016/056981 | 11/18/2016 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62256868 | Nov 2015 | US |
