WO2009055788A1 - Traitement de pneumoréduction et compositions utiles pour celui-ci - Google Patents

Traitement de pneumoréduction et compositions utiles pour celui-ci Download PDF

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WO2009055788A1
WO2009055788A1 PCT/US2008/081321 US2008081321W WO2009055788A1 WO 2009055788 A1 WO2009055788 A1 WO 2009055788A1 US 2008081321 W US2008081321 W US 2008081321W WO 2009055788 A1 WO2009055788 A1 WO 2009055788A1
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composition
lung
administration
amphiphile
surface tension
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PCT/US2008/081321
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English (en)
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Edward P. Ingenito
James A. Krom
Alexander Schwarz
Larry W. Tsai
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Aeris Therapeutics, Inc.
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Publication of WO2009055788A1 publication Critical patent/WO2009055788A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Definitions

  • Emphysema is a common, debilitating, and progressive form of chronic obstructive pulmonary disease (COPD) that affects between 2.0 and 3.0 million Americans, and 3 to 4 times that number of patients worldwide.
  • COPD chronic obstructive pulmonary disease
  • asthma and chronic bronchitis In contrast to other common forms of COPD, such as asthma and chronic bronchitis, conventional medical treatment is of limited value in patients with emphysema. Although each of these diseases causes chronic airflow obstruction, limited exercise capacity, and shortness of breath, the site and nature of the abnormalities in asthma and chronic bronchitis are fundamentally different from those of emphysema. In asthma and chronic bronchitis, smooth muscle constriction and mucus hyper-secretion result in airway narrowing, thereby causing airflow limitation. Thus, pharmacologic agents that relax airway smooth muscle and loosen accumulated secretions are effective at improving breathing function and relieving symptoms in these two diseases.
  • Such agents include beta- agonist and anti-cholinergic inhalers, oral theophylline preparations, leukotriene antagonists, steroids, and mucolytic drugs.
  • airflow limitation in emphysema is, in large part, due to loss of lung elastic recoil as a consequence of tissue destruction, rather than airway narrowing or obstruction. Loss of recoil compromises the ability to fully exhale, leading to lung hyperinflation and gas trapping.
  • bronchodilators, anti-inflammatory agents, and mucolytic agents are frequently prescribed for patients with emphysema, they are generally of limited utility since they are intended primarily for obstruction caused by airway disease.
  • Mammalian lung surfactant lines the surface of lung alveoli and modulates surface tension in the alveolar compartment at the air-liquid interface. In the absence of lung surfactant, the thin liquid film that lines the alveolar compartment would generate very high surface tension and result in lung collapse and respiratory failure. Surfactant protects the lung from collapse during exhalation by lowering surface tension at the air-liquid interface, maintaining patency of alveoli. During inhalation, lung surfactant increases the surface tension at the air-liquid interface imparting elastic recoil to the respiratory system. During the respiratory cycle, surfactant contributes approximately twice as much to lung elasticity as tissue elements.
  • Lung surfactant is comprised of a mixture of lipids and proteins, including phospholipids, such as phosphatidylcholine and phosphatidylglycerol, phosphatidylinositol, sphingomyelin, phosphatidylserine and phosphatidylethanolamine, of which the lipid dipalmitoylphosphatidylcholine (DPPC) makes up about 41% by weight.
  • DPPC dipalmitoylphosphatidylcholine
  • Changes in surfactant biochemical composition alter its interfacial properties which, in turn affect lung physiology. Certain human diseases, such as respiratory distress syndrome are caused by chemical alterations in surfactant composition which result in substantial increases in surface tension at air-liquid interface and stiffening of the lungs.
  • recoil pressure P tp
  • P tls the elastic forces of the collagen and elastin fibers
  • P ⁇ the elastic surface tension forces associated with the lung surfactant film
  • Equation (a), supra, P tp Ptis + P ⁇ + Pduct, suggests that any substance that increases surface tension ( ⁇ ), is biocompatible, and can be delivered to the alveolar air-liquid interface is capable of increasing lung recoil (i.e., P ⁇ ) and in doing so, functioning as pneumoreductive therapy (PRT) agent.
  • a therapeutically effective PRT material must, when combined with native surfactant be capable of increasing the surface tension at the alveolar air-liquid interface during lung inflation so as to increase recoil, while still permitting low surface tensions to be reached during exhalation to prevent alveolar collapse.
  • the overall consequence of such a biophysical effect in the emphysema lung would be to increase lung recoil and reduce hyperinflation without causing alveolar collapse.
  • composition for pneumoreductive therapy comprising an amphiphile, where the composition upon administration to a mammalian lung modifies the surface tension of the pulmonary surfactant, thereby increasing lung recoil.
  • composition for pneumoreductive therapy comprising an amphiphile and a spreading agent, where the composition upon administration to a mammalian lung modifies the surface tension of the pulmonary surfactant, thereby increasing lung recoil.
  • an aforementioned composition further comprising a phospholipid.
  • Another aspect of the invention relates to a method of reducing lung volume or increasing lung recoil by administering to a lung of a mammal in need thereof a therapeutically effective amount of an aforementioned composition. Additional advantages and features of the present invention will become apparent from the following detailed description of various non- limiting embodiments of the invention.
  • Figure l(a) is a graph showing the effect of systematically varying the DPPC:H ratio (at fixed tyloxapol) on ⁇ max and ⁇ min when mixed with calf surfactant (CS) at a ratio of 30:1.
  • Figure l(b) is a graph showing the effect of varying the ratio of D:H:T to CS. Increasing DHT produces a dose-dependent change in surface tension.
  • Figure l(c) is a graph show ⁇ vs. area (A) profiles (in triplicate) for samples of DHT 532 mixed with CS in a ratio of 30:1.
  • Figure 2 is a graph showing the effect of DHT 532 v. saline on lung volumes following intratracheal administration. DHT 532 caused reductions in three relevant physiological parameters: residual volume (“RV”), functional residual capacity (“FRC”), and total lung capacity (“TLC”).
  • RV residual volume
  • FRC functional residual capacity
  • TLC total lung capacity
  • Figure 3(a) is a graph showing the effects of nebulized DHT 532 on static lung compliance ("Cstat") in healthy rats for administered doses ranging from 3 to 30 mg/kg.
  • Figure 3(b) is a graph showing the effects of nebulized DHT 532 on dynamic elastance in healthy rats for administered doses ranging from 3 to 30 mg/kg.
  • Figure 3(c) is a graph showing the effects of nebulized DHT 532 on airway resistance in healthy rats for administered doses ranging from 3 to 30 mg/kg.
  • Figure 4(a) is a graph showing static compliance absolute values over time.
  • Figure 4(b) is a graph showing static compliance changes from baseline. Error bars represent one standard deviation.
  • Figure 5 is a bar graph showing percentage changes from baseline in static compliance as a function of dose (mg/kg) of OS or OTs. Error bars represent SEM.
  • a reference to "A and/or B", when used in conjunction with open-ended language, such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., Ci-C 30 for straight chain, Ci-C 3O for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • alkenyl and alkynyl are art-recognized and refer to unsaturated aliphatic and alicyclic groups analogous in length and substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction.
  • substituted is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, hydroxy, amino, amido, carboxy, ester, formyl, acetyl, alkylcarbonyl, alkoxy, cyano, halo, nitro, sulfhydryl, etc.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • compositions useful for treating patients with COPD such as emphysema.
  • Another aspect of the invention relates to methods for treating COPD using pneumoreductive therapy (PRT).
  • PRT pneumoreductive therapy
  • compositions comprising an amphiphile, wherein the composition upon administration to a mammalian lung modifies the surface tension of the pulmonary surfactant, thereby increasing overall lung recoil.
  • the pulmonary surfactant has a maximum surface tension and a minimum surface tension; wherein the increase in overall lung recoil is substantially due to an increase in the maximum surface tension of the pulmonary surfactant; and the increase in the minimum surface tension of the pulmonary surfactant is less than about 10 dyn/cm.
  • Yet another aspect of the invention relates to a composition
  • a composition comprising an amphiphile and a spreading agent, wherein the composition upon administration to a mammalian lung modifies the surface tension of the pulmonary surfactant, thereby increasing overall lung recoil.
  • the pulmonary surfactant has a maximum surface tension and a minimum surface tension; wherein the increase in overall lung recoil is substantially due to an increase in the maximum surface tension of the pulmonary surfactant; and the increase in the minimum surface tension of the pulmonary surfactant is less than about 10 dyn/cm.
  • compositions that are appropriate for use as PRT agents include combinations of C) 6 and/or Ci 8 amphiphiles, such as Ci 6 and Ci 8 amphipathic alcohols including hexadecanol and octadecanol, Ci 6 and Ci 8 fatty acids, such as palmitic acid and stearic acid, and Ci 6 and Ci 8 diacylphospholipids including DPPC and DSPC.
  • Ci 6 and Ci 8 amphiphiles such as Ci 6 and Ci 8 amphipathic alcohols including hexadecanol and octadecanol, Ci 6 and Ci 8 fatty acids, such as palmitic acid and stearic acid, and Ci 6 and Ci 8 diacylphospholipids including DPPC and DSPC.
  • Ci 6 and Ci 8 amphiphiles such as Ci 6 and Ci 8 amphipathic alcohols including hexadecanol and octadecanol
  • Ci 6 and Ci 8 fatty acids such as palmitic acid and
  • Y is a C 1 3 -Ci 9 amphiphile with the general structure of
  • R 1 -OR 2 wherein Ri is a Ci 3 -CiQ alkyl chain;
  • R 3 is CH 3 or lower alkyl to C 20 alkyl, e.g., hexadecanol, octadecanol, hexadecyl acetate
  • Y is a C1 3 -C 19 amphiphile with the general structure of: R 5 -COOR 4 ; wherein R 5 is a Ci 3 -C 19 alkyl chain; and R 4 is H or lower alkyl to Ci 8 alkyl, e.g., palmitic acid, stearic acid, ethyl palmitate, methyl stearate, hexadecyl palmitate.
  • formulations that can be used as safe and effective PRT agents comprise a composition of the general formula:
  • Y is a Ci 3 -CiQ amphiphile with the general structure of
  • Ri-OR 2 wherein Ri is a C I 3 -Ci 9 alkyl chain
  • R 3 is CH 3 or lower alkyl to C 20 alkyl, e.g., hexadecanol, octadecanol, hexadecyl acetate
  • Y is a Ci 3 -C 19 amphiphile with the general structure of: R 5 -COOR 4 ; wherein R 5 is a C I 3 -Ci 9 alkyl chain; and R 4 is H or lower alkyl to C 18 alkyl, e.g., palmitic acid, stearic acid, ethyl palmitate, methyl stearate, hexadecyl palmitate;
  • Z is a spreading agent, e.g., Triton, Tween®, Brij, cholesterol, cholesterol esters, lysophospholipids, sucrose esters.
  • the spreading agent is Triton WRl 339 or tyloxapol.
  • the spreading agent is a sucrose ester, sucrose palmitate or sucrose stearate (tradename Surfhope).
  • the compositions of the present invention when in contact with mammalian lung surfactant in a ratio of 1 : 10, cause an increase in surface tension during film expansion ( ⁇ max ) of about 1 to 15 dyn/cm. In other embodiments, the compositions increase ⁇ max by about 1 to 10 dyn/cm, or about 1 to 5 dyn/cm. In certain embodiments, while increasing ⁇ max as explained above, the compositions do not cause significant surface tension effects during film compression ( ⁇ m i n )- In certain embodiments, ⁇ mm is varied by about 0 to 10 dyn/cm, about 0 to 5 dyn/cm, or about 0 to 3 dyn/cm.
  • compositions of the present invention are capable of increasing lung recoil pressure in a mammalian lung.
  • lung recoil pressure is increased by about 10 - 100%, about 10 - 50 %, about 10 - 30%.
  • the compositions are capable of increasing mammalian lung expiratory flows (V max ). In certain embodiments, V max is increased by about 5 - 100%, about 10 - 50 %, or about 10 - 30%. In certain embodiments, the compositions are capable of increasing mammalian lung forced expiratory volume in the first second (FEVj) by about 5 - 100%, about 5 - 50 %, about 5 - 20 %. FEVj, the volume of air that can be forced out in one second, is an important measure of pulmonary function.
  • compositions of the invention are capable of reducing residual volume (RV) in a mammalian lung, the amount of gas that remains trapped in the lung and contributes to hyperinflation in emphysema.
  • RV residual volume
  • residual volume is reduced by about 5 to 30%, about 5 to 20%, about 5 - 10 %.
  • compositions of the present invention are capable of decreasing static compliance in a mammalian lung.
  • static compliance is decreased by about 5- 30 % or about 5 - 20 %.
  • compositions of the present invention are capable of increasing dynamic elastance in a mammalian lung by about 5 to 50%.
  • the compositions useful for PRT comprise a surfactant; or a surfactant and a spreading agent.
  • surfactant refers to organic compounds that are amphiphilic, meaning they contain both hydrophobic groups and hydrophilic groups.
  • surfactant and amphiphile are used interchangeably herein. Therefore, they are generally soluble in both organic solvents and water.
  • Surfactants reduce the surface tension of water by adsorbing at the liquid-gas interface.
  • the surfactants used in the compositions of the present invention can be anionic, neutral and zwitterionic.
  • the composition comprises an amphiphile.
  • amphiphile refers to compounds comprising at least one Cn to Ci 9 hydrocarbon chain, and at least one polar group, such as a carboxylic acid or an ester of a carboxylic acid, e.g., acetates.
  • exemplary amphiphiles include hexadecanol, octadecanol and hexadecyl acetate.
  • the aforementioned composition comprises a phospholipid.
  • phospholipid refers to lipids containing a phosphate group, and at least non-polar saturated or unsaturated hydrocarbon group, including saturated and unsaturated hydrocarbons.
  • General types of phospholipids include phosphoglycerides, such as phosphatidylcholines (e.g., dipalmitoylphosphatidylcholine (DPPC) and disteroylphosphatidylcholine (DSPC)), phosphatidylinositol, phosphatidylethanolamines, phosphatidylserines, and diphosphatidylglycerals; and sphingomyelins.
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC disteroylphosphatidylcholine
  • phosphatidylinositol phosphatidylethanolamines
  • phosphatidylserines phosphatidylgly
  • the phospholipid is a phosphatidylcholine. In certain embodiments, the phospholipid has the general formula I:
  • R 1 , and R 2 are for each occurrence independently selected from the group consisting of alkyl, alkenyl, alkynyl, subject to the proviso that at at least one of Ri or R 2 is selected from the group consisting of Ci 3-1 9 alkyl, Ci 3- 19 alkenyl, and C1 3 -19 alkynyl; and
  • R 3 , R 4 , and R 5 are for each occurrence independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, and lower alkynyl.
  • At least one of R 1 and R 2 of the phospholipid of Formula I is C 13 - 1 9 alkyl. In certain embodiments, at least one of R 1 and R 2 is Ci 5 or C ⁇ alkyl.
  • the phospholipid is DPPC, DSPC, PSPC, SPPC.
  • the surfactant is a fatty acid, an ester of a fatty acid, a fatty alcohol.
  • the surfactant is hexadecanol (cetyl alcohol), octadecanol, palmitic acid, an ester of palmitic acid, stearic acid or an ester of stearic acid.
  • the surfactant is selected from the group consisting of palmitic acid and hexadecanol.
  • the surfactant is selected from the group consisting of stearic acid and octadecanol.
  • a suitable counterion can be, for example, cations based on alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like.
  • spreading agent refers to a compound that facilitates the incorporation of the surfactant into the native lung surfactant.
  • spreading agents include nonionic polymers of the alkyl aryl polyether alcohol type, such as Tyloxapol.
  • Other spreading agents include Tween® 20 (polysorbate 20), Tween® 40 (polysorbate 40), and Tween® 80 (polysorbate 80), poloxamer, poloxamine, span, Brij, cholesterol, cholesterol esters, and sucrose esters.
  • the spreading agent is tyloxapol (4-(l, 1,3,3- tetramethylbutyl)phenol polymer, or Triton WR 1339).
  • Tyloxapol is a non-ionic polymeric detergent that aids in dispersion of surfactants. Tyloxapol has been utilized clinically as a dispering agent in synthetic lung surfactant formulations, and as a mucolytic agent in patients with bronchiectasis and chronic bronchitis.
  • the spreading agent is a sucrose ester, such as sucrose palmitate or sucrose stearate.
  • sucrose ester such as sucrose palmitate or sucrose stearate.
  • the proposed mechanism of action involves initial adsorption of the surfactant or the both the surfactant and the phospholipid (when the composition comprises a surfactant and a phospholipid) into the air-liquid interface in a mammalian lung, followed by incorporation into the native lung surfactant film.
  • H hexadecanol
  • P metabolite palmitic acid
  • DPPC hexadecanol
  • the ratio of the phospholipid X to the amphiphile Y ranges from about X(O-10:Y):Y(2-10). In other embodiments, the ratio is about 2:5 to about 1:2. In certain embodiments, the ratio is about 2:9 to about 1:2. hi certain embodiments, the ratio is about 3:9 to about 1 :2. hi certain embodiments, the ratio is about 16:36, about 4:9, or about 3:10.
  • the ratio of the phospholipid X to the amphiphile Y to the spreading agent Z ranges from about X(0-10:Y):Y(2-10):Z(0.01-4). In other embodiments, the ratio is about 6:2:2, 5:3:2, 4:4:2, or 3:5:2. In other embodiments, the ratio is about 5:3:2, or 5:3:1, or 5:3:0.5, or 4:9:1, or 4:9:0.5, or 4:9:0.25 or 0:9:1 or 0:3:1.
  • therapeutic agents may be incorporated in the compositions of the present invention.
  • therapeutic agents which may be incorporated include, but not limited to: anticholinergics; bronchodilators; anti-inflammatory agents, including steroidal and non-steroidal anti-inflammatory agents; anti-infective, such as antibiotics and antiviral agents (as mentioned above); analgesics and analgesic combinations; antiasthmatic agents; antidiuretic agents; antihistamines; antineoplastics; sympathomimetics; cough and cold preparations, including decongestants; immunosuppressives; parasympatholytics; naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins.
  • compositions of the present invention further comprise an additional therapeutic agent selected from bronchodilators, anticholinergics, non-steroidal antiinflammatories and steroidal anti-inflammatories.
  • Bronchodilators that may be included in the compositions of the present invention include: theophylline; beta-agonists, such as albuterol, lev-albuterol, salbutamol, epinephrine, salmeterol, formoterol, pirbuterol, and the like.
  • Anticholinergics include ipratropium bromide and the like.
  • Steroidal anti-inflammatories that may be incorporated into the compositions of the invention include: fluticasone, ciclesonide, prednisone, prednisolone, methylprednisolne, dexamethasone and its derivatives, cortisone, hydrocortisone, fludrocortisone, betamethasone, budesonide, triamcinolone, beclometasone, and the like.
  • composition of the present invention may further comprise pharmaceutically acceptable carriers and/or excipients.
  • the compositions of the invention may be in the form of a powder, which may optionally be suspended into a sterile liquid, such as water, saline, aqueous buffer, alcohols, and polyols (such as glycerol, propylene glycol, and polyethylene glycol).
  • a sterile liquid such as water, saline, aqueous buffer, alcohols, and polyols (such as glycerol, propylene glycol, and polyethylene glycol).
  • Pharmaceutical compositions of the invention also may be in the form of a suspension in a liquid, for example pharmaceutically-acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, and polyols (such as glycerol, propylene glyco
  • compositions may also contain adjuvants, such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like.
  • the surfactant, phospholipid or spreading agent used in the compositions of the present invention may be used in the form of pharmaceutically-acceptable salts derived from inorganic or organic acids.
  • pharmaceutically-acceptable salt is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically- acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically-acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq.
  • aspects of the invention relate to methods of increasing lung recoil or decreasing lung volume.
  • increased lung recoil or decreased lung volume can be accomplished non-surgically, rather than by procedures that disrupt the integrity of the chest wall [Ingenito et al, Am. J. Resp. Crit. Care Med. 2001, 164, 295-301; Ingenito et al, Am. J. Resp. Crit. Care Med. 2000, 161, A750; and Ingenito et al, Am. J. Resp. Crit. Care Med.
  • the method of lung recoil increase or lung volume decrease comprises administering by inhalation any of the aforementioned compositions of the invention to a mammalian lung, wherein the composition comprises a surfactant; or a surfactant and a spreading agent.
  • the composition further comprises an amphiphile.
  • the composition comprises the formula X:Y or X:Y:Z, as described above.
  • administration by inhalation is achieved using a nebulizer
  • a jet nebulizer e.g., a jet nebulizer, ultrasonic nebulizer or a vibrating mesh nebulizer
  • a metered-dose inhaler e.g., a metered-dose inhaler, or a dry-powder inhaler.
  • the method comprises administering a composition for PRT via a nebulizer.
  • a "nebulizer” is a device used to administer medication to people in forms of a liquid mist to the airways. Nebulizers often pump air or oxygen through a composition to turn it into a vapor, which is inhaled by a patient. The vaporized composition is inhaled through a tube-like mouthpiece, or in some instances, the composition is inhaled through a rubber face mask.
  • nebulizers/inhalers are manually activated, while others are breath activated, and do not require manual activation. These inhalers automatically sense the patient breathing in and deliver the medication.
  • the composition is administered via an asthma spacer, which is an enclosed plastic chamber that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug.
  • the composition is administered via the use of finely divided dry powder. Dry powder devices use a priming procedure to place a does of a powder ready for the patient to take. The operator puts the release end of the inhaler into his mouth and takes a deep inhalation, holding their breath for 10 seconds.
  • the composition is administered to the lung as a bolus.
  • the composition can be administered using a bronchoscope.
  • the composition may be administered intratracheal bolus administration, intermittent repeat nebulized dosing, or continuous nebulized dosing (in ventilated patients).
  • the method of increasing lung recoil or decreasing lung volume comprises administering to a mammalian lung a composition that modulates the surface tension of native lung surfactant, wherein the composition comprises a surfactant; or a surfactant and a spreading agent.
  • the mammal has emphysema. In certain embodiments, the mammalian lung is hyperinflated.
  • the administration of the composition is repeated weekly, daily, two times a day or three times a day for a period of time.
  • EXAMPLE 2 Additional studies were performed to further assess the effects of PRT on dynamic surfactant biophysical behavior using DHT 532 as an example,. These studies were performed using a second surface balance system known as a pendant drop surfactometer (PDS). Similar to the PBS system, the PDS system gives detailed information about surface tension surface area properties but is a more precise measurement. The PDS measurements were used to obtain a second, independent assessment of the biophysical effects of C16 and Cl 8 amphiphiles on surfactant behavior. In these measurements, the drop, containing surfactant with varying amounts of DHT 532, was continuously expanded by volumetric injection of the DHT components from a syringe, at a constant rate of 0.25 ⁇ L / second.
  • PDS pendant drop surfactometer
  • DHT 532 is expected to produce physiologically beneficial changes in lung elasticity without promoting a significant increase in ⁇ min .
  • Measurements of lung volumes were recorded by whole body plethysmography at three baseline time points over 30 minutes prior to dosing, and at 15 minute intervals up to 1 hour following dosing during periods of spontaneous breathing while off ventilator support.
  • Baseline values represented the average of the three pre- treatment values for each physiological parameter
  • post-treatment responses represented the average of the four values recorded during the 60 minutes following dosing.
  • the variable increases in lung volume observed following adminstration of saline alone were interpreted as reflecting gas trapping as a consequence of foaming caused by the dilutional effect of adding saline to native lung surfactant, as seen in Table 3.
  • Physiological responses to DHT 532 are summarized in Table 4 and Figure 6, where "RV” is residual volume (equal to trapped gas), “FRC” is functional residual capacity (equal to gas volume at passive end exhalation), and “TLC” is total lung capacity (equal to gas volume at full lung inflation). Results indicate that relative to saline, LVRT therapy administered as a bolus produced consistent reductions in all relevant lung volume parameters. The magnitude of changes in physiological response observed would be expected to have beneficial physiological effects in a patient with advanced emphysema.
  • nebulized DHT 532 The effect of single dose nebulized DHT 532 on lung physiology in healthy rats was then tested to confirm that delivery via nebulization produces favorable physiological effects simlar to those observed with intratracheal bolus dosing.
  • Baseline meaurements of static lung elastance (Cstat ⁇ Volume/ ⁇ Pressure over full lung inflation) and dynamic lung elastance (H) and airway resistance (R) were measured at 15 minute intervals starting 45 minutes prior to dose administration, and continuing for 45 minutes following dose administration. Baseline values represent the mean of the three pretreatment measurements, and post-treatment values the mean of the three post treatment values.
  • Results confirm that DHT 532 administered over 15 to 20 minutes as a single dose of 15 mg/kg at a concentration of 5 mg/mL in saline using an Aerogen vibrating mesh nebulizer produces statistically significant decreases in static compliance and dynamic elastance without detectable adverse effects. Changes of this type would be expected to produce physiological benefit in patients with emphysema.
  • Baseline meaurements of static and dynamic lung elastance and airway resistance were measured at 15 minute intervals starting 45 minutes prior to dose administration, and continuing for 45 minutes following dose administration. Baseline values represent the mean of the three pretreatment measurements, and post-treatment values the mean of the three post treatment measurements.
  • Table 5 Response to treatment for animals in the 3 mg/kg and 30 mg/kg group are summarized in Table 5 (saline control and 15 mg/kg group are summarized in Table 4, above). Responses across all groups are summarized in Figure 3. These results indicate a dose-response relationship between lung physiology and administered dose over the dosing range from 3 to 30 mg/kg. Physiolgical changes of this magnitude in emphysema are expected to be sufficient to produce physiological benefit. Table 5: Response to Single Dose Nebulized DHT 532 in Healthy Rats -Dose Response.
  • DHT532 Studies were performed to characterize the efficiency of DHT532 delivery using different nebulizer systems, because an effective pairing of a lipid-based drug, such as DHT 532, with an effective nebulizer will be requried for clinical application.
  • DHT 532 was suspended in saline by vortexing, nebulized through a particle sizer/impactor unit, and the amounts of D and H delivered in the form of respirable particles (defined as partciles ⁇ 4.7 microns in aerodynamic diameter) were measured.
  • nebulizers 2 vibrating mesh (the Aero gen Aeroneb ® Go and Omron NE-U22V MicroAIR ® ); 2 jet (the CIS AerotechTM II nebulizer and Pari LC Star ® ); and 2 ultrasonic (the Systam LS 290 and Sigma Neb 3060).
  • DHT 532 DHT 532
  • a uniform suspension generated by vortexing for 30 seconds.
  • the drug was then drawn into a syringe and injected into the nebulizer chamber. Preparations were aerosolized for 20 minutes while operating each nebulizer unit in accordance with manufacturer's specifications.
  • the outflow stream from the nebulizer was directed through a TSI Incorporated Single Stage Impactor, Model 3306 (particle size cut-off of 4.7 ⁇ m aerodynamic diameter) and TSI Incorporated Aerodynamic Particle Sizer, Model 3321 (TSI, St. Paul, MN).
  • Non-respirable particles (defined as those > 4.7 ⁇ m aerodynamic diameter) were collected on an impaction plate, while respirable particles (defined as those ⁇ 4.7 ⁇ m aerodynamic diameter) were collected on a glass fiber filter.
  • Nebulized material from the impactor plate and glass filter was extracted into organic solvent and analyzed by HPLC, providing quantitative assessment of fractional delivery of D and H.
  • Mass of nebulized material (Weight of nebulizer + solution prior to initiating nebulization - Weight of nebulizer + remaining solution after nebulization).
  • H+D mass of H+D deposited on the impaction plate, which represents the amount of H+D in the form of particles > 4.7 microns aerodynamic diameter.
  • H+D mass of H+D deposited on the impaction plate, which represents the amount of H+D in the form of particles ⁇ 4.7 microns aerodynamic diameter.
  • Amount theoretically nebulized Mass of nebulized material multiplied by the total percentage of solids m the starting suspension (which equals 5%).
  • Efficiency of delivery Total mass of H+D nebulized by the device, including material deposited on the plate and filter (Plate (H+D) + Filter (H+D)) divided by the amount theoretically nebulized.
  • DHT 532 A compostion of DPPC, H and tyloxapol in a 5:3:2 ratio (“DHT 532”) was prepared by dissolution of the constituents in warm t-butanol under stirring at a final concentration of 25 mg/mL. The warm solution was filtered through a 0.22 ⁇ m filter and 10 mL were filled into clear 10 mL serum vials and frozen. The frozen solution was lyophilized, sealed and capped.
  • Diarachidoylphosphocholine (DAPC; a phospholipid with a C20 acyl chain) was dissolved in tert-butylalcohol and dried under vacuum to render a powder for resuspension in saline.
  • DAPC DAPC containing hexadecanol and tyloxapol in a ratio of 5:3:2 by mass
  • DAPC containing hexadecanol in a ratio of 1:1 by mass were prepared, resuspended in saline by mixing followed by sonication, and administered via nebulizer to Tight skin (Tsk) mice, a strain with congenital emphysema as a consequence of a mutation in the fibrillin- 1 gene. Results are summarized in Table 7 below. Each test formulation was evaluated in a single test animal to explore whether DAPC prepared in this fashion showed any evidence of beneficial physiological effects.
  • DHT4/9/.25 and 4/9A5 appear to be more effective at reducing static compliance than DHT4/9/1 at both initial and steady state ratios. All three formulations increase dynamic elastance at PEEP 3 and 6 at both initial and steady state ratios. Changes of this type would be expected to produce physiological benefit in patients with emphysema.
  • Aqueous phase components (listed in Table 9 below for each experiment) were mixed and warmed on a hot plate to 70 or 80 0 C with stirring.
  • Oil phase components (listed in Table 9 below for each experiment) were melted together on a hot plate and mixed together.
  • the oil phase was poured into the aqueous phase, and the mixture was homogenized using an IKA Ultra-Turrax homogenizer at its highest setting, about 24,000 RPM. Homogenization of the two component mixture was continued until the particle size, as measured by a Malvern Mastersizer 2000E, remained constant. The homogenization typically required 30 to 60 minutes.
  • the mixture was pumped through a heat exchanger immersed in ice water, which rapidly cooled (residence time of about 1 minute) the mixture to 10 to 20 0 C.
  • the final particle size was then determined. The diameter which is greater than 90 % of the particles, on a mass basis, is reported in Table 9.
  • Experiments 121-101 and 121-121 demonstrates the use of Span 60 and Tyloxapol as excipients.
  • Aerogen nebulizer system Procedures Anesthesia was induced with ketamine 90 mg/kg and xylazine 5 mg/kg IP, and maintained with ketamine 50-100 mg/kg IP Q30-60 min. Animals were tracheostomized with a 14g stainless steel cannula, calibrated for use with a commercially available computer-controlled small animal ventilator system. The animals were mechanically ventilated with RR 150, TV 10 mL/kg. Lung physiology, including quasi-static pressure volume curves (for determining static lung compliance) and dynamic impedance (including measures of dynamic lung elastance and lung resistance measured at 3, 6, and 9 cm H2O PEEP) were measured.
  • mice were euthanized with phenobarbital 100 mg/kg administered intraperitoneally.
  • the abdominal and thoracic organs were inspected.
  • the pulmonary vasculature was flushed with saline via a catheter inserted into the right ventricle.
  • the lungs and heart were removed enbloc and inflated with 10% buffered formalin.
  • Samples of lung, heart, liver, kidney, and spleen were collected and preserved in 10% formalin for histologic processing and microscopic examination.
  • OS reduced static compliance 8.5, 11.1 and 13.7% at 14, 28, and 56 mg/kg, respectively.
  • OTSpan reduced static compliance 4.1, 9.9 and 40.5% at 14, 28, and 56 mg/kg, respectively.
  • the reduction in static compliance with OTSpan at 56 mg/kg was statistically significantly larger than OS at the same dose and OTSpan at lower doses.

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Abstract

La présente invention concerne, dans un aspect, une composition contenant un amphiphile, ladite composition modifiant, lors de l'administration à un poumon d'un mammifère, la tension superficielle du tensioactif pulmonaire, ce qui augmente la rétraction du poumon. Dans un autre aspect, l'invention concerne une composition comprenant un amphiphile et un agent de diffusion, ladite composition modifiant, lors de l'administration à un poumon d'un mammifère, la tension superficielle du tensioactif pulmonaire, ce qui augmente la rétraction du poumon. Dans un autre aspect encore, l'invention concerne une composition mentionnée ci-dessus, contenant en outre un phospholipide. Dans un autre aspect, l'invention concerne un procédé de réduction du volume du poumon ou d'augmentation de la rétraction du poumon par l'administration à un poumon d'un mammifère en ayant besoin d'une quantité thérapeutiquement efficace d'une telle composition.
PCT/US2008/081321 2007-10-26 2008-10-27 Traitement de pneumoréduction et compositions utiles pour celui-ci WO2009055788A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6998410B2 (en) * 1997-02-17 2006-02-14 Altana Pharma Ag Compositions
US20070249572A1 (en) * 2005-12-20 2007-10-25 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6998410B2 (en) * 1997-02-17 2006-02-14 Altana Pharma Ag Compositions
US20070249572A1 (en) * 2005-12-20 2007-10-25 Verus Pharmaceuticals, Inc. Systems and methods for the delivery of corticosteroids

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