AU2013368298A1 - Methods and compositions for administration of oxybutynin - Google Patents

Abstract

The present invention is directed to methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents. Oxybutynin may be selected from the group consisting of, but not limited to, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt, a laurate salt and other salts. The pharmaceutically effective agents comprise bronchodilators, antiinflammatories, corticosteroids, corticosteroid reversal agent or alveolar growth agents or other agents selected from proteinase or protease inhibitors.

Description

WO 2014/105446 PCT/US2013/074759 METHODS AND COMPOSITIONS FOR ADMINISTRATION OF OXYBUTYNIN The present invention relates generally to novel methods of administering oxybutynin, to novel forms of oxybutynin and novel dosage forms containing 5 oxybutynin designed for delivery via the pulmonary route. More specifically, the present invention comprises novel forms of oxybutynin in combination with one or more pharmaceutically effective agents. The invention will be described in particular in connection with pulmonary delivery of oxybutynin for treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), although 10 other uses such as prophylactic, therapeutic or ameliorative treatment of incontinence and intestinal hypermotility, i.e. irritable bowel syndrome, also are contemplated. Oxybutynin is a racemic compound of the chemical formula 4 diethylaminobut- 2-butynyl phenylcyclohexyl-glycolate: CH, 15 Oxybutynin is an anticholinergic medication that traditionally has been used to treat urinary incontinence, urge incontinence, frequency and over-active bladder symptoms of incontinence (hereinafter singly and collectively referred to as "urge urinary incontinence"). Oxybutynin acts by decreasing muscle spasms of the bladder. It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic 20 acetylcholine receptor. It also has weaker direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically. It is available orally in generic formulation and as the chloride salt, and as the brand-names DITROPAN* and DITROPAN XL*, and as a transdermal product as a patch under the brand-name OXYTROL* or as a gel under 25 the brand name GELNIQUETM. 1 WO 2014/105446 PCT/US2013/074759 Oxybutynin currently is administered in oral formulation as a tablet or multiple tablets and a syrup, or transdermally as a patch or topical gel for treating urge urinary incontinence. However, oral delivery of a therapeutically active amount of oxybutynin suffers from a number of disadvantages: 5 (1) Oxybutynin administered in an oral formulation is absorbed from the intestinal track at an undesirably slow and uneven rate with a variable metabolism that leads to undesirable variations in blood levels and undesirably high dosage rates to achieve a therapeutic response leading to undesirable side effects; (2) Oxybutynin administered in an oral formulation does not produce 10 desirably high blood levels in a desirably short period of time; (3) Oxybutynin administered in an oral formation may result in a significant amount not reaching targeted tissues because it is being wasted by metabolism or excretion; (4) Oxybutynin administered in an oral formation is contraindicated for 15 patients with gastrointestinal obstruction disorders because of the risk of urinary retention; and (5) Oxybutynin administered in oral formulation requires chronic dosing with significant and severe side effects, including dry mouth (xerostomia), constipation, mydriasis, blurred vision, drowsiness, nausea, palpitations, tachycardia 20 and dizziness. (6) Oxybutynin administered in the oral formulation is subject to first pass metabolism, resulting in the formation of metabolite N-desethyloxybutynin (DEO) which has been attributed to cause the majority of the aforementioned side effects. As a result, many patients discontinue oral anticholinergic therapy. These 25 adverse effects have been associated with relatively high levels of oxybutynin's primary metabolite, DEO, which circulates in concentrations approximately 4 (oxybutynin ER) to 10 (oxybutynin IR) times that of the parent compound. DEO has been shown to have a greater affinity and binding duration at receptors in the salivary glands than does oxybutynin. In other words, the metabolite DEO has shown to have 30 a higher side effect-to-efficacy ratio than the parent compound oxybutynin. Levels of DEO in oral and transdermal therapy have been reported to be approximately 10-40 ng/mL and 3 ng/mL, respectively. To completely eliminate the side effect concerns 2 WO 2014/105446 PCT/US2013/074759 of this drug, it would be advantageous to decrease the DEO levels in systemic circulation to below those found in current therapies (i.e. below 3 ng/mL). Moreover, there are other disadvantages to current oral administration of oxybutynin, including: 5 (7) Oxybutynin administered in an oral formation is administered as a tablet or multiple tablets which may lack the desirable ease of administration because some people may dislike the swallowing of tablets, or may have difficulty swallowing tablets, or are unable to swallow tablets, or may require a liquid to assist swallowing of tablets; and 10 (8) Oxybutynin-containing tablets also contain several inactive ingredients, including significant amounts of lactose, corn starch, magnesium silicate, magnesium stearate, and talc which may be considered undesirable because some people may dislike or be allergic to one or more of these inactive ingredients that comprise the oxybutynin tablets. 15 Transdermal delivery of oxybutynin has many of the aforesaid disadvantages. Additionally, some patients suffer skin irritation from transdermal patches, have difficulty maintaining and tolerating patch-to-skin contact, or dislike the aesthetics of a transdermal patch. Bronchoconstriction, a hallmark of pulmonary disease such chronic 20 obstructive pulmonary disease and asthma, involves the narrowing of air passages (bronchi and bronchioles) in the lungs due to muscle contraction. Often times the muscle contraction is a result of activation of muscarinic receptors on the membranes of smooth muscle cells. This results in the limitation of air flowing to and from the lung and causes shortness of breath and overall difficulty in breathing. 25 Pulmonary disease includes, but is not limited to, acute bronchitis, acute respiratory distress syndrome (ARDS), asbestosis, asthma, atelectasis, aspergilliosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, byssinosis, chronic bronchitis, coccidiomycosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, eosinophilic pneumonia, hantavirus pulmonary syndrome, 30 histoplasmosis, human metapneumovirus, hypersensitivity pneumonitis, influenza, lung cancer, lymphangiomatosis, mesothelioma, necrotizing pneumonia, nontuberculosis Mycobacterium, pertussis, pleural effusion, pneumoconiosis, 3 WO 2014/105446 PCT/US2013/074759 pneumonia, primary ciliary dyskinesia, primary pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, pulmonary vascular disease, respiratory syncytial virus, sarcoidosis, severe acute respiratory syndrome, silicosis, sleep apnea, sudden infant death syndrome, and tuberculosis. The most common lung diseases 5 generally comprise asthma, bronchitis, COPD, emphysema, and pneumonia. Of all pulmonary diseases, the most prevalent appears to be COPD. According to the World Health Organization estimates in the year 2004, 64 million people had COPD and 3 million people died of COPD. WHO predicts that COPD will become the third leading cause of death worldwide by 2030. The Merck Manual 10 (2011) provides that an estimated 12 million people in the US have COPD and describes COPD as the 4th leading cause of death, resulting in 122,000 deaths in 2003 compared with 52,193 deaths in 1980. From 1980 to 2000, the COPD mortality rate increased 64% (from 40.7 to 66.9/100,000). Prevalence, incidence, and mortality rates increase with age and though prevalence is higher in men, total mortality is 15 similar in both sexes, Incidence and mortality are generally higher in caucasians, blue-collar workers, and people with fewer years of formal education, probably because these groups have a higher prevalence of smoking. COPD is increasing worldwide because of the increase in smoking in developing countries, the reduction in mortality due to infectious diseases, and the widespread use of biomass fuels. 20 Current therapeutic agents for COPD predominately comprise bronchodilators administered via inhalation, including inhaled long-acting beta 2 -agonists (LABA) or long acting muscarinic antagonists (LAMA). Although oxybutynin is a LAMA, no effective pharmaceutical form, or method of administration has heretofore been developed to treat COPD using oxybutynin. Many diseases of the respiratory tract are 25 known to respond to treatment by the direct application of therapeutic agents. As these agents are most readily available in dry powdered form, their application is most conveniently accomplished by inhaling the powdered material through the nose or mouth. This powdered form can result in the better utilization of the medicament in that the drug is deposited exactly at the site desired and where its action may be 30 required; hence, very minute doses of the drug are often equally as efficacious as larger doses administered by other means, with a consequent marked reduction in the incidence of undesired side effects and medicament cost. In addition, a drug in dry 4 WO 2014/105446 PCT/US2013/074759 powder form may be used for treatment of diseases other than those of the respiratory or pulmonary system. When the drug is deposited on the very large surface areas of the lungs, it may be very rapidly absorbed into the blood stream; hence, this method of application may take the place of administration by injection, tablet, or other 5 conventional means. Although some forms of oxybutynin hydrochloride compositions have been contemplated for administration in dry powder form, no such forms have yet been successfully reduced to practice. There remains a need for oxybutynin therapeutic compositions that are clinically effective and having the appropriate physiochemical 10 properties. Thus, there is a need for improved delivery of oxybutynin, which will provide enhanced bioavailability, minimized variations in blood levels, and achieve more rapid onset of activity, as compared to oral dosage or transdermal dosage forms, while at the same time providing relative ease of administration and reduced side effects 15 compared to current oral and transdermal delivery methods for administering oxybutynin. The foregoing and other objects of the invention are achieved by providing methods and compositions for pulmonary delivery of oxybutynin to a mammalian host, particularly a human patient, whereby to provide for rapid absorption of 20 oxybutynin while avoiding the above and other disadvantages of oral and transdermal administration. More specifically, the present invention relates to novel dosage forms and compositions of oxybutynin for treating pulmonary and respiratory diseases, including but not limited to, chronic obstructive pulmonary disease and asthma. In certain embodiments, the present invention is also related to improving underlying 25 physiological dysfunction contributing to pulmonary disease. The present invention provides effective administration of therapeutic agents to specific airways of the lungs by utilizing controlled site delivery. More particularly, it has been discovered herein that oxybutynin-containing compositions can be usefully administered to mammals by pulmonary delivery at 30 lower dosage levels to elicit a therapeutic response with a marked reduction in systemic metabolites. It is understood that the major contributor to the untoward effects of oxybutynin therapy is systemic levels of the metabolite, DEO. An 5 WO 2014/105446 PCT/US2013/074759 increased contribution of DEO toward side effects is due to its greater affinity toward receptors in non-targeted tissues, i.e. salivary glands. In addition, this invention can provide enhanced bioavailability, achieve more rapid onset of activity, and ease of administration, as compared to conventional oral and transdermal methods of 5 administration, for treating urinary incontinence. Pulmonary delivery of oxybutynin provides relief for treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, as well as relief for treating both urinary incontinence and for treating stress urinary incontinence, as well as intestinal hypermotility, i.e. irritable bowel syndrome. The present invention also provides novel forms of 10 oxybutynin as well as novel dosage forms and treatment protocols for administering oxybutynin. Further features and advantages of the present invention will be seen from the following detailed description, taken in conjunction with accompanying drawings, in which: 15 Figure 1 plots inhibition of methacholine induced bronchoconstriction of oxybutynin and oxybutynin salts at 18 hours. More particularly, changes in bronchoconstriction for oxybutynin treated animals were compared the time matched lactose control animals using ANOVA followed by Dunnetts test. ** P<0.01. Figure 2 compares inhibition of methacholine induced bronchoconstriction by 20 oxybutynin, oxybutynin salts, tiotropium and glycopyrrolate at 18 hours and 24 hours. More particularly, Figure 2 plots a comparison of the bronchoconstriction evoked by methacholine (MCh, 10 pg/kg, iLv.) 18, and 24 h after lactose (2 mg, i.t., n=6), oxybutynin base (2 mg, i.t., n=6), oxybutynin HCI (2.5 mg, i.t., n=6), oxybutynin xinafoate (3 mg, i.t., n=6), tiotropium (1 mg/kg, i.t., n=6) or glycopyrrolate (1 mg/kg, 25 i.t., n=6) administration. Each bar represents the mean value and the vertical lines show s.e. mean. Changes in bronchoconstriction for oxybutynin or tiotropium treated 6 WO 2014/105446 PCT/US2013/074759 animals (anaesthetized guinea pigs) were compared the time matched lactose control animals using ANOVA followed by Dunnetts test. ** P<0.01. Figure 3 is a series of graphs comparing changes from control response evoked by methacholine over time by oxybutynin xinafoate and tiotropium in 5 pulmonary inflation pressure, mean arterial blood pressure and heart rate. More particularly, Figure 3 plots a comparison of the changes from the control response evoked by methacholine (10 ig kg 1 , i.v.) over time (h) in the presence of lactose (i.t., n=6), oxybutynin xinafoate (7.5% w/w, i.t., n=6), or tiotropium (1 mg, it., n=6) in pulmonary inflation pressure (PIP), mean arterial blood pressure (MAP) and heart rate 10 (HR). Each point represents the mean value and the vertical bars show s.e. mean. Percentage changes in oxybutynin or tiotropium treated animals were compared to the respective lactose control animals (anaesthetized guinea pigs) using ANOVA followed by Dunnetts test. * P<0.05, ** P<0.01. Figure 4 shows pharmacokinetics of pulmonary administration of oxybutynin 15 over time. More particularly, Figure 4 plots anaesthetized guinea pig (n=5) pharmacokinetic profile of Oxybutynin, Oxybutynin enatiomers, and major metabolite (desethyloxybutynin ) following dry powder insufflation. Figures 5 and 6 provide IH NMR and FT-IR structure analysis. Figure 7 provides HPLC analysis. 20 Figure 8 and 9 provide crystallinity, compound purity, and melting point determined by XRPD and DSC. The present invention may be understood more readily by reference to the following detailed description of the specific embodiments included herein. Reference is made to the accompanying drawings, which form a part hereof, and in 25 which is shown, by way of illustration, various embodiments of the present disclosure. Although the present invention has been described with reference to 7 WO 2014/105446 PCT/US2013/074759 specific details of certain embodiments thereof, it is not intended that such details should be regarded as limitations upon the scope of the invention. The entire text of the references mentioned herein are hereby incorporated in their entireties by reference including United States Patent Application Serial No. 12/904,964 filed 5 October 14, 2010, and Application Serial No. 12/130,903, filed May 30, 2008. Also incorporated by reference is United States Patent Application Serial No. 13/246,686 filed September 27, 2011. Pulmonary delivery of oxybutynin to the respiratory tract can be used advantageously to treat respiratory disease, urge urinary incontinence and symptoms 10 of stress urinary incontinence. Unlike conventional oral and transdermal delivery of oxybutynin which require chronic dosing with significant side effects and require hours to reach therapeutically active blood levels, dry powder pulmonary delivery of oxybutynin permits a patient to enjoy relief at significantly lower doses with concomitant reduction in side effects such as dry mouth. Dry powder pulmonary 15 delivery of oxybutynin also permits a patient to enjoy relief from symptoms of stress urinary incontinence on a more immediate or as-needed basis. Similarly, dry powder pulmonary delivery of oxybutynin permits a patient to achieve prophylactic relief from symptoms of respiratory distress or on an as needed basis. A feature and advantage of the present invention that results from pulmonary 20 delivery of oxybutynin is that the typical primary metabolite formation of DEO is largely avoided as are the adverse side effects resulting therefrom as above mentioned. Additionally, we have found that certain salts of oxybutynin, when administered via pulmonary delivery result in a significantly longer acting efficacy 25 effect than anticipated given that the oral half life is only 2.5 hours. These salts include a novel salt form of oxybutynin, namely the xinafoate salt of oxybutynin which heretofore has not been reported in the literature. For example, all dosing of oxybutynin is typically three times daily due to a relatively short half-life of 2.5 hours with minimal plateau levels of drug remaining at approximately eight (8) hours. On 30 the other hand, pulmonary delivery of a salt of oxybutynin unexpectedly provides a duration of activity in guinea pig lungs of up to 18 hours which would translate into one to twice daily human dosing. This is illustrated in Fig. I attached. 8 WO 2014/105446 PCT/US2013/074759 The xinafoate salt of oxybutynin is prepared by reacting oxybutynin with xinafoic acid in methyl iert-butyl ether under an inert (nitrogen) atmosphere. Other salts of oxybutynin that advantageously can be administered by pulmonary delivery include palmitate, pamoic, resinate, laurate and stearate salts and also esters of 5 oxybutnin, and can provide unexpected results of improved half-life as well as reduced adverse metabolite production. In selecting a preferred configuration of oxybutyin for therapeutic administration, the inventors herein contemplated several properties of various oxybutynin salts, including but not limited to the following: 10 Solubility -> PK, bioavailability, and changes in dissolution rate. - Surface energy -> aerosolization (dispersibility), physical stability (of particles) Hydration state -> stability, solubility - Kinetics of degradation -> stability 15 - Crystal hardness -> micronization, physical stability - Hygroscopicity -> handling, stability - Dissolution - Melting point - Dosage form to be developed 20 - Route of administration - Loading in dosage form - Toxicology of counterions, especially pulmonary toxicology As a free base, oxybutynin is poorly soluble and lipophilic, having an aqueous solubility and Log P of 0.01 mg/mL and 3.3, respectively. To improve drug 25 solubility, oral oxybutynin was formulated as a hydrochloride salt, improving the gastric solubility to 20 mg/mL (measured at pH 4) (see US Patent No. 6,087,396). For the purposes of pulmonary delivery, the inventors herein developed an alternate strategy where a less soluble, more lipophilic salt form was engineered. It has been noted previously that a slow dissolution rate and potential for lipophilic binding in 30 vivo may prolong drug retention in the lung and delay absorption into systemic circulation. The corticosteroids triameinolone acetonide and fluticasone propionate have shown mean absorption times in the lungs of 2.9 hours and 5-7 hours, 9 WO 2014/105446 PCT/US2013/074759 respectively (Patton (2007) Nature Reviews in Drug Discovers, V6, p67- 74 ). To increase the potential for lung retention, the xinafoic acid (xinofoate) salt of oxybutynin was synthesized. Other lipophilic salts, such as stearates and palmitates were attempted; however, it was experimentally determined that the thermodynamic 5 driving force indicated by the difference in pKa of oxybutynin and xinafoic acid (8.24 vs. 2.7) would more likely result in salt formation. Before conducting salt synthesis studies, the solubility of oxybutynin in various organic solvents was evaluated (Table 1). These solubility studies indicated a number of potential solvents to use during salt synthesis; however, only methyl tert 10 butyl ether (MTBE) produced crystalline salt and acceptable yields. The synthesis and crystallization methods were adapted from a method used to synthesize oxybutynin hydrochloride (US Patent No. 6,140,529). In the patented method, ethanol is added to MTBE to precipitate salt crystals; however, since the xinafoate salt is likely much less soluble than the hydrochloride, water was used to induce 15 precipitation of oxybutynin xinafoate. The results and specifications of all salt synthesis experiments are summarized in Table 2. Example 3 provides a description of the process used for synthesizing oxybutynin xinafoate salt. Table 1: Oxybutynin Solubility in Various Organic Solvents Solvent Solvent Oxybutynin Solvent Temp (C) Result Class Wt (mg) Volumes THF 11 20A4 23 Solubie Methy THF 18.4 5 23 Soluble i-PrOAc HI 20. 5 23 Soluble EtOAc III 19.5 5 23 Soluble Soluble; MTBE Ill 213.7 30 Slbc M No recrystallization Toluene22.0 3 Soluble: Ethanol 21.9 5 31 No recrystallization Soluble; 2-Propanol Ill 20.8 No recrystallization Acetone III 20.8 5 3 Souble - Il 0 -85 23 Soluble 20 --- ethanol I 1 5 23 Soluble 10 WO 2014/105446 PCT/US2013/074759 Table 2: Salt Synthesis Experiments Preferred embodiments of the present invention comprise methods and compositions for treating pulmonary disease comprising delivering directly to a 5 patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents. In certain embodiments, the oxybutynin and the pharmaceutically effective agent(s) are delivered in dry powder form. The dry powder oxybutynin may be selected from the group consisting of, but not limited to, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt, a laurate 10 salt and other salts. Pharmaceutically effective agents comprise bronchodilators, antiinflammatories, corticosteroids, corticosteroid reversal (CR) agents, alveolar growth agents or other agents selected from proteinase or protease inhibitors. In certain preferred embodiments, the bronchodilators comprise long-acting and short-acting beta agonists and derivatives or pharmaceutically acceptable salts 15 thereof. The anti-inflammatories may include inhaled corticosteroids, phosphodiesterase inhibitors or leukotriene receptor antagonists. Furthermore, the corticosteroids may comprise budesonide, fluticasone, beclomethasone, flunisolide, 1 I WO 2014/105446 PCT/US2013/074759 mometasone, triamcinolone, ciclesonide, loteprednol, fluorometholone, and derivatives or pharmaceutically acceptable salts thereof. Alternative embodiments may optionally comprise corticosteroid reversal agent comprising vitamin D, synthetic vitamin D, vitamin D analogs, vitamin D 5 receptor agonists, vitamin D receptor partial agonists, calcitriol, antioxidants, iNOS inhibitors, Phosphoinositide-3-kinase-.delta. inhibitors, p38 MAP kinase inhibitors, JNK inhibitors, MIF inhibitors, low-dose theophylline, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, statins, and equivalents thereof. In addition, the alveolar growth agents may comprise vitamin A, All Trans Retinoic Acid (ATRA), 10 retinoic acid receptor (RAR) agonists and RAR selective alveolar growth agents, RAR selective agonists, palovarotene and equivalents thereof. In preferred embodiments, the present invention comprises methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with 15 a LABA wherein the oxybutynin is present in the form of oxybutynin xinofoate and the LABA is selected from the group including, but not limited to, formoterol, salmeterol, odalaterol, carmoterol, vilanterol. In alternatively preferred embodiments, the present invention comprises methods and compositions for treating pulmonary disease comprising delivering 20 directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with a LABA wherein the oxybutynin is present in the form of oxybutynin xinofoate and the LABA is selected from the group including, but not limited to, formoterol, salmeterol, odalaterol, carmoterol, vilanterol and further comprising an inhaled corticosteroid (ICS) wherein the ICS comprises budesonide, 25 fluticasone, mometasone, or additionally, a selective agent selected from the 'soft steroid' class, for instance, ciclesonide or loteprednol. In alternatively preferred embodiments, the present invention comprises methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in 30 combination with a LABA, and further comprising a CR reversal agent wherein the oxybutynin is present in the form of oxybutynin xinofoate, the LABA is selected from the group including, but not limited to, formoterol, salmeterol, odalaterol, carmoterol, 12 WO 2014/105446 PCT/US2013/074759 vilanterol and the CR reversal agent is selected from the group including, but not limited to, vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and antagonists, calcitol and equivalents thereof. In alternatively preferred embodiments, the present invention comprises 5 methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with a LABA, a CR reversal agent, and further comprising an ICS, wherein the oxybutynin is present in the form of oxybutynin xinofoate; the LABA is selected from the group including, but not limited to, formoterol, salmeterol, 10 odalaterol, carmoterol, vilanterol; the CR reversal agent is selected from the group including, but not limited to, vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and antagonists, calcitol and equivalents thereof; and the ICS is selected from the group including, but not limited to, budesonide, fluticasone, mometasone, or additionally, a selective agent selected from the 'soft steroid' class. 15 In alternatively preferred embodiments, the present invention comprises methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with a LABA, an alveolar growth agent, wherein the LABA comprises formoterol and the alveolar growth agent is selected from the group including, but not 20 limited to, ATRA, cis-retionoic acid and palovarotene. The above embodiments may be delivered using a dry powder inhaler (DPI), a DPI comprising a piezo vibrator, metered dose inhaler (MDI) or liquid nebulizer. In addition, the therapeutic compositions of the above-described embodiments may be delivered in dry powder form having a mass median aerodynamic particle size 25 selected from the group consisting of 0.5 - 20 microns, 0.5 - 15 microns, 0.5 - 10 microns, or 0.5 - 5 microns. The dosages of the therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents is within the range of 0.001 to 20 mg per day, 0.02 to 15 mg per day, or 0.05 to 10 mg per day administered as needed. 30 13 WO 2014/105446 PCT/US2013/074759 Terms and Definitions As used herein, the term "oxybutynin" is intended to encompass not only oxybutynin as an anhydrous powder, but any salt or derivative of oxybutynin having antispasmodic, anticholinergic activity like oxybutynin, and which is non-toxic and 5 pharmacologically acceptable, for example, oxybutynin xinafoate or oxybutynin hydrochloride. Other suitable salts include but are not limited to the palmitate, pamoic, resonate and laurate salts. "An effective amount," as used herein, is an amount of the pharmaceutical composition that is effective for treating pulmonary disease, urinary incontinence or 10 irritable bowel syndrome i.e., an amount of oxybutynin of a defined aerodynamic particle size suitable for absorption in the lungs, that is able to reduce or eliminate the symptoms of COPD, asthma, urinary and stress incontinence. "A pharmaceutical composition," as used herein, means a medicament for use in treating a mammal that comprises oxybutynin in a dry powder form of a defined 15 aerodynamic particle size prepared in a manner that is suitable for pulmonary administration to a mammal. A pharmaceutical composition according to the invention may also, but does not of necessity, include a non-toxic pharmaceutically acceptable carrier. "A defined aerodynamic particle size," as used herein, means particles having 20 a size sufficiently small so as to be delivered to the lungs. For optimal delivery to the lungs, the dry powder form of the oxybutynin preferably should be micronized or spray dried to a mass median aerodynamic diameter powder size of 0.05 - 20 microns, 0.5 - 15 microns, 0.5 - 10 microns, or 0.5 - 5 microns. However, other methods for producing controlled size particles, e.g. supercritical fluid processes, 25 controlled precipitation, etc., also advantageously may be employed. "A therapeutically effective amount" as used herein will vary with the age, weight and general physical condition of the individual, frequency of dosing, severity of COPD, asthma, incontinence, and whether urge or stress incontinence, or irritable bowel syndrome is being treated. Generally for treating respiratory diseases, a 30 therapeutically effective amount will comprise the active ingredient in a quantity of from 0.001 to 20 mg per day, 0.02 to 15 mg per day, or 0.05 to 10 mg per day, administered as needed. Generally, for treating urge incontinence, a therapeutically 14 WO 2014/105446 PCT/US2013/074759 effective amount will comprise the active ingredient in a quantity of from 1 to 20 mg/day, preferably I to 10 mg/day. The active ingredient may be given once a day. Preferably, however, the active ingredient will be administered in smaller doses two or three or more times a day to maintain more consistent plasma levels. When used 5 for treating stress incontinence, or irritable bowel syndrome, a therapeutically amount will comprise the active ingredient in a quantity of from 0.1 to 15 mg per day, preferably 0.2 to 10 mg/day, generally administered as a single dose, or as needed. The active ingredient may be given once a day. Preferably, however, the active ingredient will be administered in smaller doses two or three or more times a day to 10 maintain more consistent plasma levels. The oxybutynin may be delivered in dry powder form, e.g. via a dry powder inhaler (DPI), metered dose inhaler (MDl), or dissolved in a suitable liquid for nebulization in a therapeutically effective unit dose delivery amount. For treating acute symptoms of respiratory distress, a dose of oxybutynin should be taken at the 15 first sign of respiratory distress. For treatment of chronic respiratory distress, oxybutynin should be taken daily according to a regimen recommended by a physician. Similarly, treating symptoms of stress urinary incontinence, a dose of oxybutynin should be taken at the first sign of stress, or upon onset of the first sign of urgency or just prior to anticipated onset of stress, e.g. just before a patient is 20 scheduled to talk in front of an audience. In a preferred embodiment of the invention, the dry powder oxybutynin is packaged for delivery in a piezo-electronic dry powder inhaler such as described in U.S. Patent No. 6,026,809. The terms "fine drug particles," and "aerodynamic particle size" as used herein, mean particles having a size sufficiently small so as to be delivered to the airways of the lungs, and especially 25 to the small airways. For optimal delivery to the lungs, the dry powder form of the therapeutic agents described herein preferably should be micronized, spray dried, or engineered to a maximum aerodynamic particle size in the range of 0.01 pm to 20 pm, from 0.25 pim to 5 pim, or from 0.5 pm to 4 pm. As used herein, the term "agent for reversal of CR" is intended to encompass 30 any agent that when administered at an effective level will increase the anti inflammatory response induced by a corticosteroid. This term applies not only agents for reversal of CR, but any salt or derivative of said agent having activity to reverse 15 WO 2014/105446 PCT/US2013/074759 CR, and which is non-toxic and pharmacologically acceptable. As used herein, CR reversal agents, include but are not limited to, vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and antagonists, calcitol, theophylline and equivalents thereof. Also included are CR reversal agents 5 known to those skilled in the art. As used herein, the term "vitamin D" is intended to encompass vitamin D, vitamin D2, vitamin D3, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and antagonists, calcitriol, calcitol and equivalents thereof. As used herein, the term "vitamin A" is intended to encompass those agents 10 that interact with Retinoic Acid Receptor (RAR) including but not limited ATRA, ATRA derivatives, RAR agonists, 13-cis Retinoic acid and RAR selective agonists for example, palovarotene. As used herein, the term "alveolar growth agent' is intended to encompass any agent that promotes the growth of new alveoli via the retinoic acid receptor, and 15 includes ATRA or RAR selective agent therapy. As used herein, the term "alveolar maintenance agent" is intended to encompass any agent that when administered at an effective level will increase the anti-inflammatory response induced by COPD, COPDe and emphysema and any undesirable effects of ATRA or RAR selective agent therapy. This term applies not 20 only to agents for alveolar maintenance, but any salt, hydrate, prodrug or derivative of said agent having similar activity, and which is non-toxic and pharmacologically acceptable. As used herein, bronchodilating substances include, but are not limited to, beta2-agonists (short and long acting, LABA), long acting muscarinic antagonists 25 (LAMA), anticholinergics (short acting), and theophylline (long acting). "Co administered," as used herein, means to deliver more than one pharmaceutical or therapeutic agent, for example, both corticosteroid and agent for reversal of CR as an aerosol within the same breath via the pulmonary route. "An effective amount," as used herein, is an amount of the pharmaceutical 30 composition that is effective for achieving a desired therapeutic effect, including but not limited to bronchodilation, CR reversal, anti-inflammation, alveolar regrowth. For example, 16 WO 2014/105446 PCT/US2013/074759 an effective amount of an agent for reversal of CR may comprise the specified amount of calcitriol, within a defined aerodynamic particle size range suitable for absorption in the lungs, that is able to reduce or eliminate the resistance to corticosteroids. 5 As used herein, "pharmaceutical" and "therapeutic" agents include but are not limited to any and all medicaments and pharmaceutical agents and formulations that may be administered for the treatment of pulmonary disease, including agents for preventing disease and including agents for maintaining improvement of disease condition. As used herein, such therapeutic and pharmaceutical agents include, but 10 are not limited to, corticosteroids, muscarinic antagonists, macrolides, and non steroidal anti-inflammatory drugs (NSAIDs), antioxidants, iNOS inhibitors, phosphoinositide-3-kinase-6 inhibitors, p38 MAP kinase inhibitors, JNK inhibitors, MIF inhibitors, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, and vitamin D, synthetic vitamin D, vitamin D analogs, calcitiol, vitamin A, All Trans 15 Retinoic Acid (ATRA), retinoic acid receptor (RAR) agonists, RAR selective alveolar growth agents, budesonide, fluticasone, beclomethasone, flunisolide, triamcinolone, mometasone, ciclesonide, loteprednol, fluorometholone as well as any derivative, equivalent or pharmaceutically acceptable salt thereof. A "pharmaceutical" or "therapeutic" composition as used herein, means a 20 medicament for use in treating a patient, for example, an agent for reversal of CR in a dry powder form of a defined aerodynamic particle size prepared in a manner that is suitable for pulmonary administration to a patient. A pharmaceutical composition according to the invention may optionally, include a non-toxic pharmaceutically acceptable carrier. In certain embodiments "pharmaceutical" or "therapeutic" 25 composition may comprise a singular entity (i.e. calcitriol alone), or a combination of compositions selected from the group consisting of CR reversal agents, anti inflammatory agents, bronchodilators, alveolar growth agents, and others. It should be emphasized that the above-described embodiments of the present device and process, particularly, and "preferred" embodiments, are merely possible 30 examples of implementations and merely set forth for a clear understanding of the principles of the disclosure. All these and other such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the 17 WO 2014/105446 PCT/US2013/074759 following claims. Therefore the scope of the disclosure is not intended to be limited except as indicated in the appended claims. The following specific examples will illustrate the invention as it applies to the methods of treatment using the inhaler. It will be appreciated that other examples, 5 including minor variations in procedures will be apparent to those skilled in the art, and that the invention is not limited to these specific illustrated examples. EXAMPLES Example 1 Micronization of Oxybutynin 10 Oxybutynin in crystalline form is micronized to a median aerodynamic particle size of less than 10 microns. The powder is packaged in a dry powder inhaler (DPI) made in accordance with U.S. Patent No. 6,026,809. Example 2 Micronization of Oxybutynin Chloride 15 Example I was repeated, using micronized oxybutynin chloride of median aerodynamic particle size of less than 5 microns in place of oxybutynin. Example 3 Preparation of Oxybutynin Xinafoate Example 1 was repeated, using micronized oxybutynin xinafoate salt of 20 maximum aerodynamic particle size of about 10 microns in place of oxybutynin. The oxybutynin xinafoate salt was prepared by as follows: A 250 mL, round-bottom flask was equipped with a magnetic stirrer, a thermocouple, and a nitrogen-inlet adapter. Under nitrogen, the flask was charged with oxybutynin (20.04 g, 0.056 mol.), xinafoic acid (10.69 g. 0.057 mol. 1.02 equiv, and methyl tert-butyl ether (100 mL, 5 vol). 25 The solids dissolved almost immediately at approximately 18'C. The batch was warmed to 50'C, and at approximately 21'C, crystallization started. The mixture was maintained at 50'C for one hour, was cooled to 33'C in air, and then in an ice bath to 3*C. The mixture was maintained at <5*C for one hour and was filtered, and the filter cake was washed with methyl tert-butyl ether (100 mL). The wet cake was dried in a 30 vacuum oven at 45'C for one hour. After salt synthesis, structure was confirmed by I H NMR and FT-IR (Figures 5 and 6). HPLC analysis confirmed >99% potency through quantification of AUC at 18 WO 2014/105446 PCT/US2013/074759 15.1 min (Figure 7). Crystallinity, compound purity, and melting point were also determined by XRPD and DSC (Figure 8 and 9). Both tests indicated a highly crystalline substance (DSC detected no cold crystallization) with a melting point of 105 'C. Water content was determined to be 0.057% by KF titration. 5 Example 4 Comparative Effects of Bronchodilators Example 1 was repeated, using micronized oxybutynin base, oxybutynin hydrochloride salt, and oxybutynin xinafoate salt of maximum aerodynamic particle size of about 10 microns in place of oxybutynin. The level of bronchodilator activity 10 of oxybutynin was compared to Tiotropium and Glycopyrrolate 18 and 24 hours after administration in anaesthetized guinea pigs. Figs. I and 2 shows comparative effects of pulmonary delivery of oxybutynin on anaesthetized guinea pigs. Example 5 Comparative Effects of Bronchodilators: Oxybutynin Xinofoate and Others 15 Example I was repeated, using micronized oxybutynin xinafoate salt of maximum aerodynamic particle size of about 10 microns in place of oxybutynin. The onset of action and resulting systemic levels of oxybutynin xinafoate was compared to Tiotropium for the first 6 hours after administration in anaesthetized guinea pigs. Fig. 3 compares effects of pulmonary delivery of oxybutynin to Tiotropium on 20 anaesthetized guinea pigs in the initial 6 hours after administration. Oxybutynin showed similar protection against methacholine induced airway constriction as Tiotropium; however, did not have as significant an influence on cardiovascular conditions. Fig 4 shows the resulting pharmacokinetics of pulmonary administration of oxybutynin. Systemic levels of DEO resulting from pulmonary delivery were 25 below the LOQ of the detection method and much lower than clinically relevant levels. Changes may be made without departing from the spirit and scope of the above-described invention. For example, the oxybutynin may be co-administered with other compounds or agents for reducing adverse side effects or to treat the side 30 effect. For example, cholinergic agonists such as described in PCT USO9/034018 may be co-administered with the oxybutynin to reduce the effect of dry mouth. Conclusion 19 WO 2014/105446 PCT/US2013/074759 Delivery of micronized particles of oxybutynin directly to the lungs, as needed, could be found to provide relief to patients suffering from respiratory diseases such as asthma and COPD, and also from urge urinary incontinence and symptoms of stress urinary incontinence and irritable bowel syndrome. 5 In a guinea pig model of bronchoconstriction, oxybutynin was found to have a significantly bronchoprotective effect from 0.25 to 24 hours without a prolonged significant effect on arterial pressure and heart rate. Pulmonary administration of oxybutynin also avoids significant formation of the first-pass primary metabolite DEO and thus significantly reduces adverse side 10 effects which traditionally have been associated with administration of oxybutynin via oral or transdermal delivery. Additionally, dosage amounts of oxybutynin administered via pulmonary delivery route are significantly lower than dosage amounts of oxybutynin when delivered via oral or transdermal delivery routes. Furthermore, pulmonary delivery of oxybutynin results in prolonged therapeutic 15 levels in the lungs which would permit once or twice daily dosing compared to oral delivery of oxybutynin which typically is administered three times daily. While the invention has been described in detail herein in accordance with certain preferred embodiments thereof, many modifications and changes therein may be affected by those skilled in the art. Accordingly, it is intended that the appended 20 claims cover all such modifications and changes as may fall within the spirit and scope of the invention. 20

Claims (15)

1. A method for treating pulmonary disease comprising delivering directly to a 5 patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents.

2 The method according to claim 1, wherein oxybutynin and/or pharmaceutically effective agent is delivered in dry powder form.

3. The method according to claim I or claim 2, wherein the dry powder 10 oxybutynin is selected from the group consisting of a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt and a laurate salt.

4. The method according to claim I or claim 2, wherein oxybutynin comprises oxybutynin xinafoate.

5. The method of any of claims 1-4, wherein the pharmaceutically effective 15 agents comprise bronchodilators, antiinflammatories, corticosteroids, inhaled corticosteroid, corticosteroid reversal agents, alveolar growth agents, proteinase inhibitors, or protease inhibitors.

6. The method of claim 5, wherein the pharmaceutically effective agent is selected from bronchodilators comprising long-acting beta agonists and short-acting 20 beta agonists and derivatives or pharmaceutically acceptable salts thereof, or inhaled corticosteroids, phosphodiesterase inhibitors or leukotriene receptor antagonists, or corticosteroids comprising budesonide, fluticasone, beclomethasone, flunisolide, triamcinolone, ciclesonide, loteprednol, fluorometholone, and derivatives or pharmaceutically acceptable salts thereof, or corticosteroid reversal agent comprising 25 vitamin D, synthetic vitamin D, vitamin D analogs, vitamin D receptor agonists, vitamin D receptor partial agonists, calcitriol, antioxidants, iNOS inhibitors, Phosphoinositide-3-kinase-.delta. inhibitors, p38 MAP kinase inhibitors, JNK inhibitors, MIF inhibitors, low-dose theophylline, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, statins and equivalents thereof, or an alveolar 30 growth agent comprising vitamin A, All Trans Retinoic Acid (ATRA), retinoic acid receptor (RAR) agonists and RAR selective alveolar growth agents, RAR selective agonists, palovarotene and equivalents thereof. 21 WO 2014/105446 PCT/US2013/074759

7. The method of claim 6, wherein the oxybutynin comprises oxybutynin xinofoate, and the long-acting beta agonist comprises formoterol, salmeterol, odalaterol, carmoterol or vilanterol.

8. The method of claim 7, further comprising an inhaled corticosteroid wherein the 5 inhaled corticosteroid comprises budesonide, fluticasone, or mometasone, and optionally further comprising a selective agent selected from a soft steroid class, wherein the soft steroid class comprises ciclesonide or loteprednol and/or a CR reversal agent, wherein the CR reversal agent is selected from the group consisting of vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and 10 antagonists, calcitol and equivalents thereof.

9. The method of claim 1, wherein the oxybutynin comprises oxybutynin xinofoate, the pharmaceutically effective agents comprise a long-acting beta agonist comprising formoterol, 15 and an alveolar growth agent selected from the group consisting ATRA, cis retionoic acid and palovarotene.

10. The method of any of claim 1-9, wherein the pulmonary disease comprises asthma, atelectasis, bronchitis, chronic obstructive pulmonary disease, emphysema, lung cancer, pneumonia or pulmonary edema. 20

11. The method of claim 1, wherein the pulmonary disease comprises chronic obstructive pulmonary disease, wherein the oxybutynin comprises oxybutynin xinofoate, and wherein the pharmaceutically effective agents comprise long acting muscarinic antagonists. 25

12. The method according to any of claims 1-11, wherein oxybutynin and the pharmaceutically effective agent is delivered using a dry powder inhaler (DPI) or a metered dose inhaler (MDI) or liquid nebulizer.

13. The method according to claim 12, wherein the dry powder inhaler includes a piezo vibrator. 30

14. The method according to any of claims 1-13, wherein oxybutynin is delivered in dry powder form having a mass median aerodynamic particle size selected from the group consisting of 0.5 - 20 microns, 0.5 - 15 microns, 0.5 - 10 microns, or 0.5 - 5 22 WO 2014/105446 PCT/US2013/074759 microns, and/or wherein the dosage of the therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents is within the range of 0.001 to 20 mg per day, 0.02 to 15 mg per day, or 0.05 to 10 mg per day administered as needed. 5

15. A method for treating chronic obstructive pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents, wherein oxybutynin preferably is selected from the group consisting of a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt and a laurate salt. 10 23