JP2016504358A - Methods and compositions for administering oxybutynin - Google Patents

Abstract

The present invention relates to methods and compositions for treating pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin directly to the lungs of a patient in combination with one or more pharmaceutically effective substances. The oxybutynin may be selected from the group consisting of, but not limited to, xinafoate, palmitate, pamoate, resinate, laurate and other salts. Said pharmaceutically effective substances include bronchodilators, anti-inflammatory agents, corticosteroids, corticosteroid reversing agents or alveolar proliferating agents or other substances selected from proteinases or protease inhibitors. [Selection] Figure 1

Description

  The present invention relates generally to a novel method of administration of oxybutynin, a novel form of oxybutynin, and a novel dosage form containing oxybutynin designed for delivery by the pulmonary route. More specifically, the present invention includes novel forms of oxybutynin in combination with one or more pharmaceutically effective substances. The present invention is described with respect to pulmonary delivery of oxybutynin, particularly for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), but incontinence and hyperintestinal motility, ie prevention of irritable bowel syndrome Other uses are also contemplated, such as therapeutic, therapeutic or ameliorative treatments.

Oxybutynin is a racemic compound of the chemical formula 4-diethylaminobut-2-butynyl phenylcyclohexyl-glycolate.

  Oxybutynin has long been used to treat urinary incontinence, urge urinary incontinence, frequent incontinence and overactive bladder symptoms (hereafter individually and collectively referred to as “urge urinary incontinence”) It is an anticholinergic drug. Oxybutynin works by reducing bladder muscle spasms. It competitively antagonizes the M1, M2 and M3 subtypes of muscarinic acetylcholine receptors. It also has a weak direct antispasmodic effect on bladder smooth muscle as a calcium antagonist and local anesthetic at concentrations far beyond those used clinically. It is a generic formulation orally, as a chloride salt, as brand names DITROPAN® and DITROPAN XL®, and as a transdermal formulation, as a patch under the brand name OXYTROL®, or as a brand name It is available as a gel called GELNIQUE (registered trademark).

Oxybutynin is currently administered in oral formulations as a tablet or tablets and syrup, transdermally as a patch or topical gel to treat urge incontinence. However, oral delivery of therapeutically effective amounts of oxybutynin has a number of disadvantages:
(1) Oxybutynin administered in an oral formulation is absorbed from the intestine at an undesirably slow and non-uniform rate with variable metabolism, which leads to undesired variations in blood levels and undesirably high doses Achieve a therapeutic response that leads to speed and undesirable side effects;
(2) Oxybutynin administered in an oral formulation does not produce the desired high blood concentration in the desired short term;
(3) Oxybutynin administered in an oral formulation may result in a significant amount not reaching the target tissue because it is wasted by metabolism or excretion;
(4) Oxybutynin administered in an oral formulation is contraindicated in patients with gastrointestinal obstruction disorders because of the risk of urinary retention;
(5) Oxybutynin administered as an oral formulation is administered for a long time with serious and severe side effects including dry mouth (dry mouth), constipation, mydriasis, foggy, drowsiness, nausea, motivation, tachycardia and dizziness Need
(6) Oxybutynin administered in an oral formulation undergoes first-pass metabolism and results in the formation of the metabolite N-desethyloxybutynin (DEO) that causes most of the side effects described above.

  As a result, many patients discontinue oral anticholinergic therapy. These side effects were associated with relatively high concentrations of the primary metabolite of oxybutynin (DEO, circulating at concentrations about 4 (oxybutynin ER) to 10 (oxybutynin IR) times the parent compound). DEO has been shown to have greater affinity and duration of binding to receptors in salivary glands than oxybutynin. In other words, the metabolite DEO has been shown to have a higher ratio of side effects to efficacy than the parent compound oxybutynin. The concentration of DEO in oral and transdermal treatment is reported to be about 10-40 ng / mL and 3 ng / mL, respectively. In order to completely eliminate the concern of side effects of this drug, it is desirable to reduce the DEO concentration in the systemic circulation below that observed with current treatments (ie, less than 3 ng / mL).

In addition, there are other disadvantages associated with current oral administration of oxybutynin, including:
(7) Some people don't like to swallow tablets, who have difficulty swallowing tablets, who can't swallow tablets, or liquids that help them to swallow tablets Oxybutynin administered in an oral formulation may lack the desired ease of administration when administered as a single tablet or multiple tablets; and ( 8) Oxybutynin-containing tablets also contain a number of inactive ingredients (including significant amounts of lactose, corn starch, magnesium silicate, magnesium stearate, talc), which are the inactive components that make up oxybutynin tablets Desired because some people dislike one or more ingredients or are allergic It is considered wards.

  Transdermal delivery of oxybutynin has many of the aforementioned disadvantages. In addition, some patients may experience skin irritation from transdermal patches, maintain patch-skin contact, have difficulty withstanding, or dislike the appearance of transdermal patches. .

  Bronchoconstriction (a prominent feature of lung diseases such as chronic obstructive pulmonary disease and asthma) is accompanied by narrowing of the lung airways (bronchi and bronchioles) due to muscle contraction. In many cases, the muscle contraction is the result of activation of muscarinic receptors on smooth muscle cell membranes. This results in restriction of the air flowing into and out of the lungs, causing shortness of breath and overall difficulty breathing.

  Pulmonary diseases are acute bronchitis, acute respiratory distress syndrome (ARDS), asbestosis, asthma, atelectasis, aspergillosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, cotton lung, chronic bronchitis, coccidioides , Chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, eosinophilic pneumonia, hantavirus lung syndrome, histoplasmosis, hismetapneumovirus, hypersensitivity pneumonia, influenza, lung cancer, lymphangiomatosis , Mesotheliosis, necrotizing pneumonia, nontuberculous mycobacteria, pertussis, pleural effusion, pneumoconiosis, pneumonia, primary ciliary dysfunction, primary pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, pulmonary vascular disease , RS virus, sarcoidosis, severe acute respiratory syndrome, silicosis, sleep apnea, sudden infant death syndrome, and tuberculosis. The most common lung diseases usually include asthma, bronchitis, COPD, emphysema, and pneumonia.

  Of all the lung diseases, the most prevalent is thought to be COPD. According to a 2004 estimate by the World Health Organization, 64 million people suffered from COPD and 3 million died from COPD. WHO predicts that COPD will be the third leading cause of death by 2030. According to the Merck Manual (2011), an estimated 12 million people suffer from COPD in the United States, and COPD is the fourth leading cause of death, compared to 52,193 deaths in 1980, compared to 122,000 in 2003. It is described as causing death. From 1980 to 2000, COPD mortality increased by 64% (from 40.7 to 66.9 per 100,000). Prevalence, incidence, and mortality increase with age, and prevalence is higher in men, but overall mortality is similar for both genders. Incidence and mortality rates are generally higher in Caucasians, manual workers, and those with fewer years of formal education. Perhaps because these groups have a high smoking rate. COPD is increasing worldwide due to increased smoking in developing countries, decreased mortality from infectious diseases, and widespread use of biomass fuels.

Current therapies for COPD primarily include bronchodilators administered by inhalation, including inhaled long acting beta ₂ stimulants (LABA) or long acting muscarinic receptor blockers (LAMA). Although oxybutynin is a type of LAMA, an effective pharmaceutical form or administration method for treating COPD using oxybutynin has not been developed so far. Many airway diseases are known to respond to treatment by direct application of therapeutic agents. Since these materials are most readily available in powder form, their use is most conveniently achieved by inhaling the powdered material through the nose or mouth. This powder form can result in better utilization of the drug and the drug is placed exactly where it is desired and where its action may be required; therefore, very small drug dosages Often as effective as higher doses administered by other means, resulting in a significant reduction in the incidence of unwanted side effects and drug costs. In addition, drugs in dry powder form may be used for the treatment of diseases other than the respiratory and pulmonary systems. When a drug is deposited on a very large surface area of the lung, it may be absorbed into the bloodstream very rapidly; thus, this application method is an alternative to administration by injection, tablet or other conventional means. sell.

  Several forms of oxybutynin hydrochloride compositions have been contemplated for administration in dry powder form, but such forms have not yet been successfully implemented. There remains a need for oxybutynin-containing therapeutic compositions that are clinically effective and have appropriate physiochemical properties.

  Thus, compared to oral and transdermal dosage forms, it enhances bioavailability, minimizes changes in blood levels and achieves a more rapid onset of activity, while oxybutynin is There is a need for improved delivery of oxybutynin that can simultaneously provide relatively easy administration and reduced side effects compared to current oral and transdermal delivery methods for administration.

  The foregoing and other objectives of the present invention are to provide rapid absorption of oxybutynin while pulmonary delivery of oxybutynin to mammalian hosts, particularly human patients, thereby avoiding the aforementioned and other disadvantages of oral and transdermal administration. This is accomplished by providing methods and compositions that result in 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 invention also relates to ameliorating the underlying physiological dysfunction that contributes to lung disease. The present invention utilizes controlled site delivery to provide effective administration of therapeutic agents to specific airways of the lung.

  More specifically, it has been discovered that oxybutynin-containing compositions can be usefully administered to mammals by pulmonary delivery at lower dosage levels to elicit therapeutic responses with significant reductions in systemic metabolites. . It is understood that the main cause of the adverse effects of treatment with oxybutynin is the systemic concentration of the metabolite DEO. The large contribution of DEO to side effects is due to its greater affinity for non-target tissues, ie receptors in salivary glands. In addition, the present invention provides increased bioavailability to achieve more rapid onset of activity and ease of administration compared to conventional oral and transdermal administration methods to treat urinary incontinence. can do. Pulmonary delivery of oxybutynin removes anxiety of treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, and both urinary and stress urinary incontinence and intestinal hyperactivity, i.e. irritable bowel syndrome Eliminate treatment anxiety. The present invention also provides novel forms of oxybutynin and novel dosage forms and therapeutic protocols for administering oxybutynin.

  Further features and advantages of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings.

FIG. 1 shows the inhibition of methacholine-induced bronchoconstriction at 18 hours for oxybutynin and oxybutynin salts. More specifically, changes in bronchoconstriction in animals treated with oxybutynin were compared to timed lactose control animals (using analysis of variance [ANOVA] Dunnett test ^** P <0.01). . FIG. 2 compares the inhibition of methacholine-induced bronchoconstriction at 18 and 24 hours by oxybutynin, oxybutynin salt, tiotropium, glycopyrrolate. More specifically, FIG. 2 shows lactose (2 mg, it., N = 6), oxybutynin base (2 mg, it., N = 6), oxybutynin HCl (2.5 mg, it. , N = 6), oxybutynin xinafoate (3 mg, it., N = 6), tiotropium (1 mg / kg, it., N = 6) or glycopyrrolate (1 mg / kg, it. , N = 6) Comparison of bronchoconstriction induced by methacholine (MCh, 10 μg / kg, iv) at 18 and 24 hours after administration. Each bar represents the average value, and the vertical line indicates the standard error of the average value. Changes in bronchoconstriction in oxybutynin or tiotropium treated animals (guinea pigs under anesthesia) were compared to timed lactose and control animals (using analysis of variance and Dunnett's test ^** P <0.01). FIG. 3 is a series of graphs comparing changes over time with oxybutynin xinafoate and tiotropium from control responses elicited by methacholine in lung inflation pressure, mean arterial pressure and heart rate. More specifically, FIG. 3 shows lactose (it, n = 6), oxybutynin xinafoate (7.5) in lung inflation pressure (PIP), mean arterial pressure (MAP) and heart rate (HR). % W / w, it, n = 6), or methacholine (10 μg / kg, it) over time (h) in the presence of tiotropium (1 mg, it, n = 6). Comparison of changes from control response elicited by Each point represents the average value, and the vertical bars indicate the standard error of the average value. Percent changes in oxybutynin or tiotropium treated animals were compared to their respective lactose control animals (guinea pigs under anesthesia) (using analysis of variance and Dunnett's test ^* P <0.05 ^** P <0.01). FIG. 4 shows the pharmacokinetics of pulmonary administration of oxybutynin over time. More specifically, FIG. 4 shows the pharmacokinetic profile of oxybutynin, oxybutynin enantiomer and major metabolite (desethyloxybutynin) after dry powder insufflation in anesthetized guinea pigs (n = 5). FIG. 5 provides structural analysis by 1H NMR. FIG. 6 provides structural analysis by FT-IR. FIG. 7 provides analysis by HPLC. FIG. 8 provides the crystallinity measured by XRPD. FIG. 9 provides compound purity, melting point as measured by DSC.

  The present invention will be more readily understood with reference to the following detailed description of specific embodiments contained herein. Reference is made to the accompanying drawings, which form a part hereof, and in which are shown by way of illustration various embodiments of the disclosure. While the invention will be described with reference to specific details of certain embodiments thereof, such details are not intended to be considered a limitation on the scope of the invention. The full text of the references referred to herein (including US patent application 12 / 904,964 filed October 14, 2010, and US patent application 12 / 130,903 filed May 30, 2008) is: , Incorporated herein by reference in its entirety. US patent application 13 / 246,686, filed September 27, 2011, is also incorporated by reference.

  Pulmonary delivery of oxybutynin to the respiratory tract can be advantageously used to treat symptoms of respiratory disease, urge incontinence and stress urinary incontinence. Unlike conventional oral and transdermal delivery of oxybutynin, which requires long-term administration with significant side effects and takes several hours to reach a therapeutically effective blood concentration, pulmonary delivery of oxybutynin with dry powder is The patient's pain can be reduced at significantly lower doses with reduced side effects. Pulmonary delivery with a dry powder of oxybutynin can also provide patients with relief of symptoms of stress urinary incontinence more immediately or as needed. Similarly, pulmonary delivery with a dry powder of oxybutynin allows a patient to achieve prophylactic or as needed relief of symptoms of respiratory distress.

  The features and advantages of the present invention resulting from pulmonary delivery of oxybutynin are that the formation of the typical primary metabolite DEO (as described above, from which harmful side effects arise) is greatly avoided. is there.

  In addition, we have discovered that when a salt of oxybutynin is administered by pulmonary delivery, it has a much longer effective action than expected due to an oral half-life of only 2.5 hours. . These salts include a novel salt form of oxybutynin, i.e., the xinafoate salt of oxybutynin that has not been previously reported in the literature. For example, all dosing of oxybutynin is typically 3 times a day due to a relatively short half-life of 2.5 hours with a minimum plateau concentration of drug remaining at about 8 hours . On the other hand, pulmonary delivery of oxybutynin salts unexpectedly shows sustained activity in the lungs of guinea pigs up to 18 hours, which is once or twice daily for human administration. This is illustrated in the attached FIG.

  Oxybutynin xinafoate is prepared by reacting oxybutynin with xinafoic acid in methyl tert-butyl ether under an inert (nitrogen) atmosphere. Other salts of oxybutynin that can be conveniently administered by pulmonary delivery include palmitate, pamoate, resinate, laurate and stearate and esters of oxybutynin, with improved half-life and reduced harmful Can provide unexpected results regarding metabolite production.

In selecting a preferred form of oxybutynin for therapeutic administration, the inventors now contemplate multiple properties of various oxybutynin salts, including but not limited to:
・ Solubility-> change in PK, bioavailability, and dissolution rate ・ Surface energy-> aerosolization (dispersibility), physical stability (particles)
・ Hydration state-> Stability, solubility ・ Degradation kinetics-> Stability ・ Crystal hardness-> Micronization, physical stability ・ Hygroscopicity-> Handling, stability ・ Solution ・ Melting point ・ Agent to be developed Form-Route of administration-Load in dosage form-Toxicology of counterions, especially lung toxicology

  As a free base, oxybutynin exhibits poor solubility and lipophilicity, with water solubility and Log P of 0.01 mg / mL and 3.3, respectively. To improve drug solubility, oral oxybutynin was formulated as the hydrochloride salt and gastric solubility was improved to 20 mg / mL (measured at pH 4) (see US Pat. No. 6,087,396). For the purposes of pulmonary delivery, the inventors have developed another strategy to design salt forms that are less soluble and more lipophilic. It has previously been shown that slow dissolution rates and the potential for lipophilic binding in vivo can prolong drug retention in the lungs and delay absorption into the systemic circulation. The corticosteroids triamcinolone acetonide and fluticasone propionate showed mean absorption times of 2.9 and 5-7 hours in the lung, respectively (Patton (2007) Nature Reviews in Drug Discovers, V6, p67). -74). To increase the likelihood of residual in the lung, the xinafoic acid salt of oxybutynin was synthesized. Other lipophilic salts such as stearate and palmitate have also been attempted; however, the thermodynamic driving force indicated by the difference in pKa between oxybutynin and xinafoic acid (8.24 vs 2.7) Has been experimentally identified to provide a more suitable salt formation.

  Before conducting salt synthesis studies, the solubility of oxybutynin in various organic solvents was evaluated (Table 1). These solubility studies indicate a large number of possible solvents that can be used in salt synthesis; however, only methyl tert-butyl ether (MTBE) yielded crystalline salts and acceptable yields. The synthesis and crystallization method applied the method used to synthesize oxybutynin hydrochloride (US Pat. No. 6,140,529). In the method of the patent, ethanol was added to MTBE to precipitate salt crystals; however, xinafoate appears to be much less soluble than hydrochloride, thus inducing precipitation of oxybutynin xinafoate. Water was used to do that. The results and specifications of all salt synthesis experiments are summarized in Table 2. Example 3 provides a description of the process used to synthesize the oxybutynin xinafoate salt.

  Preferred embodiments of the present invention include methods and compositions for treating pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin directly to a patient's lung in combination with one or more pharmaceutically active substances. Including things. In certain embodiments, the oxybutynin and pharmaceutically active substance (s) are delivered in the form of a dry powder. The dry powder oxybutynin may be selected from the group consisting of xinafoate, palmitate, pamoate, resinate, laurate and other salts, but is not limited thereto. Pharmaceutically effective substances include bronchodilators, anti-inflammatory agents, corticosteroids, corticosteroid reversal (CR) agents, alveolar proliferating agents or other agents selected from proteinases or protease inhibitors.

  In one preferred embodiment, the bronchodilator comprises a long-acting and short-acting β-stimulant and derivative or pharmaceutically acceptable salt. The anti-inflammatory agent may comprise an inhaled corticosteroid, a phosphodiesterase inhibitor, or a leukotriene receptor antagonist. Furthermore, the corticosteroid may include budesonide, fluticasone, beclomethasone, flunisolide, mometasone, triamcinolone, ciclesonide, loteprednol, fluorometholone, and derivatives or pharmaceutically acceptable salts thereof.

  Another embodiment is optionally vitamin D, synthetic vitamin D, vitamin D analog, vitamin D receptor agonist, vitamin D receptor partial agonist, calcitriol, antioxidant, inducible NOS (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 Corticosteroid reversing agents may be included including equivalents. Further, the alveolar proliferating agent includes vitamin A, all-trans retinoic acid (ATRA), retinoic acid receptor (RAR) agonist and RAR selective alveolar proliferating agent, RAR selective agonist, palobaroten, and Equivalents may be included.

  In a preferred embodiment, the present invention includes methods and compositions for treating pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin in combination with LABA directly to a patient's lung, wherein oxybutynin Exists in the form of oxybutynin xinafoate, and LABA is selected from the group including but not limited to formoterol, salmeterol, olodaterol, carmoterol, birantelol.

  In another preferred embodiment, the present invention comprises delivering a therapeutically effective amount of oxybutynin in combination with LABA directly into a patient's lung, wherein oxybutynin is present in the form of oxybutynin xinafoate, , Selected from the group including, but not limited to, formoterol, salmeterol, olodaterol, carmoterol, birantrol), and methods and compositions for treating lung disease, including inhaled corticosteroids (ICS) (Wherein the ICS comprises a selective substance selected from budesonide, fluticasone, mometasone, or even a “soft steroid” class such as ciclesonide or loteprednol).

  In another preferred embodiment, the present invention comprises delivering a therapeutically effective amount of oxybutynin in combination with LABA directly to the lungs of a patient and further comprising a CR reversal agent (CR recovery agent). Wherein oxybutynin is present in the form of oxybutynin xinafoate, and LABA is selected from the group including but not limited to formoterol, salmeterol, olodaterol, carmoterol, birantrol, 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 blockers, calcitol and the like.

  In another preferred embodiment, the present invention comprises delivering a therapeutically effective amount of oxybutynin directly to a patient's lung in combination with a LABA, CR reversal agent, and further comprising ICS for treating lung disease A method and composition, wherein oxybutynin is present in the form of oxybutynin xinafoate; LABA is selected from the group including but not limited to formoterol, salmeterol, olodaterol, carmoterol, birantrol; said 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 blockers, calcitol and the like; the ICS is budesonide, Fluticasone, mometasone, or even "soft sterol Selected from the group including, but not limited to, selective substances selected from the “class”.

  In another preferred embodiment, the present invention provides methods and compositions for treating pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin directly to a patient's lung in combination with LABA, an alveolar growth agent. Where LABA includes formoterol and the alveolar proliferating agent is selected from the group including but not limited to ATRA, cis-retinoic acid and parovarotene.

  The above embodiments may be delivered using a dry powder inhaler (DPI), a DPI including a piezoelectric vibrator, a metered dose inhaler (MDI) or a liquid nebulizer. Further, the therapeutic composition of the above-described embodiments has an aerodynamic power selected from the group consisting of 0.5-20 microns, 0.5-15 microns, 0.5-10 microns, or 0.5-5 microns. It may be delivered in the form of a dry powder having a biological median particle size. A therapeutically effective dose of oxybutynin in combination with one or more pharmaceutically effective substances is 0.001-20 mg / day, 0.02-15 mg / day, or 0.05-10 mg / day. It is within the range and is administered as needed.

Terms and DefinitionsThe term `` oxybutynin '' as used herein is not only oxybutynin as an anhydrous powder, but also has antispasmodic and anticholinergic activity like oxybutynin, is non-toxic and pharmacologically acceptable. It is intended to include oxybutynin salts or derivatives such as oxybutynin xinafoate or oxybutynin hydrochloride. Other suitable salts include but are not limited to palmitate, pamoate, resinate and laurate.

  As used herein, an “effective amount” is the amount of a pharmaceutical composition effective for the treatment of pulmonary disease, urinary incontinence or irritable bowel syndrome, ie COPD, asthma, urinary incontinence and stress incontinence The amount of oxybutynin with a defined aerodynamic particle size suitable for absorption in the lungs that can reduce or reduce the symptoms.

  As used herein, a “pharmaceutical composition” is used to treat a mammal comprising oxybutynin of a defined aerodynamic particle size in dry powder form, prepared in a manner suitable for pulmonary administration to a mammal. Means a drug to do. The pharmaceutical composition according to the present invention may comprise a non-toxic pharmaceutically acceptable carrier, but is not essential.

  As used herein, “defined aerodynamic particle size” means a particle having a size that is sufficiently small to be delivered to the lung. For optimal delivery to the lung, the dry powder form of oxybutynin is preferably 0.05-20 microns, 0.5-15 microns, 0.5-10 microns, or 0.5-5 microns air It should be micronized or spray dried to a powder size of kinetic median diameter. However, other methods of producing controlled sized particles, such as supercritical fluid processes, controlled precipitation, etc. may also be used advantageously.

  As used herein, “therapeutically effective amount” refers to an individual's age, weight, general health, frequency of medication, COPD, asthma, severity of incontinence, and the urgency being treated. Or whether it is stress incontinence or irritable bowel syndrome. For treating respiratory diseases, generally a therapeutically effective amount is administered as needed, 0.001-20 mg / day, 0.02-15 mg / day, or 0.05-10 mg / day. Contains an amount of active ingredient. For treating urge urinary incontinence, a therapeutically effective amount generally comprises an active ingredient in an amount of 1-20 mg / day, preferably 1-10 mg / day. The active ingredient may be administered once a day. Preferably, however, the active ingredient is administered in smaller doses 2-3 times daily or more in order to maintain a more consistent plasma concentration. When used to treat stress incontinence, or irritable bowel syndrome, the therapeutic amount is generally 0.1-15 mg / day, preferably administered as a single dose or as needed, preferably Contains active ingredient in an amount of 0.2 to 10 mg / day. The active ingredient may be administered once a day. Preferably, however, the active ingredient is administered in smaller doses 2-3 times daily or more in order to maintain a more consistent plasma concentration.

  Oxybutynin may be delivered in dry powder form, for example, by dry powder inhaler (DPI), metered dose inhaler (MDI), or suitable for nebulization with a therapeutically effective unit dose delivery. It may be dissolved in a liquid. In order to treat acute symptoms of respiratory distress, the dose of oxybutynin should be taken with the first signs of respiratory distress. In order to treat chronic respiratory distress, oxybutynin should be taken daily according to the regimen recommended by the physician. Similarly, to treat symptoms of stress urinary incontinence, the dose of oxybutynin may be administered at the first sign of stress or at the first sign of urgency, or just before the expected sign of stress, e.g. Should be taken just before it is scheduled to speak in front of the audience. In a preferred embodiment of the invention, dry powder oxybutynin is packaged for delivery in a piezoelectric dry powder inhaler as described in US Pat. No. 6,026,809. As used herein, the terms “fine drug particles” and “aerodynamic particle size” mean particles having a size that is small enough to be delivered to the lung airways and particularly to the peripheral airways. For optimal delivery to the lung, the therapeutic agent in dry powder form described herein preferably has a maximum in the range of 0.01 μm to 20 μm, 0.25 μm to 5 μm, or 0.5 μm to 4 μm. It should be atomized to aerodynamic particle size, spray dried or designed.

  As used herein, the term “CR reversing agent” (CR recovery agent) is intended to encompass substances that increase the anti-inflammatory response induced by corticosteroids when administered at effective levels. ing. This term applies not only to substances for restoring CR, but also to salts or derivatives of said substances that have activity in restoring CR, which are non-toxic and pharmaceutically acceptable.

  CR reversal agents as used herein include, but are not limited to, vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and blockers, calcitol, theophylline and the like. Not. Also included are CR reversal agents known to those skilled in the art.

  The term “vitamin D” as used herein refers to vitamin D, vitamin D2, vitamin D3, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and blockers, calcitriol, calcitol and equivalents Is intended to encompass

  As used herein, the term “vitamin A” is intended to encompass substances that interact with the retinoic acid receptor (RAR), ATRA, ATRA derivatives, RAR agonists, 13-cis retinoic acid. And RAR selective agonists such as, but not limited to, palobaroten.

  The term “alveolar proliferating agent” as used herein is intended to encompass substances that promote the growth of new alveoli via retinoic acid receptors and includes ATRA or RAR selective agent therapy.

  The term “alveolar maintenance agent” as used herein is a substance that, when administered at an effective level, enhances the anti-inflammatory response induced by COPD, COPDe and emphysema and the undesirable effects of ATRA or RAR selective agent treatment. Is intended to be included. This term is not only a substance for maintaining alveoli, but also a salt, hydrate, prodrug or derivative of said substance having similar activity, which is non-toxic and pharmacologically acceptable Also applies.

  As used herein, bronchodilators include β2-agonists (short and long acting, LABA), long acting muscarinic receptor blockers (LAMA), anticholinergic drugs (short acting) ), And theophylline (long-acting). As used herein, “simultaneous administration” refers to delivering two or more pharmaceutical or therapeutic agents (eg, delivering both a corticosteroid and a CR reversal agent as an aerosol in the same breath via the pulmonary route). means.

  As used herein, an “effective amount” is a pharmaceutical composition effective to achieve a desired therapeutic effect (including but not limited to bronchodilation, CR recovery, anti-inflammatory, alveolar regrowth). Is the amount. For example, an effective amount of CR reversal agent includes a specific amount of calcitriol that is within a defined aerodynamic particle size suitable for absorption in the lung and can reduce or reduce resistance to corticosteroids. But you can.

  As used herein, “pharmaceutical” and “therapeutic” substances include, but are not limited to, any and all drugs, pharmaceuticals and formulations that can be administered to treat lung disease. Includes substances to prevent and also includes substances to maintain amelioration of the condition. As used herein, such therapeutic and pharmaceutical agents include corticosteroids, muscarinic receptor blockers, macrolides, and nonsteroidal anti-inflammatory drugs (NSAIDs), antioxidants, inducible NOS Inhibitors, phosphoinositide-3-kinase-δ inhibitors, p38 MAP kinase inhibitors, JNK inhibitors, MIF inhibitors, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, and vitamin D, synthetic vitamin D, vitamins D analog, calcitriol, vitamin A, all-trans retinoic acid (ATRA), retinoic acid receptor (RAR) agonist, RAR selective alveolar proliferator, budesonide, fluticasone, beclomethasone, flunisolide, triamcinolone, mometasone, ciclesonide , Loteprednol, fluorometholone, And derivatives, equivalents or pharmaceutically acceptable salts thereof, but are not limited thereto.

  As used herein, a “pharmaceutical” or “therapeutic” composition is an agent for use in treating a patient (eg, pre-determined aerodynamics prepared in a manner suitable for pulmonary administration to a patient. CR reversal agent in the form of a dry powder having a specific particle size. The pharmaceutical composition according to the present invention may optionally comprise a non-toxic pharmaceutically acceptable carrier. In certain embodiments, a “medicament” or “therapeutic” composition may include only one component (ie, calcitriol alone) or a CR reversal agent, anti-inflammatory agent, bronchodilator, alveolar proliferative agent. And combinations of components selected from the group consisting of others.

  It is emphasized that the above-described embodiments, in particular the “preferred” embodiments of the apparatus and process of the present invention are merely possible examples of implementation and are presented merely for a clear understanding of the nature of the present disclosure. The All these and other such modifications and changes are intended to be included within the scope of this disclosure and protected by the following claims. Accordingly, the scope of the present disclosure is not intended to be limited except as set forth in the appended claims.

  The following specific examples illustrate the present invention as applied to treatment methods using an inhaler. Of course, other embodiments, including minor changes in procedures, will be apparent to those skilled in the art, and the invention is not limited to these specifically described embodiments.

Oxybutynin in micronized crystalline form of oxybutynin is atomized to a median aerodynamic particle size of less than 10 microns. This powder is filled into a dry powder inhaler (DPI) made according to US Pat. No. 6,026,809.

Example 1 was repeated using micronized oxybutynin chloride having a median aerodynamic particle size of less than 5 microns instead of micronized oxybutynin chloride.

Preparation of oxybutynin xinafoate Example 1 was repeated using, instead of oxybutynin, micronized oxybutynin xinafoate salt with a maximum aerodynamic particle size of about 10 microns. The oxybutynin xinafoate salt was prepared as follows: A 250 mL round bottom flask was equipped with a magnetic stirrer, thermocouple, and nitrogen injection 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). The solid dissolved almost immediately at about 18 ° C. The batch was warmed to 50 ° C. and crystallization began at about 21 ° C. The mixture was maintained at 50 ° C. for 1 hour and cooled to 33 ° C. in air and then to 3 ° C. in an ice bath. The mixture was maintained at <5 ° C. for 1 hour, filtered and the filter cake was washed with methyl tert-butyl ether (100 mL). The wet cake was dried in a vacuum oven at 45 ° C. for 1 hour.

  After salt synthesis, the structure was confirmed by 1H NMR and FT-IR (FIGS. 5 and 6). HPLC analysis confirmed over 99% potency through quantification of AUC at 15.1 minutes (FIG. 7). Crystallinity, compound purity, and melting point were also measured by XRPD and DSC (FIGS. 8 and 9). Both tests showed highly crystalline material with a melting point of 105 ° C. (DSC did not detect low temperature crystallization). The water content was determined to be 0.057% by KF titration.

Comparative Effects of Bronchodilators Example 1 was replaced by using micronized oxybutynin base having a maximum aerodynamic particle size of about 10 microns, oxybutynin hydrochloride, and oxybutynin xinafoate instead of oxybutynin. Was repeated. The level of bronchodilator effect of oxybutynin was compared to tiotropium and glycopyrrolate at 18 and 24 hours after administration to anesthetized guinea pigs. Figures 1 and 2 show a comparison of the effects of pulmonary delivery of oxybutynin on anesthetized guinea pigs.

Comparative effect of bronchodilator: Example 1 was repeated using micronized oxybutynin xinafoate with a maximum aerodynamic particle size of about 10 microns instead of oxybutynin xinafoate and other oxybutynins. It was. The onset of action and the resulting systemic concentration of oxybutynin xinafoate was compared to tiotropium for the first 6 hours after administration to anesthetized guinea pigs. FIG. 3 compares the effects of pulmonary delivery of oxybutynin and tiotropium on anesthetized guinea pigs during the first 6 hours after administration. Oxybutynin showed similar protection to tiotropium against airway stenosis induced by methacholine; however, the effect on cardiovascular status was not as significant. FIG. 4 shows the pharmacokinetics resulting from pulmonary administration of oxybutynin. The systemic concentration of DEO resulting from pulmonary delivery was below the LOQ of the detection method and was well below clinically relevant levels.

  Changes may be made without departing from the spirit and scope of the invention as described above. For example, the oxybutynin may be co-administered with other compounds or substances to reduce adverse side effects or to treat side effects. For example, cholinergic agents described in PCT US09 / 034018 may be co-administered with oxybutynin to reduce the effects of dry mouth.

CONCLUSIONS Direct delivery of oxybutynin microparticles to the lungs, as needed, for patients suffering from respiratory diseases such as asthma, COPD, and urge incontinence, stress incontinence and irritable bowel syndrome It was confirmed that the pain was reduced.

  In the guinea pig model of bronchoconstriction, it was confirmed that oxybutynin had a significant bronchoprotective effect over a period of 0.25 to 24 hours without significant long-term effects on arterial pressure and heart rate.

  Pulmonary administration of oxybutynin also avoids significant formation of DEO, the first-pass primary metabolite, and thus greatly reduces the harmful side effects traditionally associated with oral or transdermal delivery of oxybutynin . Further, the dose of oxybutynin administered via the pulmonary delivery route is much less than the dose of oxybutynin when delivered via the oral or transdermal delivery route. Furthermore, pulmonary delivery of oxybutynin results in sustained therapeutic levels in the lung compared to oral delivery of oxybutynin, which is typically administered three times a day, allowing administration once or twice a day .

  Although the present invention has been described in detail herein according to certain preferred embodiments thereof, many modifications and changes may be made by those skilled in the art. Accordingly, the appended claims are intended to cover all such modifications and changes that may be included within the spirit and scope of this invention.

Claims (15)

  A method for treating pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective substances directly to the lungs of a patient.   The method of claim 1, wherein the oxybutynin and / or pharmaceutically active substance is delivered in a dry powder form.   The process according to claim 1 or 2, wherein the dry powder oxybutynin is selected from the group consisting of xinafoate, palmitate, pamoate, resinate and laurate.   The method according to claim 1 or 2, wherein the oxybutynin comprises oxybutynin xinafoate.   The pharmaceutically active substance comprises a bronchodilator, an anti-inflammatory agent, a corticosteroid, an inhaled corticosteroid, a corticosteroid reversal agent, an alveolar growth agent, a proteinase inhibitor, or a protease inhibitor. The method of any one of 1-4.   The pharmaceutically active substance is a bronchodilator comprising a long-acting β-stimulant and a short-acting β-stimulant and its derivatives or pharmaceutically acceptable salts, or inhaled corticosteroids, phosphodiesterase inhibition Or corticosteroids containing budesonide, fluticasone, beclomethasone, flunisolide, triamcinolone, ciclesonide, loteprednol, fluorometholone, and derivatives or pharmaceutically acceptable salts thereof, or vitamin D, synthesis Vitamin D, vitamin D analog, vitamin D receptor agonist, vitamin D receptor partial agonist, calcitriol, antioxidant, inducible NOS inhibitor, phosphoinositide-3-kinase-delta inhibitor, p38 MAP kinase Inhibitors, JNK inhibitors, IF inhibitors, low-dose theophylline, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, corticosteroid reversals, including statins and the like, or vitamin A, all-trans retinoic acid (ATRA) 6. A method according to claim 5, wherein the method is selected from alveolar proliferating agents, including retinoic acid receptor (RAR) agonists and RAR selective alveolar proliferating agents, RAR selective agonists, parovarotene and the like. .   7. The method of claim 6, wherein the oxybutynin comprises oxybutynin xinafoate and the long acting beta stimulator comprises formoterol, salmeterol, olodaterol, carmoterol or birantrol.   Further, inhaled corticosteroids, including inhaled corticosteroids including budesonide, fluticasone, or mometasone, and optionally further in a soft steroid class, including a ciclesonide or loteprednol and / or a CR reversal agent. A selective substance selected from a CR reversal agent selected from the group consisting of vitamin D, vitamin D analogs, synthetic vitamin D, vitamin D receptor agonists and blockers, calcitol and the like The method of claim 7 comprising: The oxybutynin comprises oxybutynin xinafoate,
The pharmaceutically effective substance is
A long-acting β-stimulant containing formoterol, and
2. The method of claim 1, comprising an alveolar proliferating agent selected from the group comprising ATRA, cis-retinoic acid and parovarotene.   The method according to any one of claims 1 to 9, wherein the pulmonary disease comprises asthma, atelectasis, bronchitis, chronic obstructive pulmonary disease, emphysema, lung cancer, pneumonia or pulmonary edema. The lung disease comprises chronic obstructive pulmonary disease,
The oxybutynin comprises oxybutynin xinafoate,
2. The method of claim 1, wherein the pharmaceutically effective substance comprises a long acting muscarinic receptor blocker.   12. A method according to any one of the preceding claims, wherein oxybutynin and the pharmaceutically active substance are delivered using a dry powder inhaler (DPI) or metered dose inhaler (MDI) or a liquid nebulizer. .   The method of claim 12, wherein the dry powder inhaler comprises a piezoelectric vibrator.   Oxybutynin of a dry powder having an aerodynamic median particle size selected from the group consisting of 0.5-20 microns, 0.5-15 microns, 0.5-10 microns, or 0.5-5 microns A dosage of said therapeutically effective amount of oxybutynin delivered in the form and / or in combination with one or more pharmaceutically active substances is 0.001-20 mg / day, 0.02-15 mg / day, Or the method of any one of Claims 1-13 administered as needed within the range of 0.05-10 mg / day. A method of treating chronic obstructive pulmonary disease comprising delivering a therapeutically effective amount of oxybutynin directly to a patient's lung in combination with one or more pharmaceutically active substances into the patient's lung,
The method wherein the oxybutynin is preferably selected from the group consisting of xinafoate, palmitate, pamoate, resinate and laurate.

Images