WO2014105446A1 - Methods and compositions for administration of oxybutynin - Google Patents
Methods and compositions for administration of oxybutynin Download PDFInfo
- Publication number
- WO2014105446A1 WO2014105446A1 PCT/US2013/074759 US2013074759W WO2014105446A1 WO 2014105446 A1 WO2014105446 A1 WO 2014105446A1 US 2013074759 W US2013074759 W US 2013074759W WO 2014105446 A1 WO2014105446 A1 WO 2014105446A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- oxybutynin
- salt
- vitamin
- inhibitors
- agents
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates generally to novel methods of administering oxybutynin, to novel forms of oxybutynin and novel dosage forms containing oxybuty in 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 other uses such as prophylactic, therapeutic or ameliorative treatment of incontinence and intestinal hypermotility, i.e. irritable bowel syndrome, also are contemplated.
- respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD)
- COPD chronic obstructive pulmonary disease
- Oxybutynin is a racemic compound of the chemical formula 4- diethylaminobut- 2-butynyl phen lcyclohexyl-glycolate:
- Oxybutynin is an anticholinergic medication that traditionally has been 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 Ml , M2, and M3 subtypes of the muscarinic 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.
- Oxybutynin currently is administered in oral formulation as a tablet or multiple tablets and a syrup, or transderma!ly as a patch or topical gel for treating urge urinary incontinence.
- oral deliver of a therapeutically active amount of oxybutynin suffers from a number of disadvantages:
- 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;
- Oxybutynin administered in an oral formulation does not produce desirably high blood levels in a desirably short period of time;
- 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;
- Oxybutynin administered in an oral formation is contraindicated for patients with gastrointestinal obstruction disorders because of the risk of urinary retention;
- 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 and dizziness.
- Oxybutynin administered in the oral formulation is subject to first pass metabolism, resulting in the formation of metabolite N-desethyioxybutynin (DEO) which has been attributed to cause the majority of the aforementioned side effects.
- DEO metabolite N-desethyioxybutynin
- 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
- 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.
- T ransdermal delivery of oxybutynin has many of the aforesaid disadvantages.
- transdermal patch 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 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.
- Pulmonary disease includes, but is not limited to, acute bronchitis, acute respiratory distress syndrome (ARDS), asbestosis, asthma, atelectasis, aspergillosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, byssinosis, chronic bronchitis, coccidiomycosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, eosinophilic pneumonia, hantavirus pulmonary syndrome, histoplasmosis, human metapneumovirus, hypersensitivity pneumonitis, influenza, lung cancer.
- ARDS acute respiratory distress syndrome
- COPD chronic obstructive pulmonary disease
- cystic fibrosis emphysema
- eosinophilic pneumonia hantavirus pulmonary syndrome
- histoplasmosis human metapneumovirus
- hypersensitivity pneumonitis influenza, lung cancer.
- lymphangiomatosis mesothelioma, necrotizing pneumonia, nontuberculosis Mycobacterium, pertussis, pleural effusion, pneumoconiosis, 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 generally comprise asthma, bronchitis. COPD, emphysema, and pneumonia.
- Current therapeutic agents for COPD predominately comprise bronchodilators administered via inhalation, including inhaled long-acting beta ⁇ -agonists (LAB A) or long acting muscarinic antagonists (LAMA).
- LAB A long-acting beta ⁇ -agonists
- LAMA long acting muscarinic antagonists
- 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 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 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.
- a drug in dry 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 conventional means.
- oxybutynin hydrochloride compositions 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 properties.
- the present invention relates to novel dosage forms and compositions f oxybutynin for treating pulmonary and respirator ⁇ ' diseases, including but not limited to. chronic obstructive pulmonary disease and asthma.
- the present invention is also related to improving underlying physiological dysfunction contributing to pulmonary disease.
- the present invention prov ides effective administration of therapeutic agents to specific airways of the lungs by utilizing controlled site delivery.
- oxybutynin-containing compositions can be usefully administered to mammals by pulmonary delivery at lower dosage levels to elicit a therapeutic response with a marked reduction in systemic metabolites.
- DEO systemic levels of the metabolite
- An increased contribution of DEO toward side effects is due to its greater affinity toward receptors in non-targeted tissues, i.e. salivary glands.
- 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 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.
- COPD chronic obstructive pulmonary disease
- the present invention also provides novel forms of oxybutynin as well as novel dosage forms and treatment protocols for administering oxybutynin.
- 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. ** /' ⁇ ().01 .
- Figure 2 compares inhibition of methacholine induced bronchoconstriction by oxybutynin, oxybutynin salts, tiotropium and glycopyrrolate at 18 hours and 24 hours. More particularly .
- Figure 4 shows pharmacokinetics of pulmonary administration of oxybutynin over time. More particularly.
- Figures 5 and 6 provide 1 I I NMR and FT-IR structure analysis.
- Figure 7 provides HPLC analysis.
- Figure 8 and 9 provide crystallinity, compound purity, and melting point determined by XRPD and DSC.
- Pulmonary delivery of oxybutynin to the respiratory tract can be used advantageously to treat respiratory disease, urge urinary incontinence and symptoms of stress urinary incontinence.
- dry powder pulmonary delivery of oxybutynin perm its a patient to enjoy relief at significantly lower doses with concomitant reduction in side effects such as dry mouth.
- Dry powder pulmonary delivery f oxybutynin also permits a patient to enjoy relief from symptoms of stress urinary incontinence on a more immediate or as-needed basis.
- 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 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.
- salts of oxybutynin when administered via pulmonary delivery result in a significantly longer acting efficacy 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.
- 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.
- 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.
- 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 o oxybutnin. and can provide unexpected results of improved half-life as well as reduced adverse metabolite production.
- oxybutyin salts including but not limited to the following:
- Solubility -> P Bioavailability, and changes in dissolution rate.
- oxybutynin 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.
- 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).
- 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 vivo may prolong drug retention in the lung and delay absorption into systemic circulation.
- the corticosteroids triamcinolone acetonide and fluticasone propionate have shown mean absorption times in the lungs of 2.9 hours and 5-7 hours, respectively (Patton (2007) Nature Reviews in Drug Discovers, V6, p67-74).
- the xinafoic acid (xinofoate) salt of oxybutynin was synthesized.
- Other lipophilic salts, such as stearates and pa Imitates were attempted; however, it was experimentally determined that the thermodynamic 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.
- Preferred embodiments of the present invention comprise methods and compositions for treating pu lmonar disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents.
- 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 lim ited to, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt, a laurate 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.
- the bronchodilators comprise long-acting and short-acting beta agonists and derivat ives or pharmaceutical ly acceptable salts thereof.
- the anti-inflammatories may include inhaled corticosteroids, phosphodiesterase inhibitors or leukotriene receptor antagonists.
- the corticosteroids may comprise budesonide, fluticasone, beclomethasone, flunisolide, 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 receptor agonists, vitamin D receptor partial agonists, calcitriol, antioxidants, iNOS inhibitors. Phosphoinositide-3-kinase-.delta. inhibitors. p38 MAP kinase inhibitors, JNK inhibitors, M1F inhibitors, low-dose theophylline, p-glycoprotein inhibitors, macrolides, calcineurin inhibitors, statins, and equivalents thereof.
- the alveolar growth agents may comprise 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.
- ATRA All Trans Retinoic Acid
- RAR retinoic acid receptor
- 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 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.
- 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 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, odaiaterol, carmoterol, vilanterol and further comprising an inhaled corticosteroid (ICS) wherein the ICS comprises budesonide, fluticasone, mometasone, or additionally, a selective agent selected from the 'soft steroid' class, for instance, ciclesonide or loteprednol.
- ICS inhaled corticosteroid
- 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, 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, vilantcrol
- 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.
- the present invention comprises methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybiitynin in combination with a LABA, a CR reversal agent, and further comprising an ICS, wherein the oxy biitynin is present in the form of oxybiitynin xinofoate;
- the LABA is selected from the group including, but not limited to, formoterol, salmeteroi, 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;
- 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.
- the present invention comprises methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybiitynin 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 limited to, A I R A. 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 (MD1) or liquid nebulizer.
- the therapeutic compositions of the above-described embodiments may be 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 microns.
- the dosages of the therapeutically effective amount of oxybiitynin 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.
- 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 pharmacologically acceptable, for example, oxybutynin xinafoate or oxybutynin hydrochloride.
- suitable salts include but are not limited to the palmitate. pamoic, resonate and !aurate salts.
- An effective amount is an amount of the pharmaceutical composition that is effective for treating pulmonary disease, urinary incontinence or 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 means a medicament for use in treating a mammal that comprises oxybutynin in a dry powder form of a defined 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 means particles having a size sufficiently small so as to be delivered 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.
- other methods for producing controlled size particles e.g. supercritical fluid processes, controlled precipitation, etc., also advantageously may be employed.
- a therapeutically effective amount 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.
- a 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.
- a therapeutically effective amount will comprise the active ingredient in a quantity of from 1 to 20 mg/day, preferably 1 to 10 mg/day. The active ingredient may be given once a day.
- the active ingredient will be administered in smaller doses two or three or more times a day to maintain more consistent plasma levels.
- a therapeutically amount will comprise the active ingredient in a quantity of from 0.1 to 15 mg per day, preferably 0.2 to 1 0 mg/day, generally administered as a single dose, or as needed.
- the active ingredient may be given once a day.
- the active ingredient will be administered in smaller doses two or three or more times a day to maintain more consistent plasma levels.
- the oxybiitynin 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.
- DPI dry powder inhaler
- MDl metered dose inhaler
- a suitable liquid for nebulization in a therapeutically effective unit dose delivery amount for treating acute symptoms of respiratory distress, a dose of oxybiitynin should be taken at the first sign of respiratory distress.
- oxybutynin should be taken daily according to a regimen recommended by a physician.
- a dose o oxybiitynin 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.
- the dry powder oxy butynin is packaged for delivery in a piezo-electronic dry powder inhaler such as described in U.S. Patent No. 6,026,809.
- 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 ⁇ to 20 ⁇ , from 0.25 ⁇ to 5 ⁇ , or from 0.5 ⁇ to 4 ⁇ .
- agent for reversal of CR is intended to encompass any agent that when administered at an effective level will increase the antiinflammatory 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 CR, and which is non-toxic and pharmacologically acceptable.
- 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 known to those skilled in the art.
- 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.
- vitamin A is intended to encompass those agents 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.
- RAR Retinoic Acid Receptor
- alveolar growth agent is intended to encompass any agent that promotes the growth of new alveoli via the retinoic acid receptor, and includes ATRA or RAR selective agent therapy.
- 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 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.
- bronchodilating substances include, but are not limited to, beta2-agonists (short and long acting, LABA), long acting muscarinic antagonists (LAMA), anticholinergics (short acting), and theophylline (long acting).
- “Coadministered,” 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 is an amount of the pharmaceutical composition that is effective for achieving a desired therapeutic effect, including but not limited to bronchodilation, CR reversal, anti-inflammation, alveolar regrowth.
- an effective amount of an agent for reversal of C may comprise the specified amount of caleitriol, within a defined aerodynamic particle size range suitable for absorption in the lungs, that is able to reduce or eliminate the resistance to corticosteroids.
- 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.
- therapeutic and pharmaceutical agents include, but are not limited to, corticosteroids, muscarinic antagonists, macrolides, and nonsteroidal anti-inflammatory drugs (NSAlDs), antioxidants, iNOS inhibitors. phosphoinositide-3-kinase-5 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 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 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.
- "pharmaceutical” or “therapeutic” composition may comprise a singular entity (i.e. caleitriol alone), or a combination of compositions selected from the group consisting of CR reversal agents, antiinflammatory agents, bronchodilators, alveolar growth agents, and others.
- 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.
- DPI dry powder inhaler
- Example 1 was repeated, using micronized oxybutynin chloride of median aerodynamic particle size of less than 5 microns in place of oxybutynin.
- Example 1 was repeated, using micronized oxybutynin xinafoate salt of 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 /e/v-butyl ether (100 mL, 5 vol).
- 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-buty ⁇ ether (100 mL).
- the wet cake was dried in a vacuum oven at 45°C for one hour.
- Example 1 was repeated, using micron i/.ed 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 of oxybutynin was compared to Tiotropium and Glycopyrrolate 1 8 and 24 hours after administration in anaesthetized guinea pigs.
- Figs. 1 and 2 shows comparative effects of pulmonary delivery of oxybutynin on anaesthetized guinea pigs.
- 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 below the LOQ of the detection method and much lower than clinically relevant levels.
- the oxybutynin may be co-administered with other compounds or agents for reducing adverse side effects or to treat the side effect.
- cholinergic agonists such as described in PCT US09/03401 may be co-administered with the oxybutynin to reduce the effect of dry mouth.
- 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 effects which traditionally have been associated with adm inistration of oxybutynin via oral or transdermal delivery. Additionally, dosage amounts of oxybutynin administered via pulmonary delivery route are significantly lower than dosage amounts f oxybutynin when delivered via oral or transdermal delivery routes. Furthermore, pulmonary delivery of oxybutynin results in prolonged therapeutic 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.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Otolaryngology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA201591218A EA201591218A1 (en) | 2012-12-27 | 2013-12-12 | METHODS AND COMPOSITIONS FOR THE INTRODUCTION OF OXYBUTININ |
CA2895955A CA2895955A1 (en) | 2012-12-27 | 2013-12-12 | Dry powder inhalation formulation of oxybutynin and a pharmaceutically effective agent to treat respiratory disease |
AU2013368298A AU2013368298B2 (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
JP2015550444A JP2016504358A (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administering oxybutynin |
BR112015015421A BR112015015421A2 (en) | 2012-12-27 | 2013-12-12 | methods and compositions for administration of oxybutynin |
NZ628479A NZ628479A (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
CN201380068230.5A CN104955444A (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
MX2015008333A MX2015008333A (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin. |
KR1020157020335A KR20150100902A (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
EP13867956.8A EP2938329A4 (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
IL239623A IL239623A0 (en) | 2012-12-27 | 2015-06-24 | Methods and compositions for admisitration of oxybutynin |
HK16103431.3A HK1215396A1 (en) | 2012-12-27 | 2016-03-23 | Methods and compositions for administration of oxybutynin |
HK16104715.8A HK1216843A1 (en) | 2012-12-27 | 2016-04-25 | Methods and compositions for administration of oxybutynin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/728,706 | 2012-12-27 | ||
US13/728,706 US9119777B2 (en) | 2008-05-30 | 2012-12-27 | Methods and compositions for administration of oxybutynin |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014105446A1 true WO2014105446A1 (en) | 2014-07-03 |
Family
ID=51021931
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2013/074759 WO2014105446A1 (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP2938329A4 (en) |
JP (1) | JP2016504358A (en) |
KR (1) | KR20150100902A (en) |
CN (1) | CN104955444A (en) |
AR (1) | AR094287A1 (en) |
AU (1) | AU2013368298B2 (en) |
BR (1) | BR112015015421A2 (en) |
CA (1) | CA2895955A1 (en) |
EA (1) | EA201591218A1 (en) |
HK (2) | HK1215396A1 (en) |
IL (1) | IL239623A0 (en) |
MX (1) | MX2015008333A (en) |
NZ (1) | NZ628479A (en) |
UY (1) | UY35230A (en) |
WO (1) | WO2014105446A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3421049B1 (en) * | 2016-02-25 | 2020-07-29 | Hisamitsu Pharmaceutical Co., Inc. | Liquid external preparation |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011048379A2 (en) * | 2009-10-21 | 2011-04-28 | Innovata Limited | Composition |
US20110253133A1 (en) * | 2008-05-30 | 2011-10-20 | Martin Michael J | Methods and compositions for administration of oxybutynin |
US20120077786A1 (en) * | 2010-09-27 | 2012-03-29 | Byron David A | Methods and compositions for disease treatment using inhalation |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003500354A (en) * | 1999-05-20 | 2003-01-07 | セプラコール, インク. | Method for treating asthma using S-oxybutynin |
US6339107B1 (en) * | 2000-08-02 | 2002-01-15 | Syntex (U.S.A.) Llc | Methods for treatment of Emphysema using 13-cis retinoic acid |
CA2498189A1 (en) * | 2002-10-29 | 2004-05-13 | Pharmacia & Upjohn Company Llc | Quaternary ammonium compounds |
GB0410398D0 (en) * | 2004-05-10 | 2004-06-16 | Arakis Ltd | The treatment of respiratory disease |
CA2585122A1 (en) * | 2004-10-25 | 2006-05-04 | Schering Corporation | M1 and/or m3 receptor antagonists in combination with other actives for treating respiratory disorders |
CA2716936C (en) * | 2008-02-26 | 2018-06-05 | Elevation Pharmaceuticals, Inc. | Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations |
AU2010260513A1 (en) * | 2009-06-16 | 2012-02-02 | Wen Tan | Use of R-Bambuterol as inhaled medicament and combination therapies for treatment of respiratory disorders |
WO2011120779A1 (en) * | 2010-04-01 | 2011-10-06 | Chiesi Farmaceutici S.P.A. | Process for preparing carrier particles for dry powders for inhalation |
-
2013
- 2013-12-12 EP EP13867956.8A patent/EP2938329A4/en not_active Withdrawn
- 2013-12-12 JP JP2015550444A patent/JP2016504358A/en active Pending
- 2013-12-12 NZ NZ628479A patent/NZ628479A/en not_active IP Right Cessation
- 2013-12-12 CN CN201380068230.5A patent/CN104955444A/en active Pending
- 2013-12-12 BR BR112015015421A patent/BR112015015421A2/en not_active IP Right Cessation
- 2013-12-12 CA CA2895955A patent/CA2895955A1/en not_active Abandoned
- 2013-12-12 EA EA201591218A patent/EA201591218A1/en unknown
- 2013-12-12 KR KR1020157020335A patent/KR20150100902A/en not_active Application Discontinuation
- 2013-12-12 MX MX2015008333A patent/MX2015008333A/en unknown
- 2013-12-12 WO PCT/US2013/074759 patent/WO2014105446A1/en active Application Filing
- 2013-12-12 AU AU2013368298A patent/AU2013368298B2/en not_active Ceased
- 2013-12-20 UY UY0001035230A patent/UY35230A/en not_active Application Discontinuation
- 2013-12-27 AR ARP130105037A patent/AR094287A1/en unknown
-
2015
- 2015-06-24 IL IL239623A patent/IL239623A0/en unknown
-
2016
- 2016-03-23 HK HK16103431.3A patent/HK1215396A1/en unknown
- 2016-04-25 HK HK16104715.8A patent/HK1216843A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110253133A1 (en) * | 2008-05-30 | 2011-10-20 | Martin Michael J | Methods and compositions for administration of oxybutynin |
WO2011048379A2 (en) * | 2009-10-21 | 2011-04-28 | Innovata Limited | Composition |
US20120077786A1 (en) * | 2010-09-27 | 2012-03-29 | Byron David A | Methods and compositions for disease treatment using inhalation |
Non-Patent Citations (1)
Title |
---|
See also references of EP2938329A4 * |
Also Published As
Publication number | Publication date |
---|---|
KR20150100902A (en) | 2015-09-02 |
BR112015015421A2 (en) | 2017-07-11 |
JP2016504358A (en) | 2016-02-12 |
AR094287A1 (en) | 2015-07-22 |
CN104955444A (en) | 2015-09-30 |
AU2013368298A1 (en) | 2015-07-02 |
EA201591218A1 (en) | 2015-11-30 |
EP2938329A1 (en) | 2015-11-04 |
IL239623A0 (en) | 2015-08-31 |
HK1216843A1 (en) | 2016-12-09 |
NZ628479A (en) | 2016-06-24 |
EP2938329A4 (en) | 2016-08-10 |
CA2895955A1 (en) | 2014-07-03 |
MX2015008333A (en) | 2015-11-09 |
HK1215396A1 (en) | 2016-08-26 |
UY35230A (en) | 2015-01-30 |
AU2013368298B2 (en) | 2016-08-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9119777B2 (en) | Methods and compositions for administration of oxybutynin | |
TWI272106B (en) | New medicament compositions based on anticholinergically-effective compounds and beta-mimetics | |
US20240041846A1 (en) | Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist | |
US20100329996A1 (en) | Novel Combination of Therapeutic Agents | |
AU2008259864C1 (en) | Methods and compositions for administration of Oxybutynin | |
KR20140041699A (en) | Combination comprising umeclidinium and a corticosteroid | |
KR20190099245A (en) | Pharmaceutical dosage forms containing TASK-1 and TASK-3 channel inhibitors, and their use in respiratory disorder therapy | |
US8748488B2 (en) | Methods and compositions for administration of oxybutynin | |
JP2004513099A (en) | Use of tolterodine for treating asthma | |
EP4126898A1 (en) | Budesonide 21-phosphate salts and pharmaceutical compositions containing the same | |
AU2013368298B2 (en) | Methods and compositions for administration of oxybutynin | |
JP2022508217A (en) | Methods for Producing Pharmaceutical Dosses Containing TASK-1 and TASK-3 Channel Inhibitors, and Their Use in the Treatment of Respiratory Disorders | |
WO2010097114A1 (en) | Novel combination of therapeutic agents | |
US20120101076A1 (en) | Carbonate derivatives for the treatment of cough | |
KR20050094810A (en) | Synergistic combination comprising roflumilast and (r,r)-formoterol | |
EP3338764A1 (en) | Pharmaceutical dosage forms containing inhibitors for task-1 and task-3 channels and their use in therapy of respiratory disorders | |
WO2014037727A1 (en) | Carcainium salts | |
EP3338803A1 (en) | Pharmaceutical dosage forms containing inhibitors for task-1 and task-3 channels and their use in therapy of respiratory disorders | |
WO2002019995A2 (en) | Pharmaceutical combination containing salmeterol and fluticasone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13867956 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2895955 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 239623 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2015/008333 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2015550444 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2013368298 Country of ref document: AU Date of ref document: 20131212 Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2013867956 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013867956 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201591218 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 20157020335 Country of ref document: KR Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015015421 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 112015015421 Country of ref document: BR Kind code of ref document: A2 Effective date: 20150625 |