CN104955444A - Methods and compositions for administration of oxybutynin - Google Patents
Methods and compositions for administration of oxybutynin Download PDFInfo
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- CN104955444A CN104955444A CN201380068230.5A CN201380068230A CN104955444A CN 104955444 A CN104955444 A CN 104955444A CN 201380068230 A CN201380068230 A CN 201380068230A CN 104955444 A CN104955444 A CN 104955444A
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- oxibutynin
- vitamin
- inhibitor
- xinafoate
- corticosteroid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The present invention is directed to methods and compositions for treating pulmonary disease comprising delivering directly to a patient's lungs a therapeutically effective amount of oxybutynin in combination with one or more pharmaceutically effective agents. Oxybutynin may be selected from the group consisting of, but not limited to, a xinafoate salt, a palmitate salt, a pamoic salt, a resonate salt, a laurate salt and other salts. The pharmaceutically effective agents comprise bronchodilators, antiinflammatories, corticosteroids, corticosteroid reversal agent or alveolar growth agents or other agents selected from proteinase or protease inhibitors.
Description
The present invention generally relate to use the new method of oxibutynin, the new model of oxibutynin and be designed for through lung approach send containing the novel form of oxibutynin.More specifically, the present invention includes the new model of the oxibutynin of the effective agent combination with one or more pharmacy.The present invention will describe especially in the following areas: lung is sent oxibutynin and is used for the treatment of respiratory system disease such as asthma and chronic obstructive pulmonary disease (COPD), although also consider other purposes such as preventative, therapeutic or improvement process incontinence and intestinal hypermotility (intestinal hypermotility) i.e. irritable bowel syndrome.
Oxibutynin is the racemic compound of chemical formula 4-diethylamino fourth-2-butyne base phenylcyclohexyl-oxyacetate:
Oxibutynin is the anticholinergic agents of overactive bladder (be hereafter called separately and be generically and collectively referred to as " urge incontinence ") being used for the treatment of urinary incontinence, urge incontinence, frequent micturition and incontinence traditionally.Oxibutynin is worked by the muscle spasm reducing bladder.The m-AChR of its antagonism of competition ground M1, M2 and M3 hypotype.It also has more weak direct spasmolysis to smooth muscle of bladder as calcium antagonist and local anesthetic, but far away higher than under the concentration of Clinical practice.It can be common dosage form and with the form of chloride salt with trade name
with
form and with the form of transdermal product, with in trade name
under patch or with at trade name GELNIQUE
tMunder gel form per os utilize.
Oxibutynin now with the form of tablet or multi-disc agent and syrup with oral preparation drug administration or with the form transdermal administration of patch or topical gel agent for treating urge incontinence.But the oral delivery of the oxibutynin of therapeutic activity amount has many shortcomings:
(1) with the oxibutynin of oral preparation drug administration change metabolism and undesirably high close rate situation under with less desirable slow and uneven speed from intestinal absorption, the metabolism wherein changed causes the less desirable change of blood level, and undesirably high close rate obtains therapeutic response and causes less desirable side effect;
(2) within the time that expectation is short, the high blood level of expectation is not produced with the oxibutynin of oral preparation drug administration;
(3) can cause not arriving target tissue in a large number with the oxibutynin of oral preparation drug administration, because it is consumed by metabolism or excretion;
(4) patient thus blocking malfunction to trouble gastrointestinal with the oxibutynin of oral dosage form administration due to the danger that there is urine retention is taboo; With
(5) need Chronic Administration with significant and serious side effect with the oxibutynin of oral preparation drug administration, comprise dry mouth (xerostomia), constipation, platycoria, blurred vision, drowsiness, nauseating, cardiopalmus, tachycardia and dizziness.
(6) stand first pass metabolism with the oxibutynin of oral preparation drug administration, cause the formation of metabolite N-desethyloxybutynin (DEO), this is the reason causing aforementioned most of side effect.
As a result, many patients have interrupted the treatment of per os anticholinergic.These untoward reaction are relevant to the relative high levels of the primary metabolite DEO of oxibutynin, and it is with the concentration circulating of about 4 (oxibutynin ER) to 10 (oxibutynin IR) parent compound doubly.Prove that DEO has higher affinity and in conjunction with the persistent period than the receptor of oxibutynin in salivary gland.In other words, proved that metabolite DEO has higher side effect and effect ratio than parent compound oxibutynin.The DEO level had been reported in per os and skin-penetrating therapeutic is respectively about 10-40ng/mL and 3ng/mL.In order to eliminate the side effect of this medicine completely, reduce DEO level in systemic circulation to will be favourable lower than the existing level (namely lower than 3ng/mL) found in the treatment.
And the oral administration of present oxibutynin also has other shortcoming, comprising:
(7) with the oxibutynin of oral dosage form administration with the form administration of tablet or multi-disc agent, it may lack the convenient drug administration of expectation, because some may not like swallow tablet, or the difficulty of swallow tablet may be had, or can not swallow tablet, or liquid may be needed to help swallow tablet; With
(8) tablet containing oxibutynin is also containing several non-active ingredient, comprise a large amount of lactose, corn starch, magnesium silicate, magnesium stearate and Pulvis Talci, these may be considered to less desirable, because some may not like in these non-active ingredients, one or more comprise oxibutynin tablet or irritated to it.
The transdermal delivery of oxibutynin has aforesaid many shortcomings.In addition, some patients suffer the skin irritation from transdermal patch, have any problem and keep and restrain oneself contacting of patch and skin, or do not like the aesthetics of transdermal patch.
Bronchoconstriction, pneumonopathy, as the mark of chronic obstructive pulmonary disease and asthma, comprises airway narrows (bronchus and bronchioles) in the lung that shrinks due to flesh.Usual flesh contraction is the result of muscarinic receptor activation on smooth muscle cell membrane.This causes the restriction of air flowing turnover lung and causes short of breath and overall dyspnea.
Pneumonopathy includes but not limited to, acute bronchitis, adult respiratory distress syndrome (ARDS), asbestosis, asthma, pulmonary atelectasis, aspergilliosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, byssinosis, chronic bronchitis, coccidioidomycosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, eosinophilic pneumonia, Hantavirus pulmonary syndrome, histoplasmosis, people's Metapneumovirus, hypersensitivity pneumonitis, influenza, pulmonary carcinoma, Lymphangiomatosis, mesothelioma, necrotizing pneumonia, Nontuberculosis mycobacteria (nontuberculosis Mycobacterium), pertussis, hydrothorax, pneumoconiosis, pneumonia, primary ciliary dyskinesia, primary pulmonary hypertension, pulmonary hypertension, pulmonary fibrosis, Pulmonary Vascular is sick, respiratory syncytial virus, sarcoidosis, Severe Acute Respiratory syndrome, pneumosilicosis, sleep apnea, sudden infant death syndrome, and tuberculosis.Modal pneumonopathy generally includes asthma, bronchitis, COPD, emphysema and pneumonia.
In all pneumonopathy, the most general seemingly COPD.Estimate in 2004 according to World Health Organization (WHO), 64 million peoples have COPD and 3 million peoples die from COPD.WHO predicts the year two thousand thirty COPD will become the whole world the 3rd underlying cause of death.Merck Manual (2011) provides to be had COPD the U.S. 1,000 2 million people and describes the COPD as the 4th underlying cause of death, and at 1980 52,193 people's death are compared, and cause at 2003 122, and 000 people is dead.From 1980 to 2000 years, COPD mortality rate increased by 64% (from 40.7 to 66.9/100,000).Sickness rate, incidence rate and mortality rate increased with the age, although and sickness rate is higher in man, general mortality rate is similar in two kinds of sexes.Incidence rate and mortality rate usually Caucasian, blue-collar worker, be subject in the people of more juvenile regular education higher, probably because these colonies have higher smoking prevalence rate.Because increasing in developing country's smoking, due to the mortality rate reduction of infectious disease and widely using of biomass fuel, COPD is more and more in the whole world.
The therapeutic agent of present COPD mainly comprises the bronchodilator through inhalation, comprises the β that induction type is long-acting
2-agonist (LABA) or long-acting muscarine antagonist (LAMA).Although oxibutynin is a kind of LAMA, also do not develop the effective medicament forms with oxybutynin therapy COPD or medication up to now.The disease of known many respiratory tracts responds to the treatment by direct administering therapeutic agent.Because these reagent obtain the most in dry powder form, therefore their most convenient of using has been come by per nasal or mouth inhalation of dust material.This powder type can cause the more good utilisation of medicine, because medicine is accurately deposited on the site of expectation and it may need the place that acts on; Therefore, the atomic little dosage of this medicine is usually equally effective with the larger dose passing through alternate manner administration, and result is that the incidence rate of less desirable side effect and medicine cost significantly reduce.In addition, the medicine of dry powder form may be used for treating the disease except respiratory system or pulmonary system.When medicine deposits on the very high surface area of lung, it may very fast absorbing in blood flow go; Therefore, this application process can replace the administration by injection, tablet or other usual manner.
Although considered the ditropan XL compositions administration in dry powder form of some forms, this form was not also had successfully to put into practice.Still the clinical effective oxybutynin therapy compositions with having approximate physiological chemical property is needed.
Therefore, need sending of the oxibutynin improved, compared with oral or transdermal dosage form, the active onset that it can provide the bioavailability of increase, minimized blood level changes and obtain faster, and compare with transdermal delivery means with the present per os using oxibutynin simultaneously relative convenient drug administration and the side effect of reduction are provided.
Aforementioned object of the present invention and other object by provide by oxibutynin through lung be delivered to mammalian hosts, particularly people patient method and composition, while above-mentioned and other shortcoming avoiding per os and transdermal administration, provide the quick absorption of oxibutynin thus and realize.More specifically, the present invention relates to and be used for the treatment of novel form and the compositions that lung and respiratory system disease include but not limited to the oxibutynin of chronic obstructive pulmonary disease and asthma.In certain embodiments, the invention still further relates to the physiological function obstacle improving and cause the basis of pneumonopathy.The invention provides by using in check site to send specific air flue therapeutic agent being effectively applied to lung.
More specifically, the present invention has been found that compositions containing oxibutynin is effectively applied to mammal reacts with excitation therapy systemic metabolism product is significantly reduced while by sending with the lung of lower dosage level.Should be appreciated that the significant contributor of the detrimental effect of oxibutynin is the system level of metabolite DEO.The contribution of DEO to the increase of side effect is due to its affinity higher to the receptor in non-target tissue and salivary gland.In addition, compare with transdermal administration process with the traditional per os being used for the treatment of urinary incontinence, the present invention can provide the bioavailability of increase, the convenience obtaining active onset faster and use.The lung of oxibutynin sends the alleviation and treatment urinary incontinence and treatment stress urinary incontinence and intestinal hypermotility (intestinal hypermotility) the i.e. alleviation of irritable bowel syndrome that provide treatment respiratory system disease such as chronic obstructive pulmonary disease (COPD) and asthma.The present invention also provides the new model of oxibutynin and uses novel form and the therapeutic scheme of oxibutynin.
Other features and advantages of the present invention by by following detailed description, find out together with accompanying drawing, wherein:
Accompanying drawing 1 describes oxibutynin and oxibutynin salt at 18 hours suppression figure to the bronchoconstriction of methacholine induction.More specifically, after employing ANOVA, Dunnetts inspection compares the change of the bronchoconstriction of the animal of oxybutynin therapy and the lactose control animal of time match.**P<0.01。
Accompanying drawing 2 compares oxibutynin, oxibutynin salt, tiotropium bromide (tiotropium) and glycopyrronium bromide 18 hours and the suppression to the bronchoconstriction of methacholine induction in 24 hours.More specifically, accompanying drawing 2 is depicted in lactose (2mg, i.t., n=6), oxibutynin alkali (2mg, i.t., n=6), oxibutynin HCl (2.5mg, i.t., n=6), oxibutynin xinafoate (3mg, i.t., n=6), tiotropium bromide (1mg/kg, i.t., n=6) or glycopyrronium bromide (1mg/kg, i.t., n=6) after administration 18 and the comparison diagram of bronchoconstriction that brings out of 24h methacholine (MCh, 10 μ g/kg, i.v.).Each represents meansigma methods and vertical line represents standard error meansigma methods.Dunnetts inspection after ANOVA is adopted to compare the change of bronchoconstriction of the animal (Cavia porcellus of anesthesia) of oxibutynin or tiotropium bromide in treating and the lactose control animal of time match.**P<0.01。
Control reaction time dependent a series of chart on lung expansion pressure, mean arterial blood pressure and heart rate that accompanying drawing 3 brings out methacholine for comparing oxibutynin xinafoate and tiotropium bromide.More specifically, accompanying drawing 3 is depicted in methacholine (10 μ g kg under the existence of lactose (i.t., n=6), oxibutynin xinafoate (7.5%w/w, i.t., n=6) or tiotropium bromide (1mg, i.t., n=6)
-1, i.v.) and the control reaction brought out (h) comparison diagram of changing in time on lung expansion pressure (PIP), mean arterial blood pressure (MAP) and heart rate (HR).Each point represents meansigma methods and vertical bar represents standard error meansigma methods.Dunnetts inspection after ANOVA is adopted to compare the percentage ratio change of the animal of oxibutynin or tiotropium bromide in treating and each lactose control animal (Cavia porcellus of anesthesia).*P<0.05,**P<0.01。
Accompanying drawing 4 represents the time dependent pharmacokinetics of oxibutynin pulmonary administration.More specifically, anaesthetized guinea pig (n=5) the pharmacokinetic curve figure of oxibutynin, oxibutynin enantiomer and major metabolite (desethyloxybutynin) after dry powder sprays described by accompanying drawing 4.
Accompanying drawing 5 and 6 provides 1H NMR and FT-IR structural analysis.
Accompanying drawing 7 provides HPLC to analyze.
Fig. 8 and 9 provides the degree of crystallinity, compound purity and the fusing point that are measured by XRPD and DSC.
The present invention is by being easier to understand with reference to the detailed description of the following specific embodiments be included in herein.With reference to accompanying drawing, wherein accompanying drawing forms a application's part, and shows multiple embodiment disclosed in the present application in the accompanying drawings by way of example.Although the present invention describes by reference to the detail of its some embodiment, and be not intended to such details and should be considered to limitation of the scope of the invention.Which is hereby incorporated by reference for the full text of the list of references mentioned in the application, comprises the application serial 12/130,903 of the u.s. patent application serial number submission on May 30th, 12/904,964 and 2008 submitted on October 14th, 2010.The u.s. patent application serial number 13/246 of JIUYUE in 2011 submission on the 27th, 686 are also incorporated herein by reference.
The lung of oxibutynin can be advantageously used to be delivered to the symptom of respiratory tract therapeutic respiratory tract disease, urge incontinence and stress urinary incontinence.From there is remarkable side effect need Chronic Administration and need a few hours to reach traditional oxibutynin per os of therapeutic activity blood level different with transdermal delivery, the dry powder lung of oxibutynin is sent and is allowed patient to enjoy remarkable compared with the side effect simultaneously of the alleviation under low dosage reduction as corresponding in dry mouth.The dry powder lung of oxibutynin sends the symptom alleviation also allowing patient to enjoy stress urinary incontinence more immediately or as required.Similarly, the dry powder lung of oxibutynin sends the preventative alleviation allowing patient to obtain respiratory distress symptom as required.
The features and advantages of the present invention of being sent generation by the lung of oxibutynin are being formed of the typical primary metabolite avoiding DEO widely, and this is the adverse side effect produced by it as mentioned above.
In addition, we have found that some salt of oxibutynin, produce when sending administration through lung than the oral delivery half-life be only 2.5 little time expection the significantly more long-acting effect of effect.These salt comprise the new salt form of oxibutynin, the xinafoate of the oxibutynin namely also do not reported in the literature up to now.Such as, the medication of all oxibutynin, because relatively short half-life of 2.5 hours are simultaneously the plateau of about eight (8) little medicines minimally constantly, typically is every day three times.On the other hand, the lung of oxibutynin salt sends the persistent period unexpectedly providing maximum 18 hours activity in Guinea pig lung, and it is converted into people's dosed administration every day one to twice.This shows in fig. 1.
The xinafoate of oxibutynin reacts to prepare by making oxibutynin and former times naphthoic acid (xinafoic acid) under inertia (nitrogen) atmosphere in methyl tertiary butyl ether(MTBE).Other oxibutynin salt sending administration by lung comprises palmitate, pamoic acid, resinate, laruate and stearate, also comprise the ester of oxibutynin (oxybutnin), and beyond thought result can be produced: the metabolite of the half-life of improvement and the bad of reduction produces.
Be used for the treatment of in the preferred configuration of the oxibutynin of administration in selection, the present inventor considers several character of various oxibutynin salt, includes but not limited to following:
Dissolubility-> PK, bioavailability, and the change of dissolution rate.
Surface energy-> aerosolized (dispersibility), (granule) physical stability
Hydration status-> stability, dissolubility
Kinetics-> the stability of degraded
Hardness of crystals-> micronization, physical stability
Hygroscopicity-> processes, stability
Stripping
Fusing point
Dosage form leaved for development
Route of administration
Carrying capacity in dosage form
The toxicology of counter ion counterionsl gegenions, especially lung toxicology
As free alkali, oxibutynin is poorly soluble and be lipophilic, has water solublity and the log P of 0.01mg/mL and 3.3 respectively.In order to improve drug solubility, oral oxibutynin being mixed with hydrochlorate, improving gastric solubility to 20mg/mL (measuring under pH4) (see United States Patent (USP) 6,087,396).In order to send by lung, the present inventor has developed the strategy substituted, and wherein devises poor solubility, more lipophilic salt form.It has been observed that the potentiality of dissolution rate and lipotropy combination in vivo slowly can absorb in body circulation in prolong drug retention and delay in lung before.Corticosteroid triamcinolone acetonide and fluticasone propionate have shown distinguishes 2.9 hours and mean absorption time (Patton (2007) Nature Reviews in Drug Discovers, V6, p67-74) in the lung of 5-7 hour.In order to improve lung retention potentiality, synthesize former times naphthoic acid (xinafoate) salt of oxibutynin.Attempt other Lipophilic salts, as stearate and palmitate; But, be determined through experimentation with oxibutynin and former times naphthoic acid the thermodynamic driving force that represents of pKa difference (8.24 to 2.7) more will may cause the formation of salt.
Before carrying out salt study on the synthesis, evaluate the dissolubility (table 1) of oxibutynin in various organic solvent.These solubility studies show the many potential solvent that will use in salt building-up process; But only methyl tertiary butyl ether(MTBE) (MTBE) produces crystalline salt and acceptable productive rate.Synthesis and method for crystallising are improved by the method (United States Patent (USP) 6,140,529) for the synthesis of ditropan XL and form.In patented method, ethanol is joined in MTBE with deposited salt crystal; But, because xinafoate may be poorer than hydrochloride salt many, thus use the precipitation of water induction oxibutynin xinafoate.Result and the explanation of all salt compound experiments gather in table 2.Embodiment 3 describes the method for the synthesis of oxibutynin xinafoate.Table 1: the dissolubility of oxibutynin in various organic solvent
Table 2: salt compound experiment
The preferred embodiment of the invention comprises the method and composition for the treatment of pneumonopathy, comprises the lung oxibutynin of the treatment effective dose with the effective agent combination of one or more pharmacy being directly delivered to patient.In certain embodiments, oxibutynin and the effective reagent of pharmacy are sent in dry powder form.Dry powder oxibutynin can be selected from but be not limited to xinafoate, palmitate, embonate, resinate (resonate), laruate and other salt.The effective reagent of pharmacy comprises bronchodilator, anti-inflammatory agent, corticosteroid, corticosteroid reverse (CR) agent, alveolar growth stimulator or is selected from other reagent of proteolytic enzyme or protease inhibitor.
In certain preferred aspects, bronchodilator comprises long-acting and fugitive beta-agonists and their derivant or officinal salt.Anti-inflammatory agent can comprise induction type corticosteroid, phosphodiesterase inhibitor or LTRA.In addition, corticosteroid can comprise budesonide, fluticasone, beclometasone, flunisolide, mometasone, triamcinolone, ciclesonide, loteprednol, fluorometholone and their derivant or officinal salt.
Alternative embodiment optionally comprises corticosteroid inversion agent, and it comprises vitamin D, synthesis of vitamin d, novel vitamin D analogues, Vitamin D receptor agonist, vitamin D receptor partial agonist, calcitriol, antioxidant, iNOS inhibitor, phosphoinositide-3-kinases-δ inhibitor, p 38 map kinase inhibitor, jnk inhibitor, MIF inhibitor, low-dose theophylline, p-glycoprotein inhibitors, macrolide, calcineurin inhibitor, Statins and their equivalent.In addition, alveolar growth stimulator can comprise vitamin A, all-trans retinoic acid (ATRA), retinoic acid receptors (RAR) agonist and RAR selectivity alveolar growth stimulator, RAR selective agonist, para Luo Ting and their equivalent.
In preferred embodiments, the present invention includes the method and composition for the treatment of pneumonopathy, it comprises the lung oxibutynin of the treatment effective dose combined with LABA being directly delivered to patient, and wherein oxibutynin exists with the form of oxibutynin xinafoate and LABA is selected from and includes but not limited to formoterol, salmaterol, odalaterol, Ka Moteluo, Wei Lanteluo (vilanterol).
In preferred embodiment as an alternative, the present invention includes the method and composition for the treatment of pneumonopathy, it comprises the lung oxibutynin of the treatment effective dose combined with LABA being directly delivered to patient, wherein oxibutynin exists with the form of oxibutynin xinafoate and LABA is selected from and includes but not limited to formoterol, salmaterol, odalaterol, Ka Moteluo, Wei Lanteluo (vilanterol), and comprise induction type corticosteroid (ICS) further, wherein ICS comprises budesonide, fluticasone, mometasone, or be selected from the selective agent such as ciclesonide or loteprednol of ' soft steroid ' classification in addition.
In preferred embodiment as an alternative, the present invention includes the method and composition for the treatment of pneumonopathy, it comprises the lung oxibutynin of the treatment effective dose combined with LABA being directly delivered to patient, and comprise CR inversion agent further, wherein oxibutynin exists with the form of oxibutynin xinafoate, LABA is selected from and includes but not limited to formoterol, salmaterol, odalaterol, Ka Moteluo, Wei Lanteluo (vilanterol) and CR inversion agent are selected from and include but not limited to vitamin D, novel vitamin D analogues, synthesis of vitamin d, Vitamin D receptor agonist and antagonist, calcitol and their equivalent.
In preferred embodiment as an alternative, the present invention includes the method and composition for the treatment of pneumonopathy, it comprises the lung oxibutynin of the treatment effective dose combined with LABA, CR inversion agent being directly delivered to patient; And comprise ICS further, wherein oxibutynin exists with the form of oxibutynin xinafoate; LABA is selected from and includes but not limited to formoterol, salmaterol, odalaterol, Ka Moteluo, Wei Lanteluo; CR inversion agent is selected from and includes but not limited to vitamin D, novel vitamin D analogues, synthesis of vitamin d, Vitamin D receptor agonist and antagonist, calcitol and their equivalent; And ICS is selected from the selective agent including but not limited to budesonide, fluticasone, mometasone or be selected from ' soft steroid ' classification in addition.
In preferred embodiment as an alternative, the present invention includes the method and composition for the treatment of pneumonopathy, it comprises the lung oxibutynin of the treatment effective dose combined with LABA, alveolar growth stimulator being directly delivered to patient, and wherein LABA comprises formoterol and alveolar growth stimulator is selected from and includes but not limited to ATRA, cis-retionoic acid and para Luo Ting.
Above-mentioned embodiment can adopt Diskus (DPI) to send, and wherein DPI comprises pressure vibration device, metered dose inhaler (MDI) or liquid dispenser.In addition, the therapeutic combination of above-mentioned embodiment can be sent in dry powder form, and wherein dry powder has the mass median aerodynamic granularity being selected from 0.5-20 micron, 0.5-15 micron, 0.5-10 micron or 0.5-5 micron.With the dosage of the oxibutynin of the treatment effective dose of the effective agent combination of one or more pharmacy in the scope of 0.001 to 20mg every day, 0.02 to 15mg every day or 0.05 to 10mg every day, administration as required.
Term and definition
The term " oxibutynin " used in the application refers to the oxibutynin not only comprising anhydrous powder form, and comprise spasmolytic, the anticholinergic activity and be nontoxic and the pharmacologically salt of acceptable any oxibutynin or derivant, such as oxibutynin xinafoate or ditropan XL with similar oxibutynin.Other suitable salt includes but not limited to palmitate, pamoic acid, resinate (resonate) and laruate.
" effective dose " that use in the application, for the amount to treatment pneumonopathy, urinary incontinence or irritable bowel syndrome drug composition effective, namely have the amount of the oxibutynin be suitable in systemic the defined aerodynamic particle size of lung, it can reduce or eliminate COPD, asthma, urinary incontinence and stress incontinence.
" pharmaceutical composition " that use in the application, refers to be used for the treatment of mammiferous medicine, and it comprises and is suitable for being applied to the mammiferous oxibutynin with the dry powder form of defined aerodynamic particle size prepared in a certain way through lung.Pharmaceutical composition of the present invention also can but must not comprise nontoxic pharmaceutically suitable carrier.
" aerodynamic particle size defined " that use in the application, refers to have the granule being small enough to the size being delivered to lung.In order to most desirably be delivered to lung, the oxibutynin of dry powder form preferably should micronization or spraying dry to the mass median aerodynamic diameter powder size of 0.05-20 micron, 0.5-15 micron, 0.5-10 micron or 0.5-5 micron.But, also advantageously can use other method preparing controlled size granule such as supercritical fluid method, in check precipitation etc.
" the treatment effective dose " that use in the application by with individuality age, body weight and overall physical condition, the frequency of medication, the order of severity, asthma, the incontinence of COPD and whether treating appetency or stress incontinence or irritable bowel syndrome and changing.Generally for treatment respiratory system disease, treatment effective dose will comprise the active component of amount of 0.001 to 20mg every day, 0.02 to 15mg every day or 0.05 to 10mg every day, administration as required.Usually, in order to treat urge incontinence, treatment effective dose will comprise the active component of 1 to 20mg/ sky, the preferably amount in 1 to 10mg/ sky.Active component can give once a day.But preferably, active component is by with less dosage one day twice or three times or more to maintain more consistent blood plasma level.When being used for the treatment of stress incontinence or irritable bowel syndrome, therapeutic dose by comprising the active component of 0.1 to 15mg every day, the preferably amount in 0.2 to 10mg/ sky, usually with single dose or administration as required.Active component can give once a day.But preferably, active component is by with less dosage one day twice or three times or more to maintain more consistent blood plasma level.
Oxibutynin can be sent in dry powder form, such as, send through Diskus (DPI), metered dose inhaler (MDI), or is dissolved in suitable liquid for being atomized to treat effective unit dose delivering amount.In order to treat the acute symptom of respiratory distress, the oxibutynin of doses should be absorbed when the initial sign of respiratory distress.Poverty-stricken in order to treat chronic respiratory, the scheme should recommended according to doctor absorbs oxibutynin every day.Similarly, the symptom for the treatment of stress urinary incontinence, should stress sign initial or when urgent sign the earliest show effect or just expect stress show effect before such as absorb the oxibutynin of doses before giving a lecture just before audience faced by patient is scheduled.In a preferred embodiment of the present invention, dry powder oxibutynin packaging is used for sending in pressure electronic Diskus (as be described in United States Patent (USP) 6,026, in 809).The term " thin drug particles " used in the application and " aerodynamic particle size ", refer to have the granule being small enough to be delivered to lung airway, being especially delivered to the size of small airway.In order to most desirably be delivered to lung, the therapeutic agent of the dry powder form described in the application preferably should micronization, spraying dry or be processed into 0.01 μm to 20 μm, 0.25 μm to 5 μm or 0.5 μm to the maximum aerodynamic particle size within the scope of 4 μm.
The term that uses in the application " reverses the reagent of CR " and refers to and comprises when with will any reagent of anti-inflammatory response of enhancing corticosteroid-induced during effect level administration.This term is not only applicable to reverse the reagent of CR, and is applicable to have the activity that reverses CR and is nontoxic and pharmacologically any salt of acceptable described reagent or derivant.
The CR inversion agent used in the application, includes but not limited to vitamin D, novel vitamin D analogues, synthesis of vitamin d, Vitamin D receptor agonist and antagonist, calcitol, theophylline and their equivalent.In CR inversion agent well known by persons skilled in the art is also included within.
The term " vitamin D " used in the application refers to and comprises vitamin D, vitamin D2, vitamin D3, novel vitamin D analogues, synthesis of vitamin d, Vitamin D receptor agonist and antagonist, calcitriol, calcitol and their equivalent.
The term " vitamin A " used in the application refers to and comprises those and retinoic acid receptors (RAR) interactional reagent, includes but not limited to ATRA, ATRA derivant, RAR agonist, Accutane and RAR selective agonist such as para Luo Ting.
The term " alveolar growth stimulator " used in the application refers to any reagent comprising and promote new alveolar to grow by retinoic acid receptors, and comprises the treatment of ATRA or RAR selective agent.
The term " alveolar maintaining agent " used in the application refers to and comprises when will strengthen any reagent of anti-inflammatory response during effective level administration, and any less desirable effect that wherein inflammatory reaction is treated by COPD, COPDe and emphysema and ATRA or RAR selective agent is brought out.This term is not only applicable to the reagent for alveole maintenance, and is applicable to have shares activity and is nontoxic and pharmacologically any salt of acceptable described reagent, hydrate, prodrug or derivant.
The bronchiectasis material used in the application includes but not limited to β 2-agonist (fugitive and long-acting, LABA), long-acting muscarine antagonist (LAMA), cholilytic drug (fugitive) and theophylline (long-acting)." co-administered " that use in the application, refers to send more than one medicines or therapeutic agent, such as, in same breathing, send the corticosteroid of aerosol form through lung approach and reverse two kinds of reagent of CR.
For effectively obtaining, " effective dose " that use in the application, expects that therapeutic effect includes but not limited to the amount of the pharmaceutical composition that bronchiectasis, CR reverse, anti-inflammatory, alveolar regenerate.Such as, the reagent of the reverse CR of effective dose can comprise can reduce or eliminate to the resistance of corticosteroid, be suitable at the systemic calcitriol within the scope of defined aerodynamic particle size, specified quantitative of lung.
" medicine " and " treatment " agent used in the application includes but not limited to be administered for any and all medicines for the treatment of pneumonopathy and medicament and preparation, comprises for prophylactic reagent and the reagent that comprises for maintaining disease condition improvement.As used in this application, such therapeutic agent and medicament include but not limited to, corticosteroid, muscarine antagonist, macrolide, with NSAID (non-steroidal anti-inflammatory drug) (NSAID), antioxidant, iNOS inhibitor, phosphoinositide-3-kinases-δ inhibitor, p 38 map kinase inhibitor, jnk inhibitor, MIF inhibitor, p-glycoprotein inhibitors, macrolide, calcineurin inhibitor, and vitamin D, synthesis of vitamin d, novel vitamin D analogues, calcitiol, vitamin A, all-trans retinoic acid (ATRA), retinoic acid receptors (RAR) agonist, RAR selectivity alveolar growth stimulator, budesonide, fluticasone, beclometasone, flunisolide, triamcinolone, mometasone, ciclesonide, loteprednol, fluorometholone and their any derivant, equivalent or officinal salt.
" medicine " or " treatment " compositions used in the application, refers to the medicine being used for the treatment of patient, such as, be suitable for through lung having of being applied to prepared by the mode of patient the reagent of reverse CR of dry powder form of definition aerodynamic particle size.Pharmaceutical composition of the present invention optionally can comprise nontoxic pharmaceutically suitable carrier." medicine " or " treatment " compositions can comprise single entity (namely independent calcitriol) or be selected from the combination of CR inversion agent, antibiotic medicine, bronchodilator, alveolar growth stimulator and other compositions in certain embodiments.
It should be emphasized that the above-mentioned embodiment of equipment of the present invention and method, special and " preferably " embodiment, be only the example that possible implement and carry out setting forth the principle be only used to disclosed in clear understanding.This improvement of all these and other and change are all intended to be included in the scope that disclosed in the present application and following claim protects in this application.Therefore scope disclosed in the present application is not intended to be restricted, except claims describe.
Following specific embodiment is by example the present invention, because it is applicable to the Therapeutic Method adopting inhaler.Be to be understood that the less change that other embodiment comprises method will be apparent for a person skilled in the art, and the invention is not restricted to these concrete exemplified embodiments.
Embodiment
Embodiment 1
The micronization of oxibutynin
The oxibutynin of crystal form is micronized to median aerodynamic granularity lower than 10 microns.Powder packaging according to United States Patent (USP) 6, in the Diskuses (DPI) of 026,809 preparations.
Embodiment 2
The micronization of oxybutynin chloride
Adopt median aerodynamic granularity lower than the micronized oxybutynin chloride replacement oxibutynin of 5 microns, repeat embodiment 1.
Embodiment 3
The preparation of oxibutynin xinafoate
Adopt the micronized oxibutynin xinafoate of maximum aerodynamic particle size about 10 microns to replace oxibutynin, repeat embodiment 1.Oxibutynin xinafoate is prepared as follows: 250mL round-bottomed flask is installed magnetic stirring apparatus, thermocouple and nitrogen inlet adapter.Under a nitrogen, flask is loaded oxibutynin (20.04g, 0.056mol.), former times naphthoic acid (10.69g.0.057mol.1.02 equivalent) and methyl tertiary butyl ether(MTBE) (100mL, 5 volumes).Solid almost dissolves immediately at about 18 DEG C.This batch of material is warmed to 50 DEG C, and at about 21 DEG C, starts crystallization.Mixture is remained on 50 DEG C one hour, be cooled to 33 DEG C in atmosphere, then in ice bath, be cooled to 3 DEG C.Mixture remained on < 5 DEG C one hour and filter, and filter cake methyl tertiary butyl ether(MTBE) (100mL) is washed.By wet cake in vacuum drying oven in 45 DEG C of dryings one hour.
After salt synthesis, structure confirms (accompanying drawing 5 and 6) by 1H NMR and FT-IR.HPLC analyzes and confirms > 99% effect (accompanying drawing 7) by the quantification of the AUC when 15.1min.Also determine degree of crystallinity, compound purity and fusing point (accompanying drawing 8 and 9) by XRPD and DSC.Two tests high crystalline material of instruction (DSC does not detect cold crystallization), wherein fusing point is 105 DEG C.Be 0.057% by KF titration determination water content.
Embodiment 4
The comparative effectiveness of bronchodilator
Adopt the micronized oxibutynin alkali of maximum aerodynamic particle size about 10 microns, ditropan tablete and oxibutynin xinafoate to replace oxibutynin, repeat embodiment 1.The level of the bronchodilator activity of oxibutynin and tiotropium bromide and glycopyrronium bromide were compared in after administration 18 and 24 hours in anaesthetized guinea pig.Attached Fig. 1 and 2 is presented at the comparative effectiveness of the oxibutynin that lung on anaesthetized guinea pig is sent.
Embodiment 5
The comparative effectiveness of bronchodilator: oxibutynin xinafoate and other bronchodilator
Adopt the micronized oxibutynin xinafoate of maximum aerodynamic particle size about 10 microns to replace oxibutynin, repeat embodiment 1.The onset of action of oxibutynin xinafoate and the system level of generation were compared with tiotropium bromide in after administration initial 6 hours in anaesthetized guinea pig.The oxibutynin that accompanying drawing 3 initial 6 hours lungs are more after administration sent and the effect of tiotropium bromide on anaesthetized guinea pig.Oxibutynin shows the protective effect of the airway contraction of similar to tiotropium bromide anti-methacholine induction, but, not with the tiotropium bromide equally significant impact on cardiovascular disorder.The pharmacokinetics that the oxibutynin that Fig. 4 shows pulmonary administration produces.The system level of being sent the DEO of generation by lung is more much lower than clinical relevant level lower than the LOQ of detection method.
Can change when not deviating from the spirit and scope of invention described above.Such as, oxibutynin can with other compound or reagent co-administered to reduce adverse side effect or to process side effect.Such as, the cholinergic agonist described in cholinergic agonist such as PCT US09/034018 can with oxibutynin co-administered to reduce dry mouth effect.
conclusion
As required the micronized particle of oxibutynin being directly delivered to lung, can finding to provide alleviation to suffering from the patient of respiratory system disease as asthma and COPD and trouble urge incontinence and stress urinary incontinence symptom and irritable bowel syndrome.
In the guinea pig model of bronchoconstriction, find that oxibutynin has the significant bronchus protective effect of 0.25 to 24 hour, and to arterial pressure and heart rate, not there is long remarkable effect.
The pulmonary administration of oxibutynin is also avoided firstly crossing the remarkable formation of primary metabolite DEO and reducing adverse side effect significantly thus, and wherein to use oxibutynin to per os or transdermal delivery traditionally relevant for adverse side effect.In addition, the dosage of oxibutynin when the dosage of the oxibutynin that lung route of delivery is used significantly is sent lower than per os or transdermal delivery approach.In addition, the lung of oxibutynin is sent and is caused long treatment level in lung, and this will allow once a day or twice medication compared with the oral delivery of the oxibutynin of typically three administrations every day.
Although the present invention is according to it, some preferred embodiment has been described in detail in this application, and those skilled in the art can carry out many improvement and change wherein.Therefore, be intended to claims and cover this improvement and change that likely fall within the spirit and scope of the present invention.
Claims (15)
1. treat a method for pneumonopathy, comprise the lung oxibutynin of the treatment effective dose with the effective agent combination of one or more pharmacy being directly delivered to patient.
2. method according to claim 1, wherein oxibutynin and/or the effective reagent of pharmacy are sent in dry powder form.
3., according to the method for claim 1 or claim 2, wherein dry powder oxibutynin is selected from xinafoate, palmitate, embonate, resinate (resonate) and laruate.
4., according to the method for claim 1 or claim 2, wherein oxibutynin comprises oxibutynin xinafoate.
5. the method for any one of claim 1-4, the effective reagent of its Chinese materia medica comprises bronchodilator, anti-inflammatory agent, corticosteroid, induction type corticosteroid, corticosteroid inversion agent, alveolar growth stimulator, proteinase inhibitor or protease inhibitor.
6. the method for claim 5, the effective reagent of its Chinese materia medica is selected from bronchodilator and comprises long-acting beta-agonist and fugitive beta-agonists and their derivant or officinal salt, or induction type corticosteroid, phosphodiesterase inhibitor or LTRA, or corticosteroid comprises budesonide, fluticasone, beclometasone, flunisolide, triamcinolone, ciclesonide, loteprednol, fluorometholone, with their derivant or officinal salt, or corticosteroid inversion agent comprises vitamin D, synthesis of vitamin d, novel vitamin D analogues, Vitamin D receptor agonist, vitamin D receptor partial agonist, calcitriol, antioxidant, iNOS inhibitor, phosphoinositide-3-kinases-δ inhibitor, p 38 map kinase inhibitor, jnk inhibitor, MIF inhibitor, low-dose theophylline, p-glycoprotein inhibitors, macrolide, calcineurin inhibitor, Statins and equivalent thereof, or alveolar growth stimulator comprises vitamin A, all-trans retinoic acid (ATRA), retinoic acid receptors (RAR) agonist and RAR selectivity alveolar growth stimulator, RAR selective agonist, para Luo Ting and equivalent thereof.
7. the method for claim 6, wherein oxibutynin comprises oxibutynin xinafoate (xinofoate) and long-acting beta-agonist comprises formoterol, salmaterol, odalaterol, Ka Moteluo or Wei Lanteluo.
8. the method for claim 7, also comprise induction type corticosteroid, wherein induction type corticosteroid comprises budesonide, fluticasone or mometasone, and optionally also comprise the selective agent being selected from soft steroid classification, wherein soft steroid classification comprises ciclesonide or loteprednol and/or CR inversion agent, and wherein CR inversion agent is selected from vitamin D, novel vitamin D analogues, synthesis of vitamin d, Vitamin D receptor agonist and antagonist, calcitol and their equivalent.
9. the method for claim 1,
Wherein oxibutynin comprises oxibutynin xinafoate (xinofoate),
The effective reagent of pharmacy comprises
Long-acting beta-agonist, comprises formoterol,
With alveolar growth stimulator, be selected from ATRA, cw-retinoic acid (retionoic acid) and para Luo Ting.
10. the method for any one of claim 1-9, wherein pneumonopathy comprises asthma, pulmonary atelectasis, bronchitis, chronic obstructive pulmonary disease, emphysema, pulmonary carcinoma, pneumonia or pulmonary edema.
11. the process of claim 1 wherein that pneumonopathy comprises chronic obstructive pulmonary disease,
Wherein oxibutynin comprises oxibutynin xinafoate (xinofoate),
The effective reagent of its Chinese materia medica comprises
Long-acting muscarine antagonist.
12. according to the method for any one of claim 1-11, and wherein oxibutynin and the effective reagent of pharmacy adopt Diskus (DPI) or metered dose inhaler (MDI) or liquid dispenser to send.
13. methods according to claim 12, wherein Diskus comprises pressure vibration device.
14. according to the method for any one of claim 1-13, wherein oxibutynin is sent in dry powder form, there is the mass median aerodynamic granularity being selected from 0.5-20 micron, 0.5-15 micron, 0.5-10 micron or 0.5-5 micron, and/or the dosage of the oxibutynin of the treatment effective dose wherein combined with one or more pharmacy potent agents is in the scope of 0.001 to 20mg every day, 0.02 to 15mg every day or 0.05 to 10mg every day, administration as required.
15. 1 kinds of methods for the treatment of chronic obstructive pulmonary disease, comprise the lung oxibutynin of the treatment effective dose with the effective agent combination of one or more pharmacy being directly delivered to patient, wherein oxibutynin is preferably selected from xinafoate, palmitate, embonate, resinic acid (resonate) salt and laruate.
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| US13/728,706 | 2012-12-27 | ||
| US13/728,706 US9119777B2 (en) | 2008-05-30 | 2012-12-27 | Methods and compositions for administration of oxybutynin |
| PCT/US2013/074759 WO2014105446A1 (en) | 2012-12-27 | 2013-12-12 | Methods and compositions for administration of oxybutynin |
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| CN104955444A true CN104955444A (en) | 2015-09-30 |
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| JP (1) | JP2016504358A (en) |
| KR (1) | KR20150100902A (en) |
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| EP1191930A2 (en) * | 1999-05-20 | 2002-04-03 | Sepracor Inc. | Methods for treatment of asthma using s-oxybutynin |
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| WO2009134524A2 (en) * | 2008-02-26 | 2009-11-05 | Elevation Pharmaceuticals, Inc. | Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations |
| GB0918450D0 (en) * | 2009-10-21 | 2009-12-09 | Innovata Ltd | Composition |
| CA2812952A1 (en) * | 2010-09-27 | 2012-04-12 | Microdose Therapeutx, Inc. | Methods and compositions for disease treatment using inhalation |
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2013
- 2013-12-12 NZ NZ628479A patent/NZ628479A/en not_active IP Right Cessation
- 2013-12-12 KR KR1020157020335A patent/KR20150100902A/en not_active Application Discontinuation
- 2013-12-12 CA CA2895955A patent/CA2895955A1/en not_active Abandoned
- 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 BR BR112015015421A patent/BR112015015421A2/en not_active IP Right Cessation
- 2013-12-12 EA EA201591218A patent/EA201591218A1/en unknown
- 2013-12-12 CN CN201380068230.5A patent/CN104955444A/en active Pending
- 2013-12-12 AU AU2013368298A patent/AU2013368298B2/en not_active Ceased
- 2013-12-12 MX MX2015008333A patent/MX2015008333A/en unknown
- 2013-12-12 WO PCT/US2013/074759 patent/WO2014105446A1/en active Application Filing
- 2013-12-20 UY UY0001035230A patent/UY35230A/en not_active Application Discontinuation
- 2013-12-27 AR ARP130105037A patent/AR094287A1/en unknown
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2015
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2016
- 2016-03-23 HK HK16103431.3A patent/HK1215396A1/en unknown
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| WO2002009679A2 (en) * | 2000-08-02 | 2002-02-07 | F. Hoffmann-La Roche Ag | Use of 13-cis retinoic acid for the treatment of emphysema |
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| US20110253133A1 (en) * | 2008-05-30 | 2011-10-20 | Martin Michael J | Methods and compositions for administration of oxybutynin |
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| WO2011120779A1 (en) * | 2010-04-01 | 2011-10-06 | Chiesi Farmaceutici S.P.A. | Process for preparing carrier particles for dry powders for inhalation |
Also Published As
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| NZ628479A (en) | 2016-06-24 |
| AU2013368298A1 (en) | 2015-07-02 |
| UY35230A (en) | 2015-01-30 |
| HK1215396A1 (en) | 2016-08-26 |
| AR094287A1 (en) | 2015-07-22 |
| IL239623A0 (en) | 2015-08-31 |
| AU2013368298B2 (en) | 2016-08-11 |
| HK1216843A1 (en) | 2016-12-09 |
| KR20150100902A (en) | 2015-09-02 |
| EP2938329A1 (en) | 2015-11-04 |
| BR112015015421A2 (en) | 2017-07-11 |
| EA201591218A1 (en) | 2015-11-30 |
| WO2014105446A1 (en) | 2014-07-03 |
| CA2895955A1 (en) | 2014-07-03 |
| EP2938329A4 (en) | 2016-08-10 |
| MX2015008333A (en) | 2015-11-09 |
| JP2016504358A (en) | 2016-02-12 |
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