CN110381931A - The treatment method and device of the bioavilability of improved leukotriene receptor antagonists - Google Patents

Abstract

Disclose the method for administration and device of a kind of bioavilability for improved leukotriene receptor antagonists.This method and device are related to a kind of basic surface pH oral film dosage form, are designed to leukotriene receptor antagonists, such as montelukast (Montelukast) is delivered to stomach in the form of the amorphous sediment object being suspended in aqueous medium.Also disclose a kind of device and method for treating disease, the disease such as neurodegenerative disease or illness associated with the neuroinflamation that leukotriene induces.The device is the film unit dosage forms of the montelukast with basic surface pH film layer and safe and effective amount.The device is configured and is configured to mainly realize the intestinal delivery of montelukast.This method includes the montelukast that the safe and effective amount of blood-brain barrier can be passed through to person in need for the treatment of or animal intestinal delivery.

Description

The treatment method and device of the bioavilability of improved leukotriene receptor antagonists

Cross reference to related applications

This application claims the priority for the Provisional Application No. 62/478,876 that on March 30th, 2017 submits, the provisional applications It is incorporated herein by reference in their entirety.

Technical field

This disclosure relates to for improving leukotriene receptor antagonists or leukotriene synthesis inhibition for treating obstacle The preparation and treatment method and pharmaceutical dosage form of the bioavilability of agent.

Background technique

Brain generates the ability of neoblast as aging loses, and existing cell loss function, including anti-hemostasis Inflammatory mediator in liquid passes through the ability of blood-brain barrier (BBB).Meanwhile old brain tend to produce higher levels of inflammation because Son, such as leukotriene, and some abilities for resisting inflammatory mediator effect are lost, lead to neuroinflamation and cognitive impairment.Nerve The main reason for inflammation is leukotriene.Evidence suggests leukotriene receptor antagonists, such as Montelukast Sodium, having reduces mind Through inflammation and restore the potentiality of function of brain cell.Such treatment can effectively treat various neurodegenerative diseases and illness, Including Huntington disease, Parkinson's disease, memory function forfeiture, spinal cord and cerebral injury and apoplexy.

Montelukast (MTL) sodium is commonly used for patient of the treatment with chronic asthma and for seasonal allergic rhinitis Remission Orally active leukotriene receptor antagonists.During the inflammatory reaction of eupnea road, cysteinyl leukotriene With the inflammation in the zygotic induction respiratory tract approach of leukotriene receptor, asthma symptoms are generated.The function of MTL is by with high affine Power and selectivity inhibit this inflammatory reaction in conjunction with leukotriene receptor, so that blocking causes the physiology of section for a long time anti- The approach answered.Recently, the neuroinflamation in brain is related into dull-witted and neurodegenerative disease related with the age.It has shown Show, the MTL applied under these biotic factors significantly reduces neuroinflamation, improves hippocampal neural and occurs and improve geriatric animals Learning and memory.

Currently, Montelukast Sodium existsIt is sold in form of tablets under title.It uses in form of tablets The ultimate challenge of MTL first is that bioavilability is inconsistent.Although MTL is soluble easily in water, in the acidity being typically found in stomach Under the conditions of its solubility reduce.This has caused relatively slow and has inconsistently been absorbed into blood flow, and wherein maximum concentration is only in 2-4 Occur after hour, so that it is restricted to chronic application rather than quick acute treatment.Experimental study shows that limiting MTL absorbs Major obstacle be related to its solubility, from tablet platform dissolve out rate and across biomembrane transhipment/infiltration rate.

U.S. Patent number 8,575,194 and 9,149,472 is disclosed by being released with the application of single dose unit comprising extending It puts (ER) component and releases immediately the single tablet or capsule of (IR) component to improve the method for cognitive impairment.The method includes The dosage unit is applied to provide the initial burst of IR active pharmaceutical ingredient (API) and enter system, then in 12 hours mistakes ER API is provided in journey, to maintain constant effective plasma level level.Disclosed embodiment includes having ER core and IR shell Tablet or the mixture containing ER the and IR bead (bead) combined with specific ratios capsule, to realize desired effect Fruit.In alternative embodiment, dosage regimen (regimen) generally by the MTL of initial 10mg high dose then after It is formed during 12 hours every about 2 hours 5mg dosage.These patents discuss blood plasma level for realizing that cognition improves It is vital.

However, MTL is only crossing over blood-brain barrier (BBB) and is accumulating in cerebrospinal fluid (CSF) with enough concentration levels Its therapeutic effect of competence exertion when middle.The blood plasma and CSF concentration level of MTL is not all discussed in these patents.

In addition, with the concentration dependent pharmacokinetic of MTL CSF (http://www.accessdata.fda.gov/ Drugsatfda_docs/nda/2000/20830S008_Singulair_biopharmr.p df) it indicates (referring to the medicine generation of page 7 Dynamics research file) MTL is not since 99% or more in conjunction with plasma protein and it is expected that pass through BBB.During this investigation it turned out, by The rat that radiolabeled MTL is administered, which only shows across the minimum of blood-brain barrier, to be distributed.

Surge is being proposed for improving in the method that can speed up the tablet formulation of API releaseMeng Lu Take charge of special tablet.This method attempts to improve the solubility of MTL under one's belt.SurgeProduct may be nevertheless suffered from and is similar toThe gastric emptying period of tablet and the limitation of food effect and be masticable.Chewable tablets also include solid Body MTL.

Therefore a kind for the treatment of method for overcoming prior art disadvantage is needed.

Summary of the invention

It discloses a kind of for improving the alkaline oral film type of the bioavilability of leukotriene antagonist inhibitor.Cause This, which delivers leukotriene antagonist inhibitor, such as montelukast, the city form Shi Qiyu of the oral film dosage form It sells peroral dosage form and compares and be suitable for improved bioavilability.The basic surface pH of disclosed oral film dosage form is preferably greater than 7.5, More preferably greater than 8, it is optimal to be greater than 8.5.

Disclose a kind of leukotriene receptor antagonists that improved bioavilability is shown compared with existing peroral dosage form Dosage form.

Disclose exemplary dose of a kind of improved bioavilability for showing montelukast leukotriene receptor antagonists Type.

It discloses a kind of for delivering the leukotriene receptor antagonists of safe and effective amount to brain for reducing neuritis The dosage form of disease.

Disclose it is a kind of for brain delivering safe and effective amount montelukast with the example for reducing neuroinflamation Property dosage form.

The invention discloses a kind of pharmaceutical dosage forms for human pharmaceutical use, and it includes the unit doses for being suitable for being administered orally Montelukast salt, free alkali or the prodrug of type.Dosage form can be configured for the intestinal delivery of activating agent.According to disclosed dosage form Montelukast salt, free alkali or prodrug may be configured to in aqueous suspension amorphous form reach stomach.

Disclose the montelukast being dissolved in peroral dosage form.Peroral dosage form is administered orally, such as on tongue, oral cavity or Sublingual administration.After dosage form and saliva contacts, dosage form is preferably dissolved out and/or is disintegrated.The dissolution and/or disintegration of peroral dosage form will be molten The montelukast of solution is converted into suspension and/or insoluble precipitate, forms the dosage form of predissolve, prepare to absorb in the oral cavity and/ Or it swallows.

According to one aspect of the present disclosure, compared with equivalent tablet or chewable peroral dosage form, predissolve dosage form changes It has been apt to the bioavilability of montelukast.

Montelukast can be delivered by using the film layer with basic surface pH.As a result, by montelukast salt, free Alkali or prodrug are placed in the polymer film suitable for oral administration or on polymer film.The film can be formulated for activating agent Micron or nano particle fater disintegration in the gastrointestinal tract and distribution.

In certain embodiments, the activating agent in film type is Montelukast Sodium.

According to an aspect of the invention, there is provided one kind tool when compared with it can swallow and can be chewed oral tablet dosage form There is the basic surface pH montelukast oral film dosage form of improved bioavilability.

A kind of method of illness treated and leukotriene is needed to inhibit is also disclosed (by blocking leukotriene synthesis of receptor itself Realize), this method includes the oral film dosage form for having basic surface pH to patient with this need's application, and the dosage form is as needed Containing about 0.5mg to the montelukast of about 25mg, the accumulated dose of up to daily 25mg, for treating neuroinflamation.

Can by present disclosure treat specific illness include but is not limited to neuroinflamation, neurodegenerative disease and Cognitive impairment.

Particularly, this disclosure relates to the pharmaceutical unit dosage form compositions comprising about 0.5mg to about 25mg montelukast.

The unit dosage forms are suitable for treating the oral administration of neuroinflamation.Unit dosage forms contain about 10mg compound and every Day application is once or twice.

Also disclose a kind of method for treating neurodegenerative disease or neuroinflamation sexual dysfunction.This method includes following step It is rapid: via film type by the leukotriene receptor antagonists intestinal delivery of safe and effective amount to need to treat neurodegenerative disease or The people of neuroinflamation sexual dysfunction or other animals, wherein the amount of montelukast is daily about 0.5mg to about 25mg, preferably about 1mg to about 10mg, and wherein sediment intestinal delivery of the leukotriene receptor antagonists as suspension in an aqueous medium, wherein The sediment is oral when oral film dosage form dissolves out and/or is disintegrated to be generated.

A kind of oral film dosage form is also disclosed, it includes: the film layer with basic surface pH；With the safety in incorporation film layer A effective amount of leukotriene receptor antagonists.Film layer, which is formulated into when contacting with aqueous solution, to be dissolved out and/or is disintegrated.Leukotriene receptor Antagonist is preferably mixed in film layer with amorphous form, and is most preferably dissolved in film layer.Preferred film type includes Meng Lu Department is special, and with about 0.5mg to about 25mg, preferably about 5mg is to about 15mg and optimally the amount of about 10mg is selected to exist.

A kind of oral film dosage form is also disclosed, there is the film layer with basic surface pH；With the safety in incorporation film layer A effective amount of leukotriene receptor antagonists, wherein film layer contacts dissolution and/or disintegration with aqueous solution.Basic surface pH is preferably greater than PH 7.5, more preferably greater than pH 8.0, it is optimal to be greater than pH 8.5.Also disclose a kind of mouth with non-cushioned basic surface pH Oral dosage form.

A kind of oral film dosage form is also disclosed, there is the film layer with basic surface pH；With the safety in incorporation film layer A effective amount of leukotriene receptor antagonists, wherein film layer contacts dissolution and/or disintegration with aqueous solution, and wherein film layer includes more Kind stabilizer.Plurality of stable agent can selected from p-hydroxybenzoate (parabens), EDTA, BHT and p-hydroxybenzoate, The combination of EDTA and BHT.

The film type comprising montelukast is also disclosed, wherein area under the curve (AUC) is in about 3120ng*h/mL to about Between 4700ng*h/mL and/or wherein Cmax is in about 475ng/ml between about 720ng/ml.

It also discloses a kind of by including the film layer containing montelukast to person in need for the treatment of or the application of other animals Film type come treat at least partly by leukotriene induce neurodegenerative disease and illness method.Film layer (one or more) It is configured for intestinal delivery activating agent.

Film layer may be further configured for transmucosal or sublingual.

These and other feature, advantages of various embodiments are better understood with reference to following description and claim And purpose.

Detailed description of the invention

Fig. 1 is the schematic diagram of the dissolution of swallowable tablets.

Fig. 2 is the explanatory view that oral film dosage form is absorbed when being applied to subject.

Fig. 3 is the explanatory view of the behavior of active material (active) in stomach after applying oral film to subject.

Fig. 4 is the explanatory view through mucosa absorption after applying oral film to subject.

Fig. 5 is the pictorial diagram that data are dissolved out shown in table 12.

Fig. 6 is the pictorial diagram of solubility limit of the MTL in the solution containing EDTA.

Specific embodiment

According to present disclosure in some terms, providing applying for the bioavilability for improved leukotriene inhibitors Use method and apparatus.This method and device are related to a kind of peroral dosage form, are designed to leukotriene inhibitors such as Meng Lusi Spy is delivered to oral cavity with the amorphous form for the amorphous sediment object being suspended in aqueous medium (for example, saliva and/or gastric juice) Stomach function regulating.

According to present disclosure in some terms, providing for treating the neurological at least partly induced by leukotriene The method of property disease and/or other illnesss.These methods include intestinal delivery montelukast or transmucosal, sublingual or transmucosal and It is both sublingual to combine delivering montelukast together with enteral.Montelukast is safely and effectively to measure in incorporation film layer, to reduce patient The neuroinflamation that middle leukotriene induces.

It can include but is not limited to that memory function forfeiture is (long-term or short according to the neurodegenerative disease that present disclosure is treated Phase), it is dull-witted, apathy, depressed, tired it is (acute or chronic), cognition lose, attention lose, sexual anesthesia and orientation barrier Hinder.It can include Huntington disease, Parkinson's disease and Alzheimer disease with the disease specific illness that disclosed method is treated.This After class treatment can also effectively treat the nervous system disease, neurodegenerative disease, neuroinflamation sexual dysfunction, traumatic or wound Obstacle, blood vessel or central nervous system disorder more precisely after neurovascular disorders, anoxic sexual dysfunction and infection.Term " nerve Degenerative disease " or " neurological disease " or " neuroinflamation sexual dysfunction " refer to any disease for influencing central or peripheral nervous system Disease, obstruction and illness, including ADHD, AIDS- neurological complication, transparent diaphragm missing, acquired epileptic aphasia, urgency Property diseminated encephalomyelitis, adrenoleukodystrophy, agenesis of corpus callus, agnosia, aicardi's syndrome (Aicardi Syndrome), Alexander disease (Alexander Disease), Alpers disease (Alpers'Disease), Alternating hemiplegia (alternating hemiplegia), Alzheimer disease, amyotrophic lateral sclerosis (ALS), anencephaly are abnormal Shape, aneurysm, angelman syndrome (Angelman Syndrome), angiomatosis, air hunger, aphasia, parectropia, spider Omental cyst, archnoiditis, Arnold-Chiari malformation (Arnold-Chiari Malformation), arteriovenous malformation, Ah This Ba Tian (aspartame), it A Si Burger syndrome (Asperger Syndrome), ataxia telangiectasia, is total to Ji imbalance, attention deficit hyperactivity disorder, self-closing disease, autonomic nervous function imbalance, backache, Pasteur's syndrome (Barth Syndrome), shellfish Deng Shi disease (Batten Disease), white match disease (Behcet's Disease), Bell's palsy (Bell's Palsy), benign Idiopathic blepharospasm (benign essential blepharospasm), benign focal amyotrophia, good Property intracranial hypertension, bernhardt-Roth syndrome (Bernhardt-Roth Syndrome), Binswanger disease (Binswanger's Disease), blepharospasm, Bloch-Sulzberger syndrome (Bloch-Sulzberger Syndrome), brachial plexus nerve go out Raw damage, brachia plexus injury, Bradberry-Eggleston syndrome (Bradbury-Eggleston Syndrome), Cerebral aneurysm, cerebral injury, brain and tumor of spine, Brown-Se&1&quard syndrome (Brown-Sequard Syndrome), oblongata flesh Meat atrophy (bulbospinal muscular atrophy), canavan's disease (Canavan Disease), complication of wrist, Cusalgia, cavernoma (cavernomas), cvernous hemangioma, spongy deformity, Central Cervical marrow syndrome (central Cervical cord syndrome), central cord syndrome (central cord syndrome), central pain it is comprehensive Sign, head obstacle, cerebellum degeneration, cerebellar hypoplasia, cerebral aneurysm, cerebral arteriovenous malformation, encephalatrophy, brain tinea pedis disease (cerebral beriberi), cerebral gigantism, cerebral anoxia, brain paralysis, cerebro-oculo-facio-skeletal syndrome (cerebro-oculo- Facio-skeletal syndrome), peroneal muscular atrophy obstacle (Charcot-Marie-Tooth Disorder), Cha Lishi Deformity (Chiari Malformation), chorea, dancing acanthocytosis, the multiple mind of chronic inflammation demyelinating It is not tolerated through sick (CIDP), chronic orthostatic, chronic ache, II type neil-ingwall syndrome (Cockayne Syndrome Type II), coriolis & apos (Coffin Lowry Syndrome), stupor (including persistent vegetative state), complex region pain The spongy deformity of pain syndrome, congenital facial diplegia, congenital myasthenia, congenital myopathy, congenital vascular, cortex base Coxopodite denaturation, cranial arteritis, craniosynostosis, Creutzfeldt-Jakob disease (Creutzfeldt-Jakob Disease), cumulative bad traumatic disorders, Cushing syndrome (Cushing's Syndrome), cytomegalic inclusion disease (CIBD), Cytomegalovirus infection, dance eye wave sufficient syndrome (dancing eyes-dancing feet syndrome), Dan Di-Wall gram Gloomy disease (the Dawson Disease), Di Mosier syndrome (De in syndrome (Dandy-Walker Syndrome), road Morsier's Syndrome), klumpke-Dejerone paralysis (Dejerine-Klumpke Palsy), old delirium (delir in Elderly), delirium, the dementia-multiple infarctions, subcortical dementias (dementia-subcortical), Louis of wound induction Body dementia (dementia with Lewy Bodies), dermatomyositis, developmental character dyskinesia, Devi klinefelter syndrome (Devic' S Syndrome), diabetic neuropathy, diffusivity hardening, baby's severe myoclonic epilepsy (Dravet's Syndrome), autonomic nerve abnormal (dysautonomia), dysgraphia, alexia, dysphagia, dyskinesia, Muscle tensility The epileptic encephalopathy of obstacle, premature babies, Syringo-subarachnoid shunting syndrome (Empty Sella Syndrome), lethargic encephalitis (encephalitis lethargica), encephalitis and meningitis, Naoning tablet, encephalopathy, brain trigemino-vascular tumor, epilepsy, Earl Bu Shi benumbs (Erb's Palsy), Ai Erbu-Du Xinghe klumpke-Dejerone paralysis (Erb-Duchenne and Dejerine- Klumpke Palsies), Fa Buruishi sick (Fabry's Disease), Farr's Cotard (Fahr's Syndrome), dusk It faints, dysautonomia, familial hemangioma, the calcification of familial idiopathic basal ganglion, the spastic fiber crops of familial Numbness, febrile convulsion (for example, GEFS and GEFS+), fischer Cotard (Fisher Syndrome), floppy infant syndrome (Floppy Infant Syndrome), friedreich's ataxia (Friedreich's Ataxia), Gaucher disease (Gaucher's Disease), Gerstmann syndrome (Gerstmann's Syndrome), Ge-this Er Shi disease (Gerstmann-Straussler-Scheinker Disease), giant cell arteritis, giant cell forgive disease, sphaerocyst brain Leukodystrophy, glossopharyngeal neuralgia, actue infectious polyradiculoneuritis (Guillain-Barre Syndrome), HTLV-1 correlation Myelopathy, Hallervorden Spatz disease (Hallervorden-Spatz Disease), head injury, headache, the inclined head of continuity (hemicrania continua), facial spasm, crossed hemiplegia (hemiplegia alterans), inherited neurological bitterly Disease, hereditary spastic paraplegia, heredopathia atactica polyneuritiformis (heredopathia atactica Polyneuritiformis), zoster oticus (Herpes Zoster Oticus), shingles zoster (Herpes Zoster), Pingshan Mountain syndrome (Hirayama Syndrome), holoprosencephaly, Huntington disease, hydranencephaly, normal pressure hydrocephalus (NPH) (hydrocephalus-normal pressure), hydrocephalus, hydromyelia, hypercortisolism, hypersomnia, tension are high Into, hypotony, air hunger, immune-mediated encephalomyelitis, inclusion body myositis, bloch-Siemens syndrome, baby's hypotony, baby Phytanic acid storage disease, baby's Refsum disease (infantile refsum disease), infantile spasm, inflammatory myositis, intestines Road lipodystrophia, entocranial cyst, intracranial hypertension, Isaac syndrome (Isaac's Syndrome), Zhu Baite syndrome (Joubert Syndrome), Kearns-Sayre syndrome (Kearns-Sayre Syndrome), Kennedy disease (Kennedy' S Disease), golden this Berne syndrome (Kinsbourne syndrome), Kleine-Levin syndrome (Kleine-Levin Syndrome), Klippel Feil syndrome (Klippel Feil Syndrome), Ke Lipeier-spy's brain receive syndrome (Klippel-Trenaunay Syndrome, KTS), Krul-Bu Xi syndrome (Kluver-Bucy Syndrome), section's Sa Ke husband amnestic syndrome (Korsakoffs Amnesic Syndrome), Krabbe disease (Krabbe Disease), Tim Koogle shellfish Lattice-Károly Wieland disease (Kugelberg-Welander Disease), kuru (kuru), Lambert-Eton myasthenic syndrome (Lambert-Eaton Myasthenic Syndrome), Lan Da-Clive's syndrome (Landau-Kleffner Syndrome), nervus cutaneus femoris lateralis card pressure (lateral femoral cutaneous nerve entrapment), outside oblongata Side syndrome, learning disorder, Lei's disease (Leigh's Disease), lennox-Gastaut syndrome (Lennox- Gastaut Syndrome), Lai Shi-Ni Han syndrome (Lesch-Nyhan Syndrome), leukodystrophy, Lai Wen- Critchely syndrome (Levine-Critchley Syndrome), dementia with Lewy body, congenital agyria, block comprehensive disease It is lost after (locked-in syndrome), Lu Geli Graves disease (Lou Gehrig's Disease), lupus-nervous system Disease, Lyme disease-neural complication (Lyme Disease-Neurological Complications), Machado-Joseph disease (Machado-Joseph Disease), macrencephaly (macrencephaly), megalencephaly (megalencephaly), Mei-sieve Er Shi Syndrome (Melkersson-Rosenthal Syndrome), meningitis, Menkes disease (Menkes Disease) feel different Perseverance meralgia, metachromatic leukodystrophy, microcephaly, migraine (migraine), Miller-Fei Sheer syndrome (Miller Fisher Syndrome), cockleshell, mitochondrial myopathy, mobius syndrome (Mobius Syndrome), Monomer amyotrophia, motor neuron disease, Moyamoya Disease (Moyamoya Disease), Mucolipidosis (mucolipidoses), It is mucopolysaccharidosis (mucopolysaccharidoses), multiple infarct dementia (multi-infarct dementia), more Stove kinesitherapy nerve lesion, multiple sclerosis (MS), multisystem atrophy (MSA-C and MSA-P), multisystem atrophy are with upright Property low blood pressure, muscular dystrophy, congenital myasthenia, myasthenia gravis, demyelinate diffusivity harden (myelinoclastic Diffuse sclerosis), myoclonic encephalopathy of infant, myoclonia, congenital myopathy, thyrotoxic myopathy, myopathy, elder generation Nature myotonia, myotonia, Narcolepsy disease, Neuroacanthocytosis, neurological are with brain deposition of iron, nerve fibre Tumor disease, neuroleptic malignant syndrome, AIDS neural complication, the neural clinical manifestation of Pang Beishi disease, neuromyelitis optica, The waxy lipofuscin of neuromyotonia, neuron stores up disease, neuronal migration obstacle, hereditary neuropathy, neurosarcoidosis, mind Through toxicity, naevus cavernosus (nevus cavemosus), Niemann-Pick disease (Niemann-Pick Disease), Sullivan-difficult to understand It is macLeod syndrome (O'Sullivan-McLeod Syndrome), occipital neuralgia, invisible spinal dysraphism sequence, big Field original syndrome (Ohtahara Syndrome), olvopontocerebellar atrophy, opsoclonia myoclonia, the low blood of orthostatic Pressure, overuse syndrome, chronic ache, paraneoplastic syndrome, cacesthesia, Parkinson's disease, paramyotonia congenita (parmyotonia congenita), paroxysmal choreoathetosis, paroxysmal hemicrania, osteochondrodystrophia fetalis (Parry- Romberg), Pei-Mei Shi sick (Pelizaeus-Merzbacher Disease), Pei Na-Shu Kaier II pattern synthesis levy (Perra Shokeir II Syndrome), peripheral nerve tumour, periodic paralysis, peripheral neuropathy, periventricular leukomalacia, hold Continuous property vegetative state, pervasive developmental disorders, phytanic acid storage disease, Pick's disease (Pick's Disease), pyriformis are comprehensive Sign, hypophysoma, polymyositis, Pang Beishi disease, porencephalia, post poliomyelitis syndrome, postherpetic neuralgia, infection It is post encephalomyelitis, postural hypotension, Postural orthostatic tachycardia syndrome, Postural Orthostatic Tachycardia Syndrome in Children, primary Property lateral sclerosis, prion disease, progressive unilateral facial atrophy, progressive motor ataxia, the multifocal white matter brain of progressive Disease, progressive hardenability poliodystrophia, stein-leventhal syndrome, pseudotumor cerebri, pyridoxine dependency and pyridoxol are rung Answering property epilepsy, I type Ramsay Hunter syndrome (Ramsay Hunt Syndrome Type I), II type Ramsay Hunter are comprehensive Simulator sickness, La Simusenshi encephalitis (Rasmussen's Encephalitis) and other autoimmune epilepsies, reflectivity are sympathetic Neuratrophia syndrome, baby's Refsum disease (refsum disease-infantile), Refsum disease, repetition Property dyskinesia, repeated stress damage, restless legs syndrome, retrovirus associated myelopathy, thunder spy's Cotard (Rett Syndrome), Reye syndrome (Reye ' s Syndrome), Riley Day syndrome (Riley-Day Syndrome), SUNCT headache, sacral nerve root, Saint Vitus dance (Saint Vitus Dance), salivary gland disease, Sandhoff disease (Sandhoff Disease), periaxial encephalitis (Schilder's Disease), Schizencephaly, epilepsy, Depending on-every depauperation, infancy severe myoclonic epilepsy (SMEI), rock baby's syndrome (shaken baby Syndrome), shingles zoster (shingles), Shy Drager syndrome (Shy-Drager Syndrome), dry synthesis Levy (Sjogren's Syndrome), sleep apnea, difussa, rope support syndrome (Soto's Syndrome), spasm State, spina bifida, spinal infarction, spinal cord injury, tumor of spinal cord, Duchenne-Arandisease, Spinocerebellar Atrophy, Si Dier-Li Cha Sen-Ao Erxie Paderewski syndrome (Steele-Richardson-Olszewski Syndrome), stiff people's syndrome (Stiff-Person Syndrome), striatum substantia nigra degeneration (striatonigral degeneration), apoplexy, Si Te Surprise-weber's syndrome (Sturge-Weber Syndrome), subacute sclerosing panencephalitis, binswanger disease, Aphetite disorder, Sydenham chorea (Sydenham Chorea), syncope, syphilis myelosclerosis, spinal cord empty ponding disease (syringohydromyelia), syringomyelia, systemic loupus erythematosus, tabetic crisis, tardive dyskinesia, tower love capsule Swollen (Tarlov Cysts), Tai Yi-saxophone's Er Shi disease (Tay-Sachs Disease), temporal arteritis, tethered cord syndrome (tethered spinal cord syndrome), poikiloderma congenitale (Thomsen Disease), syndrome of chest outlet, first Shape gland toxicity myopathy, trigeminal neuralgia (Tic Douloureux), Tuo Deshi benumb (Todd's Paralysis), Dole Leix Syndrome (Tourette Syndrome), transient ischemic attack, transmissible spongiform encephalopathy, transverse myelitis, wound Property cerebral injury, tremble, trigeminal neuralgia (trigeminal neuralgia), tropical spastic lower limb paralysis, tuberous sclerosis, Vascular erection tumour, Feng's Economo's disease (Von Economo's Disease), is wished at vasculitis (including temporal arteritis) Pei Er lindau's syndrome (Von Hippel-Lindau disease, VHL), Feng's Lei Kelinhaosenshi disease (Von Recklinghausen's Disease), Wallenberg's syndrome (Wallenberg's Syndrome), Wei Denixi-suddenly Graceful disease (the Werdnig-Hoffman Disease), Wernicke-Korsakoff syndrome (Wemicke-Korsakoff of husband Syndrome), west's syndrome (West Syndrome), whipple's disease (Whipple's Disease), WILLIAMS-DARLING Ton Syndrome (Williams Syndrome), Wilson's disease (Wilson's Disease), the chain spinobulbar muscular atrophy of X- With Zellweger Cotard (Zellweger Syndrome).

Disclosed dosage form and method is estimated to be selected from the mind comprising group that is following or being made up of especially suitable for treatment Through degenerative disease and neuroinflamation sexual dysfunction: Alzheimer disease, Parkinson's disease, Creutzfeldt-Jakob disease (CJD), new variant (nvCJD), Hallervorden Spatz disease, the Huntington disease, polyphyly of Creutzfeldt-Jakob disease System property atrophy, dementia, Frontotemporal dementia, multiple spontaneous or genetic background motoneuron disorders, amyotrophic lateral sclerosis (ALS), Duchenne-Arandisease, Spinocerebellar Atrophy (SCAs), schizophrenia, the disturbance of emotion, weight depression, meningoencephalitis, carefully Bacterium property meningoencephalitis, Viral encephalomeningitis, CNS autoimmune disease, multiple sclerosis (MS), acute ischemia/Hypoxic It is lesion, apoplexy, CNS and spinal cord injuries receptor, head and spinal trauma, cerebral trauma damage, artery sclerosis, atherosclerosis, micro- Angiopathic dementia, Binswanger disease (leukoaraiosis), cochlea denaturation, cochlear deafness, AIDS related dementia, fragile X Correlation tremor/ataxia syndrome (FXTAS), stein-leventhal syndrome (PSP), striatum substantia nigra degeneration (SND), olive Olive body pontocerebellar is denaturalized (olivopontocerebellear degeneration, OPCD), Shy Drager syndrome (SDS), age-dependend memory defect, neurodevelopmental disorder relevant to dementia, Down's syndrome (Down's Syndrome), it is total to nucleoprotein disease, superoxide dismutase mutation, Trinucleotide repeats obstacle (such as Huntington disease), wound, lacks Oxygen disease, vascular diseases, vascular inflammation, CNS aging.The age-dependent that stem cell update can also be solved reduces.

Disclosed dosage form and method is estimated to be selected from the mind comprising group that is following or being made up of especially suitable for treatment Through degenerative disease and neuroinflamation sexual dysfunction: Alzheimer disease, Parkinson's disease, Huntington disease, amyotrophic lateral sclerosis (ALS), hydrocephalus, CNS and spinal cord injuries receptor (such as spinal cord injury, head and spinal trauma), traumatic brain injury, cochlear Deaf, AIDS related dementia, Trinucleotide repeats obstacle (such as Huntington disease) and CNS aging.

Term " treatment (treatment) ", " treatment (treating) " and its modification refer to healing, mitigation or alleviate disease Disease, medical conditions or the symptom of damage.

As used herein, " non-cushioned (unbuffered) " film layer be the film layer without weak acid or weak base, the weak acid or Weak base effectively maintains pH near selected value when another acid or alkali is added.In other words, non-cushioned film layer is free of Buffer, such as borate, citrate or phosphate.

Intestinal delivery instigates activating agent to pass through gastrointestinal tract, perhaps opens naturally via oral cavity and esophagus or by artificial Mouth (for example, stoma) simultaneously absorbs activating agent in intestines.

Leukotriene inhibitors include the leukotriene receptor antagonists and/or leukotriene synthesis suppression for blocking 5- lipoxygenase activity Preparation.Such leukotriene inhibitors include but is not limited to leukotriene receptor antagonists, such as montelukast, zafirlukast (Zafirlukast), pranlukast (Pranlukast), cinalukast (cinalukast), Fu Lusite (probilukast), Yi Lusite (iralukast) and Sulukast (sulukast).It unless otherwise directed, can be with various Activating agent existing for form (alkali form (base form), salt, ester, prodrug etc.) is by reference to basic pharmaceutical (base Drug it) is included.For example, term " montelukast " is intended to cover form of ownership, including salt (for example, Montelukast Sodium), ester And prodrug.

Term " unbodied " refers to the non-crystalline forms of solid, the i.e. state of the rule crystallization tissue of shortage atom.Without fixed The solid of shape is usually more readily soluble than their crystallization counterpart, faster dissolves out, is easier to absorb in gastrointestinal tract or oral cavity, and more It is unstable.Use the method for a variety of maturations, including isothermal calorimetry, powder X-ray diffractometry (PXRD), Raman spectroscopy, difference Show scanning calorimetry (DSC), continuous relative humidity perfusion microcalorimetric method (cRHp) and dynamic vapor sorption method (DVS), Ke Yizhun Really and accurately assess the amorphous content (amorphism) of solid.In the publication, amorphous also refer to of term shows 30% Or more than 30% amorphous materials, the activating agent (one or more) of more preferably above 50% amorphous materials.

Term " activating agent (one or more) " or API (active pharmaceutical ingredient) refer mainly to active pharmaceutical ingredient, but can also Cause biology variation (such as, but not limited to elimination disease to refer to the subject's chemical interaction being usually administered to it Symptom or adjust biological function) any medicament.

Term " stable " refer to when product be exposed to for a long time normal table condition (such as 25 DEG C/60%RH and 40 DEG C/ When 75%RH), dissolution curve and the rate of recovery (or measurement) do not change or change very limited product.

" oral film dosage form " is often referred to the edible composition that one kind can be absorbed by subject (human or animal), with to tested Person is oral, buccal or sublingual administration predetermined amount activating agent (one or more), and wherein the composition is in membrane form.

" surface p H " is the pH measured on the surface of the film, the top surface or bottom surface of such as monofilm, or in multilayer mouth Take the pH measured on the exposed surface of the layer in film containing active material.(added according to the needs that pH is tested by slightly wetting film Add water, such as one to three drop) film of the preparation for pH test.Then it is measured by contacting electrode with the surface of oral film pH.This measurement of surface p H preferably carries out on several films of same recipe.Term " film " and " film layer " refer to the component of dosage form Or layer, it is significantly different with pill, tablet, caplet (caplet) and capsule, and wherein dosage form is thin-band material.Such film is logical Normal fater disintegration or Fast Stripping, but longer disintegration and/or dissolution time can also be shown when needed.Film is usually enough to It is flexible to allow to be bent or to be even folded without fracture.Film layer is the flaky material that thickness is much smaller than its length or width. For example, although thicker film or film may be it is suitable, the thickness of oral transmucosal device is generally approximate about 50 μm To 500 μm of (i.e. 0.05mm to 0.5mm)；And width and length dimension are generally approximate about 5mm to 40mm, but can be used Greater or lesser size.

In entire present disclosure, unless otherwise directed, it should be appreciated that specifically referring to for " MTL " or " montelukast " Mean that other leukotriene receptor antagonists can be substituted.

Film type may include single film layer or multiple layers.For example, in the case where oral cavity or sublingual pellicles type, using containing The biocompatible layer (for example, bioadhesive layer) on active dose and non-adhering barrier layer with prevent or reduce activating agent (it is a kind of or It is a variety of) intake and ensure in activating agent it is all or most of pass through apply bioadhesive layer mucous membrane be beneficial.Term " bioadhesion " means that the composition of film layer is formulated into and adheres on selected mucous membrane, passes through passing for the mucous membrane target activity agent It send, and covers term " mucosal adhesive ".For example, should select for the bioadhesive polymer with film in target mucous membrane Environment in show enough adhesivenesses, to ensure that bioadhesive layer keeps the mucosal contact applied with it, and allow to live Property agent is directly entered blood flow by mucous membrane.

Activating agent can be combined or be mixed with film forming polymer and/or bioadhesive polymer, be suitable for taking orally to obtain The property combination of the balance of delivery apparatus, as the uniformity, hydration rate, drug of flexibility, tensile strength, film and drug are released It puts, disintegration time, palatability (taste, smell, quality and pleasant impression), mouthfeel, mucosal adhesive and chemistry and physical stability.

Show the suitable film forming polymer of bioadhesive example include hydroxypropyl cellulose, hydroxymethyl cellulose, Natural or synthetic natural gum, polyvinyl alcohol, polyethylene oxide, with polyalkenyl (polyalkenyl) polyethers or divinyl alcohol and cross linking Homopolymer and copolymer, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, sodium alginate, pectin, the gelatin malt of acrylic acid Magma essence chitosan and polylysine.In the certain embodiments or aspect of present disclosure, activating agent can in film forming Property polysaccharide (such as pulullan polysaccharide (pullulan)) combine.

Can with or alternatively use penetration enhancers to further increase the absorption rate of activating agent and/or total absorb Amount.Can advantageously with the examples of penetration enhancers include 2,3- lauryl ether, phosphatidyl choline, Aprotinin, polyoxy second Alkene, azone, polysorbate80, benzalkonium chloride, polyoxyethylene, cetylpyridinium chloride, phosphatidyl choline, cetyl three Methyl bromide ammonium, EDETATE SODIUM, cyclodextrin, chitosan, NaGC, 16 Glycodeoxrycholic acid of dextran sulfate.Other are seeped Saturating reinforcing agent includes surfactant, bile salt (by extracting memebrane protein or lipid, being fluidized, by film by generating in film Reverse micelle simultaneously forms aqueous channels), fatty acid (being worked by destroying intercellular lipid accumulation), azone is (by cell Between mobility region is formed in lipid), pore former (for example, be inserted into lipid film and formed API can by the molecule in hole, peptide, Nucleic acid or particle) and alcohols (by recombination lipid structure domain and by changing protein conformation), sulfoxide (dimethyl sulfoxide, the last of the ten Heavenly stems Methyl sulfoxide), pyrrolidones (2 pyrrolidones, 2P), alcohols/alkanols (ethyl alcohol or decyl alcohol), ethylene glycol (propylene glycol), terpene Alkene (1,8- Cineole (1,8-cineole), menthol and menthones, D- limonene), fatty acid (oleic acid, sodium caprate) and bile Salt (NaTDC, deoxidation Sodium Glycinate).It was found that by using within the scope of present in preparation 0.05% to 8.00% dry w/w Single or combined penetration enhancers, infiltration and absorption greatly enhance.

Can advantageously with antioxidant and chelating agent example include disodium-EDTA, EDETATE SODIUM calcium, citric acid, L-cysteine, vitamin E, ascorbyl palmitate, butylated hydroxy anisole, butylated hydroxytoluene, pyrosulfurous acid Potassium, propylgallate, sodium pyrosulfite, sodium thiosulfate, 3,4- dihydroxy-benzoic acid.

It includes poly- for can be used for enhancing permeability of the membrane and/or wetability to promote the example of the surfactant of adhesiveness Sorbitol ester (Tween^TM、Span^TM), lauryl sodium sulfate (NaLS), lauryl dimethyl amine oxide, 16 Alkyl trimethyl ammonium bromide (CTAB), polyethoxylated alcohols, polyoxyethylene sorbitan Octoxinol (Triton X100^TM), N, N- dimethyl dodecylamine-N- oxide, cetyl trimethylammonium bromide (HTAB), polyethylene glycol (polyoxyl) 10 lauryl ethers, Brij 721^TM, bile salt (NaTDC, sodium taurocholate), Cremophor EL (Cremophor^TM), nonyl phenol ethoxylate (Tergitol^TM), cyclodextrin, lecithin, benzethonium chloride (Hyamine^TM)。

The dissolution rate and disintegration curve of film can influence the bioavilability of drug.Therefore, certain embodiment party of film platform Disintegrating agent containing specific quantity is controlled the residence time of film in the oral cavity by case.Some form of drug products can containing with The disintegrating agent of quality meter 0% to 10%.The example for the disintegrating agent that can be used is maltodextrin, citric acid, sodium starch, ethyl alcohol Acid esters, crosslinked polyvinylpyrrolidone (Crospovidone), croscarmellose sodium, calcium silicates, alginic acid and vinylpyridine Pyrrolidone-vinyl acetate copolymer.

Term " predissolve " as used herein refers to the dosage form comprising activating agent, and the activating agent is after application in the oral cavity Undergo phase transformation.For example, the MTL of predissolve form can be the precipitating applied in membrane matrix of the MTL previously as dissolution MTL.The sediment of predissolve does not dissolve out, but its form (for example, the very small particle of dispersion in a liquid) is such as sudden and violent It is easy and fast to dissolve out after being exposed to the higher pH environment of intestines.

Term " matrix " or " membrane matrix " refer to the environment or medium for constituting film layer, wherein activating agent (for example, montelukast) Dissolution or distribution, and generally comprise the mixture of polymer and excipient.The film forming matrix of API is supported in oral film dosage form It may include the film layer of about 40.0% to 99.0% dry w/w.

Stability enhancer can be added in film to prevent light degradation, oxidation and/or microbial contamination.Light degradation suppression Preparation includes ultraviolet absorbing agent and pigment.Ultraviolet absorbing agent includes dihydroxy benaophenonel and hydroxy phenyl benzotriazole.It can It include various metal oxides with the pigment being added in film, such as titanium dioxide (TiO₂), di-iron trioxide (Fe₂O₃), four oxygen Change three-iron (Fe₃O₄) and zinc oxide (ZnO).It, can be by using individual pouch (pouch) in the case where oral film dosage form Mitigate the light degradation possibility of film type as final packaging material.According to an embodiment, pouch is by laminated material system At, comprising some aluminium or reflection foil material, the light degradation of product for preventing film and wherein containing.Microbial contamination can be by making With antimicrobial (such as methyl p-hydroxybenzoate, ethyl-para-hydroxybenzoate or propylparaben, benzoic acid Sodium, benzoic acid, sorbic acid, potassium sorbate, propionic acid or combinations of the above) it controls.

Other additives (such as excipient or adjuvant) that can be mixed in film include flavoring agent, sweetener, colorant (example Such as, dyestuff), plasticizer and other be not adversely affected by the transmucosal delivery of activating agent, oral mucosa adhesiveness or they The conventional additives of important membrane property.

The film can be used with single layer, bilayer or other multilayer forms.

According to an embodiment, duplicature dosage form comprising the first layer with API and has medicament (such as taste masking (taste masking) agent, the backing agent for protecting first layer and/or penetration enhancers) the second layer.The second layer can also be with For promoting the orientation by oral mucosa to absorb (unidirectional to absorb).Other embodiments can have existing in the second layer Identical API or different API and with controlled release profile intestinal delivery active material.Alternatively, the activating agent in the second layer It can be used for changing the absorption of activating agent in first layer.

Safe and effective amount is often referred to provide beneficial or treatment effectiveness amount, that is, disease or disease symptoms are provided cure or Mitigate the amount of effectiveness, but when transmucosal and/or enteral administration and delivering activating agent, the amount is sufficiently low to avoid serious or danger And the side effect of life.

The solubility of montelukast in an aqueous medium depends on pH.It has been found that MTL is showed in 7.5 or more alkaline pH Increased solubility out, and it was found that the rapid precipitation in the medium below of pH 7.5.This by Okumu et al. (Okumu, Pharm.Res, 25,12,2008) it is demonstrated experimentally that wherein MTL is individually or in the presence of surfactants only in pH referring to Fig. 6 7.5 or more show dramatically increasing for solubility.Although this research is it is also shown that the influence of surfactant may slightly increase Add MTL solubility, but only MTL is just soluble under alkaline pH environment.However, the other parameters in addition to solubility can influence The dissolution rate of montelukast, i.e. dosage form, which seem to have dissolution rate, to be significantly affected.In certain embodiments, montelukast It is present in dosage form substrate as dissolution form, will dissolve out in the oral cavity and/or is disintegrated to allow MTL before swallowing in saliva It is precipitated in liquid.On the contrary, Fig. 1 shows the schematic diagram of the dissolution of MTL peroral dosage form (such as conventional tablet).Figure 1A depicts tablet Initial burst under one's belt.Figure 1B depicts the disintegration of tablet after 10 minutes to 15 minutes, wherein due to slower disintegration, tablet Fragment (tablet piece) keeps focus on limitation dissolution and the part of potential absorption clusters in (cluster).Since MTL exists Poor solubility in acidic environment (such as stomach), this restricted obstruction are further exacerbated by.Due to the solubility of MTL at a low ph It is especially low, therefore the MTL of high concentration further increases the insoluble of MTL after disintegration of tablet, it is possible to further decreasing The bioavilability of API.

In certain embodiments, activating agent can be with the formal distribution of micron or nano particle in membrane matrix.

According to an aspect of the present invention, in order to mitigate above-mentioned montelukast tablet peroral dosage form the shortcomings that, is disclosed herein A kind of film peroral dosage form, wherein leukotriene receptor antagonists (for example, MTL) is individually inhaled via intestinal absorption (Fig. 2 B) or via intestines It receives and is administered in combination with oral transmucosal and/or sublingual absorption (Fig. 2A).In certain embodiments, film peroral dosage form is designed to It is disintegrated in the oral cavity and the activating agent of dissolution is made to precipitate and be swallowed in the oral cavity, thus using API as being suspended in aqueous Jie Fine precipitates in matter are delivered in stomach.Referring now to Fig. 3 A, with the relatively large solid particle containing activating agent or The slow disintegrating tablet dosage form that fragment enters stomach is compared, and after reaching stomach, the API sediment swallowed in suspension is significantly more evenly Ground is distributed in entire stomach.In this way, it is believed that the intake of film peroral dosage form is less subject to the limitation in gastric emptying period.Lack The solid matrix for retaining API is conducive to transhipment of the API in entire stomach, to alleviate the low solubility of API at a low ph Effect.According to dissolution curve (Fig. 5), which is clearly illustrated, once dosage form dissolution and/or disintegration and MTL in saliva It is precipitated in liquid, the dissolution rate in intestines is faster compared to the dissolution rate of tablet.Assuming that the MTL precipitated in saliva has Much smaller granular size and stomach can be escaped out via pylorus as the very thin particle to float on a liquid, to permit Perhaps faster with higher absorption.

In certain embodiments, the film layer containing activating agent is dissolved out and/or is disintegrated in the oral cavity when with saliva contacts. When film dissolves out and/or is disintegrated, montelukast (or other leukotriene receptor antagonists) precipitates (montelukast API in saliva Precipitated in 8 or less pH), to form API precipitate suspension in saliva.Then the API to suspend is swallowed and as dispersion Sediment reach stomach, improve the bioavilability of montelukast API.The film of predissolve at least alleviates and montelukast exists The associated dissolution problem of poor solubility under the conditions of the acidic stomach of patient.Poor solubility is typically due to the MTL's of conc forms In the presence of and amplify.Although being likely to occur oral cavity and/or sublingual absorption, drug is mainly intestinal absorption.As a result, when with solid Body or when not dissolving out the Montelukast Sodium that form is present in stomach, oral film dosage can be used for that encountered solubility is overcome to ask Topic.According to disclosed peroral dosage form embodiment, montelukast membrane granule is reached with suspension/precipitation form Stomach, this means that montelukast is dissolved in dosage form and precipitates in oral cavity and/or esophagus, causes the montelukast sediment to suspend It is delivered in stomach.The montelukast of the predissolve in dosage form has improved bioavilability as a result, this is at least partly derived from API is with dispersing and be therefore delivered to than the form that conventional tablet is less concentrated the fact in stomach.Therefore, with must before absorption The tablet that must be dissolved out first under one's belt is compared, and the sediment of suspension shows the improvement of bioavilability.Improved biological utilisation Degree may cause to activating agent and increase across the transhipment of blood-brain barrier, to allow lower dosage and/or more effectively treatment.To stomach Middle application montelukast API suspension is at least alleviated in other montelukast peroral dosage forms or is taken orally with other montelukasts The solubility relevant issues that dosage form (can such as swallow and chewable tablets) occurs together.However, a reality according to the present invention Scheme is applied, is at least alleviated by film type application suspended form usually associated with the API applied by liquid medium steady Qualitative question.In addition, the montelukast of oral precipitating may be than the montelukast of other peroral dosage forms or other leukotriene receptors Antagonist passes through more quickly pylorus and reaches small intestine.According to an aspect of the present invention, using preferred oral film dosage form, daily most The dosage of more 20mg montelukasts is enough ease symptom or treatment illness associated with neuroinflamation.Such oral film dosage form Fundamental, which maintains montelukast for it, promotes its solubility, i.e. ability under conditions of alkaline pH.According to some implementations Scheme, montelukast oral film have basic surface.Basic surface pH indicates that film maintains montelukast in alkaline condition, is conducive to Its solubility and the recrystallization for preventing montelukast.The recrystallization of montelukast is associated with unstable oral film.Meng Lusi The surface p H of special oral film is preferably greater than pH 7.5, preferably greater than 8.0, more preferably greater than 8.5.

Another embodiment of peroral dosage form includes the capsule formulation containing leukotriene inhibitors (for example, gelatin or fibre Tie up plain base rubber capsule), which dissolves or is distributed as amorphous sediment object in the polymer matrix, the polymer matrix Matter is disintegrated or dissolves out in an aqueous medium.According to the dosage form, the peroral dosage form of montelukast is taken orally by patient.After reaching stomach, glue Softgel shell is dissolved, so that the dissolution of montelukast (or other leukotriene receptor antagonists) or amorphous sediment object are delivered to stomach Aqueous medium in.Such sediment will be distributed in rapidly in entire stomach, and mitigate lack related with tablet and chewable tablets Point.It has been in due to activating agent in the dissolution of suspended form or the liquid medium of amorphous sediment object, oral capsule dosage form Effectively alleviate low dosage bioavailability concerns.Therefore, montelukast capsule allows montelukast as pre- in suspension The amorphous sediment object of dissolution reaches stomach.The stomach condition for being unfavorable for montelukast tablet and chewable tablets dissolution may cause Meng The some precipitatings of Lu Site under one's belt.However, since montelukast has been in dissolved form or dispersion in an aqueous medium heavy In starch, the degree of precipitating should be less than and need montelukast tablet dissolved associated power loss of tests under one's belt.

Ieukotriene blocking agents or inhibitor (i.e. leukotriene receptor antagonists and leukotriene synthesis inhibitors) can be by subtracting Lack the Neuroinflammation of intracerebral to improve cognitive impairment.Therefore, Ieukotriene blocking agents (such as MTL) have to pass through blood-brain barrier And it is gathered in cerebrospinal fluid.Therefore, during clinical test, the CSF water of MTL is carried out to patient behind 3 hours and 7 hours respectively Flat test (referring to table 1).Most, it is surprising that between 3 hours and 7 hours test points, the concentration of MTL continues for this discovery Increase.This is especially unexpected, because blood plasma level shows the Tmax value between 2 hours to 4 hours, indicates rapid in blood Reach cumulative maximum concentration.It is aqueous as being suspended in that Rapid Accumulation of the montelukast in blood samples of patients is attributable to montelukast Amorphous sediment object in medium is delivered to the enteral administration of stomach.Due to only acquiring two numbers during our clinical research Strong point, therefore whether unclear 7 hours time points represented Cmax, or as more MTL are accumulated but are removed more slowly, Whether Cmax occurs after 7 hours.When compared with known treatment methods, this is extremely important, in known treatment methods, needs Stringent continuous dosing regimens are to maintain effective MTL level to improve for recognizing.According to present disclosure, up to daily about The maximum dose of 20mg or 25mg is enough to treat neuroinflamation illness.

According to disclosed method and dosage form, the effective concentration of the montelukast in CSF is obtained via application montelukast. Reach the montelukast of enough levels in CSF, because montelukast reaches stomach in the form of predissolve, to enhance Meng Lu Take charge of special absorption and bioavilability.Therefore, the method for disclosed treatment nervus retrogression or neuroinflamation sexual dysfunction includes warp By film type, have safely to the people for needing to treat neurodegenerative disease or neuroinflamation sexual dysfunction or other animal intestinal deliveries The step of montelukast of the dissolution of effect amount.

Our data clearly demonstrate that, periodically take within every 2 hours montelukast oral film for maintaining MTL in CSF Effective level is not required.The relatively high bioavilability of montelukast is since the administration dosage of montelukast makes in CSF Activating agent is delivered to stomach as the suspended sediment in aqueous medium, to mitigate the montelukast swallowable tablets that dissolve in the stomach Or the related obstacle of chewable tablets.Therefore, montelukast is applied under liquid dosage form or dosage form for Orally dissolving --- Wherein API is precipitated in saliva and is generated API suspension in saliva --- increase biology of the montelukast in subject Availability.Therefore, it is necessary to which a form of montelukast (or other leukotriene receptor antagonists) are administered orally, to reach Peroral dosage form is dissolved out or is disintegrated before stomach.

The pharmacokinetic data of table 1:CSF concentration

Sample	3 hour concentrations (ng/ml)	7 hour concentrations (ng/ml)
			MTL03 film	3.60	4.20

We have carried out clinical research to our product, and the medicine generation to determine the API being loaded into the drug platform is dynamic Mechanics.Our film product andProduct contains 10mg MTL free alkali.For the city of MTL Preparation is sold, asthmatic patient is commonly used in.It is made of the API tablet that 10mg is loaded.Cmax value and Tmax value is listed below, joins It is shown in Table 2.As a result it indicates, withWith reference to comparing, our cmax value and AUC value is about its 1.5 times.We These higher values of film mean that we can load less API into film product, and obtain withWith reference to The identical Cmax/AUC of product.Disclosed Intelgenx prototype andBetween the main distinction be that MTL is arrived Up to the physical state after stomach.?In product, MTL reaches stomach with compression solid state, it is therefore necessary to unfavorable Under the conditions of dissolve under one's belt.On the contrary, disclosed MTL03 oral film dosage form includes the MTL of dissolution, place it in oral cavity and Make its dissolution before swallowing.After disclosed MTL03 oral film dosage form dissolution, MTL is precipitated in the oral cavity, and remaining of dosage form Partial disintegration and/or dissolution form the MTL sediment being finally suspended in aqueous medium (i.e. saliva).Disclosed in as a result, The MTL for including in MTL03 prototype reaches stomach with the state of predissolve, this means that matrix has been dissolved out or has been disintegrated, makes MTL sediment It is exposed to gastric juice.Then MTL is transferred to small intestine via pylorus.Since MTL has been used as suspended sediment to exist, MTL can Small intestine is more easily reached with (leaking) pylorus by leakage.It is well known that pylorus is not leakproof, and even if Its closed position also allows some liquid to flow through.The MTL of MTL03 film amount disclosed in as a result, once under one's belt, is regarded as More easily pass pylorus.MTL, which is carried out enteral administration as the suspended sediment in aqueous medium, improves bioavilability.For The fact that the further bioavilability for supporting MTL to show raising when applying by such dosage form, we compare The pharmacokinetics of the MTL of FDA is supplied under New Drug Application (NDA) 020830 (referring to table 2).Table 2 shows chewable oral agents Type is easier biological utilisation than solid dosage.Masticable MTL dose fraction dissolution, therefore its bioavilability is raw better than tablet Object availability.Particularly, when applying in fasted subjects, the bioavilability that dosage form can be chewed is about 1.17 times higher than tablet (compared with can be with bioavailability data shown in the table 2).Therefore, by comparing inferring, when the area under comparison curves (AUC) when, (it contains is dissolved in membrane matrix and is deposited in saliva after stromatolysis disclosed MTL03 film amount MTL) it has been proved to 1.5 times (referring to table 3 and tables 4) higher than the bioavilability of tablet.It is believed that when with corresponding tablet and can When chewable tablet is compared, the biological utilisation of MTL is improved using MTL as the precipitate suspension application without film or tablet matrix Degree.It is believed that this improved bioavilability is at least partly caused by the contact area increase of sediment API.In addition, MTL with than The mode that corresponding tablet and masticable peroral dosage form are less concentrated is delivered under one's belt (referring to Fig. 1 and Fig. 3).

Table 2: the bioavilability between tablet and masticable peroral dosage form compares

According to an embodiment, the method for treating neurodegenerative disease or neuroinflamation sexual dysfunction includes following Step: (a) via film type, into the people for needing to treat neurodegenerative disease or neuroinflamation sexual dysfunction or other animal intestines Deliver the montelukast of safe and effective amount.Preferably, montelukast via comprising MTL or any other its suitable salt, ester or The oral film dosage of prodrug is administered orally.According to this treatment method, montelukast is at least substantially dissolved in film type, and with Membrane matrix is administered orally together, when in the oral cavity, dissolves out and/or collapses when which contacts with aqueous medium (such as saliva) Solution.MTL precipitating after membrane matrix dissolves out in the saliva in human or animal oral cavity.In addition, disclosed MTL03MTL dosage form Pharmacokinetic data display, which absorbs, is significantly higher than commodity montelukastProduct (tablet).Therefore, with Meng Lu Department spy be maintained at resist activating agent dissolution with absorb dosage form substrate in oral tablet or capsule compare, using MTL as have There are Fast Stripping or disintegration (to dissolve out or be disintegrated i.e. in less than 10 minutes, preferably between 2 minutes to 7 minutes, and more preferably exist In 3 minutes to 5 minutes) matrix film type application, to generate precipitate suspension in an aqueous medium before reaching stomach, Significantly improve the bioavilability of montelukast.According to the preferred aspect of present disclosure, leukotriene receptor antagonists, such as Montelukast is dissolved in oral film dosage form.

According to another aspect of the present invention, leukotriene receptor antagonists exists as the seed activity object in oral film dosage form In film.In such alternate embodiment of the invention, particle API is maintained in oral membrane matrix, and wherein membrane matrix exists It will dissolution and/or disintegration when being contacted with aqueous medium (i.e. saliva).After membrane matrix dissolves out and/or is disintegrated, particle API is by conduct Particle suspension liquid is present in aqueous medium.Particle API is in amorphous form preferably in membrane matrix.

Table 3: the pharmacokinetic data of plasma concentration

Table 4: the comparison of bioavilability between different dosage forms

Once application, oral film are preferably applied on the oral mucosa of subject, it will be adhered to subject there And the saliva contacts with subject.The film in contact dissolution and/or disintegration oral cavity between film and saliva.Dissolution and/or disintegration Oral membrane matrix advantageously allow for activating agent to precipitate in the oral cavity of subject.As suspension precipitating in an aqueous medium Object, sediment are swallowed for carrying out enteral administration.

The preferred amounts of the MTL of per unit dosage form are about 0.5mg to about 25mg, preferably about 1mg to about 25mg, more preferably About 5mg to about 10mg.

The illustrative and not restrictive example for being used to prepare the preparation of MTL oral film is shown in table 5 into table 11.

Table 5:MTL01

Table 6:MTL02

Table 7:MTL03

Table 8:MTL04

Table 9:MTL05

Table 10:MTL06

Table 11:MTL07

The preparation of film product generally comprise by liquid film preparation cast (cast) or otherwise thin-layer coating in substrate On, from dry (for example, evaporation) all or most of solvent of film to generate thin solid film material piece, and by solid film material piece It is cut into individual unit dosage forms.

Fig. 5 show when withWhen MTL tablet is compared, the dissolution rate of MTL film peroral dosage form of the invention Increase.In addition, allowing for the dissolution of the inventive film peroral dosage form of oral delivery method disclosed in Fig. 5.In these experiments In, " film dissolved out in advance " refers to special conditional when applying membranes to people experimenter oral mucosa to simulate by pretreatment Film.Under the conditions of this analoglike, film is slowly disintegrated before carrying out dissolution experiment.This method for swallow tablet behavior in stomach with Swallow the more representative comparison of film behavior；The film is faster again.In general, dissolution carries out under the following conditions.Dosage by The film or tablet of 10mg unit form.USP dissolution instrument is for measuring API release profiles.Each dissolution vessel filling has 900mL Phosphate base simulates Saliva buffer liquid, pH 6.8.Paddle speed is set as 50rpm, and temperature is maintained at 37 DEG C.Each drawing point (pull point) is made of 8mL, and time point takes 1,2.5,5,7.5,10,15,20,30,45.It is inhaled using the UV under 273nm Contracture analyses sample.The montelukast film of predissolve is prepared by mixing single film unit in 2mL simulation Saliva buffer liquid Leachable.The volume is considered as the representative of the saliva volume usually found in the oral cavity under normal condition.Data Summary is in table In 12.

Table 12

Sample	Reach the time (minute) of 80%API release
		Montelukast-film MTL03&MTL10	6
Montelukast-the film dissolved out in advance	1
		Montelukast-tablet	10

It was found that MTL03- film and MTL10- film reach 80% API release after about 6 minutes, and MTL- tablet reaches phase Same API emission levels need 10 minutes.This has highlighted the fater disintegration advantage based on film platform.However, when by tablet and in advance When the MTL03- film and MTL10- film of dissolution are compared, the most significant improvement of the membrane technology using us is observed.The reality Test it is particularly interesting because how the test more typically compares API from gulping down under comparable environmental condition The MTL- tablet of pharynx is discharged with the MTL03- film and MTL10- film swallowed., it is surprising that the MTL03- film dissolved out in advance and MTL10- film only just reaches the API of 80% release in about 1 minute.This clearly demonstrates that MTL03- film platform and MTL10- film How platform than MTL- tablet dose quickly discharges MTL.It is believed that this helps to observe during our I phase clinical research The improved bioavilability arrived.

As described above, the oral film of MTL is (predominantly compared with presently commercially available tablet/particle or suspension product MTL03 improved bioavilability) is shown.It is believed that the bioavilability increase of MTL is related with the state of MTL in oral film. According to some embodiments, the improved bioavilability of oral film dosage form mixes close in alkaline oral film with the MTL that will be dissolved Cut phase is closed, it is ensured that is easy to the quick release of the therapeutic agent of absorbed predissolve in oral cavity and enteron aisle.Pass through the surface p H of film The basicity of the oral film of measurement is conducive to dissolution of the MTL in film.It is believed that partially due to the presence of residual solvent, the certain journeys of MTL Keep solvable in film on degree.Our PRELIMINARY RESULTSs from manufacturing process prove that there are the residual solvents of 5% to 9% dry w/w. Therefore, it is intended that the basic surface pH oral film (MTL01, MTL03, MTL05, MTL06 and MTL 07) of MTL showed to observe The bioavilability of MTL03 increases.Alkaline film layer is designed to for MTL being maintained under advantageous dissolution conditions, the dissolution conditions It is easy to form amorphous sediment object in saliva when film is administered orally.

A significant challenge for taking orally film preparation accordingly, with respect to montelukast was related in manufacture, processing and long term storage phase Between the stability of API that dissolves.Although the API of dissolution significantly improves the bioavilability of drug, it may also accelerate API Degradation/decomposition approach, generate unwanted impurity.Present disclosure elaborates why to realize that the MTL of stable dissolution is produced Product are unexpected challenging to those skilled in the art, and by using specific critical excipients with API ratio and mixing condition can realize the process of the product.

It is well known that montelukast is degraded over time when being exposed to light, moisture or heat with solid state or liquid condition (M.M.Al Omari et al.) generates catabolite, such as montelukast sulfoxide (SO) and montelukast cis-isomer {Journal of Journal of Pharmaceutical and Biomedical Analysis,45,2007,465- 471}.It exposes in the sunChewable tablet shows the montelukast sulfoxide of 2.4% incrementss after 3 weeks Impurity.In addition, montelukast is exposed to sodium vapor lamp 6 hours in 0.1M hydrochloric acid solution, cause the montelukast m- isomery scale of construction Increase by 14.6%.

Therefore, because maintaining the MTL of dissolution for ensuring in film type long-time storage during preparation, production and processing Consistent bioavilability afterwards is necessary, therefore the selection of stabilizer or antioxidant may be critically important.Antioxidant/steady The selection for determining agent is limited to not will lead to the molecule of API generation sediment or will not interact with API so that generating sediment Molecule.This challenge will not be encountered in tablet formulation, because MTL is saved and used with solid state.The MTL of dissolution is to pH ring The variation in border is especially sensitive, and precipitates under lower pH (such as less than 8).The MTL of dissolution is also negatively charged, this can cause Undesirable complexing.Therefore, the selection of antioxidant and amount are further restricted, and eliminate peracidity molecule or can be with The molecule that API covalently or non-covalently is combined to form infusible precipitate compound and/or aggregate material.

Experimental study discloses, and when MTL is in its dissolved state, is particularly susceptible to metal catalytic degradation and other oxygen Change or the influence of photo induced decomposition approach.Existing MTL dosage form exists as tablet, tablet modification or suspension, and wherein MTL is Solid or suspension.In these formulations, antioxidant/stabilizer can be used as solid material and be directly added into or be applied indirectly to produce Product (spray coating, shell or membrane coat).It is not necessary to the antioxidant for considering to make the MTL in Tabules to precipitate/stabilizer phase Interaction, because Tabules have been solids.

Our research indicate that the MTL film formulation using only BHT as antioxidant is at equalization chamber (25 DEG C/65%RH) In increased impurity is shown after 3 months.Therefore, we have studied the uses of chelating agent, to prevent the palliating degradation degree observed. The example of chelating agent includes but is not limited to following molecule, such as disodium ethylene diamine tetraacetate (EDTA), tetrasodium ethylenediamine tetraacetate, Calcium disodium chelate, pentaacetic acid (pentetic acid, DTPA), citric acid (CA), DL-2,3- dimercapto -1- Propane sulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), list isopentyl DMSA (MiADMSA), alpha lipoic acid (ALA), glutathione, N-acetylcystein (NAC), vitamin C, (2) -2- amino -3- methyl -3- sulfonyl butyric acid, dithioglycerol, N- (α-L- Arabinofuranosidase -1- base)-L-cysteine (cystein) or nitrilotriacetic acid (NTP).In some cases, chelating agent (such as EDTA) is provided as different salt, these salt show more alkaline pH effectiveness to aqueous medium, however these points Son, such as tetrasodium ethylenediamine tetraacetate or the calcium disodium chelate table in terms of maintaining MTL stability in studying for a long period of time It is existing bad.

It is well known that chelating agent (such as EDTA) chelating be responsible for catalysis sulfoxide impurity formed metal ion in terms of very Effectively.EDTA concentration is bigger, and the stability of MTL API is higher.However, chelating agent is added in an aqueous medium would generally cause chela Mixture deprotonation is simultaneously then acidified aqueous blend.This is problematic, because MTL solubility is special to the variation of environment pH Sensitivity and the rapid precipitation at the pH lower than 8.In fact, seen in following Fig. 1, before observing sediment, can only by Limited amount EDTA is added in MTL solution.

Table 13:EDTA concentration increases and MTL and water quantity holding are constant, EDTA concentration (w/w is dry).

It is low

It is high

%EDTA

0%

0.427%

0.855%

1.711%

2.832%

4.542%

MTL solubility

It is

It is

It is

It is

It is no

It is no

The solubility and stability of MTL is the key parameter to be considered when preparing oral film, which will generate can be again Raw target organism availability and stable product.Therefore, the optimum formula of MTL will need to balance the amount of API and EDTA, to reach To required stability, while maintaining the drug component of dissolution.This can be realized by following several strategies: (1) balancing EDTA With the ratio (MTL sheet is as basifier) of MTL, (2) compensate the EDTA of incrementss, and (3) alkali using alkali modification excipient The application of property buffer components.

Testing to provide below can combine about these excipient to realize required API stability while maintain dissolution The details of the ratio of API.

MTL stability when EDTA increases

The result of stability of the MTL when EDTA concentration increase at 50 DEG C in up to 2 weeks is analyzed.In general, seeing Observe SO impurity increase with time, and Cis impurity is more stable.We have tracked SO impurity, are that EDTA prevents SO impurity shape At the effect of index, referring to the following table 1.In general, the amount of EDTA is bigger, the SO impurity of formation is fewer.Generally speaking, these results Instruction, using 1.6%EDTA, total SO impurity is maintained at 0.5% or less by us.

The stability result of MTL when table 14:EDTA concentration increases:

Prototype	Total SO impurity: W0	Total SO impurity: W1	Total SO impurity: W2
				0% dry w/w EDTA	0.19	0.59	1.26
0.4% dry w/w EDTA	0.17	0.43	0.69
				0.8% dry w/w EDTA	0.43	0.36	0.58
1.6% dry w/w EDTA	0.23	0.43	0.48
				2.5% dry w/w EDTA	0.12	0.35	0.44
3.3% dry w/w EDTA	0.11	0.17	0.20

The holding research of MTL solubility in the presence of EDTA

Second surprising challenge for stablizing MTL using EDTA is that the concentration regardless of EDTA is all observed several 100% EDTA can be precipitated at any time.The ETDA of higher concentration causes MTL to accelerate precipitating in several minutes, and lower dense Degree only causes to precipitate after 10 days.This point is especially important, observes because it means that the retention time of blend should not be longer than Sedimentation time.These are the binary mixture in water, in the blend with more high viscosity and more excipient, blend Character may difference (but similar).This is important for the wet blend retention time during manufacture.

Table 15:MTL supernatant and precipitation capacity:

Sample	EDTA(g)	Supernatant (mg/ml)	% dissolution	% precipitating	Sedimentation time
						1	0.035	0.642	1.60	98.4	10 days
2	0.070	0.536	1.33	98.67	7 days
						3	0.150	0.494	1.23	98.77	7 days
4	0.225	0.494	1.23	98.77	1 hour
						5	0.400	0	0	100	At once

* MTL is held constant at 1.125g

MTL solubility and EDTA: the application of basifier

Whether inspected basifier (that is, causing the increased additive of pH) can be used for remaining molten with the addition for determining them The MTL of solution, while increasing the horizontal stability to obtain improvement of EDTA.In these experiments, we using ion salt and have Both machine alkali is with the blend that alkalizes.

Table 16:

Reference material A and reference material B are compared, it was demonstrated that may be added to that in solution while maintaining MTL solubility Maximum EDTA amount threshold value.A part of NaOH basifier is added into these mixtures allows to be added more EDTA, simultaneously Maintain the MTL of dissolution.However, this ratio is not linear scale.For example, the 1M NaOH of 1g is enough to deposit in 0.225g EDTA In lower dissolution MTL, but if EDTA is increased to 0.300g by us, then MTL will not be dissolved NaOH amount is increased three times. In the presence of the MTL of precipitating, these blends of the NaOH containing incrementss show surprising viscosity and quality increases, Generate white milk cream shape blend；It may indicate that there are problems for excipient and API interaction in high alkalinity salt environment.It uses Organic bases triethylamine (TEA) has carried out similar experiment., it is surprising that when using the organic base of dissolution, TEA and EDTA Ratio can directly scale；When we add more TEA, we can add more EDTA in proportion, maintain simultaneously The MTL of dissolution.TEA is added in hydrotropism's blend may cause it to be converted into corresponding ammonium salt, therefore be directly added into ammonium conduct Basifier will generate identical result.Using TEA another it is surprising for the use of be, although having dissolved MTL, dissolution The color of API is dramatically different.When using TEA, with using when NaOH it is observed that usually bright clear yellow solution It compares, blend is actually only very light yellow.It has analyzed using both NaOH and TEA to maintain MTL solubility Sample with determine color change whether with MTL degradation and impurity formed it is related.It was found that without aobvious between the impurity of both samples The impurity that work difference, actually yellow solution are shown is less than with the glassy yellow blend of NaOH.It is summarized referring to Fig. 6, the Fig. 6 This series of experiments.Therefore, for using EDTA to stablize for montelukast film, liquid or water-soluble weak organic bases are used (such as TEA) is preferred.

Fig. 6 is the diagram of solubility limit of the MTL in the solution containing EDTA.In these experiments, the MTL that uses and The amount of water is kept constant and proportional to the amount found in formula.Using the basifier (NaOH and TEA) and EDTA of incrementss, The precipitating of our visual monitoring MTL.When MTL is precipitated out from solution, the arrow for each sample listed is terminated.It was found that In solution only containing water and MTL, we can be added up to the EDTA of 0.15g, and later due to the acidification from EDTA, MTL is opened Begin precipitating.More EDTA are added in addition basifier permission in the case where not precipitating MTL into solution；In the feelings using TEA It is most to find that the EDTA amount being added increases under condition.

So that blend is alkalized with compensate the third acid possibility of EDTA and other chelating agents actually increase it is molten The amount of MTL out.MTL itself has contributed much the alkalinization of solution, and can freely be dissolved in pure water.In other no alkali In the case where agent, MTL is responsible for alkalization/buffering needed for carrying out at basic ph to blend, to allow to mix stability institute The EDTA of the minimum needed.However, adding excessive MTL unexpectedly has significant bear to the mechanical performance of film and blending Face is rung.With the increase of MTL%w/w, film becomes more and more crisp and viscous, and strong lining is caused to interact, which prevent Easy release of the product in packaging step.From the point of view of this second angle, MTL relative to EDTA range and ratio to Guan Chong It wants, so as not to generate the product of the flexibility with difference, mechanical strength and lining release, this will hinder manufacturing scale. MTL also shows as amphiphile, amphiphilic molecule in the solution, in the presence of under high relative concentration, plays in stabilized blends during mixing Bubble and foam effect.This will slow down manufacture, since it is desired that using longer degassing conditions.Therefore, the ratio of MTL and EDTA Example is quite sensitive for the exploitation of functional drug product.Therefore, for using EDTA to stablize for montelukast film, liquid is used Body or water-soluble weak organic bases (such as TEA) are preferred.

According to some embodiments of disclosed oral film dosage form, film layer includes 0.01% to 0.04% dry w/w's The EDTA (disodium ethylene diamine tetraacetate) of the dry w/w of BHT and 1.6% to 2.0%

The ratio of MTL and EDTA

According to some embodiments, MTL and EDTA's is preferably in a proportion of about 1.00MTL ratio about 0.15EDTA.This preferably compares Example balance MTL solubility and stability.According to preferred embodiment, the ratio of MTL and EDTA in 13:1 between 3:2, with It maintains montelukast to dissolve in film and prevents from precipitating.

MTL solubility and EDTA: the application of ealkaline buffer

For by more EDTA mix blend in improve stability and meanwhile maintain MTL solubility it is final strategy for add Enter alkaline buffer component.Alkaline buffer is by (free protons would generally make blend with any free protons from EDTA Acidification) reaction, to allow to add more EDTA in the case where not changing pH.In general, suitable slow by preparing first Fliud flushing prepares these mixtures.Buffer used in our experiments is selected for maintaining alkaline environment；CHES.

Table 17: the buffer of MTL solubility is maintained

Sample	MTL(g)	Buffer system	EDTA(g)	pH	The solubility of MTL
						Compare A	1.125	Nothing	0.087	8	Dissolution, clear yellow
Compare B	1.125	Nothing	0.150	8-9	Dissolution, clear yellow
						Compare C	1.125	Nothing	0.225	8-9	Precipitate MTL
1	1.125	CHES	0.225	9.3	Precipitate MTL
						2	1.125	CHES	0.500	9.3	Precipitate MTL

As a result it indicates, when using pH to be maintained to 9.3 CHES buffer, MTL is insoluble after overnight mixing Solution.

The illustrative and unrestricted example of preparation for preparing MTL oral film using EDTA is shown In table 18 into table 24.

Table 18:MTL08

Table 19:MTL09

Table 20:MTL10

Table 21:MTL11

Table 22:MTL12

Table 23:MTL13

Table 24:MTL14

Measure the surface p H (table 25) of every kind of preparation.

The surface p H of table 25:MTL oral film

When withCan swallow or when chewable tablets are compared, formula MTL01, MTL03, MTL05, MTL06, MTL07, MTL08, MTL10, MTL12, MTL13 and MTL14 are it is believed that be suitable for maintaining at least part MTL into the dissolution shape in film Under formula, and improve the bioavilability of montelukast oral film.MTL02, MTL03, MTL09 and MTL11 provide one kind and are not intended to Dosage form, wherein montelukast precipitates, therefore cannot provide the required improved bioavilability from basic surface pH.

Above description is to be considered only as the description of preferred embodiment (one or more).For those skilled in the art with And the personnel of shown embodiment are made or used, it will expect the modification to these embodiments.It will be understood, therefore, that above-mentioned reality Apply what scheme (one or more) was merely exemplary, it is no intended to limit the scope of the disclosure, the model of present disclosure It encloses and is limited by the appended claims explained according to the Patent Law principle for including doctrine of equivalents.

Claims (31)

1. a kind of oral film dosage form, includes:

Film layer, the film layer have basic surface pH；With

The leukotriene inhibitors of the leukotriene inhibitors of safe and effective amount, the safe and effective amount mix in the film layer.

2. oral film dosage form according to claim 1, wherein the film layer is dissolved out and/or collapsed when contacting with aqueous solution Solution.

3. oral film dosage form according to claim 2, wherein the leukotriene receptor antagonists is montelukast.

4. oral film dosage form according to claim 3, wherein the surface p H of the film layer is greater than pH 7.

5. oral film dosage form according to claim 3, wherein the surface p H of the film layer is greater than pH 7.5.

6. oral film dosage form according to claim 3, wherein the surface p H of the film layer is greater than pH 8.

7. oral film dosage form according to claim 3, wherein the surface p H of the film layer is greater than pH 8.5.

8. oral film dosage form according to claim 3, wherein the surface p H of the film layer is between pH 8 to pH 12.

9. oral film dosage form according to claim 3, wherein the surface p H of the film layer is between pH 8.5 to pH 9.5.

10. oral film dosage form according to any one of claim 1 to 9, wherein the film layer is non-cushioned.

11. oral film dosage form according to any one of claim 1 to 10, wherein the film layer includes plurality of stable agent.

12. oral film dosage form according to claim 11, wherein the plurality of stable agent include p-hydroxybenzoate, EDTA and BHT.

13. oral film dosage form according to claim 12, wherein the amount of EDTA is greater than the amount of p-hydroxybenzoate, and Wherein the amount of p-hydroxybenzoate is greater than the amount of BHT.

14. oral film dosage form according to any one of claim 1 to 10, wherein the film layer also includes EDTA, and Wherein the ratio of montelukast and EDTA are in 13:1 between 3:2.

15. oral film dosage form according to claim 14, wherein the ratio of montelukast and EDTA are about 1:0.15.

16. according to claim 1 to oral film dosage form described in any one of 15, wherein the leukotriene receptor antagonists is with nothing Amorphous form mixes in the film layer.

17. according to claim 1 to oral film dosage form described in any one of 16, wherein the leukotriene receptor antagonists dissolves In the film layer.

18. according to claim 1 to oral film dosage form described in any one of 17, wherein when the film layer dissolves out in saliva And/or when disintegration, the leukotriene receptor antagonists precipitating.

19. oral film dosage form according to claim 1, wherein the leukotriene receptor antagonists is with about 0.5mg to about Montelukast existing for the amount of 25mg.

20. oral film dosage form according to claim 1, wherein the leukotriene receptor antagonists is with about 5mg to about Montelukast existing for the amount of 15mg.

21. oral film dosage form according to claim 1, wherein the leukotriene receptor antagonists is deposited with the amount of about 10mg Montelukast.

22. according to claim 1 to oral film dosage form described in any one of 21, wherein the film layer is bioadhesion film layer.

23. according to claim 1 to oral film dosage form described in any one of 22, wherein the film was included at 3 minutes to 7 minutes Clothes, oral or sublingual dissolution, and wherein the leukotriene receptor antagonists precipitates in saliva.

24. according to claim 1 to oral film dosage form described in any one of 23, wherein when being dissolved out in advance in the saliva in simulation When, the film dissolved 80% in 1 minute.

25. oral film dosage form according to claim 21, wherein area under the curve (AUC) is in about 3120ng*h/mL to about Between 4700ng*h/mL.

26. oral film dosage form according to claim 21, wherein Cmax is in about 475ng/ml between about 720ng/ml.

27. a kind of multilayer orally film type, includes:

First film layer, first film layer have basic surface pH and include the leukotriene inhibitors of safe and effective amount；With

The composition of at least the second film layer, second film layer is different from the composition of the first layer.

28. multilayer orally film type according to claim 27, wherein second film layer be prevent or reduce it is described white The non-adhering barrier layer of leukotriene inhibitor intake.

29. the multilayer orally film type according to any one of claim 27 or 28, wherein second film layer is formulated At the activating agent different from the leukotriene inhibitors in first film layer for intestinal delivery.

30. the multilayer orally film type according to any one of claim 27 to 29, wherein second film layer includes to cover Taste agent.

31. the multilayer orally film type according to any one of claim 27 to 30, wherein second film layer include with The identical or different activating agent of leukotriene inhibitors in first film layer, wherein the second layer is formulated into offer Controlled release profile.