CN103687483A - Compositions, methods & systems for respiratory delivery of two or more active agents - Google Patents

Compositions, methods & systems for respiratory delivery of two or more active agents Download PDF

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Publication number
CN103687483A
CN103687483A CN201180072341.4A CN201180072341A CN103687483A CN 103687483 A CN103687483 A CN 103687483A CN 201180072341 A CN201180072341 A CN 201180072341A CN 103687483 A CN103687483 A CN 103687483A
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suspension
approximately
altogether
patient
shorter
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Inventor
R·维宁
M·S·哈特曼
D·莱丘加-巴列斯特罗
A·E·史密斯
V·B·乔希
S·K·德威维迪
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Pearl Therapeutics Inc
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Pearl Therapeutics Inc
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Priority to CN201510242737.9A priority Critical patent/CN105106200A/en
Publication of CN103687483A publication Critical patent/CN103687483A/en
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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
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L9/00—Disinfection, sterilisation or deodorisation of air
    • A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
    • A61L9/02—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air by heating or combustion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions

Abstract

Compositions, methods and systems are provided for pulmonary or nasal delivery of two or more active agents via a metered dose inhaler. In one embodiment, the compositions include a suspension medium, active agent particles, and suspending particles, in which the active agent particles and suspending particles form a co-suspension within the suspension medium.

Description

For breathing composition, the method and system of sending two or more activating agents
Technical field
The present invention relates generally to composition, the method and system of sending two or more activating agents by respiratory tract.In certain embodiments, the present invention relates to send through respiratory tract composition, the method and system of two kinds or many activating agents, wherein at least one activating agent is selected from long-acting muscarinic antagonist (" LAMA "), long-acting beta 23 adrenergic receptor agonists (" LABA ") and corticosteroid activating agent.
Background technology
Target administration method at action site active agent delivery is often yearning.For example, the target administration of activating agent can reduce undesirable side effect, reduces dosage demand and treatment cost.In the situation of respiratory administration, inhalator is a kind of device to patients with respiratory tract active agent delivery of knowing, and existing multiple different inhalator system now business can purchase.Three kinds of common inhalators comprise Diskus, sprayer and metered dose inhaler (MDI).
MDI can be used for sending the medicine of dissolving or suspended form.Typically, when being activated, MDI use has the relatively propellant of high-vapor-pressure the aerosol droplets that contains activating agent is pushed to respiratory tract.Thereby the getter action of the common dependent patient of Diskus sucks respiratory tract by the medicine of dry powder form.On the other hand, thus sprayer is formed for the aerosol medicine sucking by the energy that acts on liquid solution or suspension.
MDI utilizes propellant to produce the active delivery apparatus of pressure.Traditionally, Chlorofluorocarbons (CFC) because of its hypotoxicity, there is the propellant that required vapour pressure and the stable suspension of suitable formation are used as MDI system.Yet traditional C FC propellant is considered to produce negative environmental effect, thereby produced, it is believed that for example development of perfluorochemical (PFC) and hydrofluoroalkane (HFA) of more eco-friendly alternative propellant.
The activating agent of sending by MDI is provided by the particulate form being scattered in a kind of propellant or two kinds and above propellant (that is, propellant " system ") conventionally.In order to form particulate, conventionally activating agent is carried out to micronize.The activating agent particulate being suspended in propellant or Propellant System tends to assemble fast or flocculation.This phenomenon of activating agent for particulate form is especially real.The gathering of these particulates or flocculation may cause sending of activating agent complicated then.For example, gathering or flocculation can cause mechanical breakdown, such as stopping up the fault that cause by the valve port of aerosol container.The gathering of disgusting drug particles or flocculation also can cause the fast deposition of drug particles or solidifying thick, and it is inconsistent that these behaviors may cause that dosage sends, its trouble especially for efficient low-dose drugs.Plant therewith another problem that suspension MDI preparation is relevant and be the crystal growth during medicine storage, this can cause the uniformity of aerosol performance and this MDI dosage delivered along with the time declines.Recently, the solution for the MDI preparation that contains anticholinergic drug has been proposed, such as disclosed method in the U.S. patent No. 6,964,759.
Improve the method for aerosol performance in Diskus and introduce exactly a subparticle carrier, such as lactose.For MDI, also do not carry out any on a large scale for the research of using this fine excipient.In nearest report, " the The influence of micronized particulates on the aerosolization properties of pressurized metered dose inhalers " that Young etc. deliver; Aerosol Science40, pgs.324-337 (2009) finds in MDI, to use this kind of subparticle carrier in fact can cause the reduction of aerosol performance.
In traditional C FC system, when the activating agent in MDI preparation is dissolved in propellant or Propellant System, conventionally use the surface of surfactant covering activating agent to reduce or to prevent the appearance of rendezvous problem and maintain the substantially even of dispersion liquid.Surfactant is used sometimes with which and is called as " stablizing " suspension.Yet the many CFC of being dissolved in systems effectively surfactant are invalid in HFA and PFC Propellant System, because these surfactants present different dissolubility properties in non-CFC propellant.
accompanying drawing summary
The figure of Fig. 1 shows the dosage delivered uniformity of the common suspension that contains Glycopyrrolate and formoterol fumarate prepared according to the present invention.
The figure of Fig. 2 shows the dosage delivered ratio of the common suspension formulation in Fig. 1.
The figure of Fig. 3 shows the dosage delivered uniformity of the second common suspension preparation that contain formoterol fumarate and Glycopyrrolate prepared according to the present invention.
The figure of Fig. 4 shows the dosage delivered ratio of suspension preparation altogether of second in Fig. 3.
The figure of Fig. 5 shows while storing under specified different condition, the Glycopyrrolate according to the present invention in prepared common suspension preparation and the dosage delivered uniformity of formoterol fumarate.
The figure of Fig. 6 shows while storing under specified different condition, and the exemplary particle diameter that be total in suspension preparation prepared according to the present invention distributes.
The figure of Fig. 7 shows while storing under specified condition, and the exemplary altogether particle diameter that suspension is realized that contains Glycopyrrolate and formoterol fumarate combination distributes.
The figure of Fig. 8 shows the contrast situation of the particle diameter distribution of the exemplary suspension altogether that contains Glycopyrrolate and formoterol fumarate and the particle diameter distribution of the preparation that only contains Glycopyrrolate or formoterol fumarate.
The figure of Fig. 9 shows and gives after the prepared exemplary altogether suspension that contains Glycopyrrolate and formoterol fumarate of the present invention the situation of change of the concentration level of Glycopyrrolate and formoterol fumarate in serum along with the time.The serum-concentration that Fig. 9 also shows Glycopyrrolate that exemplary combination preparation realizes and formoterol fumarate is along with the situation of change of the time comparing result with the situation of change of the composition that only contains Glycopyrrolate or formoterol fumarate.
The particle diameter that the figure of Figure 10 shows the binary prepared according to the present invention Formoterol that suspension is realized altogether distributes with the contrast situation of the common suspension that only contains lenticular formoterol fumarate, this binary suspension contains microcrystalline form altogether formoterol fumarate and Glycopyrrolate active agent particle.
The figure of Figure 11 shows the binary prepared according to the present invention Glycopyrrolate particle diameter that suspension is realized altogether and distributes, this binary Glycopyrrolate active agent particle that suspension contains microcrystalline form altogether and formoterol fumarate active agent particle or the spray-dired formoterol fumarate with the microcrystalline form of two kinds of different-grain diameters distributions (representing with " carefully " and " slightly ").
The second binary formoterol fumarate particle diameter that suspension is realized altogether that the figure of Figure 12 shows the Glycopyrrolate active agent particle of the formoterol fumarate that contain microcrystalline form prepared according to the present invention and microcrystalline form distributes, the comparable situation between the formoterol fumarate particle diameter of realizing with the common suspension of the Glycopyrrolate active agent particle that contains microcrystalline form and spray-dired formoterol fumarate particle distributes.
The figure of Figure 13 shows the exemplary binary prepared according to the present invention altogether Glycopyrrolate in suspension preparation and the dosage delivered uniformity of formoterol fumarate.
The figure of Figure 14 shows the dosage delivered uniformity of the every kind of activating agent comprising in the common suspension preparation of exemplary ternary of the Glycopyrrolate, formoterol fumarate and the momestasone furoate active agent particle that contain microcrystalline form.
Comparable situation between the binary formoterol fumarate aerodynamic size that suspension is realized altogether that the figure of Figure 15 shows the ternary formoterol fumarate aerodynamic size distribution that suspension is realized altogether of the Glycopyrrolate that contains microcrystalline form prepared according to the present invention, formoterol fumarate and momestasone furoate active agent particle and contains Glycopyrrolate and formoterol fumarate distributes.
Comparable situation between the binary Glycopyrrolate aerodynamic size that suspension is realized altogether that the figure of Figure 16 shows the ternary Glycopyrrolate aerodynamic size distribution that suspension is realized altogether of the Glycopyrrolate that contains microcrystalline form prepared according to the present invention, formoterol fumarate and momestasone furoate active agent particle and contains Glycopyrrolate and formoterol fumarate distributes.
The figure of Figure 17 shows the ternary prepared according to the present invention Glycopyrrolate that suspension is realized altogether and TB aerodynamic size distributes, and this common suspension also contains the active agent particle of the microcrystalline form of formoterol fumarate and momestasone furoate except Glycopyrrolate or TB.
The aerodynamic size that the figure of Figure 18 shows the two kind binary prepared according to the present invention and a kind of one-component formoterol fumarate that suspension is realized altogether distributes.It shows two kinds of binary dose ratio between suspension and between binary and the common suspension of one-component altogether.
The figure of Figure 19 shows the two kind binary prepared according to the present invention and the aerodynamic size of two kinds of one-component formoterol fumarates that suspension is realized altogether distributes.It shows the dose ratio between two kinds of binary and two kinds of common suspension of one-component and between binary and the common suspension of one-component.
The figure of Figure 20 shows the formoterol fumarate one-component dosage delivered uniformity that suspension is realized altogether of the ultra low-volume prepared according to the present invention.
The figure of Figure 21 shows two kinds of administrations and treats accumulating of first day and reply over time, wherein use as combination (GP/FF72/9.6 and GP/FF36/9.6) the send single-activity agent (be only send Glycopyrrolate-GP36, another be only send Tiotropium Bromide-Si Lihua) different from two kinds of common suspension composition described in the invention compares.A part as the clinical research described in embodiment 12, gives patient by these compositions.Especially, in figure, shown and obtained FEV 1improve>=12% patient's percentage and reach the required time of above-mentioned percentage.
The figure of Figure 22-Figure 24 has shown that the part as the clinical research described in embodiment 12 gives patient by different seminar compound, FEV when treatment the 7th day (the 7th day) 1aUC 0-12the mean change amount of comparing with basic value.(one is only to send Glycopyrrolate-GP36 with the multiple different activities composition of sending single-activity agent with placebo to use as described in the present invention two kinds of treatments (GP/FF72/9.6 and GP/FF36/9.6) of the combination of suspension composition altogether, second is only to send Tiotropium Bromide-Si Lihua, and the 3rd is only to send formoterol fumarate-FF7.2, FF9.6 and Foradil) compare.
Figure 25 has shown that the part as the clinical research described in embodiment 12 gives patient by each activity research composition, the FEV in the time of the 7th day 1aUC 0-12.In figure, shown and compared the FEV that each activity research composition provides with placebo 1aUC 0-12improvement.
Figure 26 has shown that the treatment of GP/FF36/9.6 in the time of the 7th day compares reached FEV with GP36, FF9.6, Si Lihua and Foradil active control 1aUC 0-12between difference.By reference to Figure 26, can easily understand, GP/FF36/9.6 treatment has improved FEV significantly better 1aUC 0-12.
Figure 27 has shown that the part as the clinical research described in embodiment 12 gives patient by different seminar compound, at the peak FEV that treats the 1st day (the 1st day) and reach for the 7th day 1.The peak FEV of described demonstration 1representative: in specified research day, compare with placebo, each activity research composition provides the FEV with respect to basic value 1peak change.
Figure 28 shown with Si Lihua and compared with Foradil active control, the peak FEV that GP/FF36/9.6 treatment reaches when the 1st day and the 7th day 1difference.By reference to Figure 28, can easily understand, compare with described activating agent, GP/FF36/9.6 treatment has improved peak FEV significantly better 1.
Figure 29 has shown that the part as the clinical research described in embodiment 12 gives the paddy FEV in early morning that seminar's compound that patient is different reaches 1improvement situation.In figure, shown and compared each activity research composition with placebo to paddy FEV in early morning 1the improvement situation of value.
Figure 30 has shown and in the clinical research shown in embodiment 12, has used use described herein altogether two kinds of treatments (GP/FF72/9.6 and GP/FF36/9.6) and different single-activity agent positive controls and the FEV before administration in the 7th day each other of the combination of suspension composition 1the difference of recruitment.By reference to Figure 30, can easily understand, compare with described single-activity agent positive control, GP/FF72/9.6 and GP/FF36/9.6 treatment have improved the front FEV of administration significantly better 1but there is not each other significant difference in it.
Figure 31 has shown the part as the clinical research described in embodiment 12, compare with placebo, the gulp capacity (IC) that the active positive control composition of two kinds of treatments (GP/FF72/9.6 and GP/FF36/9.6) of the combination of the common suspension composition of use and Si Lihua provides was the 1st day and the peak value of the 7th day and the improvement situation before administration in the 7th day.
Figure 32 has shown the order of severity of the chronic obstructive pulmonary disease of suffering from regardless of patient, has all obtained consistent patient and reply in the clinical research described in embodiment 12.
detailed Description Of The Invention
The invention provides composition, method and system for sending two or more activating agents through breathing.In a particular embodiment, the invention discloses and by MDI, through respiratory tract, send pharmaceutical composition, the system and method for two or more activating agents, at least one activating agent is selected from long-acting muscarinic antagonist (" LAMA "), long-acting beta in certain embodiments 23 adrenergic receptor agonists (" LABA ") and corticosteroid activating agent.Composition of the present invention can be formulated into by MDI through lung or nasal delivery there.The method of the invention comprises the method for stablizing the preparation that comprises two or more activating agents for sending through breathing, and through lung, sends the method that two or more activating agents are used for the treatment of PUD D or symptom by MDI.The present invention has also described for sending the MDI system of two or more activating agents, and the method for preparing this system.
The challenge that faces of pharmaceutical composition that preparation contains two or more activating agents conventionally can be owing to, between activating agent, occur being difficult to expect or do not wish the interaction that occurs, or add the variation that has caused preparation after multiple actives.This interaction is commonly referred to " share effect ", in the situation that sending suspension formulation by MDI, share effect and can show as the preparation that for example comprises the preparation of single-activity agent and comprise the combination of two or more activating agents and occurred to depart from following similitude aspect one or more: the aerosol performance that preparation provides and particle diameter characteristic distributions; The dosage delivered uniformity of one or more activating agents; Sending or absorbing capacity of one or more activating agents; Or the dose ratio of viewed one or more activating agents.
In a particular embodiment, mixed suspension composition altogether of the present invention has been avoided the share effect relevant to combination preparation.For purposes of the present invention, composition has avoided share effect, in combination preparation selected activating agent aspect aerosol performance, Size Distribution and dosage delivered uniformity all the activating agent selected with only containing this as the Comparative formulation of activating agent, compare deviation do not occur.In certain embodiments, selected activating agent does not have and share effect this point and can be proven in the following manner: in combination preparation the plasma concentration of the target dosage delivered of selected activating agent along with the situation of change of time with only contain this selected activating agent as activating agent the plasma concentration of sending this selected activating agent in the Comparative formulation of selected activating agent with identical dosage along with the situation of change of time is compared and do not departed from.
For given parameter, the term in the application " do not occur departing from " represent performance that combination preparation is realized can reach only contain a kind of activating agent in combination preparation Comparative formulation ± 20%.In certain embodiments, the performance that combination preparation is realized is compared and is not changed with the Comparative formulation that only contains a kind of activating agent in combination preparation.For example, during one or more in meeting following condition, can think that effect does not appear share in the common suspension that comprises two or more activating agents described in the application: for every kind of this type of activating agent of given dose, its combination altogether in suspension the aerosol performance that shows, particle diameter distribution character, dosage delivered uniformity and plasma concentration along with the variation of time is in, only contain respective value that the Comparative formulation of single kind of activating agent reaches ± 20% scope in.In certain embodiments, combination of the present invention aerosol performance, particle diameter distribution character, dosage delivered uniformity and plasma concentration that altogether the activating agent of each given dose is realized in suspension composition only contains along with one or more in the situation of change of time are in respective value that the Comparative formulation of single-activity agent reaches ± 15% scope.In other embodiments, combination of the present invention aerosol performance, particle diameter distribution character, dosage delivered uniformity and plasma concentration that altogether the activating agent of each given dose is realized in suspension composition only contains along with one or more in the situation of change of time are in respective value that the Comparative formulation of single-activity agent reaches ± 10% scope.In certain embodiments, for the activating agent of each given dose, combination of the present invention altogether suspension composition is compared with the Comparative formulation that only contains a kind of activating agent following and not there are differences aspect one or more: the aerosol performance of preparation; Particle diameter distribution character; Dosage delivered uniformity; And plasma concentration is along with the situation of change of time.
In certain embodiments, the benefit that is included in the combination of two or more activating agents in composition of the present invention and can provides surpasses the pharmaceutical preparation that only contains single-activity agent.For example, when the combination of two or more activating agents is sent simultaneously, when it is sent separately with any one in the activating agent being used in combination, compare, the treatment effective dose of these two kinds of activating agents all can correspondingly reduce, thereby avoids or reduce contingent side effect.In addition, compare when any one in the activating agent share sent separately, when two or more activating agents share, can realize the treatment benefit that onset is more rapid or the duration is longer.
In a particular embodiment, method of the present invention comprises and can send the methods for the treatment of that suspension composition altogether of the present invention is treated PUD D or symptom by breathing.For example, composition of the present invention, method and system can be used for treating inflammatory or obstructive disease of lung or symptom.In a particular embodiment, composition of the present invention, method and system can be used for treatment and are selected from asthma, chronic obstructive pulmonary disease (COPD), the airway hyperreactivity of other drug treatment secondary worsens, allergic rhinitis, nasosinusitis, lung vessel retraction, inflammation, irritated, respiratory disorder, Respiratory Distress Syndrome(RDS), pulmonary hypertension, lung vessel retraction, and those can be to independent for example LAMA, LABA, the treatment of corticosteroid or other activating agents of the present invention produces any other respiratory disease of replying or the combination results of these activating agents and other therapies being replied, symptom, proterties, genotype or phenotype.In a particular embodiment, composition of the present invention, method and system can be used for lung inflammation and the obstruction that treatment is relevant to cystic fibrosis.As used in the present invention, term " COPD " and " chronic obstructive pulmonary disease " comprise chronic obstructive disease of lung (COLD), chronic obstructive airway disease (COAD), chronic airflow limited (CAL) and chronic obstructive respiratory disease (CORD), and comprise chronic bronchitis, bronchiectasis and pulmonary emphysema.Term used in the present invention " asthma ", no matter refer to the asthma of which kind of type or origin, comprises the asthma of bringing out after endogenous (nonallergic) asthma and exogenous (hypersensitivity) asthma, mild asthma, moderate bronchial asthma, severe asthma, bronchial astehma, exercise-induced asthma, occupational asthma and bacterium infect.Asthma also can be understood to comprise wheezy-infant syndrome (wheezy-infant syndrome).
Compare with the composition of only sending single-activity agent, when suffering from the patient of PUD D, the embodiment of suspension composition altogether of the present invention significantly increases the testing result of one or more PFTs or capacity.In some such embodiment, and only containing the composition of single-activity agent, compare, send the common suspension composition that comprises as described in the present invention two or more activating agents and make FEV 1with a kind of in respiratory capacity (IC) or both significantly increase.
Be to be understood that embodiment of the present invention is exemplary.Various embodiment in follow-up detailed Description Of The Invention are not intended to limit the scope of the invention, and it is only as the example of various examples.Therefore the content that, the present invention records can comprise the theme that those independently can be granted patent.In addition,, in the situation that not departing from protection domain of the present invention, those skilled in the art can change step or the order of action of correlation technique in embodiment disclosed by the invention.In other words, unless the certain order of step or effect is necessary for suitably implementing embodiment, otherwise can revise the order of particular step or effect.
i. definition
Unless have other clear and definite explanation, otherwise technical term used in the present invention had the implication that field of living in is understood conventionally.Object for clear, defines following term.
Term used in the present invention " activating agent " comprises any reagent, medicine, compound, composition or other materials that can be used for using or giving because of the needs of any object human or animal, comprises reagent and the immunomodulator for the treatment of use, pharmaceutical purpose, pharmacologically active, diagnosis use, cosmetic and prevention use.Term " activating agent " can be replaced and use with term " medicine ", " medicine ", " medicament ", " bulk drug " or " therapeutic agent "." activating agent " used in the present invention also comprises those and it has been generally acknowledged that the natural or hahnemannian product (homeopathic product) without therapeutic activity.
Term " association ", " with ... associate " or " association " refer to that chemical individual, composition or structure are when neighbouring surface for example during contiguous another chemical entities, composition or structure surperficial, the interaction occurring or correlation between them.Association for example comprises and adsorbing, sticks, your (Lifshitz-van der Waals) effect and the polarity effect of covalently bound, hydrogen bond, ionic bond and electrostatic attraction, Li Fuxizi-Van der Waals.It is a kind of association form that term " sticks ", and it is used as all general designations that can make particle or agglomerate have the power that attracted to surperficial tendency." stick " thus also refer to that those impel and keep contacting with each other between particle and make substantially not exist the segregation phenomenon that can observe, this segregation phenomenon to be because the different buoyancy of particle in propellant are caused under normal operation between particle.In one embodiment, those adhere to or are connected to surperficial particle and are included in the scope that term " sticks ".Normal condition can comprise storage or the storage under acceleration of gravity under room temperature.As described herein; active agent particle can associate to form common suspension mutually with suspended particulate, wherein between suspended particulate and active agent particle or its flocculate, does not substantially have those segregation phenomenons that cause because of their buoyancy difference in propellant that can observe.
" suspended particulate " refers to that those are applicable to breathe material or the combination of materials of the carrier of sending and can be used as active agent particle.Thereby interacting, suspended particulate and active agent particle can repeatedly activating agent be given, is delivered to or be transported to namely respiratory tract of target site.Suspended particulate of the present invention is dispersed in the suspension media that comprises propellant or Propellant System, and has and can be mixed with any shape, size or the surface characteristic that the suspension stability that is suitable for reaching required or activating agent are sent performance.Exemplary suspended particulate comprises that those have the particle of the particle diameter that is conducive to breathe active agent delivery, and those have and are suitable for preparation and send the particle of the physical arrangement of stable suspension of the present invention.
Term " suspension altogether " refers to the suspension of the particle in suspension media with different two or more types that form, and wherein part association at least occurs for the particle of a type and one or more other grain types.There is one or more specific visual variations at least one grain type that association can cause being suspended in suspension media.The caused specific change of association for example can comprise one or more following variations: assemble or the density of the namely sedimentation of speed, the rate of departure and character of flocculation or solidifying thick, paste or precipitum, with the adhesion of chamber wall, with adhesion and dispersion rate and the degree when stirring of valve module.
For judging whether to exist the illustrative methods of common suspension to comprise as follows: the weight density of another kind of grain type is less than propellant if a kind of weight density of grain type is greater than propellant, can adopt solidifying thick or this method of sedimentation behavior of visible observation to determine whether common suspension exists.Term " weight density " refers to that those form the density of the material of particle, wherein get rid of the space in particle.In one embodiment, material can be mixed with to the form that is suitable for visualization, thereby or also can by substance transfer in transparent bottle normally vial be suitable for visualization.After initial stirring, the standing sufficiently long time of bottle, to form sedimentation or solidifying thick layer, is generally to 24 hours.If the sedimentation of observing or solidifying thick layer are simple layers uniformly completely evenly or substantially, show to exist common suspension.Term " suspension altogether " comprises part suspension altogether, and wherein association has occurred at least most two kinds of grain types each other, yet, also can observe a little separation (being namely less than majority) of at least two kinds of grain types.
Exemplary common suspension detects test can carry out under different propellant temperatures, to highlight those, has sedimentation or the solidifying thick behavior with the approaching grain type of the propellant density under room temperature.If it is whole sedimentations or all solidifying thick that different grain types has identical separating property, can determine whether to exist common suspension by measuring other characteristics of suspension, such as measure gathering or flocculation rate, the rate of departure, paste or precipitum density, with the adhesion of chamber wall, with adhesion and dispersion rate and the degree when stirring of valve module, and the individual features of single kind grain type of above-mentioned feature and similar suspension is contrasted.Those skilled in the art can adopt the various analytical methods of knowing to measure these characteristics.
When being used in those, contain or composition that the aggregation that can suck, particle, drop etc. are provided for example during composition of the present invention, term " minuteness particle dosage " or " FPD " refer to the dosage being within the scope of can suction, and it can represent or represent by nominal standard dose or the ratio that indicates dosage by gross mass.Be in the dosage that the dosage within the scope of can suction can be deposited on outside cascade impactor throat level by measurement in vitro and determine, namely under the flow velocity of 30l/min the 3rd level of ram of new generation (Next Generation Impactor) to the summation of the dosage delivered of filter.
When being used in the composition that contains or the aggregation that can suck, particle, drop etc. are provided for example in composition of the present invention time, term " minuteness particle mark " or " FPD " refer to that the delivered substance that is within the scope of can suction is with respect to the ratio of dosage delivered (the namely delivery apparatus amount that for example starter of MDI discharges).The amount that is in the delivered substance within the scope of can suction is the amount outside cascade impactor venturi level that is deposited on recording in vitro, for example the summation of the delivered substance from level 3 to filter in ram of new generation under the flow velocity of 30l/min.
Term used herein " inhibition " refers to that measurable minimizing trend or minimizing degree have appearred in phenomenon, symptom or situation.Term " inhibition " or its arbitrary form have the implication of broad sense, and comprise and minimize, prevent, alleviate, suppress, prevent, retrain, force, limit, slow down development and similar meaning.
Term used in the present invention " the dynamic diameter of mass median " or " MMAD " refer to aerocolloidal special air kinetic diameter, the particle that the aerosol of 50% quality is less than MMAD by aerodynamic diameter under this numerical value is formed, and MMAD can calculate according to the method in American Pharmacopeia (" USP ") monograph 601.
Term used herein " optical diameter " for example refers to, by adopting Fraunhofer diffraction pattern and using laser diffraction particle size analyzer with dry powder dispenser (Sympatec GmbH, Clausthal-Zellerfeld, Germany) measured particle diameter.
The transformation of term solution mediation refers to a specific phenomenon, the better solid matter form of a kind of solubility property in this phenomenon (particle (it can be used as the driving force of Ostwald (Ostwald) slaking) namely with small curvature radius, or amorphous substance) thereby can occur is dissolved and recrystallization forms the more stable crystal form can propellant solution equilibria saturated with it coexisting.
" patient " refers to that activating agent combination of the present invention has the animal for the treatment of effect to it.In one embodiment, patient is the mankind.
" porous microstructure " refers to the suspended particulate with structural matrix, this structural matrix presents, limits or comprise those can make suspension media around permeate, load or spread to space, pore, defect, hollow, space, gap space, hole, perforation or the hole of microstructure, such as people such as Weers in U.S. patent the 6th, material and the preparation in 309, No. 623, recorded.The original form of porous microstructure is conventionally unimportant, and any structure of the desired preparation characteristic of the present invention that can provide all contains within the scope of the invention.Therefore, in one embodiment, porous microstructure can comprise intimate spherical structure, for example hollow, suspend, spray-dired microballoon.But those are also suitable at original form or there is depression, wavy, distortion or broken particulate aspect aspect ratio.
As suspended particulate of the present invention, porous microstructure is formed by any material that degraded substantially can not occur in selected suspension media or dissolve and have biocompatibility.Although can form particle with various materials, structural matrix and surfactant associate or it has comprised surfactant for example phosphatide or fluorinated surfactant in certain embodiments.Although optional, in porous microstructure or more general introduce compatible surfactant can improve and breathe the stability of disperseing the preparation that increases pulmonary deposition and be conducive to suspension in suspended particulate.
Term used in the present invention " suspension media " refers to the material that continuous phase is provided, thereby active agent particle and suspended particulate can be dispersed in formation in this continuous phase, is total to suspension preparation.The suspension media that suspension preparation is used of the present invention altogether comprises propellant.Term used in the present invention " propellant " refers to the material of one or more pharmacology inertia, thereby it can produce sufficiently high vapour pressure the medicament in MDI tank is pushed to patient under common room temperature condition when starting MDI metering valve.Therefore, term " propellant " refers to a kind of propellant or two or more different propellants combination formed " Propellant System " simultaneously.
Term " can suck " and typically refer to its size and can make it be inhaled into the particle, aggregation, drop etc. that arrive lung airway.
When being used to refer to suspension composition altogether of the present invention, term " physical stability " and " physically stable " refer to a kind of composition, and said composition can be resisted due to one or more phenomenons in changing of the gathering that the effect of solution mediated transformation causes, flocculation and particle diameter and can substantially be maintained MMAD and the minuteness particle dosage of suspended particulate.In one embodiment, physical stability can be measured by allowing composition bear accelerated degradation condition, and for example temperature cycling of the present invention is processed.
When for activating agent, term " effectively " refers at 0.01mg/kg to about 1mg/kg dosage range or when lower than this dosage range, treats effective activating agent.The common dosage of effective active agent is the scope to about 100mg at approximately 100 μ g generally.
When for activating agent, term " efficiently " refers to treats effective activating agent at 10 μ g/kg dosage or when lower than this dosage.The common dosage range of high-efficiency activated dose is generally up to approximately 100 μ g.
Term " stability of suspension " and " stable suspension " refer to the suspension preparation of the common suspension character that can maintain within a certain period of time active agent particle and suspended particulate.In one embodiment, stability of suspension can be assessed by the dosage delivered uniformity of suspension composition altogether of the present invention.
Term " substantially insoluble " refers to that composition is insoluble to specific solvent completely or composition is insoluble in this specific solvent.Term " substantially insoluble " refers to that the solvability of specific solute in every 100 parts of solvents is lower than 1 part of solute.Term " substantially insoluble " also comprises defined " sl. sol. " (100 to 1000 parts of solvents of every 1 part of solute), " very slightly soluble " (every 1 part of solute 1000 to 10,000 part of solvent) and " insoluble,practically " (every 1 part of solute is more than 10,000 part of solvent), with reference to The Science and Practice of Pharmacy, 21st ed.Lippincott, Williams & Wilkins, 2006, the 212 page table 16-1.
Term used in the present invention " surfactant " refers to the reagent that is preferentially adsorbed to two interfaces between immiscible phase, for example the interface between water and organic polymer soln, the interface between water/air or the interface between organic solvent/air.Therefore surfactant has hydrophily module and hydrophobicity module conventionally, and when being adsorbed onto particulate, they tend to that module is presented to those and can not adsorb by the continuous phase of the similar particle being coated, thereby reduce particle aggregation.In certain embodiments, surfactant can also promote drug absorption and increase the bioavilability of medicine.
" treatment effective dose " refers to and can realize disease or the symptom that suppresses patient, or can prophylactically suppress or prevent the amount of the compound that disease or symptom occur.Treatment effective dose can be by the amount of one or more diseases of patient or remission compound to a certain extent; The amount that those partially or completely can be returned to normal compound with one or more relevant physiology of disease or the symptom origin cause of formation or biochemical parameters; And/or can reduce the amount of the compound of the possibility that disease or symptom occur.
Term " chemically stable " and " chemical stability " refer to a kind of suspension formulation altogether, the various catabolites of the activating agent in said preparation maintain lower than supervision and require specified bottom line (for example desired 1% total chromatographic peak area in ICH guide Q3B (R2)) in the term of validity for people's product, and between activating agent analyte wherein and total degradation product, are in acceptable mass balance level (as defined level in ICH guide Q1E).
iI. composition
Composition of the present invention is a kind of suspension altogether, and it comprises two or more activating agents and comprises suspension media, one or more active agent particles and one or more suspended particulates.Certainly, if necessary, composition of the present invention also can comprise one or more other component.In addition also can use, version and the combination of the component of composition of the present invention.
Suspension composition altogether of the present invention can be made into multiple different preparation.In certain embodiments, the first activating agent providing with active agent particle form is provided composition of the present invention, and this active agent particle and the suspended particulate that at least one contains the second activating agent suspend altogether.In other embodiments, two or more activating agents that provide with two or more multi-form active agent particles are provided composition of the present invention, these active agent particles suspend altogether with at least one suspended particulate, and this suspended particulate contains activating agent and this activating agent is different from the activating agent that active agent particle comprises.In some other embodiment, two or more activating agents that provide with two or more multi-form active agent particles are provided composition of the present invention, these active agent particles suspend altogether with at least one suspended particulate, and it is identical or different that this suspended particulate contains the activating agent that activating agent and this activating agent can comprise with active agent particle.In other embodiment, two or more activating agents that provide with two or more multi-form active agent particles are provided composition of the present invention, and these active agent particles suspend altogether with one or more suspended particulates that do not contain activating agent.When composition of the present invention comprises two or more active agent particles, this kind of composition can be called to " polynary " suspension altogether.For example, the composition that comprises two kinds of active agent particles that suspend altogether with one or more suspended particulates can be called binary suspension altogether, and the composition that comprises three kinds of active agent particles that suspend altogether with one or more suspended particulates can be called ternary suspension etc. altogether.
In composition of the present invention, even active agent particle and suspended particulate also present association when multiple different active agent particle is present in composition, thereby active agent particle and suspended particulate can be coexisted in suspension media.Conventionally, owing to having density variation between dissimilar particle and its residing suspension media (as propellant or propulsion system), so buoyancy can cause that those occur solidifying thick and cause the particle generation sedimentation that those are higher than propellant density than the low density particle of propellant.Therefore; in the suspension forming at the dissimilar granulate mixture by thering are different densities or different tendency of flocculation, estimate that every kind of dissimilar particle has special sedimentation or coagulates thick behavior and then can estimate sedimentation or coagulate thick behavior meeting and cause dissimilar particle that separation occurs in suspension media.
Yet; the combination of propellant of the present invention, active agent particle and suspended particulate provides a kind of common suspension that contains two or more activating agent combinations; wherein active agent particle and suspended particulate are co-located in propellant (namely; thereby active agent particle and suspended particulate mutually associate and make suspended particulate and active agent particle substantially there will not be each other separated; for example, by differential sedimentation or the solidifying thick separation not detecting each other, even after having experienced the time that is enough to form solidifying thick or settled layer, all do not detect) yet.In a particular embodiment, for example, composition of the present invention forms common suspension, wherein suspended particulate stood temperature fluctuation and/or under acceleration ranges up to and beyond for example 1g, 10g, 35g, 50g and 100g, carry out still maintaining under strong buoyancy centrifugal and that cause and active agent particle between association.But, should be appreciated that suspension altogether of the present invention is not subject to the restriction of specific critical association power.For example; can successfully obtain a kind of common suspension of wanting required for the present invention, thereby wherein active agent particle and suspended particulate mutually associate and make under conventional patient's service condition by suspension media active agent particle and suspended particulate in formed continuous phase substantially can not be separated from each other.
The common suspension of active agent particle of the present invention and suspended particulate has chemical stability, suspension stability and the activating agent of expectation and sends characteristic.For example, in a particular embodiment, in the time of in being present in MDI tank, suspension altogether of the present invention can suppress or reduce one or more following situations: the flocculation of activating agent material; The differential sedimentation of active agent particle and suspended particulate or solidifying thick; The solution mediated transformation effect of activating agent material; The chemical degradation of the component in the preparation that contains activating agent material or surfactant; And the loss of activating agent in seal of vessel system surfaces is especially in the lip-deep loss of metering valve.When sending common suspension preparation by MDI, still can realize above-mentioned performance characteristics and maintain the performance of suspended particulates, thereby make can reach and maintain desired minuteness particle mark, minuteness particle dosage and these characteristics of dosage delivered uniformity in the overall process of the common suspension preparation in emptying MDI tank.In addition, when with a kind of relatively simple and it is also when adding cosolvent, anti-solvent, solubilizer or adjuvant and do not improve the HFA suspension media of its performance, suspension altogether of the present invention also can provide preparation stable on a kind of physics and chemistry and make its two or more contained activating agents have consistent administration characteristic, even if work as the obvious difference of dosage delivered of these activating agents, also can realize.Further, composition prepared in accordance with the present invention, when utilizing MDI to send, it can eliminate or substantially avoid the common pharmacy effect of preparation that contains multiple actives.For example, as described in detail in the embodiment of the present application, the delivery characteristics that the delivery characteristics of each activating agent in the activating agent that combination preparation of the present invention comprises is reached when being prepared separately and sending respectively with identical activating agent is suitable.
The suspension that is total to provided by the present invention also can be simplified the preparation of activating agent, send and administration process.Be not subject to the constraint of any particular theory, what can expect is, by this form of common suspension of active agent particle and suspended particulate, the sending of the activating agent that this dispersion liquid is contained, physical stability and administration characteristic just can be controlled by controlling size, composition, form and the relative quantity of suspended particulate substantially, thereby can reduce the degree of dependence to the size of active agent particle and morphological character.In addition, in a particular embodiment, pharmaceutical composition of the present invention can be prepared by being substantially devoid of non-CFC propellant or the Propellant System of anti-solvent, solubilizer, cosolvent or adjuvant.
According to the present invention, the common suspension composition of training centre preparation can suppress physics and the chemical degradation of wherein contained activating agent.For example, in a particular embodiment, composition of the present invention can suppress to be included in chemical degradation, flocculation, gathering and the solution mediated transformation of the activating agent in composition active one or more.The chemistry that altogether suspension preparation of the present invention provides and suspension stability can make multiple actives in composition all with a kind of, can reach the required inhomogeneity mode of dosage delivered and send (" DDU in the whole process of emptying MDI tank "), even if work as at least one sent activating agent, be that the difference of efficient and various activating agents in dosage delivered still can reach when very large.
The DDU of every kind of activating agent that the common suspension composition that contains two or more activating agents of the present invention is contained can reach ± and 30% or higher.In this kind of embodiment, the DDU of every kind of activating agent that altogether suspension composition of the present invention is contained can reach ± and 25% or higher.In another this kind of embodiment, the DDU of every kind of activating agent that altogether suspension composition of the present invention is contained can reach ± and 20% or higher.In addition, suspension composition altogether of the present invention can substantially maintain FPF and FPD performance in the overall process of emptying MDI tank, even under the condition in accelerated degradation.Such as, even if composition of the present invention also can maintain 80%, 90%, 95% or more of its initial value by FPF or FPD performance under the condition of accelerated degradation.
When using non-CFC propellant to prepare, suspension composition altogether of the present invention can provide the additional benefit that realizes this kind of performance.In a particular embodiment, when using the suspension medias only comprise one or more non-CFC propellants of modifying without performance to prepare, composition of the present invention can realize target DDU, FPF or FPD in one or more, the method that wherein said performance is modified can be for example to add one or more cosolvents, anti-solvent, solubilizer, adjuvant or other propellant decorative material.
(i) suspension media
The suspension media that composition of the present invention comprises contains one or more propellants.Generally speaking, the suitable propellant using as suspension media be can under room temperature pressure, liquefy and for suck or local use for be harmless propellant gas in safe those toxicology.In addition, wish relatively between selected propellant and suspended particulate and active agent particle not react.Exemplary suitable propellant comprises, hydrofluoroalkane (HFA), perfluorochemical (PFC) and Chlorofluorocarbons (CFC).
Can be used for forming the present invention altogether the particular instance of the propellant of the suspension media of suspension comprise, HFA 134a (CF 3cH 2f) (HFA-134a), 1,1,1,2,3,3,3-seven fluorine n-propane (CF 3cHFCF 3) (HFA-227), hexafluoroethane, a chloro fluoromethane, 1,1 Difluoroethane and their combination.Further, suitable propellant for example comprises: short hydrocarbon; C 1-4contain hydrochlorofluorocarazeotropic such as CH 2clF, CCl 2fCHClF, CF 3cHClF, CHF 2cClF 2, CHClFCHF 2, CF 3cH 2cl and CClF 2cH 3; C 1-4contain HFC (as HFA) such as CHF 2cHF 2, CF 3cH 2f, CHF 2cH 3and CF 3cHFCF 3; Also has perfluorocarbon such as CF 3cF 3and CF 3cF 2cF 3.
Can be used as the specific fluorine carbon of suspension media or the classification of fluorinated compound and include but not limited to, fluorine heptane, fluorine cycloheptane, methyl fluoride cycloheptane, fluorine hexane, fluorine cyclohexane, amyl fluoride, fluorine pentamethylene, methyl fluoride pentamethylene, fluorine dimethylcyclopentane, methyl fluoride cyclobutane, fluorine dimethyl cyclobutane, fluorine trimethyl cyclobutane, fluorine butane, fluorine cyclobutane, fluoro-propane, fluorine ether, perfluoroalkyl polyether and fluorine triethylamine.These compounds can be used separately or have more volatile propellant with those and be used in combination.
Except above mentioned fluorine carbon and hydrofluoroalkane, can also use various typical Chlorofluorocarbons and the fluorinated compound that is substituted as suspension media.In this respect, noticing may exert an influence to environment in the situation that, can also use following material: FC-11 (CCl 3f), FC-11B1 (CBrCl 2f), FC-11B2 (CBr 2clF), FC12B2 (CF 2br 2), FC21 (CHCl 2f), FC21B1 (CHBrClF), FC-21B2 (CHBr 2f), FC-31B1 (CH 2brF), FC113A (CCl 3cF 3), FC-122 (CClF 2cHCl 2), FC-123 (CF 3cHCl 2), FC-132 (CHClFCHClF), FC-133 (CHClFCHF 2), FC-141 (CH 2clCHClF), FC-141B (CCl 2fCH 3), FC-142 (CHF 2cH 2cl), FC-151 (CH 2fCH 2cl), FC-152 (CH 2fCH 2f), FC-1112 (CClF=CClF), FC-1121 (CHCl=CFCl) and FC-1131 (CHCl=CHF).Similarly, each in these compounds can be used separately or be used in combination to form stable suspension of the present invention with other compounds (that is, the fluorocarbons of low volatility).
In certain embodiments, suspension media can be formed by single propellant.In other embodiments, suspension media can being combined to form by propellant.In certain embodiments, the compound of relative volatility can mix with low-vapor pressure component mutually so that suspension media has this specific physical characteristic of bioavilability that can improve its stability or strengthen the activating agent wherein disperseing.In certain embodiments, compared with the compound of low-vapor pressure, comprise that those boiling points are greater than the fluorinated compound of 25 ℃ (as fluorocarbon).In certain embodiments, for can comprising compared with the fluorinated compound of low-vapor pressure of suspension media, perfluoro bromide octane C 8f 17br (PFOB or Perflubron), dichloro fluoro-octane C 8f 16cl 2, perfluoro capryl ethane C 8f 17c 2h 5(PFOE), PFDB compound C 10f 21br (PFDB) or perfluoro butyl ethane C 4f 9c 2h 5.In certain embodiments, these exist level relatively low compared with the compound of low-vapor pressure.These compounds can directly be added in suspension media or with suspended particulate and associate mutually.
The suspension media that the present composition comprises can be formed by the propellant or the Propellant System that do not basically contain other material, and wherein said other material comprises for example anti-solvent, solubilizer, cosolvent or adjuvant.For example, in certain embodiments, suspension media can be formed by non-CFC propellant or Propellant System, such as not basically containing HFA propellant or the Propellant System of other material.These embodiments have been simplified those preparation and production processes of containing the common suspension composition that is suitable for breathing active agent delivery.
But, in other embodiments, depending on the character of selected propellant, suspended particulate or the character of the activating agent sent, suspension media used can also comprise other material except propellant or Propellant System.These other materials for example can comprise, one or more suitable anti-solvent, solubilizer, cosolvent or adjuvants are to be used for regulating for example solvability of vapour pressure, stability or the suspended particulate of preparation.For example, can in the propellant in suspension media, add propane, ethanol, isopropyl alcohol, butane, iso-butane, pentane, isopentane or dialkyl ethers such as dimethyl ether.Similarly, suspension media can contain volatile fluorine carbon.In other embodiments, can in suspension media, add one or both in polyvinylpyrrolidone (" PVP ") or polyethylene glycol (" PEG ").In suspension media, add PVP or PEG can realize one or more required functional characteristics, in one embodiment, the inhibitor that PVP or PEG can be used as crystal growth joins in suspension media.Conventionally, when using volatility cosolvent or adjuvant, can from known hydrocarbon or fluorocarbon, select these volatile cosolvent or adjuvants, and its shared ratio is propellant up to about 1%w/w.For example, when suspension media contains cosolvent or adjuvant, suspension media contains and is less than approximately 0.01%, 0.1% or cosolvent or the adjuvant of 0.5%w/w.When suspension media contains PVP or PEG, this component can account at the most suspension media up to about 1%w/w, or be less than approximately 0.01%, 0.1% or 0.5%w/w.
(ii) active agent particle
The present invention altogether contained active agent particle of suspension is formed by those materials that those can be dispersed in or be suspended in suspension media and its formed size is conducive to inhalable particles to deliver from common suspension.Therefore, in one embodiment, active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 90% volume ratio is approximately 7 μ m or less.In other embodiments, active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 90% volume ratio is that approximately 7 μ m are to approximately 1 μ m, approximately 5 μ m to approximately 2 μ m, approximately 3 μ m to approximately 2 μ m.In a further embodiment, active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 90% volume ratio is approximately 6 μ m or less, approximately 5 μ m or less, approximately 4 μ m or less, approximately 3 μ m or less.In other embodiments, active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 50% volume ratio is approximately 4 μ m or less.In a further embodiment, active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 50% volume ratio is approximately 3 μ m or less, approximately 2 μ m or less, approximately 1.5 μ m or less, approximately 1 μ m or less.In embodiment further; active agent particle provides with the form of micronize material, and wherein the optical diameter of the active agent particle of at least 50% volume ratio is that approximately 4 μ m are to approximately 1 μ m scope, approximately 3 μ m to approximately 1 μ m scope, approximately 2 μ m to approximately 1 μ m scope, approximately 1.3 μ m and approximately 1.9 μ m.
Active agent particle can be made by activating agent or also can be made by the combination that comprises one or more activating agents and one or more excipient or adjuvant completely.In a particular embodiment, being present in activating agent in active agent particle can be completely or be lenticular substantially, that is to say that most of active agent molecules arrange with regular repetition form along the long-range of crystrallographic plane.In another embodiment, active agent particle can comprise the activating agent existing with lenticular or amorphous form.In another embodiment, active agent particle can comprise the activating agent substantially existing with amorphous form, and active agent molecule itself is noncrystal shape completely and along long-range, does not maintain regular repeated arrangement.In another embodiment, in active agent particle, there are two or more activating agents, these all activating agents can with lenticular or substantially the form of lenticular exist.At other, exist in the embodiment of two or more activating agents, at least one this kind of activating agent can with lenticular or substantially lenticular form exist and at least another kind of activating agent can exist with unbodied form.
When combination that active agent particle of the present invention comprises one or more activating agents and one or more excipient or adjuvant, this excipient or adjuvant can be selected according to the chemistry of used activating agent and physical property.In addition, be applicable to can the excipient associating occurring with suspended particulate for what prepare that the excipient of active agent particle comprises that those the present invention record.In a particular embodiment, for example, active agent particle can be prepared with one or more materials that are selected from following group: the surface active material that lipid, carbohydrate, amino acid, organic salt, peptide, protein, alditol, synthetic or natural polymer or surface active material of the present invention for example can associate with suspended particulate.
In other embodiments, for example, activating agent can be joined in the formed solution of one or more materials that is selected from following group, then spraying is dried and forms suspended particulate, the contained activating agent of this suspended particulate is among those materials that form suspended particulate, and this group comprises lipid, phosphatide, carbohydrate, amino acid, slaine, organic salt, peptide, protein, alditol, synthetic or natural polymer or surfactant material.
Can use any suitable method can be used as or be included in the micronize activating agent in active agent particle or suspended particulate to obtain those.Can use various method to generate and be suitable for use in the active agent particle in suspension preparation altogether of the present invention; these methods include but not limited to, by pulverizing or method for grinding, crystallization or recrystallization method, utilize that the method for overcritical or near supercritical solvent precipitation, spraying are dry, the method for atomizing freeze drying or freeze-drying carries out micronize processing.Instruct the referenced patent of the proper method that obtains micronize activating agent to comprise, for example the U.S. patent No. 6,063; 138, U.S, the patent No. 5; 858,410, the U.S. patent No. 5,851; 453, the U.S. patent No. 5; 833,891, U.S, the patent No. 5,707; 634, and international patent application no WO2007/009164.Active agent particle wherein comprises the activating agent material of preparing together with one or more excipient or adjuvant; micronized activating agent can form by one or more said methods, uses said method to obtain and has the particle diameter distribution of expectation and the active agent particle of grain structure.
Active agent particle can exist in suspension media with any suitable concentration.For example, in certain embodiments.The concentration of active agent particle can be at about 0.01mg/mL between about 20mg/mL.At some in this kind of embodiment, the concentration of active agent particle can about 0.05mg/ml between about 20mg/ml, at about 0.05mg between about 10mg/ml and at about 0.05mg between about 5mg/ml.
Various treatment reagent or prevention reagent can be used in suspension altogether of the present invention.Exemplary activating agent comprises that those can be with the activating agent of the form administration of aerosol medicine, be suitable for use in activating agent in composition of the present invention and comprise that thereby those can exist or can be formulated into specific form with specific form and (for example be dispersed in selected suspension media, substantially insoluble or in suspension media, present the solvability that substantially maintains common suspension preparation form), and can form common suspension with suspended particulate, and can absorb by breathing the activating agent of its physiology effective dose.The activating agent that is used to form active agent particle of the present invention can have various physiologically actives.
The example of the particular active agent that the present composition comprises can be for example fugitive beta-agonists, as bitolterol, Carbuterol, fenoterol, Hexoprenaline, isoprel (isopropyl (going first) adrenaline), levosalbutamol, orciprenaline (orciprenaline), pirbuterol, Procaterol, Rimiterol, salbutamol (salbutamol), Terbutaline, tulobuterol, Reproterol, ipratropium and adrenaline; Long-acting beta 23 adrenergic receptor agonists (" LABA "), as bambuterol, clenbuterol, Formoterol and salmeterol; Super long effective β 23 adrenergic receptor agonists, as Carmoxirole, rice water sieve, QAB-149 and containing the derivative β of adamantyl of saligenin or indoles 2activator; Cortical steroid, as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone; Antiinflammatory, as FLUTICASONE PROPIONATE, beclomethasone dipropionate, flunisolide, budesonide, three Pai Dinuo (tripedane), cortisone, metacortandracin, prednisolone, dexamethasone, betamethasone or Triamcinolone acetonide; Pectoral, as coscopin; Bronchodilator, as ephedrine, adrenaline, fenoterol, Formoterol, isoprel, orciprenaline, salbutamol, salbutamol, salmeterol, Terbutaline; And muscarinic antagonist, comprise long-acting muscarinic antagonist (" LAMA ") as Glycopyrrolate, enlightening Xipi sieve Nimes (dexipirronium), hyoscine, Tropicamide, pirenzepine, dramamine, tiotropium, Da Tuoping, aclidinium bromide, hold in the palm these product, ipratropium, atropine, benzatropine or oxitropine.
While needing, the activating agent that the present composition comprises can also include but not limited to, those activating agents of herein recording especially for example, are used with the form of its salt (, alkali metal salts or ammonium salt or acid-addition salts), ester, solvate (hydrate) or free alkali.In addition, activating agent can be the mixture of various crystal forms or isomeric form or isomeric form, for example, can be pure isomer, mixture, racemic modification or its mixture of isomer.In this respect, thus can select suitable activating agent form that the activity of activating agent and/or stability optimization and/or the solvability of activating agent in suspension media are minimized.
Because composition disclosed in this invention can be sent the very activating agent of low dosage repeatedly, in certain embodiments, the activating agent that composition of the present invention comprises can be selected from one or more effective or efficient activating agents.For example, in certain embodiments, composition of the present invention can comprise one or more by the effective active agent of sending to be selected from the dosage of following group: each dosage approximately 100 μ g between about 100mg, approximately 100 μ g between about 10mg, approximately 100 μ g are between about 10mg.In other embodiments, composition of the present invention can comprise two or more by the combination of effective or high-efficiency activated dose of sending to be selected from the dosage of following group: each dosage up to approximately 80 μ g, up to approximately 40 μ g, up to approximately 20 μ g, up to approximately 10 μ g or approximately 10 μ g between approximately 100 μ g.In addition, in certain embodiments, composition of the present invention can comprise two or more by the combination of high-efficiency activated dose of sending to be selected from the dosage of following group: between each dosage approximately 0.1 to approximately 2 μ g, between approximately 0.1 to approximately 1 μ g, between approximately 0.1 to approximately 0.5 μ g.
In certain embodiments, the activating agent that composition of the present invention comprises is LABA activating agent.In this kind of embodiment, the combination that composition comprises a kind of LABA activating agent and a kind of LAMA activating agent or corticosteroid activating agent.In another this kind of embodiment, the combination that composition comprises a kind of LAMA activating agent and a kind of LABA activating agent and corticosteroid.In this kind of embodiment, LABA activating agent can be selected from bambuterol for example, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and containing the derivative β of adamantyl of saligenin or indyl 2activator and any its pharmaceutically acceptable salt, ester, isomer or solvate.At some, in this kind of embodiment, activating agent is selected from Formoterol and pharmaceutically acceptable salt, ester, isomer or solvate.
Formoterol can be used for treatment such as those inflammatories of the present invention or obstructive disease of lung or symptom.Chemistry (±)-2-hydroxyl-5-[(1RS by name of Formoterol)-1-hydroxyl-2-[[(1RS)-2-(4-methoxyphenyl)-1-Methylethyl]-ammonia] ethyl] formailide, it is used in pharmaceutical composition with the form of racemic fumarate dihydrate conventionally.In appropriate circumstances, Formoterol can be used the form of its salt (for example alkali metal salts or ammonium salt or acid-addition salts) or ester or solvate (hydrate).In addition, Formoterol can be the mixture of any crystal form or isomeric form or isomeric form, for example, and pure isomer, the mixture of isomer, racemic modification or its mixture.In this respect, thus can select suitable Formoterol form make activity and/or the stability optimization of Formoterol and/or the solvability of Formoterol in suspension media is minimized.Formoterol pharmaceutically acceptable salt comprises that for example inorganic acid salt is such as hydrochloric acid, hydrobromic acid, sulfonic acid and phosphoric acid; And organic acid salt is such as fumaric acid, maleic acid, acetic acid, lactic acid, citric acid, tartaric acid, ascorbic acid, succinic acid, glutaric acid, gluconic acid, tricarballylic acid, oleic acid, benzoic acid, P-methoxybenzoic acid, salicylic acid, neighbour or P-hydroxybenzoic acid, parachlorobenzoic-acid, Loprazolam, p-methyl benzenesulfonic acid and 3-hydroxyl-2-naphthalene-carboxylic acid.The hydrate of Formoterol has for example been documented in the U.S. patent No. 3,994,974 and the U.S. patent No. 5,684,199.Specific crystal form has for example been documented in WO95/05805, and the specific isomer of Formoterol has also been documented in the U.S. patent No. 6,040,344.
In a particular embodiment, the Formoterol material that is used to form Formoterol particle is formoterol fumarate, and in this kind of embodiment, formoterol fumarate exists with the form of dihydrate.When composition of the present invention comprises Formoterol, in certain embodiments, the Formoterol concentration that composition of the present invention comprises can realize the dosage delivered that is selected from following group: MDI at every turn startup effect can produce approximately 0.5 μ g between approximately 30 μ g, 0.5 μ g to approximately 1 μ g, approximately 1 μ g between approximately 10 μ g, approximately 2 μ g between approximately 5 μ g, approximately 2 μ g between approximately 10 μ g, approximately 5 μ g between approximately 10 μ g, approximately 3 μ g are between approximately 30 μ g.In other embodiments, thus the Formoterol that composition of the present invention comprises q.s can provide the dosage delivered that is selected from following group: MDI at every turn startup effect can produce up to approximately 30 μ g, up to approximately 10 μ g, up to approximately 5 μ g, up to approximately 2.5 μ g, up to approximately 2 μ g or up to approximately 1.5 μ g.In order to realize dosage delivered of the present invention, when composition of the present invention comprises Formoterol as activating agent, in a particular embodiment, the amount of the Formoterol that composition comprises for example can be selected from about 0.01mg/ml between about 1mg/ml, about 0.01mg/ml is between about 0.5mg/ml, and about 0.03mg/ml is between about 0.4mg/ml.
When common suspension pharmaceutical composition of the present invention comprises LABA activating agent, activity can be salmeterol in certain embodiments, comprises its any pharmaceutically acceptable salt, ester, isomer or solvate.Salmeterol can be used for treatment for example those inflammatories of the present invention or obstructive disease of lung or symptom.In addition,, when using salmeterol as LABA activating agent, at some, in this kind of embodiment, composition can also comprise LAMA or corticosteroid activating agent.In other this kind of embodiment, composition comprises the combination of salmeterol and LAMA activating agent and corticosteroid.Salmeterol and pharmaceutically acceptable salt thereof and their preparation method have for example been documented in the U.S. patent No. 4,992,474, the U.S. patent No. 5,126,375 and U.S. patent 5,225,445.
When comprise as LABA activating agent salmeterol time, the concentration of the salmeterol that in certain embodiments, composition of the present invention comprises can realize the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce approximately 2 μ g between approximately 120 μ g, approximately 4 μ g between approximately 40 μ g, approximately 8 μ g between approximately 20 μ g, approximately 8 μ g between approximately 40 μ g, approximately 20 μ g between approximately 40 μ g, approximately 12 μ g are between approximately 120 μ g.In other embodiments, thus composition of the present invention can comprise the salmeterol of q.s can provide the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce up to approximately 120 μ g, up to approximately 40 μ g, up to approximately 20 μ g, up to approximately 10 μ g, up to approximately 8 μ g or up to approximately 6 μ g.For realizing target dosage delivered of the present invention, when composition of the present invention comprises salmeterol as activating agent, the amount of the salmeterol that composition comprises in a particular embodiment for example can be selected from about 0.04mg/ml between about 4mg/ml, about 0.04mg/ml between about 2.0mg/ml and about 0.12mg/ml between about 0.8mg/ml.For example, composition of the present invention can comprise enough salmeterols to realize the target dosage delivered be selected from following group: approximately 4 μ g between approximately 120 μ g, approximately 20 μ g between approximately 100 μ g and approximately 40 μ g between approximately 120 μ g.In other embodiments, thus composition of the present invention can comprise the salmeterol of q.s provide the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce up to approximately 100 μ g, up to approximately 40 μ g or up to approximately 15 μ g.
In certain embodiments, composition of the present invention comprises long-acting muscarinic antagonist (LAMA) activating agent.In composition of the present invention, the example of operable LAMA activating agent comprises Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, bent chloramines, aclidinium bromide and the Da Tuoping of taking charge of, and comprises its any pharmaceutically acceptable salt, ester, isomer or solvate.In certain embodiments, the combination that composition of the present invention comprises LAMA activating agent and LABA activating agent or corticosteroid.In other this kind of embodiment, the combination that composition of the present invention comprises LAMA activating agent and LABA and corticosteroid activating agent.When composition comprises LAMA activating agent, in a particular embodiment, can select Glycopyrrolate, comprise its any pharmaceutically acceptable salt, ester, isomer or solvate.
Glycopyrrolate can be used for treating inflammatory or obstructive disease of lung or symptom, for example those those diseases of the present invention or symptoms.Glycopyrrolate as anticholinergic agents can serve as bronchodilator and secretion depression effect is provided, thereby is that those PUD D or symptoms that increase to feature with mucous membrane secretion are brought into play useful treatment application.Glycopyrrolate is a kind of tetravalence ammonium salt.In appropriate circumstances, Glycopyrrolate can be used the form of its salt (as alkali metal salts or ammonium salt or as acid-addition salts) or ester or solvate (hydrate).In addition, Glycopyrrolate can be the mixture of various crystal forms or isomeric form or isomeric form, for example, can be pure isomer, mixture, racemic modification or its mixture of isomer.In this respect, thus can select the suitable form of Glycopyrrolate make activity and/or the stability optimization of Glycopyrrolate and/or the solvability of Glycopyrrolate in suspension media is minimized.Suitable equilibrium ion is pharmaceutically acceptable equilibrium ion, for example comprise: fluoride, chloride, bromide, iodide, nitrate, sulphate, phosphate, formates, acetate, trifluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, parachlorobenzoic-acid salt, diphenyl acetic acid salt or triphenylacetic acid salt, septichen salt, p-hydroxybenzoate, 1-hydroxyl naphthyl-2-carboxylate, 3-hydroxyl naphthyl-2-carboxylate, mesylate and benzene sulfonate.In the specific embodiment of composition of the present invention; using the hydrobromate of Glycopyrrolate is GP, and it can adopt the U.S. patent No. 2; in 956,062, disclosed method is prepared.
When composition of the present invention comprises Glycopyrrolate, in certain embodiments, thus said composition can comprise enough Glycopyrrolates can provide the dosage delivered that is selected from following group: each MDI startup effect can produce approximately 10 μ g between approximately 100 μ g, approximately 15 μ g between approximately 100 μ g, approximately 15 μ g between approximately 80 μ g and approximately 10 μ g between approximately 80 μ g.In other this kind of embodiment, thereby comprising enough Glycopyrrolates, said preparation can provide the dosage delivered that is selected from following group: each MDI startup effect can produce up to approximately 100 μ g, up to approximately 80 μ g, up to approximately 40 μ g, up to approximately 20 μ g or up to approximately 10 μ g.In a further embodiment, thus said preparation can comprise enough Glycopyrrolates can provide the dosage delivered that is selected from following group: each MDI startup effect can produce approximately 9 μ g, approximately 18 μ g, approximately 36 μ g and approximately 72 μ g.For realizing the dosage delivered of the present invention expectation, when composition of the present invention comprises Glycopyrrolate as activating agent, the amount of the contained Glycopyrrolate of composition for example can be selected from a particular embodiment, and about 0.04mg/mL is between about 2.25mg/mL.
In other embodiments, Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, can be used as LAMA activating agent and is included in composition of the present invention.Tiotropium Bromide is a kind ofly known to be suitable for treatment as described in the present invention to lung inflammation or block the long-acting anticholinergic thing of relevant disease or symptom.Tiotropium Bromide comprises that the form of its crystal form and pharmaceutically acceptable salt has for example been documented in the U.S. patent No. 5,610,163, U.S. patent No. RE39820, the U.S. patent No. 6,777,423 and the U.S. patent No. 6.908,928.When composition of the present invention comprises Tiotropium Bromide, thereby said composition can comprise enough Tiotropium Bromides the dosage delivered that is selected from following group can be provided in certain embodiments: each MDI startup effect can produce approximately 2.5 μ g between approximately 25 μ g, approximately 4 μ g between approximately 25 μ g and approximately 2.5 μ g between approximately 20 μ g and approximately 10 μ g between approximately 20 μ g.In other this kind of embodiment, thereby can comprising enough Tiotropium Bromides, said preparation can provide the dosage delivered that is selected from following group: each MDI startup effect can produce up to approximately 25 μ g, up to approximately 20 μ g, up to approximately 10 μ g, up to approximately 5 μ g or up to approximately 2.5 μ g.In a further embodiment, thus said preparation can comprise enough Tiotropium Bromides can provide the dosage delivered that is selected from following group: each MDI startup effect can produce approximately 3 μ g, 6 μ g, 9 μ g, 18 μ g and 36 μ g.For realizing dosage delivered of the present invention, when composition of the present invention comprises Tiotropium Bromide as activating agent, the amount of the contained Tiotropium Bromide of composition for example can be selected from about 0.01mg/mL between about 0.5mg/mL in a particular embodiment.
In other embodiments, composition of the present invention comprises corticosteroid.This kind of activating agent can be selected from for example beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and fluoxyprednisolone, comprises its any pharmaceutically acceptable salt, ester, isomer or solvate.In certain embodiments, this kind of combination that composition comprises corticosteroid activating agent and LAMA or LABA activating agent.In other this kind of embodiment, the composition that composition comprises corticosteroid activating agent and LAMA and LABA activating agent.When composition comprises corticosteroid activating agent, can select Mometasone in a particular embodiment.
Mometasone and pharmaceutically acceptable salt thereof for example preparation method of momestasone furoate and these materials are known and have for example been documented in the U.S. patent No. 4,472,393, the U.S. patent No. 5,886,200 and the U.S. patent No. 6,177,560.Mometasone be suitable for treatment as described in the present invention those to lung inflammation block relevant disease or symptom (reference example is as the U.S. patent No. 5,889,015, the U.S. patent No. 6,057,307, the U.S. patent No. 6,057, and 581, the U.S. patent No. 6,677,322, the U.S. patent No. 6,677, and 323 and the U.S. patent No. 6,365,581).
When composition of the present invention comprises Mometasone, the Mometasone that composition comprises q.s in a particular embodiment (comprising any its pharmaceutically acceptable salt, ester, isomer or solvate) thus can realize the target dosage delivered that is selected from following group: each MDI startup effect can produce approximately 20 μ g between approximately 400 μ g, approximately 20 μ g between approximately 200 μ g, approximately 50 μ g between approximately 200 μ g, approximately 100 μ g between approximately 200 μ g, approximately 20 μ g between approximately 100 μ g and approximately 50 μ g between approximately 100 μ g.In other embodiments, composition of the present invention can comprise the Mometasone (comprising any its pharmaceutically acceptable salt, ester, isomer or solvate) of q.s thereby the target dosage delivered that is selected from following group can be provided: each MDI startup effect can produce up to approximately 400 μ g, up to approximately 200 μ g or up to approximately 100 μ g.
In other embodiments, composition of the present invention comprises the corticosteroid that is selected from fluticasone and budesonide.Fluticasone and budesonide be all applicable to treat of the present invention those to lung inflammation or block relevant illness.Fluticasone, its pharmaceutically acceptable salt for example preparation method of FLUTICASONE PROPIONATE and these materials are all known and are documented in for example U.S. patent No. 4,335,121, the U.S. patent No. 4,187,301 and U.S. patent publication No. US2008125407 in.Budesonide is also known and is for example documented in the U.S. patent No. 3,929,768.In certain embodiments, the fluticasone that composition of the present invention can comprise q.s comprises any its pharmaceutically acceptable salt, ester, isomer or solvate, thus can realize the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce approximately 20 μ g between approximately 200 μ g, approximately 50 μ g between approximately 175 μ g and approximately 80 μ g between approximately 160 μ g.In other embodiments, the fluticasone that composition of the present invention can comprise q.s comprises any its pharmaceutically acceptable salt, ester, isomer or solvate, thus can provide the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce up to approximately 175 μ g, up to approximately 160 μ g, up to approximately 100 μ g or up to approximately 80 μ g.In a particular embodiment, the budesonide that composition of the present invention can comprise q.s comprises any its pharmaceutically acceptable salt, ester, isomer or solvate, thus can provide the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce approximately 30 μ g between approximately 240 μ g, approximately 30 μ g between approximately 120 μ g and approximately 30 μ g between approximately 50 μ g.In other embodiments, composition of the present invention can comprise the budesonide of q.s, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate, thus can provide the target dosage delivered that is selected from following group: MDI at every turn startup effect can produce up to approximately 240 μ g, up to approximately 120 μ g or up to approximately 50 μ g.
In each embodiment, composition of the present invention comprises two or more activating agents.In certain embodiments, the combination that composition comprises two or more active agent particles that can suspend altogether with single suspended particulate.Alternatively, composition can comprise two or more active agent particles of suspending altogether of suspended particulate that can be different from two or more.As other, select, composition of the present invention can comprise single-activity agent particle and single suspended particulate suspends, and wherein single-activity agent particle comprises one or more activating agents, and single suspended particulate comprises one or more active agent particles.Further, composition of the present invention can comprise two or more activating agents, and these active groups are combined in single active agent particle.For example, when preparing active agent particle with one or more auxiliary materials or adjuvant and activating agent material, this active agent particle can comprise the particle that contains two or more different activities agent.
(iii) suspended particulate
The suspended particulate that suspension composition comprises of the present invention altogether can promote stability and the delivery performance that those are included in the activating agent in composition.Although can use multi-form suspended particulate, suspended particulate is formed by the material of pharmacology inertia conventionally, and this material can be inhaled into and it is insoluble in selected propellant.Conventionally, most of suspended particulate has the size within the scope of can incoming call.Therefore, in a particular embodiment, the MMAD of suspended particulate is no more than approximately 10 μ m, but is not less than again about 500nm.In another optional embodiment, the MMAD of suspended particulate in approximately 5 μ m between about 750nm.In another embodiment, the MMAD of suspended particulate in approximately 1 μ m between approximately 3 μ m.When being used in the MDI embodiment of nasal delivery there, the MMAD of suspended particulate is between 10 μ m to 50 μ m.
For the suspension particle diameter that makes to suck is within the scope of described MMAD, suspended particulate has between approximately 0.2 μ m conventionally to the volume intermediate value optical diameter between approximately 50 μ m.In one embodiment, suspended particulate has the volume intermediate value optical diameter that is no more than approximately 25 μ m.In another embodiment, suspended particulate has the volume intermediate value optical diameter that is selected from following group: approximately 0.5 μ m between approximately 15 μ m, approximately 1.5 μ m between approximately 10 μ m and approximately 2 μ m between approximately 5 μ m.
The concentration of the suspended particulate that composition of the present invention comprises can be adjusted according to the amount of the active agent particle for example used and suspension media.The concentration of the suspended particulate that in one embodiment, suspension media comprises is selected from following group: about 1mg/ml is to about 15mg/ml, about 3mg/ml to about 10mg/ml, about 5mg/ml to about 8mg/ml and about 6mg/ml.The concentration of the suspended particulate that in another embodiment, suspension media comprises is up to about 30mg/ml.The concentration of the suspended particulate that in another embodiment, suspension media comprises is up to about 25mg/ml.
By selecting the relative quantity of suspended particulate and activating agent can realize the desired common suspension of the present invention.When surpassing the amount of active agent particle in mass, the amount of suspended particulate can realize common suspension composition.For example, in a particular embodiment, the ratio of suspended particulate gross mass and active agent particle gross mass can be between about 3:1 to about 15:1 or alternatively, between about 2:1 to 8:1.Alternatively, the character that depends on used suspended particulate and active agent particle, the ratio of suspended particulate gross mass and active agent particle gross mass can be greater than 1, such as up to approximately 1.5, up to approximately 5, up to approximately 10, up to approximately 15, up to approximately 17, up to approximately 20, up to approximately 30, up to approximately 40, up to approximately 50, up to approximately 60, up to approximately 75, up to approximately 100, up to approximately 150 and up to approximately 200.In embodiment further, the ratio of suspended particulate gross mass and active agent particle gross mass can be selected between approximately 10 to approximately between 200, approximately 60 to approximately between 200, approximately 15 to approximately between 60, approximately 15 to approximately between 170, approximately 15 to approximately between 60, approximately 16, approximately 60 and approximately 170.
In other embodiments, the amount of suspended particulate is less than the quality of active agent particle in mass.For example, in a particular embodiment, the gross mass of suspended particulate can be low to moderate 20% of active agent particle gross mass.Yet in certain embodiments, the gross mass of suspended particulate also can approximate or equal the gross mass of active agent particle.
The suspended particulate that is applicable to composition of the present invention can be formed by one or more pharmaceutically acceptable materials or excipient, and it is suitable for by inhalation delivery and substantially non-degradable or be dissolved in suspension media.In one embodiment, the defined porous microstructure of the present invention can be used as suspended particulate.The Exemplary excipients that can be used for forming suspended particulate of the present invention includes but not limited to: (a) carbohydrate, as monose, such as fructose, galactose, glucose, D-MANNOSE, sorbose etc.; As disaccharide, such as sucrose, lactose, trehalose, cellobiose etc.; Cyclodextrin, such as 2-HP-BETA-CD; And polysaccharide, such as raffinose, maltodextrin, dextran, starch, chitin, shitosan, synanthrin etc.; (b) amino acid, such as alanine, glycine, arginine, asparatate, glutamic acid, cysteine, lysine, leucine, isoleucine, valine etc.; (c) metal being made by organic bronsted lowry acids and bases bronsted lowry and organic salt, such as sodium citrate, sodium ascorbate, magnesium gluconate, gluconic acid sodium salt, trometamol hydrochloride etc.; (d) peptide and protein, such as Aspartame, three leucines, human serum albumins, collagen, gelatin etc.; (e) alditol, such as mannitol, xylitol etc.; (f) synthetic or natural polymer or its combination, such as PLA, PLA lactide, cyclodextrin, polyacrylate, methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, polyanhydride, poly-lactam, polyvinyl chloride pyrrolidones, hyaluronic acid, polyethylene glycol; And (g) comprise and fluoridize or the surfactant of nonfluorinated compound, such as saturated and undersaturated lipid, nonionic detergent, non-ionic block copolymer, ionic surface active agent and combination thereof.In a particular embodiment, suspended particulate can comprise calcium salt, as calcium chloride, referring to for example U.S. patent No. 7,442,388.
In addition, can use phosphatide preparation natural and synthetic source to be applicable to the suspended particulate of composition of the present invention.In a particular embodiment, selected phosphatide has the transformation mutually from gel to liquid crystal when being greater than 40 ℃.Exemplary phosphatide is relative long-chain (that is, C 16-C 22) saturated phospholipid and can comprise saturated phospholipid, such as thering are 16C or 18C(palmityl and 18 acyls) phosphatid ylcholine of acyl chain length.Exemplary phosphatide comprises, phosphoglyceride is such as Dioctonoyl pnosphotidyl choline, distearyl acid acyl phospholipids phatidylcholine, two peanut ester acyl phospholipids phatidylcholines, two mountain Yu acyl phospholipids phatidylcholines, diphosphatidylglycerol, short-chain phospholipid phatidylcholine, long-chain saturated phospholipid acyl monoethanolamine, long-chain saturated phospholipid acyl serine and long-chain saturated phospholipid acyl inositol.More excipient has been disclosed in International Patent Publication No. WO 96/32149 and the U.S. patent No. 6,358,530,6,372,258 and 6,518,239.
In a particular embodiment, suspended particulate can be by forming with one or more lipids of the present invention, phosphatide or carbohydrate.In certain embodiments, suspended particulate comprises one or more surfactants.By one or more surfactants, formed or the use of the suspended particulate that comprises this surfactant can promote the absorption of selected activating agent, thereby increase its bioavilability.Suspended particulate of the present invention, for example by the suspended particulate that uses one or more lipids to form, can present the surface roughness (rugosity) of expectation, thereby further reduce intergranular interaction and promote aerosolized effect by reducing the surf zone of particle-particle interphase interaction.In embodiment further, in suitable situation, can form suspended particulate with those natural lipids being present in lung, more long-life controlled release granule because having, this suspended particulate reduces the potentiality that help the effect of biting (therefore can reduce the phagocytosis of pulmonary alveolar macrophage), so can be provided in lung.
On the other hand, be similar in international patent application no WO2005/000267 disclosed, thereby composition of the present invention can the suitable suspended particulate of choice for use increases the bin stability of selected activating agent.For example, in one embodiment, suspended particulate can comprise pharmaceutically acceptable and have an excipient of the stabilization of at least 55 ℃, at least 75 ℃ or at least 100 ℃ Tg.The glass forming agent that is applicable to composition of the present invention includes but not limited to, one or more three leucines, sodium citrate, sodium phosphate, ascorbic acid, synanthrin, cyclodextrin, polyvinylpyrrolidone, mannitol, sucrose, lactose, trehalose, proline.The more examples that form the excipient of glass have been disclosed in U.S. patent No. RE37, in 872,5,928,469,6,258,341 and 6,309,671.
Can come as required to suspended particulate design, thereby size and shaping can provide the stability of expectation and activating agent to send characteristic.In an exemplary embodiment, suspended particulate contains porous microstructure of the present invention.When using porous microstructure as suspended particulate in composition of the present invention, it can be by forming with one or more excipient of the present invention.For example, in a particular embodiment, porous microstructure can comprise at least one in following material: the fluorinated surfactant of lipid, phosphatide, nonionic detergent, non-ionic block copolymer, ionic surface active agent, biocompatibility and their combination, especially those have been approved for the material of lung.The specific surfactant that can be used for preparing porous microstructure comprises, PLURONICS F87, poloxamer188 and Pluronic/Lutrol F 108.Other specific surfactants comprise oleic acid or its alkali metal salt.In one embodiment, porous microstructure comprises the surfactant that is greater than about 10%w/w.
In certain embodiments, suspended particulate can prepare by the mode of using fluorocarbon oil (as perfluoro bromide octane, perfluorodecalin) to form emulsion oil-in-water, and this fluorocarbon oil can be by with carrying out emulsification as the surfactant of long-chain saturated phospholipid.Can use high-pressure homogenizer to homogenize to reduce droplet size the perfluorocarbon in the aqueous emulsion of gained subsequently.Perfluorocarbon emulsion can be fed in spray dryer, if wish, in porous microstructure, comprising activating agent can charging together with activator solution alternatively.As everyone knows, spraying is dry is a kind ofly liquid feedstock conversion can be become to the technique of dry particles form.Spraying is dried and has been used to be provided for the powder medicaments that various different way of administration comprise inhalation.Can prepare required particle size by adjusting the operating condition (such as entrance and outlet temperature, feed rate, atomizing pressure, dry gas flow velocity and nozzle arrangements) of spray dryer, and then make dry microstructure.These methods of preparing exemplary porous microstructure have been disclosed in the people's such as Weers U.S. patent 6,309,623.
Porous microstructure of the present invention also can and then be pulverized or prepared by micronized method by first freeze-drying.Freeze-drying is freeze-dried technique, and the water in freezing rear composition can be sublimated to be removed.This technique can be dried under the condition that does not need high temperature.In embodiment further, suspended particulate can be by preparing with drying process with atomizing, and for example U.S. patent 5,727, record in 333 like that.
In addition, suspended particulate of the present invention can contain filling agent, such as aggregated particles.Polymerizable polymer can be formed by biocompatibility and/or Biodegradable polymeric, copolymer or its mixture.In one embodiment, can use the polymer that can form the light fine particles of aerodynamics, such as functionalized polyester graft copolymer and biodegradable polyanhydride.For example, can use the filling of poly-based on containing (hydroxy acid) polyester to corrode polymer.Can use polyglycolic acid (PGA), PLA (PLA) or its copolymer to form suspended particulate.Polyester can comprise charged group or group that can be functionalized, such as amino acid.For example, suspended particulate can (PLGA) be formed by poly-(D, L lactic acid) and/or poly-(D, Pfansteihl-altogether-glycolic), and it comprises for example DPPC of surfactant.
Other possible candidate's polymer for suspended particulate can comprise, polyamide, Merlon, polyene is as polyethylene, polypropylene, polyethylene glycol, poly-(oxirane), poly-(PETP), polyvinyl compounds is as polyvinyl alcohol, polyvinylether and polyvinyl ester, the polymer of acrylic acid and methacrylic acid, cellulose and other polysaccharide, and peptide or protein, or their copolymer or mixture.Can be for need to the carrying out choice for use those have suitable stability and the polymer of degradation speed in vivo of different controlled release drug delivery applications, or make these polymer there is this suitable stability and degradation speed by modification.
Composition of the present invention can comprise the suspended particulate of two or more types.Further, composition of the present invention can comprise the suspended particulate that wherein contains one or more activating agents.When activating agent is included in suspended particulate, this suspended particulate should have the size that can suck and can method and material are prepared and produced as described in the present invention by example.
According to the composition of training centre of the present invention preparation can composite inhibiting in the degraded of activating agent.For example, in a particular embodiment, composition of the present invention can suppress to be included in active one or more phenomenons of flocculation, gathering and solution mediated transformation of the activating agent in composition.Pharmaceutical composition of the present invention is applicable in a kind of specific mode, carrying out respiratory drugs by MDI and sends, which can make every kind of activating agent that the combination of two or more activating agents comprises all reach the dosage delivered uniformity (" DDU ") of expectation, or even also can reach when this combination contains effective and efficient activating agent.As described in detail in the embodiment the present invention includes, even when sending two or more activating agents of unusual low dosage, composition of the present invention also can reach the DDU of every kind of activating agent in the whole process of emptying MDI tank ± 30% or higher.In this kind of embodiment, composition of the present invention can reach the DDU of every kind of activating agent in the whole process of emptying MDI tank ± and 25% or higher.In another this kind of embodiment, composition of the present invention can reach the DDU of every kind of activating agent in the whole process of emptying MDI tank ± and 20% or higher.
Composition of the present invention can also substantially remain unchanged FPF and FPD performance in the whole process of emptying MDI tank, even if under accelerated degradation condition.Such as, composition of the present invention can maintain 80%, 90%, 95% or more of its initial value by FPF and FPD performance in the whole process of emptying MDI tank, even if under the condition of accelerated degradation.When using non-CFC propellant to prepare and eliminate or substantially avoided the drug effect that those compositions that comprise multiple actives exist conventionally, composition of the present invention still can provide the additional benefit that realizes this kind of performance.In a particular embodiment, when adopting, only contain one or more not when adding for example cosolvent, anti-solvent, solubilizer, adjuvant or other propellants and modify one or more suspension medias that its performance was carried out to improved non-CFC propellant in material and prepare, composition of the present invention still can realize target DDU, FPF and FPD performance in a kind of or whole.
In one embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby there is association between wherein said the first and second active agent particles and described multiple suspended particulate, forms common suspension.In this kind of embodiment, the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby there is association between wherein said the first and second active agent particles and described multiple suspended particulate, forms common suspension.In this kind of embodiment, the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the multiple actives particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; And contain the multiple suspended particulate that sucks that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, wherein said multiple suspended particulate has approximately 1.5 μ m is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g to the volume intermediate value optical diameter between approximately 10 μ m and its concentration in suspension media, thereby these suspended particulates can form suspension altogether with described multiple actives particle generation association.In this kind of embodiment, the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the multiple actives particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; And contain the multiple suspended particulate that sucks that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, the wherein said multiple suspended particulate that sucks has approximately 1.5 μ m and is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g to the volume intermediate value optical diameter between approximately 10 μ m and its concentration in suspension media, thereby these can suck suspended particulate and can form suspension with described multiple actives particle generation association.In this kind of embodiment, the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; The 3rd activating agent, it contains and is selected from the corticosteroid that beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and fluoxyprednisolone comprise any their pharmaceutically acceptable salts, ester, isomer or solvate; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby wherein said first, second, and third active agent particle forms common suspension with described multiple suspended particulate generation association.In this kind of embodiment, at least 90% first, second, and third active agent particle has the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of first, second, and third active agent particle is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; Contain the 3rd active agent particle that budesonide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 30 μ g to the budesonide dosage delivered between approximately 50 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby wherein said first, second, and third active agent particle forms common suspension with described suspended particulate generation association.In this kind of embodiment, at least 90% first, second, and third active agent particle has the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of first, second, and third active agent particle is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; Contain the 3rd active agent particle that budesonide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 30 μ g to the budesonide dosage delivered between approximately 50 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby wherein said first, second, and third active agent particle forms common suspension with described multiple suspended particulate generation association.In this kind of embodiment, at least 90% first, second, and third active agent particle has the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of first, second, and third active agent particle is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; Contain the 3rd active agent particle that Mometasone comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 20 μ g to the Mometasone dosage delivered between approximately 100 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby wherein said first, second, and third active agent particle forms common suspension with described multiple suspended particulate generation association.In this kind of embodiment, at least 90% first, second, and third active agent particle has the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of first, second, and third active agent particle is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; Contain the 3rd active agent particle that Mometasone comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 20 μ g to the Mometasone dosage delivered between approximately 100 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this suspended particulate has 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby wherein said first, second, and third active agent particle forms common suspension with described multiple suspended particulate generation association.In this kind of embodiment, at least 90% first, second, and third active agent particle has the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of first, second, and third active agent particle is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; Multiple the sucked suspended particulate that comprises porous microstructure, wherein said porous microstructure contains and is selected from the corticosteroid that beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and fluoxyprednisolone comprise any their pharmaceutically acceptable salts, ester, isomer or solvate, wherein said suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second described active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this porous microstructure contains budesonide and comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, thereby containing each startup effect that enough budesonides can make metered dose inhaler, this suspended particulate can produce approximately 30 μ g to the budesonide dosage delivered between approximately 50 μ g, this suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second described active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio of the gross mass of the gross mass of suspended particulate and the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Glycopyrrolate comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 15 μ g to the Glycopyrrolate dosage delivered between approximately 80 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this porous microstructure contains Mometasone and comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, wherein thereby this suspended particulate contains each startup effect that enough Mometasones can make metered dose inhaler and can produce approximately 20 μ g to the Mometasone dosage delivered between approximately 100 μ g, this suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second described active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; The sucked suspended particulate that contains porous microstructure, this porous microstructure contains and is selected from the corticosteroid that beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and fluoxyprednisolone comprise any their pharmaceutically acceptable salts, ester, isomer or solvate, wherein suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that contains porous microstructure, this porous microstructure contains budesonide and comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, thereby containing each startup effect that enough budesonides make metered dose inhaler, this suspended particulate can produce approximately 30 μ g to the budesonide dosage delivered between approximately 50 μ g, this suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
In another embodiment, the common suspension composition of sending by metered dose inhaler of the present invention comprises: the suspension media that contains pharmaceutically acceptable HFA propellant; Contain the first active agent particle that Tiotropium Bromide comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 5 μ g to the Tiotropium Bromide dosage delivered between approximately 20 μ g; Contain the second active agent particle that Formoterol comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, this active agent particle is suspended in suspension media and the concentration of its existence is enough to make each startup effect of metered dose inhaler can produce approximately 2 μ g to the Formoterol dosage delivered between approximately 10 μ g; And multiple the sucked suspended particulate that comprises porous microstructure, this porous microstructure contains Mometasone and comprises its any pharmaceutically acceptable salt, ester, isomer or solvate, thereby containing each startup effect that enough Mometasones make metered dose inhaler, this suspended particulate can produce approximately 20 μ g to the Mometasone dosage delivered between approximately 100 μ g, this suspended particulate has approximately 1.5 μ m to the volume intermediate value optical diameter between approximately 10 μ m, thereby and forms suspension altogether with the first and second active agent particle generation associations.In this kind of embodiment, the first and second active agent particles of at least 90% have the optical diameter that is less than 7 μ m by volume, and the ratio between the gross mass of suspended particulate and the gross mass of the first and second active agent particles is selected from about 3:1 between about 15:1 and between about 2:1 to 8:1.
quantitative intake system
As mentioned in the inventive method, composition disclosed in this invention can be used in MDI system.MDI can be configured to send the medicine of the aerosol form of specified quantitative.In one embodiment, MDI system comprises the container tank for store compressed liquid phase preparation, and it is arranged on the starter with nozzle.MDI system can comprise preparation of the present invention, the active agent particle that said preparation comprises suspension media, at least one type and the suspended particulate of at least one type.Container tank for MDI can be any suitable structure, and in an exemplary embodiment, container tank can have about 5mL to the volume range of about 25mL, such as having the volume of 19mL.After jolting device, nozzle is inserted between the lips and teeth of patient mouth Palestine and China.Conventionally, patient exhales deeply to empty lungs, then when starting MDI cartridge case, carries out deep and slow respiration.
In the inside of exemplary medicinal cupping, it is metering valve, it,, with the measuring room that can hold the preparation (volume that can hold as 63 μ l or any metering valve that other can obtain by commercial channel) of designated volume, is released to the preparation of this volume in the expansion chambers of valve stem end when starting.Starter is controlled container tank, and can comprise the port with starter nozzle, and this starter nozzle can be used for holding the valve rod of metering valve.When starting, the preparation of designated volume can enter into expansion chambers, thereby from starting nozzle, discharges and form the lung that high velocity fog enters patient.
iV. method
The invention provides the compound method of sending the pharmaceutical composition that comprises at least two kinds of activating agents of the present invention through breathing.In one embodiment, the method comprising the steps of: a kind of suspension media, one or more active agent particles and one or more suspended particulates are provided, these components are combined to form active agent particle of the present invention and suspended particulate associate mutually and the common suspension preparation of common point in suspension media.In this kind of embodiment, active agent particle and the association of suspended particulate make they can be because of it different buoyancy in propellant and occur separated.The method that should be appreciated that preparation drug combination preparation of the present invention can comprise, the combination of active agent particle and one or more suspended particulates of two or more types is provided.In a further embodiment, the method can comprise, the combination of two or more suspended particulates and two or more active agent particles is provided according to certain mode, and described mode can make this be combined to form common suspension.In yet another embodiment, one or more active agent particles of the present invention can combine with one or more suspended particulates.In a particular embodiment, the activating agent material comprising at active agent particle is selected from one or more in LABA, LAMA or corticosteroid activating agent.In certain embodiments, active agent particle is comprised of activating agent material and other auxiliary materials, adjuvant and stabilizing agent etc. substantially.
In the specific embodiment of method of stable composition that two or more activating agents are provided, the invention provides the method for the solution mediated transformation effect of the activating agent in the pharmaceutical composition that a kind of inhibition sends through lung.In one embodiment, can obtain the suspension media that suspension media of the present invention is for example formed by HFA propellant.Also can obtain active agent particle, thereby and suspension media, suspended particulate and active agent particle can be combined and form suspension altogether, wherein active agent particle and suspended particulate associate also common point mutually in the formed continuous phase by suspension media.When not comparing containing contained active agent particle in the identical suspension media of suspended particulate with those, can find that the solution mediation inversion of phases effect that suspension altogether of the present invention causes irreversible crystal aggregation phenomenon for those has higher tolerance, thereby it can improve stability and dose uniformity.
In a further embodiment, the method that forms the stable composition of sending through lung that contains two or more activating agents comprises, keeps FPF and/or the FDP of composition in the whole process of emptying MDI tank.At those, keep in the specific embodiment of the FPF of lung delivering drugs preparation and/or the method for FPD, a kind of common suspension that sucks of the present invention can be provided, this common suspension in the whole process of emptying MDI tank, FPD and/or FPF can be maintained respectively its initial FPD and/or FPF ± 20%, ± 10% or even ± 5% in.Box lunch is total under the condition of suspension in accelerated degradation, still can realize this performance.In one embodiment, can obtain suspension media of the present invention such as the suspension media being formed by HFA propellant.Also can obtain or make suspended particulate of the present invention.Also can obtain the active agent particle of the present invention of one or more types, and thereby suspension media, suspended particulate and active agent particle are combined and form suspension altogether, wherein active agent particle and suspended particulate associate also common point mutually in suspension media.Even if after this kind of composition is exposed to one or many temperature cycling and processes, altogether suspension before also FPD or FPF can being maintained to composition and being exposed to one or many temperature cycling and processing ± 20%, ± 10% or even ± 5% in.
The application discloses preparation can send through lung the method for the MDI of two or more activating agents.In certain embodiments, this method can comprise with active agent particle and suspended particulate and loads container tank of the present invention.Starter valve can be arranged on to one end the airtight container tank of container tank.Thereby can adjust starter valve make MDI at every turn startup effect can send the quantitative activating agent in common suspension composition that is included in.Can be with pharmaceutically acceptable suspension media such as propellant of the present invention is loaded container tank, thus active agent particle and suspended particulate can form stable common suspension in suspension media.
Using composition of the present invention to send in the method for two or more activating agents through breathing, said composition can be sent by MDI.Therefore, in the specific embodiment of this kind of method, can obtain the MDI that is filled with composition of the present invention, and by the startup effect of MDI, two or more activating agents are delivered to patient through lung.For example, in one embodiment, the method comprises through lung sends two or more activating agents, after jolting MDI device, by connecing mouth, is inserted between the lips and teeth of patient's face.Conventionally, then first dark expiration of patient once deeply breathes to empty lungs when starting MDI medicinal cupping.When starting, the preparation of designated volume can be introduced into expansion chambers, then from starting nozzle, discharges formation high velocity fog and enters into patient lung.In one embodiment, in the whole process of emptying MDI tank, the dosage delivered of every kind of activating agent can not surpass higher than 30% of average delivered dosage, can not be less than lower than 30% of average delivered dosage yet.Therefore, the application can provide the DDU of two or more activating agents that a kind of MDI of making sends to reach the method for desirable value.In this kind of embodiment, the method can be in the overall process of the emptying MDI tank of sending common suspension, make the DDU of every kind of activating agent in two or more activating agents that MDI tank sends reach for example ± 30% or higher DDU, ± 25% or higher DDU and ± 20% or higher DDU.
Those suffer the patient's of inflammatory or obstructive disease of lung or symptom method to the invention provides treatment.In certain embodiments, this kind of method comprises the pharmaceutical composition of the present invention through lung delivery treatments effective dose, at some in this kind of embodiment, by use MDI delivering compositions with realize pharmaceutical preparation through lung administration.Intending the disease for the treatment of or symptom can be selected from and anyly can produce to for example activating agent of the present invention inflammation or obstructive lung disease or the symptom of responsing reaction.In certain embodiments, activating agent combination comprises at least one activating agent being selected from LAMA, LABA or corticosteroid activating agent.In a particular embodiment, pharmaceutical composition of the present invention can be used for treatment and is selected from disease or the symptom of following group: the airway hyperreactivity deterioration of asthma, COPD, other drug therapy secondary, allergic rhinitis, nasosinusitis, lung vessel retraction, inflammation, allergy, respiratory disorder, Respiratory Distress Syndrome(RDS), pulmonary hypertension, lung vessel retraction, pulmonary emphysema and anyly can produce to activating agent administering drug combinations of the present invention other pulmonary disease and symptoms, proterties, genotype or the phenotype of responsing reaction.In certain embodiments, pharmaceutical composition of the present invention can be used for lung inflammation and the obstruction that treatment is relevant to cystic fibrosis.
In addition the pharmaceutical composition of the present invention that, MDI sends can provide required pharmacodynamics (PD) performance.In a particular embodiment, send pharmaceutical composition of the present invention can make lung volume occur significantly to improve fast through lung, this can use patient's FEV1 (FEV 1) improvement degree characterize.For example, in a particular embodiment, the application provides a kind of clinical FEV that realizes 1the method significantly increasing, this kind of method comprises to be provided the common suspension composition of the LABA of containing of the present invention or LAMA activating agent and by this composition, gives the patient that those suffer lung inflammation or block by MDI.In this kind of embodiment, the activating agent that composition comprises comprises the combination of a kind of combination being selected from following group: LABA and LAMA activating agent, the combination of LABA and corticosteroid activating agent, the combination of LAMA and corticosteroid activating agent, and the combination of LABA, LAMA and corticosteroid activating agent.With regard to object of the present invention, clinical FEV 1significantly recruitment is 100ml or more, in the specific embodiment of the method for the invention, gives patient can in 1 hour or shorter time, make FEV by the present composition 1there is the remarkable increase on clinical meaning.In other this kind of embodiment, by MDI, by composition of the present invention, give patient and can in 0.5 hour or shorter time, make FEV 1there is the remarkable increase on clinical meaning.
In a further embodiment, the invention provides and can make FEV 1increase method more than 100ml.For example, in a particular embodiment, described method is included in and is selected from 0.5 hour or makes FEV in shorter, 1 hour or shorter and 1.5 hours or shorter time 1increase 150ml or more than.In other embodiments, described method can make be selected from 0.5 hour or making FEV in shorter, 1 hour or shorter and 1.5 hours or shorter and 2 hours or shorter time 1increase 200ml or more than.In another other these type of embodiment, described method can make be selected from 0.5 hour or making FEV in shorter, 1 hour or shorter and 1.5 hours or shorter and 2 hours or shorter time 1increase 250ml or more than.In another other these type of embodiment, described method can make be selected from 0.5 hour or making FEV in shorter, 1 hour or shorter and 1.5 hours or shorter and 2 hours or shorter time 1increase 300ml or more than.In another other these type of embodiment, described method can make be selected from 0.5 hour or making FEV in shorter, 1 hour or shorter and 1.5 hours or shorter and 2 hours or shorter time 1increase 350ml or more than.In specific this kind of embodiment, the contained activating agent of composition comprises the combination of a kind of combination being selected from following combination: LABA and LAMA activating agent, the combination of LABA and corticosteroid activating agent, the combination of LAMA and corticosteroid activating agent, the combination of LABA, LAMA and corticosteroid activating agent, wherein said composition is delivered to patient by MDI.
In embodiment further, the application provides a kind of FEV that realizes and maintain 1the method of the remarkable increase on clinical meaning.In a particular embodiment, when by MDI, give patient's dose be formulated into the activating agent of the composition described in the application time, can be selected from 0.5 hour or make FEV in shorter, 1 hour or shorter and 1.5 hours or shorter time 1reach the remarkable increase on clinical meaning, and FEV 1remarkable increase on this clinical meaning can maintain 12 hours even longer.In specific this kind of embodiment, FEV 1recruitment can be selected from 150ml or more, 200ml or more, 250ml or more, 300ml or more mainly with and 350ml or more, and FEV 1recruitment time of maintaining the significant quantity on clinical meaning can be selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours and up to 12 hours or longer.In specific this kind of embodiment, the contained activating agent of composition comprises the combination of a kind of combination being selected from following combination: LABA and LAMA activating agent, the combination of LABA and corticosteroid activating agent, the combination of LAMA and corticosteroid activating agent, the combination of LABA, LAMA and corticosteroid activating agent, wherein said composition is delivered to patient by MDI.
Composition of the present invention, system and method are not only suitable for realizing at short notice required pharmacodynamics performance, and it is also very high in patient, to realize the ratio of this kind of result.For example, method of the present invention 50% more suffer lung inflammation or the patient of blocking in can make FEV 1recruitment reach 10% or higher.For example, in a particular embodiment, make patient's FEV 1increase by 10% or higher method comprise, the common suspension composition that contains activating agent combination of the present invention is provided, wherein at least one activating agent is selected from LABA of the present invention, LAMA and corticosteroid activating agent, and by this composition, gives the patient that those suffer lung inflammation or block by MDI.In specific this kind of embodiment, give composition can be selected from 0.5 hour or shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours in make 50% or more patient's FEV 1recruitment reaches 10% or higher.In other this kind of embodiment, give composition and can be selected from 0.5 hour or make in shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours or shorter time 60% or more patient's FEV 1recruitment reaches 10% or higher.In other this kind of embodiment, give composition and can be selected from 0.5 hour or make in shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours or shorter time 70% or more patient's FEV 1recruitment reaches 10% or higher.In other this kind of embodiment, give composition and can be selected from 0.5 hour or make in shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours or shorter time 80% or more patient's FEV 1recruitment reaches 10% or higher.In specific this kind of embodiment, the contained activating agent of composition comprises the combination of a kind of combination being selected from following combination: LABA and LAMA activating agent, the combination of LABA and corticosteroid activating agent, the combination of LAMA and corticosteroid activating agent, the combination of LABA, LAMA and corticosteroid activating agent, wherein said composition is delivered to patient by MDI.
In a particular embodiment, method of the present invention can be treated those patients who suffers lung inflammation or block, wherein the method comprises provides the common suspension composition that contains activating agent combination of the present invention and by this composition, gives the patient that those suffer lung inflammation or block by MDI, by MDI, gives the FEV that said composition can make those patients 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.In specific this kind of embodiment, give composition can 50% or more patient within 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter time, make FEV 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.In other this kind of embodiment, give composition can 60% or more patient within 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter time, make FEV 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.In other this kind of embodiment, give composition can 70% or more patient within 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter, 2.5 hours or shorter and 3 hours or shorter time, make FEV 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.In other this kind of embodiment, give composition can 80% or more patient within 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter, 2.5 hours or shorter and 3 hours or shorter time, make FEV 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.At some in this kind of embodiment, the activating agent that composition comprises comprises a kind of in the combination of combination, LAMA and corticosteroid activating agent of the combination, LABA and the corticosteroid activating agent that are selected from LABA and LAMA activating agent and the combination of LABA, LAMA and corticosteroid activating agent, and wherein said composition is delivered to patient by MDI.
In certain embodiments, of the present invention for realizing and maintain the FEV of the remarkable increase on clinical meaning 1method make FEV 1increase, this shows that the improvement providing with the composition of only sending single-activity agent compares FEV 1obtained remarkable improvement.For to composition of the present invention with only send the FEV that sends of single-activity agent 1the object that performance compares, by FEV 1remarkable improvement be defined as improve 60ml or more than.For example, in a particular embodiment, realize the FEV that tool is significantly improved that improves providing with respect to the composition of only sending single-activity agent 1method comprise altogether suspension composition of the present invention be provided, described composition comprises the combination of activating agent, wherein at least one activating agent is selected from LABA of the present invention, LAMA and corticosteroid activating agent, and such composition is given to suffer from the patient of lung inflammation or obstruction by MDI.In some this type of embodiment, with the FEV reaching by sending the composition of single-activity agent 1aUC 0-12compare, give common suspension composition and make FEV 1aUC 0-12improve at least 70ml.In other these type of embodiment, with the FEV reaching by sending the composition of single-activity agent 1aUC 0-12compare, give common suspension composition and make FEV 1aUC 0-12improve at least 80ml.In another other embodiment, with the FEV reaching by sending the composition of single-activity agent 1aUC 0-12compare, give common suspension composition and make FEV 1aUC 0-12improve at least 90ml.
In other embodiments, realize the FEV that tool is significantly improved that improves providing with respect to the composition of only sending single-activity agent 1method comprise altogether suspension composition of the present invention be provided, described composition comprises the combination of activating agent, wherein at least one activating agent is selected from LABA of the present invention, LAMA and corticosteroid activating agent, by MDI, such composition is given to experience the patient of lung inflammation or obstruction, described administration makes the peak FEV reaching with the composition of sending single-activity agent 1compare FEV 1peak variable quantity (peak FEV 1) significantly improve.In some this type of embodiment, the peak FEV reaching with the composition of sending single-activity agent 1compare, give the peak FEV that suspension composition reaches altogether of the present invention 1improve at least 70ml.In other these type of embodiment, the peak FEV reaching with the composition of sending single-activity agent 1compare, give the peak FEV that suspension composition reaches altogether of the present invention 1improve at least 80ml.In further this type of embodiment, the peak FEV reaching with the composition of sending single-activity agent 1compare, give the peak FEV that suspension composition reaches altogether of the present invention 1improve at least 90ml.
The application also provides a kind of patient respiratory capacity (IC) that makes to suffer from lung inflammation or obstruction to occur the method for clinical remarkable increase.As used herein, when IC is defined as complete air-breathing after normal expiration, can suck the maximum volume of the gas of lung, the clinical remarkable increase of IC refers to 70ml or above increase.For example, in a particular embodiment, the method of improving as described in the present invention IC comprises provides suspension composition altogether of the present invention, described composition comprises the combination of activating agent, wherein at least one activating agent is selected from LABA of the present invention, LAMA and corticosteroid activating agent, by MDI, such composition is given to suffer from the patient of lung inflammation or obstruction, wherein said composition make IC increase 70ml or more than.In some this type of embodiment, give composition of the present invention make IC increase 100ml or more than.In other these type of embodiment, give composition of the present invention make IC increase 200ml or more than.In other these type of embodiment, give composition of the present invention make IC increase 300ml or more than.In other these type of embodiment, give composition of the present invention make IC increase 350ml or more than.In specific other these type of embodiment, described IC increases sharply.For example, in each described method, can be selected from 1 hour or in following and 2 hours or following time, patient's the clinical remarkable increase of IC or IC increase be selected from 100ml or above, 200ml or above, 300ml or more than, or 350ml or more than.
The method of increase IC of the present invention not only can realize rapidly the clinical remarkable increase of IC in the short period of time, and it can also be for maintaining the clinical remarkable increase of IC in a period of time.For example, outstanding having shown of clinical effectiveness providing in embodiment 12: after administration, patient's clinical remarkable increase of IC that experience is provided by method of the present invention rapidly, after administration, reach 12 hours or in longer time period, the increase of IC has maintained clinical significance, even for example,, after long term administration (, many days successive administrations), the increase of IC has still maintained clinical significance.
And the IC being provided by the composition of only sending single-activity agent is provided in the IC increase providing according to composition of the present invention increases.In the embodiment of the method for increase of the present invention IC, give the IC that suspension composition provides of the present invention altogether increase than the IC at least high 70ml of increase being provided by the composition of only sending single-activity agent or more than.In this type of embodiment, the IC that giving altogether suspension composition of the present invention provides increase than the IC at least high 100ml of increase being provided by the composition of only sending single-activity agent or more than.In another this type of embodiment, the IC that giving altogether suspension composition of the present invention provides increase than the IC at least high 125ml of increase being provided by the composition of only sending single-activity agent or more than.
In certain embodiments, of the present invention for reach required pharmacodynamic action method be characterized as the activating agent of sending relatively low amount.In some this type of embodiment, for example of the present invention for reaching FEV 1the method of clinical remarkable increase comprises and gives altogether suspension of the present invention, described suspension altogether comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, give at the most described in patient suspension altogether every day for twice, and total dosage delivered that each administration total dosage delivered of giving patient's Glycopyrrolate is no more than 150 μ g and Formoterol is no more than 12ug.In other these type of embodiment, of the present invention for reaching FEV 1the method of clinical remarkable increase comprises and gives altogether suspension of the present invention, described suspension altogether comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, give at the most described in patient suspension altogether every day for twice, and total dosage delivered that each administration total dosage delivered of giving patient's Glycopyrrolate is no more than 100 μ g and Formoterol is no more than 12ug.In other these type of embodiment, of the present invention for reaching FEV 1the method of clinical remarkable increase comprises and gives altogether suspension of the present invention, described suspension altogether comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, give at the most described in patient suspension altogether every day for twice, and total dosage delivered that each administration total dosage delivered of giving patient's Glycopyrrolate is no more than 80 μ g and Formoterol is no more than 12ug.In other embodiments, of the present invention for reaching FEV 1the method of clinical remarkable increase comprises and gives altogether suspension of the present invention, described suspension altogether comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, give at the most described in patient suspension altogether every day for twice, and total dosage delivered that each administration total dosage delivered of giving patient's Glycopyrrolate is no more than 50 μ g and Formoterol is no more than 12ug.
In certain embodiments, of the present inventionly for reaching the method for the clinical remarkable increase of IC, comprise by metered dose inhaler and give patient altogether suspension composition of the present invention, wherein said suspension altogether comprises Glycopyrrolate and Formoterol activating agent, by metered dose inhaler, give at the most described in patient suspension altogether every day for twice, and total dosage delivered that each administration total dosage delivered of giving patient's Glycopyrrolate is no more than 150 μ g and Formoterol is no more than 12ug.In some this type of embodiment, for example of the present inventionly for reaching the method for the clinical remarkable increase of IC, comprise and give altogether suspension of the present invention, described altogether suspension comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, gives at the most described in patient total dosage delivered that total dosage delivered that suspension altogether and each administration give patient's Glycopyrrolate is no more than 100 μ g and Formoterol every day for twice and is no more than 12ug.In other these type of embodiment, of the present inventionly for reaching the method for the clinical remarkable increase of IC, comprise and give altogether suspension of the present invention, described altogether suspension comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, gives at the most described in patient total dosage delivered that total dosage delivered that suspension altogether and each administration give patient's Glycopyrrolate is no more than 80 μ g and Formoterol every day for twice and is no more than 12ug.In other these type of embodiment, of the present inventionly for reaching the method for the clinical remarkable increase of IC, comprise and give altogether suspension of the present invention, described altogether suspension comprises the combination of Glycopyrrolate and Formoterol activating agent, wherein by metered dose inhaler, gives at the most described in patient total dosage delivered that total dosage delivered that suspension altogether and each administration give patient's Glycopyrrolate is no more than 50 μ g and Formoterol every day for twice and is no more than 12ug.
The composition that provides in method of the present invention and send can comprise common suspension composition, and it comprises the combination of any activating agent as described in the present invention.For example, in a particular embodiment, of the present invention for reaching FEV 1or the method for the clinical remarkable increase of IC comprises the common suspension composition that comprises two or more activating agents is provided, wherein at least one in those activating agents is selected from LABA of the present invention, LAMA or corticosteroid, and such composition given to suffer from the patient of lung inflammation or obstruction by MDI.In this type of embodiment, at the described described activating agent being total in suspension composition, comprise and be selected from one of following combination: the combination of the combination of the combination of the combination of LABA and LAMA activating agent, LABA and corticosteroid activating agent, LAMA and corticosteroid activating agent and LABA, LAMA and corticosteroid activating agent.In the specific embodiment of the method for the invention, the common suspension composition that provides and give can be any specific detailed in this article suspension composition altogether.
Specific embodiment in the application is only for the object of example, and not will be understood that it forms any restriction to the application.In addition, the disclosed composition of the application, system and method are described in those relative specific embodiments, many details are wherein only the object of example, the application can comprise other embodiment, in the situation that not departing from basic principle of the present invention, can change the described specific detail of the application, this point is that appearance is intelligible to those skilled in the art.Any activating agent or the reagent that in the following example, use can obtain by commercial channel, or can by the technique in normative document, be made by those skilled in the art under the instruction providing in the application help.The full content of all publications, granted patent and the patent application of the reference of the application institute all by reference to mode be incorporated in the application.
embodiment 1
Prepare exemplary suspension composition altogether of the present invention, and it is assessed.The combination that said composition comprises Glycopyrrolate (GP) and formoterol fumarate (FF) activating agent.GP is that the form with micronized lenticular active agent particle is present in propellant.It suspends altogether with spray-dired suspended particulate, and this suspended particulate contains the FF being dispersed in those materials that form suspended particulate.For realizing this object, FF crystal is suspended in to those and is used for preparing in the raw material of the suspended particulate based on lipid.
Thereby form GP active agent particle by using jet mill to carry out micronize processing to Glycopyrrolate.For example, by the particle diameter that uses laser diffraction particle size analyzer with dry powder dispenser (Sympatec GmbH, Clausthal-Zellerfeld, Germany) to measure Glycopyrrolate active agent particle with Fraunhofer diffraction pattern, distribute.The active agent particle of 50% volume presents the optical diameter that is less than 1.7 μ m, and the particle of 90% volume presents the optical diameter that is less than 3.5 μ m.
Adopt the suspended particulate that preparation contains FF with the following method: preparation 654mL is used the PFOB(perfluoro bromide octane of the stable water bag fluorine carbon of phosphatide) emulsion; By high-shear mixer by 26.5g phosphatide, DSPC(1,2-distearyl acyl group-sn-glycerol-3-phosphocholine) and 2.4g calcium chloride be dissolved in 276mL hot water (80 ℃) and carry out homogeneity processing; In dispersion process, add lentamente 142mL PFOB.Under the pressure up to 170MPa, use the further thick emulsion 5 times of homogenizing gained of high-pressure homogenizer (C3 type, Avestin, Ottawa, CA).552mg FF is dissolved in 273mL hot water (50 ℃), by high-shear mixer, most solutions and emulsion is mixed.Use following spraying drying condition emulsion to be sprayed dry under nitrogen: 95 ℃ of inlet temperatures; 68 ℃ of outlet temperatures; Emulsion feed speed 2.4mL/min; And total gas flow rate 498L/min.The final mass of Formoterol in a spray-dried powders minute rate is 2%.
Use similar approach to prepare the suspended particulate that contains FF of second batch.In this batch, the final mass mark of FF in spray-dried powders is 1%.The 3rd batch of prepared suspended particulate do not contain FF.
Use the particle diameter distribution (VMD) of determination of laser diffraction suspended particulate.For two batches of suspended particulates that contain FF, to be wherein less than the geometric standard deviation of 3.5 μ m and distribution be 1.7 to the particle of 50% volume.For not containing the suspended particulate of FF, to be wherein less than the geometric standard deviation of 3.2 μ m and distribution be 1.8 to the particle of 50% volume.
Take active agent particle and the suspended particulate of aim parameter and be filled in the 19mL volume aluminium pot (Presspart, Blackburn, UK) applying through fluoroethylene polymer (FEP), thereby making metered dose inhaler.63 μ l valves for container tank (#BK357, Bespak, King ' s Lynn, UK) are curled sealing and via valve rod, in overvoltage mode, are loaded 12.4g HFA134a(1,1,1,2-HFC-134a) (Ineos Fluor, Lyndhurst, UK).Suppose that starter deposition is 20%, table 1a has listed suspension concentration and the target dosage delivered of three kinds of different preparation groups (preparation group 1A to 1C).After injecting propellant, the ultrasonic processing of container tank 15 seconds is also vibrated 30 minutes on wrist type shaking table.
Container tank disposes the polypropylene starter (#BK636, Bespak, King ' s Lynn, UK) with 0.3mm aperture.
table 1a: the combination of the Glycopyrrolate of embodiment 1-formoterol fumarate is the preparation situation of suspension altogether
Metered dose inhaler after loading is stored under two kinds of different conditions in the situation that valve is downward: there is no 5 ℃ of refrigerations under the condition of external packing, and under 25 ℃/60%RH room temperature, storing under the condition of paper tinsel outer wrapping.In different time point determining aerosol performances and dosage delivered uniformity.Aerosol performance is immediately according to USP<601>(American Pharmacopeia monograph 601 after preparation) evaluate.Using ram of new generation (NGI) under the flow velocity of 30L/min, to measure particle diameter distributes.Shuttle tank is arranged in a starter, and this starter has other consume startup effect of twice consume startup effect and twice.In the NGI with USP throat, collect the material that 5 startup effects produce.Use solvent flush valve, starter, throat, NGI cup, (stages) at different levels and the filter of capacity distribution.Use the chromatography working sample solution of drug specificity.With defining minuteness particle mark by 3rd level to the total amount of filter.According to USP<601> using dosage uniformity sampling apparatus, measure the dosage delivered uniformity in use procedure.Fixing and the pre-inhalator of loading according to preceding method.At leading portion, stage casing and the latter end of use procedure, collect the material that twice startup effect produce and measure.
During research, (3 months) do not observe aerosol performance and the dosage delivered uniformity trend that changes, or it changes along with storage temperature.Therefore the result that, gathers all aerosol performance tests.Table 1b has listed the average behavior of different preparation groups.Minuteness particle dosage be 3rd level at impactor to the collected quality summation of filter, and calibrate with sign dosage.The average aerosol performance of all three preparation groups is equal to.
table 1b: the average aerosol performance that is total to suspension in embodiment 1
Tested in combination product the dosage content uniformity of two kinds of activating agents in the container tank term of validity.Fig. 1 and 2 shows respectively the dosage that the starter of preparation group 1A and 1B disengages, and with the actual sign dosage of container tank, calibrates.Suppose that starter deposition is 20%, to disengage dosage be 80% to the starter of two kinds of activating agent targets.The dosage of FF and GP represents with point and triangle respectively.Closed line represents the mean value of Formoterol dosage, and broken line represents the mean value of Glycopyrrolate dosage.Fig. 3 and 4 shows respectively the ratio of the dosage that preparation group 1A and the 1B starter after calibration disengages.Result demonstration, in the term of validity of container tank, dose ratio remains unchanged.In addition, the changeability of dose ratio is far below the changeability of individual dose, and this has shown to form a kind of common suspension with constant carrier/activating agent ratio, and it can remain unchanged in the container tank term of validity.
Result shows, when carrying out preparation according to the inventive method, can use the suspended particulate that contains a kind of active constituents of medicine to form the common suspension of combination product, is FF in this example.Thereby can regulate suspended particulate and active agent particle ratio realize target dosage content uniformity and maintain similar aerosol performance.
embodiment 2
Preparation contains FF, GP or both MDI, and wherein the aimed concn of FF and GP is respectively each startup effect 2.4 and 18 μ g.GP active agent particle is carried out to micronize processing, the d that it is recorded by the laser diffractometry described in embodiment 1 10, d 50, d 90be respectively 0.6,1.7,3.6 and 1.9 μ m with span.FF is incorporated in spray-dired suspended particulate, thereby and is prepared and obtains a kind of 2%FF of containing, 91.5%DSPC and 6.5%CaCL according to the method described in embodiment 1 2composition.Take active agent particle and the suspended particulate of aim parameter and be filled into the 19mL volume applying through fluoroethylene polymer (FEP) aluminium pot (Presspart, Blackburn, UK) thus in make the MDI of GP, FF and GP+FF.50 μ l valves for container tank (#BK357, Bespak, King ' s Lynn, UK) are curled sealing and via valve rod, in overvoltage mode, are loaded 10.2g HFA134a(1,1,1,2-HFC-134a) (Ineos Fluor, Lyndhurst, UK).After injecting propellant, the ultrasonic processing of container tank 15 seconds is also vibrated 30 minutes on wrist type shaking table.Container tank disposes the polypropylene starter (#BK636, Bespak, King ' s Lynn, UK) with 0.3mm aperture.
Assess long-time stability and the delivery characteristics of these MDI compositions.Particularly, according to the method described in embodiment 1 according to USP<601>, measure these compositions aerosol particle diameter under various conditions and distribute and dosage delivered characteristic, condition determination can extend up to 12 months in some embodiments.For example; as shown in Figure 5; according to the dosage delivered uniformity of the prepared composition of embodiment 1, substantially remain unchanged; even said composition be at 5 ℃, store 12 months after or under 25 ℃ and 60% relative moisture (RH), sample is placed on to aluminium foil bag in store 4.5 months after (; " shielded storage "), wherein sample being placed on can be so that the moisture entering in MDI container tank minimizes in aluminium foil bag.
Also to said composition under not protected storage requirement the aerosol performance in up to 12 months and under shielded storage requirement the aerosol performance in up to 6 months assess.As shown in Figure 6, store 12 months and store after 6 months under 25 ℃ and the not protected condition of 60%RH under 5 ℃ of shielded conditions, the GP of this common suspension composition and FF particle diameter distribute and substantially remain unchanged.As shown in Figure 7, even (40 ℃, 75%RH), the GP delivering from metered dose inhaler after 6 months and FF do not show obvious decline particle diameter distributes yet bearing under the condition of pressure.
In order to assess with the composition that only contains a kind of activating agent, compare, whether the preparation that simultaneously contains the combination of GP and FF there will be decline this point in aerosol performance, and by the aerosol performance of common suspension composition, the aerosol performance with the suspension composition that only contains a kind of activating agent contrasts the application.
Visible according to Fig. 8, the combination that comprises GP and the FF activating agent aerosol performance that aerosol performance and the suspension composition that comprises independent FF or independent GP of suspension composition are realized does not altogether have difference, and this aerosol performance that shows each activating agent that the common suspension of one-component or binary composition is realized is substantially the same.
embodiment 3
Pharmacokinetics and the safety of the metered dose inhaler of the common suspension that in clinical testing, those is contained to Glycopyrrolate and formoterol fumarate combination are assessed.This clinical testing is the crossing research of monocentric, random, double blinding, single dose, the fourth phase a, quadruple chemotherapy, and it is used for assessing 4 kinds by the inhalation therapy of MDI administration.After comprising formoterol fumarate (FF) inhalation aerosol, Glycopyrrolate (GP) inhalation aerosol, GP+FF inhalation aerosol and send GP inhalation aerosol, four kinds of therapies send continuously immediately FF inhalation aerosol.The preparation method of GP+FF inhalation aerosol and FF inhalation aerosol and GP inhalation aerosol as described in Example 2.GP+FF inhalation aerosol is also referred to as " fixing " combination of GP and FF, and sends " loose " combination that the therapy of sending continuously immediately FF inhalation aerosol after GP inhalation aerosol is called GP and FF.
Under study for action experimenter's Random assignment is become to four treatment groups, each treatment group comprises four kinds of all treatments.Each experimenter accepts the treatment of 4 kinds of single doses, the interval time of 7 to 21 days between every kind of therapy.There are 16 experimenters eligible and be used as safety analysis.So have 3 experimenters because do not accept one or more in therapy in 4 excludes it from PK analyzes, thereby so separately have two experimenters because the reason that the poor reason of suction technology causes dosage to make a mistake cannot be assessed excludes it from PK analyzes.
Give GP+FF inhalation aerosol, make every experimenter receive the GP of 72 μ g dosage, tetra-startup effects of FF(of 9.6 μ g dosage, each startup effect 18 μ gGP and 2.4 μ g FF).Give GP inhalation aerosol, make every experimenter receive tetra-startup effects of GP(of 72 μ g dosage, each startup effect 18 μ g GP).Give FF inhalation aerosol, make every experimenter receive tetra-startup effects of FF(of 9.6 μ g dosage, each startup effect 2.4 μ g FF).For the consideration of blind state, carrying out first by MDI, giving placebo four times before aforementioned three kinds of therapies.Give the described loose combination of sending continuously immediately FF inhalation aerosol after GP inhalation aerosol of sending, make every experimenter receive tetra-startup effects of FF(of GP and the 9.6 μ g dosage of 72 μ g dosage, each startup effect 18 μ g GP, four startup effects subsequently, each startup effect 2.4 μ g FF).
Loose combination and the fixed Combination of GP and FF all have good safety and tolerance, and the result of other three kinds of therapies of assessing in the security features of fixed Combination and clinical testing is similar.The blood sample of 2,5,15 and 30 minutes and 1,2,4,6,8 and 12 hour before collecting administration and after administration, thus to measure the plasma concentration of GP and FF, calculate various PK parameters.Fig. 9 shows the situation of change of the plasma concentration of the GP in 12 hours and FF after administration along with the time.As shown in Figure 9, while giving the fixed Combination of GP and FF, after administration, the plasma concentration of GP and FF is suitable with the result that gives GP and the loose combination of FF.For the vitro delivered dose of mentioning in embodiment 2 and particle diameter characteristic distributions, do not observe in vivo the fixed Combination of GP+FF inhalation aerosol and share effect.
embodiment 4
Prepare the metered dose inhaler that exemplary binary of the present invention is total to suspension composition and contains said composition.The combination that composition comprises Glycopyrrolate (GP) and formoterol fumarate (FF), wherein every kind of activating agent all provides with the material of micronized lenticular form.By semi-automatic suspension completion method, prepare the interwoven crystal shape MDI tank of suspension altogether.Binary altogether suspension is comprised of active constituents of medicine (being also referred to as " API " of " APIs " or the singulative) GP of two kinds of microcrystalline form and the combination of FF, and wherein this active constituents of medicine and suspended particulate suspend altogether in HFA134a propellant.The common suspension of binary is formulated into each startup effect can provide 18 μ g GP and 4.8 μ g FF.When preparation binary is total to suspension composition, in specific composition, FF API material used represented with " slightly ", and FF API material used represented with " carefully " in other compositions.No matter this common suspension composition contains thick FF or thin FF, said composition is all formulated into the dosage delivered that each startup effect provides 4.8 μ g FF.Table 2 has at length been listed in the present embodiment for preparing the grain diameter characteristic of described suspension composition altogether thick FF used, thin FF and GP API material.Except the common suspension composition of binary, the application has also prepared the common suspension composition of monotherapy that only contains FF activating agent material.This FF monotherapy altogether suspension is used thick FF API.With this FF monotherapy, be total to suspension and prepare monotherapy MDI, and FF monotherapy MDI is mixed with to the dosage delivered that each startup effect can provide 4.8 μ g FF.
Suspended particulate is prepared by spray-dried emulsion; material concentration is 80mg/mL; this emulsion is a kind of DSPC(1 of 93.44% that contains, 2-distearyl acyl group-sn-glycerol-3-phosphocholine) with the composition (DSPC:CaCl that is equivalent to mol ratio 2:1 of 6.56% anhydrous calcium chloride 2), in emulsion preparation process, by DSPC and CaCl 2high-shear mixer by 8000-10000rpm is dispersed in the container that contains hot water (80 ± 3 ℃), adds lentamente PFOB in this process.Then by emulsion, in high-pressure homogenizer, (10000-25000psi) processes 6 times.Then emulsion is by disposing 0.42 " spray dryer of atomizer nozzle sprays dry under the atomizer air-flow of the 18SCFM setting.Dry gas flow velocity is set as to 72SCFM, and inlet temperature is 135 ℃, and emulsion flow velocity is 58mL/min.
For preparation MDI, use in such a way medicine to add container (DAV) and carry out suspension filling: first add the suspended particulate of half amount, then load the material of microcrystalline form, finally add the suspended particulate that remains half amount to top.In the humidity of <10%RH, control environment and lower material is joined in container.Then DAV is connected with 4L suspension container, thereby use HFA134a propellant to rinse, then carries out gentle married operation formation paste.Then paste is transferred back in suspension mixer and with HFA-134a and is diluted, thereby form the final suspension with aimed concn by the stirring of agitator arm gentleness.In the production process of whole batch, all the temperature in container is maintained to 21-23 ℃.After recycle 30min, by 50 μ L valves (Bespak, King ' s Lynn, UK), slurry compositions is filled in the aluminium pot (Presspart, Blackburn, UK) that 14mL fluoroethylene polymer (FEP) applied.The random shuttle tank that is used for carrying out all container tank determination tests of selecting is to guarantee correct amount of formulation.Optical diameter and the particle diameter of by the laser diffraction method described in embodiment 1, measuring the micronize Formoterol particle of two batches distribute.Table 2 has been listed the d of different batches micronize material used 10, d 50and d 90value.D 10, d 50and d 90representative reaches 10%, 50% and 90% particle diameter with the cumulative volume that particle size determination instrument records respectively.
To according to the particle diameter of the prepared common suspension preparation of embodiment 4, distribute and distribute and compare according to the particle diameter of the prepared common suspension preparation of embodiment 1.Table 3 has been listed comparative result, and wherein " %FPF FF " and " %FPF GP " represents by NGI 3rd level to the minuteness particle quality of the particular active agent of filter divided by starter quality and be multiplied by 100 result.
table 2: for the preparation of the binary micronize formoterol fumarate of suspension and the distribution of the particle diameter of Glycopyrrolate altogether
Title d 10(μm) d 50(μm) d 90(μm) Span
Thick FF API 0.6 1.9 4.4 2.0
Thin FF API 0.5 1.3 2.3 1.5
GP?API 0.5 1.3 3.0 1.9
table 3: the different exemplary GP/FF altogether particle diameter of suspension distributes
Figure BDA0000457533880000511
The aerosol performance that those are total to suspension composition according to the prepared binary of the present embodiment is measured, and is followed those according to the prepared common suspension composition of embodiment 1, to compare, and wherein measures the method for aerosol performance as described in Example 1.Figure 10 to 12 shows comparative result.According to these figures, can be readily seen that, with binary altogether suspension lenticular Formoterol material used be thick or thin irrelevant, basic identical in the binary common suspension composition that the FF of suspension composition and the particle diameter of GP distribute with embodiment 1 altogether.
In addition, according to the method described in embodiment 1, the common GP of suspension composition of the binary in the present embodiment and the dosage delivered uniformity of FF are measured.Result as shown in figure 13.Binary altogether suspension preparation can provide the DDU characteristic of GP and the FF of expectation because all startup effects can send mean value ± 25% within the dosage of this expectation.
embodiment 5
The application also provides the binary of salmeterol xinafoate (SX) active agent particle and FLUTICASONE PROPIONATE (FP) active agent particle to be total to suspension preparation.FP in propellant and SX are micronized lenticular particles.This micronize active agent particle of two types and spray-dired suspended particulate suspend altogether.
Micronized SX(4-hydroxyl-alpha 1-[[[6-(4-phenyl butoxy) hexyl] ammonia] methyl]-1,3-benzene dimethanol, 1-hydroxyl-2-naphthoic acid ester) be to locate to buy and be used as active agent particle from manufacturer (Inke SA, Germany).Particle diameter by determination of laser diffraction SX distributes.The micronised particles of 50% volume presents the optical diameter that is less than 2 μ m, and the particle of 90% volume presents the optical diameter that is less than 3.9 μ m.
Micronized FP(S-(methyl fluoride) 6 α, 9-bis-fluoro-11 β-17-dihydroxy-16 α-methyl-3-oxo androstane-Isosorbide-5-Nitrae-diene-17 β-thiocarboxylic, 17-propionic ester) from manufacturer (Hovione FarmaCiencia SA, Loures Portugal), locate to buy and be used as active agent particle.Particle diameter by determination of laser diffraction FP distributes.The micronised particles of 50% volume presents the optical diameter that is less than 2.6 μ m, and the particle of 90% volume presents the optical diameter that is less than 6.6 μ m.
Adopt and prepare with the following method suspended particulate: preparation 150mL is used the PFOB(perfluoro bromide octane of the stable water bag fluorine carbon of phosphatide) emulsion.In 100mL hot water (70 ℃), use high-shear mixer to 12.3g phosphatide, DSPC (DSPC) and 1.2g calcium chloride carry out homogeneity processing.In Homogenization, add lentamente 65mL PFOB.Under the pressure up to 140MPa, use the further thick emulsion 3 times of homogenizing gained of high-pressure homogenizer (C3 type, Avestin, Ottawa, CA).
Emulsion is used in nitrogen following spraying drying condition spray dry: 90 ℃ of inlet temperatures, 69 ℃ of outlet temperatures, emulsion feed speed 2.4mL/min, total gas flow rate 498L/min.Use the particle diameter distribution VMD of determination of laser diffraction suspended particulate.The suspended particulate of 50% volume is less than 2.7 μ m, and the geometric standard deviation of distribution is 2.0.In addition, the aerodynamic size by time-of-flight method particle size analyzer mensuration suspended particulate distributes.The suspended particulate of 50% volume has the aerodynamic particle diameter that is less than 1.6 μ m.Greatest differences between aerodynamic particle diameter and optical diameter shows that suspended particulate has the low grain density of <0.5kg/L.This result has also obtained the confirmation of electron microscope, and it shows that suspended particulate has the form of hollow, thin-walled.
Take micronize FP, SX and the suspended particulate of aim parameter, and by they be filled into the 19mL volume applying through fluoroethylene polymer (FEP) aluminium pot (Presspart, Blackburn, UK) thus in make MDI.63 μ l valves for container tank (#BK357, Bespak, King ' s Lynn, UK) are curled to sealing and via valve rod, in overvoltage mode, are loaded 10mL HFA134a(1,1,1,2-HFC-134a) (Ineos Fluor, Lyndhurst, UK).After injecting propellant, the ultrasonic processing of container tank 15 seconds is also vibrated 30 minutes on wrist type shaking table.Container tank disposes the polypropylene starter (#BK636, Bespak, King ' s Lynn, UK) with 0.3mm aperture.After making, according to the method described in embodiment 1, according to USP601, measure aerosol performance immediately.Table 4 has been listed test result.
table 4: the result of the common suspension of FLUTICASONE PROPIONATE in embodiment 5 (FP) and salmeterol xinafoate (SX)
Figure BDA0000457533880000521
Figure BDA0000457533880000531
* do not observe trend
Dosage delivered uniformity in use procedure is measured, wherein all each dosage delivered all mean value ± 20% in, relative standard deviation (also referred to as " RSD ") is 6.1%.By vial, carry out the visualization of common suspension, do not observe active agent particle settlement action has occurred.Suspension occurs lentamente to flocculate and forms uniform single paste layer.
embodiment 6
The combination that the application also provides salmeterol xinafoate (SX) active agent particle and FLUTICASONE PROPIONATE (FP) suspended particulate to form is total to suspension composition.SX in propellant is micronized lenticular particle.It and spray-dired suspended particulate suspend altogether, and wherein this suspended particulate contains the micronize FP being dispersed in those materials that form suspended particulate.For realizing this object, FP crystal is suspended in to those and is used for preparing in the raw material of the suspended particulate based on lipid.The same with described in embodiment 5 of the FP that is used to form active agent particle in the present embodiment and suspended particulate and SX.
Adopt the suspended particulate that preparation contains FP with the following method: preparation 200mL is used the PFOB emulsion of the stable water bag fluorine carbon of phosphatide.By high-shear mixer, 3.3g phosphatide (DSPC) and 0.8g micronize FP and 0.3g calcium chloride dihydrate are dispersed in or are dissolved in 100mL hot water (70 ℃).In dispersion process, add lentamente 44mL PFOB.Under the pressure of 140MPa, use the thick emulsion 3 times of the further homogenizing gained of high-pressure homogenizer.By homogenizing, process the particle diameter of the FP crystal that reduces to suspend.Use following spraying drying condition emulsion to be sprayed dry under nitrogen: 95 ℃ of inlet temperatures; 72 ℃ of outlet temperatures; Emulsion feed speed 2.4mL/min; And total gas flow rate 525L/min.
Take the micronize SX active agent particle of aim parameter and the suspended particulate that contains FP, and by they be filled into the 19mL volume applying through fluoroethylene polymer (FEP) aluminium pot (Presspart, Blackburn, UK) thus in make MDI.63 μ l valves for container tank (#BK357, Bespak, King ' s Lynn, UK) are curled sealing and via valve rod, in overvoltage mode, are loaded 10mLHFA134a(1,1,1,2-HFC-134a) (Ineos Fluor, Lyndhurst, UK).After injecting propellant, the ultrasonic processing of container tank 15 seconds is also vibrated 30 minutes on wrist type shaking table.Container tank disposes the polypropylene starter (#BK636, Bespak, King ' s Lynn, UK) with 0.3mm aperture.After making, according to the method described in embodiment 1, according to USP601, measure aerosol performance immediately.Table 5 has been listed test result.
table 5: the result of salmeterol xinafoate (SX) active agent particle and the common suspension of the suspended particulate that contains FLUTICASONE PROPIONATE.
* there is slight ascendant trend
Dosage delivered uniformity in use procedure is measured, wherein all each dosage delivered all mean value ± 25% in, the RSD of FP is that the RSD of 9.0%, SX is 13%.The visualization of suspension is carried out in vial altogether, does not observe active agent particle settlement action has occurred.By bottle in the situation that not stirring standing 24 hours.Suspension occurs lentamente to flocculate and has formed uniform single paste layer, and this shows that SX, with suspended particulate, separated sign does not occur.
embodiment 7
The application also provides the binary that contains budesonide active agent particle and momestasone furoate active agent particle to be total to the preparation of suspension composition.Budesonide in propellant (BD) and momestasone furoate (MF) are all micronized lenticular particles, and they and spray-dired suspended particulate suspend altogether.
From manufacturer (AARTI, Mumbai, India), locate to obtain micronized BD, 16,17-(butylidene two (oxygen base))-11,21-dihydroxy-, (11-β, 16-α)-pregnant steroid-Isosorbide-5-Nitrae-diene-3,20-diketone, and used as active agent particle.Particle diameter by determination of laser diffraction budesonide distributes.The micronised particles of 50% volume presents the optical diameter that is less than 1.9 μ m, and the particle of 90% volume presents the optical diameter that is less than 4.3 μ m.
From manufacturer (AARTI, Mumbai, India), locate to obtain micronized MF, 9 α, chloro-11 β of 21-bis-, pregnant steroid-Isosorbide-5-Nitrae-diene-3 of Alpha-Methyl, 17-dihydroxy-16,20-diketone 17-(2--furoate), and used as active agent particle.Particle diameter by determination of laser diffraction momestasone furoate distributes.The micronised particles of 50% volume presents the optical diameter that is less than 1.6 μ m, and the particle of 90% volume presents the optical diameter that is less than 3.5 μ m.
Adopt and produce with the following method suspended particulate: preparation 500mL is used the PFOB(perfluoro bromide octane of the stable water bag fluorine carbon of phosphatide) emulsion.In 400mL hot water (75 ℃), use the high-shear mixer 18.7g phosphatide that homogenizes, DSPC(1,2-distearyl acyl group-sn-glycerol-3-phosphocholine) and 1.3g calcium chloride.In Homogenization, add lentamente 100mL PFOB.Under the pressure up to 170MPa, use the further thick emulsion 5 times of homogenizing gained of high-pressure homogenizer (C3 type, Avestin, Ottawa, CA).Use following spraying drying condition emulsion to be sprayed dry under nitrogen: 95 ℃ of inlet temperatures; 72 ℃ of outlet temperatures; Emulsion feed speed 2.4mL/min; And total gas flow rate 498L/min.
Take micronize active agent particle and the suspended particulate of aim parameter, thereby and they are filled in the vial with 15mL volume applying and make MDI.63 μ l valves (Valois, Les Vaudreuil, France) for container tank are curled to sealing and via valve rod, in overvoltage mode, are loaded 9.2g HFA134a(1,1,1,2-HFC-134a) (Ineos Fluor, Lyndhurst, UK).After injecting propellant, the ultrasonic processing of container tank 15 seconds is also vibrated 30 minutes on wrist type shaking table.The suspension concentration of BD active agent particle is 0.8mg/mL, and the suspension concentration of MF is 1.1mg/mL, and the suspension concentration of suspended particulate is 6mg/mL.The ratio of suspended particulate and active agent particle is 7.5 for MF, to be 5.5 for BD.
The visualization result of suspension configuration group shows altogether, and settlement action does not appear in active agent particle.Suspension has occurred to flocculate and has formed paste layer.By bottle in the situation that not stirring standing 16 hours.Any active agent particle is not found in bottom at common suspension bottle.These results show, the dissimilar active agent particle that the budesonide of lenticular and momestasone furoate form, with suspended particulate, association has occurred, thereby form suspension altogether of the present invention.The intensity of the association between active agent particle and suspended particulate is enough to overcome the impact of buoyancy, thereby can successfully suppress the sedimentation of active agent particle.
embodiment 8
The suspended particulate that use contains momestasone furoate (MF) or budesonide (BD) is prepared binary suspension composition altogether, and prepares the MDI that contains said composition.Altogether suspension composition comprises the lenticular Glycopyrrolate (GP) that suspends altogether with the suspended particulate that contains MF or BD and the combination of formoterol fumarate (FF).Every kind of API provides with micronized lenticular material.
Adopt with the following method preparation and contain 50%(w/w) suspended particulate of BD or MF: in 400mL hot water (75 ℃), use the high-shear mixer high shear processing that homogenizes to contain 2.8g DSPC(1; 2-distearyl acyl group-sn-glycerol-3-phosphocholine) and the dispersion of 0.26g calcium chloride, add lentamente 56.6g PFOB simultaneously.By the mass ratio of micronize MF or BD(and DSPC, be 1:1) join in the thick emulsion of gained, further use high-pressure homogenizer (C3 type, Avestin, Ottawa, CA) to homogenize under the pressure up to 170MPa and process 3 to 5 times.Use following spraying drying condition to spray to emulsion dry: inlet temperature 90-95 ℃; Outlet temperature 95-72 ℃; Emulsion feed speed 2-8mL/min; Total dry nitrogen flow velocity 525-850L/min.Particle diameter by determination of laser diffraction gained powder distributes, and the suspended particulate of 50% volume is less than 1.8 μ m, and distribution span is 1.6 μ m.
Use HFA134a propellant to load to include those and contain 50%(w/w) tank of the suspended particulate of MF or BD, make its each startup effect can produce the target dose of 50 μ gMF or 100 μ g BD.According to the method described in embodiment 1, measure aerocolloidal particle diameter and distribute, result is as listed in table 6.Prepare the tank that a series of use is made comparisons, these tanks include those suspended particulates that contain MF or BD and GP and FF active agent particle.The micronize GP of q.s and FF API material are filled in these tanks, and amount of fill is enough to make each startup effect can produce the target dosage delivered of 36 μ g GP and 6 μ g FF.According to method described herein, prepare other blank suspended particulate that does not contain any activating agent (also referred to as " placebo " suspended particulate), and make total suspension concentration reach 5.5mg/mL with its filling tank.
According to the method described in embodiment 1, measure the present embodiment aerosol particle diameter distribution of suspension composition altogether, result is as listed in table 7.Being equal in the dynamic diameter of mass median of the corticosteroid in one pack system suspension and triple combination preparation,, this triple combination preparation is used two kinds of dissimilar active agent particles and is total to it suspended particulate that contains BD or MF suspending and prepares.As the common suspension composition that contains two kinds of different activating agent combinations, according to the present invention, prepared ternary is total to suspension composition and has avoided combined effect.
table 6: the suspension MDI of the HFA134a propellant that contains corticosteroid suspended particulate.The aerosol performance recording by drug specificity cascade impact method, quality air kinetic diameter and minuteness particle mark.
Figure BDA0000457533880000561
table 7: comprise the suspended particulate (momestasone furoate or budesonide), the LAMA(Glycopyrrolate that contain corticosteroid)
With LABA(formoterol fumarate) HFA134a propellant triple combination suspension MDI.By the cascade impact method of the drug specificity measured dynamic diameter of aerosol performance, mass median and minuteness particle mark.
Figure BDA0000457533880000562
Figure BDA0000457533880000571
Added blank suspended particulate
embodiment 9
Prepare ternary of the present invention suspension composition altogether, and prepare the MDI that contains said composition.The combination that composition contains Glycopyrrolate (GP), formoterol fumarate (FF) and momestasone furoate (MF) active agent particle, every kind of activating agent all provides with the form of micronized lenticular API material.
By semi-automatic suspension completion method, prepare ternary suspension altogether.The ternary active pharmaceutical ingredient that suspension forms three kinds of microcrystalline form of three kinds of different activities agent particles by those altogether forms: MF(corticosteroid); GP(LAMA); And FF(LABA).Suspended particulate in the active agent particle of this three types and HFA134a propellant suspends altogether.This ternary is total to suspension preparation to be become can provide following target dosage delivered: each startup effect produces 50 μ g MF; Each startup effect produces 36 μ g GP; And each startup effect produces 4.8 μ g FF.Except the common suspension of ternary, also prepared the common suspension of monotherapy that only contains MF.Monotherapy MF altogether suspension is included in propellant the MF active agent particle suspending altogether with suspended particulate described in the present embodiment, and the target dosage delivered that can provide each startup effect to produce 50 μ g MF is provided.
Suspended particulate is prepared by spray-dried emulsion; material concentration is 80mg/mL; this emulsion is to contain 93.44% DSPC(1,2-distearyl acyl group-sn-glycerol-3-phosphocholine) with the composition (DSPC:CaCl that is equivalent to mol ratio 2:1 of 6.56% anhydrous calcium chloride 2).In emulsion preparation process, by DSPC and CaCl 2high-shear mixer by 8000-10000rpm is dispersed in the container that contains hot water (80 ± 3 ℃), in this process kind, adds lentamente PFOB.Then emulsion is processed 5 times in high-pressure homogenizer (10000-25000psi).Then by emulsion by disposing 0.42 " the spray dryer of atomizer nozzle with the atomizer air-flow of 18SCFM, spray and is dried.The rate setting of dry gas stream is 72SCFM, and inlet temperature is 135 ℃, and outlet temperature is 70 ℃, and emulsion flow velocity is 58mL/min.
For preparation MDI, according to using in the following manner medicine to add container (DAV), load suspension: first add the suspended particulate of half amount, then load crystallite material, finally add the suspended particulate that remains half amount to top.In the humidity of <10%RH, control environment and lower material is joined in container.Then DAV is connected with 4L suspension container, uses HFA134a propellant to rinse, and then mix with magnetic stirring bar.In the production process of whole batch, all the temperature in container is maintained to 21-23 ℃.After recycle 30min, by 50 μ LEPDM valves, slurry compositions is filled in container tank.The random shuttle tank that is used for all container tank determination tests of selecting is to guarantee correct amount of formulation.Before starting product property analysis, first the ternary of new system is total to suspension MDI batch of isolation one week.Adopt similar suspension loading method to prepare the MDI that only contains momestasone furoate.
According to the method for embodiment 1, adopt the initial particle of all crystallite API of determination of laser diffraction to distribute, result is as listed in table 9.According to the method described in embodiment 1, adopt drug specificity cascade impact method to measure the aerodynamic size of all components when starting suspension MDI and distribute and the dynamic diameter of mass median, result is as listed in table 9.
table 9: the ternary crystallite in HFA134a propellant MDI is suspension altogether.The initial particle recording by laser diffractometry (Sympatec) distributes.
Figure BDA0000457533880000581
table 10: the corticosteroid that contains microcrystalline form (momestasone furoate), LABA(formoterol fumarate) and LAMA(Glycopyrrolate) HFA134a propellant ternary suspension MDI altogether.The dynamic diameter of aerosol performance, mass median and the minuteness particle mark that (NGI) method records impacted in cascade by drug specificity.
Figure BDA0000457533880000582
The ternary of according to the method described in embodiment 1 being prepared by the present embodiment altogether aerosol performance and the dosage delivered uniformity of suspension is assessed.Figure 14 shows two container tank that only contain MF and two GP, FF that realize according to the prepared container tank that contains MF, GP and FF of the present embodiment and the DDU of MF.The DDU of the MF that MF monotherapy configuration group is sent is equal to the DDU of the ternary MF that suspension composition is realized altogether.The ternary of also being prepared by the present embodiment altogether suspension composition compares at aerosol aspect of performance with those combination preparations that contain two kinds of activating agent FF and GP.As shown in Figure 15 and 16, the FF that the composition that contains two kinds of activating agents is sent with the composition that contains three kinds of activating agents and the aerodynamic size of GP distribute and are equal to mutually respectively.
The common suspension composition that contains two kinds of different activities agent combinations as those, according to the present invention, prepared ternary is total to suspension composition and has avoided combined effect.
embodiment 10
The metered dose inhaler that preparation is total to suspension composition and contains said composition according to exemplary ternary of the present invention.Ternary altogether suspension comprises Glycopyrrolate (GP) or TB (TB) with the combination of formoterol fumarate (FF) and momestasone furoate (MF) activating agent, and every kind of API used provides with micronized lenticular material form.
The suspension MDI of two different batches of preparation, it contains three kinds of active constituents of medicine (API): corticoid, LAMA and LABA.API provides with the form of crystallite material, and its form with active agent particle suspends altogether with the prepared suspended particulate of the present invention.Thereby active agent particle and suspended particulate are joined to the ternary that makes in HFA134a propellant described in the present embodiment suspension composition altogether.
The common suspension (ternary GFM) of the ternary of first batch is mixed with to each startup effect and can sends following dosage: 40 μ g MF; 13 μ g GP; And 4.8 μ g FF.Active agent particle suspends altogether with suspended particulate, and wherein suspended particulate is by dry the contain 93.46%DSPC(1,2-distearyl acyl group-sn-glycerol-3-phosphocholine of spraying) and the emulsion of 6.54% anhydrous calcium chloride prepare, material concentration is 80mg/mL.DSPC:CaCl in suspended particulate 2mol ratio be 2:1.Suspended particulate and activating agent are combined in propellant, thereby preparation obtains the preparation that concentration of suspended particles is 6mg/mL.According to the method described in embodiment 1, by Sympatec laser diffraction method, measure the initial particle of crystallite active agent particle, result is as shown in table 11.
Use different LAMA API, anhydrous Tiotropium Bromide (TB) thus replace GP and prepare the ternary of second batch suspend altogether (TFM).The ternary of second batch is total to suspension preparation becomes each startup effect can send following dosage: 50 μ g MF; 9 μ g TB; And 4.8 μ g FF.According to ternary GFM, be total to method used in suspension and prepare suspended particulate, make active agent particle follow suspended particulate to suspend altogether, wherein the concentration of suspended particulate in suspension is 6mg/mL.According to the method described in embodiment 1, adopt Sympatec laser diffraction method to measure the initial particle of crystallite active agent particle, result is as listed in table 12.
Adopt ternary GFM and ternary TFM to be total to suspension composition and prepare MDI, according to the method described in embodiment 1, measure aerosol performance, minuteness particle mark and the dynamic diameter of mass median.Table 13 has been listed MMAD and the FPF performance of ternary GFM and ternary TFM, and Figure 17 shows the aerosol performance (showing respectively the dynamic particle diameter distribution that ternary GFM and ternary TFM realize) of ternary GFM and the ternary TFM expectation that suspension is realized altogether.
table 11: the initial particle of the ternary GFM recording by laser diffraction (Sympatec) method distributes.
table 12: the initial particle of the ternary TFM recording by laser diffraction (Sympatec) method distributes.
Figure BDA0000457533880000602
table 13: the ternary GFM recording by drug specificity cascade impact and the dynamic diameter of aerosol performance, mass median and the minuteness particle mark of ternary TFM
embodiment 11
Prepare exemplary binary of the present invention suspension composition altogether, and preparation contains this binary MDI of suspension composition altogether.The combination that composition comprises Glycopyrrolate (GP) and formoterol fumarate (FF), wherein every kind of activating agent all provides with the form of micronized lenticular material, and its particle diameter distributes as listed in table 14.The GP of microcrystalline form and FF material provide the active agent particle of two types, and suspended particulate is prepared according to the method described in embodiment 4.When the binary described in preparing the present embodiment is total to suspension, GP active agent particle, FF active agent particle and suspended particulate are combined in HFA134a propellant.
By first appropriate micronize GP and FF active agent particle and suspended particulate being distributed to medicine that inside has humidity control room (RH<5%) adds container (DAV) thus in make binary described in the present embodiment suspension altogether.Then DAV is sealed and is connected under nitrogen the suspension container that contains 12kg HFA-134a.Subsequently 0.5-1kg HFA-134a is joined to DAV, thereby then it is shifted out from suspension container and carry out gentle rotation, form paste.Then paste is transferred back in suspension mixer and with HFA-134a and is diluted, thereby carry out gentle stirring by agitator arm, form the final suspension with aimed concn.Then suspension is recycled in fill system via pump with the shortest time before starting filling.In whole filling process, continue to mix and recycle.Valve is arranged in MDI container tank, then by the curling method of vacuum or HFA-134a douche, removes air, carry out subsequently the curling processing of valve.By valve, appropriate suspension is filled in the container tank of curling subsequently, can regulates with hopper.
table 14: the particle diameter of Glycopyrrolate and formoterol fumarate distributes.
Title d 10(μm) d 50(μm) d 90(μm) Span
FF?API 0.6 1.9 4.1 1.8
GP?API 0.5 1.3 3.0 1.9
By first appropriate micronize Glycopyrrolate and formoterol fumarate crystal and suspended particulate being filled into medicine that inside has humidity control room (RH<5%) adds container (DAV) thus in make pressure filling suspension.In the present embodiment, by three equal parts mode, add suspended particulate carrier, after adding for the first time and for the second time, add GP and FF respectively.DAV is sealed and is connected in the suspension container that contains 12kg HFA-134a under nitrogen.Subsequently 0.5-1kg HFA-134a is joined to DAV, thereby then it is shifted out and carry out gentle rotation from suspension container, form paste.Then paste is transferred back in suspension mixer and with HFA-134a and is diluted, thereby carry out gentle stirring by agitator arm, form the final suspension with aimed concn.Then suspension is recycled in fill system via pump with the shortest time before starting filling.In whole filling process, continue to mix and recycle.Valve is arranged in container tank, then by the curling method of vacuum or HFA-134a douche, removes air, carry out subsequently the curling processing of valve.By valve, appropriate suspension is filled in the container tank of curling subsequently, can regulates with hopper.
The MDI that preparation contains the common suspension of binary described in the present embodiment, it contains respectively GP and the FF of two kinds of various dose.Particularly, the common suspension composition of first batch of binary making at every turn startup effect can produce 18 μ g GP and 4.8 μ g FF(" low dosage "), the common suspension composition of second batch of binary making at every turn startup effect can produce 36 μ g GP and each startup effect 4.8 μ g FF(" high dose ").Except binary is total to suspension composition, also prepared monotherapy FF and GP suspension composition altogether.Except only containing the active agent particle (GP or FF) of a type, the preparation method of the common suspension composition of monotherapy is with binary suspension composition the same altogether.By monotherapy altogether suspension and monotherapy MDI be mixed with following target dosage delivered can be provided: each startup effect 18 μ g GP, each startup effect 0.5,1.0,3.6 or 4.8 μ g FF.Composition and MDI that each startup effect produces 0.5 μ g FF and 1 μ g FF are called as " ultralow " dosage.
The aerodynamics distribution of sizes of the drug specificity that the MDI of the common suspension composition that contains the present embodiment according to the method mensuration described in embodiment 1 realizes.Figure 18 shows, the ratio of the GP aerodynamics distribution of sizes that the common suspension of binary of low dosage and high dose is realized, and the equivalence between binary and the common suspension of monotherapy.In an identical manner, Figure 19 shows the ratio of the binary that contains ultra low-volume, low dosage and high dose composition and the monotherapy FF aerodynamics distribution of sizes that suspension is realized altogether.
According to the method described in embodiment 1, measure the dosage delivered uniformity of ultra low-volume FF monotherapy MDI.Figure 20 shows those to be had each startup effect and produces the composition of 1 μ g and 0.5 μ g FF and the MDI that system realizes.Even if also can realize desired dosage under ultra low-volume, send uniformity.
embodiment 12
In clinical testing, assessed by metered dose inhaler (MDI) and given safety, validity and the PK performance of the combination of suspension composition altogether of the present invention.The described combination of suspension composition altogether contains Glycopyrrolate and formoterol fumarate.Described clinical testing is to suffer from moderate to random, the double blinding of carrying out in the patient of very serious chronic obstructive pulmonary disease (COPD), customization, non-equilibrium, incomplete district group, intersection, multicenter study.By the combination of two kinds of different common suspension compositions as herein described and placebo and four kinds of active positive control compositions only sending one of two kinds of activating agents that the combination of described composition comprises compare.
Two kinds of combinations of the common suspension composition comprising in described clinical research comprise Glycopyrrolate (GP) and formoterol fumarate (FF) activating agent of sending with fixed Combination.Substantially as described in Example 4, described GP and FF active agent particle provide with micronize, crystalline GP and FF raw material form in the preparation of the described combination of suspension altogether, and described suspended particulate is to comprise DSPC and CaCl 2spray-dried granules, described suspension media is formed by HFA134a.As described herein, the described combination of suspension composition altogether that preparation is sent to patient by MDI, and be made into GP and the FF activating agent of being convenient to give two kinds of various dose.By described first suspend altogether combination composition make MDI at every turn startup effect to patient, send 36 μ g GP and 4.8 μ g FF, and for giving patient 72 μ g GP and 9.6 μ g FF(every days twice every day for twice, give twice MDI startup effect).In the present embodiment and accompanying drawing, also described the first composition and treatment are called to " GP/FF72/9.6 " and " GP/FF72/9.6 treatment ".By described second suspend altogether combination composition make MDI at every turn startup effect to patient, send 18 μ g GP and 4.8 μ g FF, and for giving patient 36 μ g GP and 9.6 μ g FF(every days twice every day for twice, give twice MDI startup effect).In the present embodiment and accompanying drawing, also described the second composition and treatment are called to " GP/FF36/9.6 " and " GP/FF36/9.6 treatment ".
Using described GP/FF72/9.6 and GP/FF36/9.6 treatment and placebo with contain one of FF, GP or Tiotropium Bromide and compare as five kinds of single-activity agent different active compounds.The first composition is active control, Si Lihua inhalator (Tiotropium Bromide suction pulvis).Si Lihua is a kind of Diskus (DPI) product, gives patient every day once, and each DPI capsule comprises the Tiotropium Bromide of 18 μ g dosage.The second composition F oradil Aerolizer(formoterol fumarate sucks pulvis) be also a kind of active control.Foradil is also DPI product, but gives patient twice its every day, and each DPI capsule comprises the FF of 12 μ g dosage.The third composition is only to contain GP as the common suspension composition of activating agent.Single therapy GP is total to suspension composition (GP36) and makes the product to pulmonary delivery by MDI, and be administered twice every day, the GP of 36 μ g dosage is sent in each administration to patient.All the other two kinds of compositions are two kinds of different only common suspension compositions (FF9.6 and FF7.2) of single therapy as activating agent containing FF.By the FF of single therapy altogether suspension composition make the product to pulmonary delivery by MDI, and be administered twice every day, the FF(FF9.6 of 9.6 μ g dosage is sent in each administration to patient) or the FF(FF7.2 of 7.2 μ g dosage).Use micronize, crystalline GP or FF material as active agent particle, comprise DSPC and CaCl 2spray-dried granules as suspended particulate and HFA134a, as suspension media, prepare GP and FF single therapy suspension composition altogether.
118 patients were included at random in to research and gave seminar's compound within 7 day time period.Treatment the 7th day, assess every patient and giving each seminar's compound FEV after 12 hours 1improvement situation, and calculate the FEV provide at 12 hours Duan Neige seminar compounds 1tG-AUC (AUC with respect to the improvement situation of basic value 0-12).AUC in the time for the treatment of the 7th day (the 7th day) 0-12main terminal as research.Secondary endpoints be included in the 1st day and the compound administration of the 7th Tian Ge seminar after FEV 1peak change (peak FEV 1), after long term administration in continuous 7 days but before administration in the 7th day patient's paddy FEV 1(early morning paddy FEV 1) and safety evaluation.Described two kinds of GP/FF altogether suspension composition are safe with well-tolerated.
When treatment the 1st day (the 1st day), compare with basic value>=12%FEV 1patient's the percentage improving and the ratio of this type of improvement are referring to Figure 21.As shown in figure 21, GP/FF72/9.6 and GP/FF36/9.6 treatment provide cumulative acknowledgements and initial rate are significantly higher than cumulative acknowledgements and the initial rate that Si Lihua provides.Compare with the active compound only with single-activity agent, in the time of the 7th day, GP/FF72/9.6 and GP/FF36/9.6 treatment provide the higher FEV with respect to basic value 1change (seeing Figure 22-Figure 24).
For main terminal, GP/FF72/9.6 and GP/FF36/9.6 are better than all positive controls.Figure 25 has shown and has compared the FEV that in the time of the 7th day GP/FF72/9.6, GP/FF36/9.6 and each active positive control are realized with placebo 1aUC 0-12improvement.As shown in figure 25, compare with each positive control composition, in the time of the 7th day, GP/FF72/9.6 and GP/FF36/9.6 provide obviously better FEV 1aUC 0-12improve the FEV that in the time of the 7th day, GP/FF72/9.6 and GP/FF36/9.6 provide 1aUC 0-12improve than each positive control composition height 80ml at least.As shown in figure 26, FEV the 7th day time 1aUC 0-12difference further outstanding, for example compare the FEV that GP/FF36/9.6 composition provides the 7th day time with GP36, FF9.6, Si Lihua and Foradil positive control 1aUC 0-12improvement more obvious.
The FEV that uses GP/FF72/9.6 treatment to provide 1aUC 0-12improve point in contrast, when Figure 32 has shown the 7th day GP/FF36/9.6 and each positive control all patients, suffer from the patient of moderate COPD and suffer from the FEV that severe extremely provides in the patient of severe COPD 1aUC 0-12improve percentage.The result showing in Figure 32 shows: regardless of the order of severity of COPD, replying of patient is consistent.
For the secondary endpoints of research, GP/FF72/9.6 and GP/FF36/9.6 are also better than other all positive controls.Peak FEV shown in Figure 27 1show administration the 1st day during with the 7th day each activity research composition the variation all providing with respect to basic value is provided with placebo.As shown in figure 27, when the 1st day and the 7th day, GP/FF72/9.6 and GP/FF36/9.6 provide better peak FEV 1.Figure 28 has given prominence to when the 1st day and the 7th day, compares the peak FEV that GP/FF72/9.6 and GP/FF36/9.6 provide with Si Lihua with Foradil 1improvement.Figure 29 has shown with placebo and has compared, the paddy FEV in early morning that GP/FF72/9.6, GP/FF36/9.6 and each active positive control provide 1improvement.By reference to Figure 29, can easily understand, by two kinds of better FEV that the combination of suspension provides altogether 1increase can maintain a period of time better, compares with other active positive controls, and GP/FF72/9.6 and GP/FF36/9.6 composition are to paddy FEV in early morning 1approximately 50% improvement is provided.
Figure 30 has shown the front FEV of administration in the 7th day that GP/FF72/9.6 and GP/FF36/9.6 provide 1increase and the administration in the 7th day that provides of GP36, FF9.6, Si Lihua and Foradil positive control before FEV 1increase between difference.By reference to Figure 30, can easily understand, compare with GP36, FF9.6, Si Lihua and Foradil positive control, GP/FF36/9.6 treats the FEV before administration in the 7th day 1obviously higher improvement is provided.
Except specific research secondary endpoints, also assessed the improvement of respiratory capacity (IC).When the 1st day and the 7th day, the IC that GP/FF72/9.6 and GP/FF36/9.6 provide increases all higher than each positive control.For the patient of use GP/FF72/9.6, GP/FF36/9.6 and Si Lihua, Figure 31 has shown that the IC peak occurring in the time of the 1st day improves (the 1st day peak), the patient's who still keeps before specific testing combination administration in the 7th day IC improves (before administration in the 7th day), and the IC peak that patient occurs after particular composition administration in the 7th day improves (the 7th day peak).

Claims (61)

1. in patient, treat a method for PUD D or illness, described method comprises:
Pharmaceutically acceptable suspension is altogether provided, and described suspension altogether comprises:
The suspension media that contains pharmaceutically acceptable propellant;
Two or more activating agents;
The sucked active agent particle of one or more types; With
The sucked suspended particulate of one or more types, wherein said active agent particle is combined in suspension media, to form suspension altogether with suspended particulate; With
By described altogether suspension, with the form of the aerosol that can suck, give described patient, wherein saidly give described suspension altogether and comprise two or more bioactive agent deliveries for the treatment of effective dose are delivered to described patient.
2. method according to claim 1, wherein providing pharmaceutically acceptable suspension altogether to comprise provides the common suspension that comprises two or more activating agents, wherein said activating agent to be selected from fugitive beta-agonists, long-acting and super long effective β 23 adrenergic receptor agonists (LABA), corticosteroid, antiinflammatory agent, antitussive, bronchodilators, muscarinic antagonist and long-acting muscarinic antagonist (LAMA) activating agent, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate.
3. method according to claim 2, wherein said PUD D or illness are selected from asthma, COPD, chronic bronchitis, pulmonary emphysema, bronchiectasis, allergic rhinitis, nasosinusitis, lung vessel retraction, inflammation, allergy, respiratory disorder, Respiratory Distress Syndrome(RDS), pulmonary hypertension, lung vessel retraction, the lung inflammation relevant to cystic fibrosis and at least one in blocking of relevant lung with cystic fibrosis.
4. method according to claim 3, wherein providing pharmaceutically acceptable suspension altogether to comprise provides a kind of suspension altogether, in the suspended particulate of described at least one type in described suspension altogether, at least one comprises activating agent, and described two or more activating agents are selected from LAMA activating agent, it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; LABA activating agent, the derivative β of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl 2activator; And corticosteroid activating agent, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
5. method according to claim 3, wherein providing pharmaceutically acceptable suspension altogether to comprise provides a kind of suspension altogether, described suspension altogether comprises at least two kinds of dissimilar active agent particles, each of the active agent particle of described at least two types includes different activating agents, and described different activating agent is selected from LAMA activating agent, it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; LABA activating agent, the derivative β of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl 2activator; And corticosteroid activating agent, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
6. method according to claim 5, wherein providing pharmaceutically acceptable suspension altogether to comprise provides a kind of suspension altogether, described suspension altogether comprises at least three kinds of dissimilar active agent particles, each of the active agent particle of described at least three types includes different activating agents, and described different activating agent is selected from LAMA activating agent, it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; LABA activating agent, the derivative β of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl 2activator; And corticosteroid activating agent, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
7. method according to claim 3, wherein providing pharmaceutically acceptable suspension altogether to comprise provides a kind of suspension altogether, described suspension altogether comprises at least two kinds of dissimilar active agent particles, each of the active agent particle of described at least two types includes different activating agents, at least one in the suspended particulate of described at least one type comprises the third activating agent, and described different activating agent is selected from LAMA activating agent, it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; LABA activating agent, the derivative β of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl 2activator; And corticosteroid activating agent, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
8. method according to claim 3, the wherein said bioactive agent delivery by two or more treatment effective dosies is given patient and is comprised the following activating agent of delivery treatments effective dose simultaneously: LAMA activating agent, and it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; And LABA activating agent, the derivative β of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl 2activator, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
9. method according to claim 3, the wherein said bioactive agent delivery by two or more treatment effective dosies is given patient and is comprised the following activating agent of delivery treatments effective dose simultaneously: LAMA activating agent, and it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; And corticosteroid, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
10. method according to claim 3, the wherein said bioactive agent delivery by two or more treatment effective dosies is given patient and is comprised the following activating agent of delivery treatments effective dose simultaneously: LABA activating agent, the derivative β2agonists of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl; And corticosteroid, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
11. methods according to claim 3, the wherein said bioactive agent delivery by two or more treatment effective dosies is given patient and is comprised the following activating agent of delivery treatments effective dose simultaneously: LAMA activating agent, and it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping; LABA activating agent, the derivative β2agonists of adamantyl that it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149 and contains saligenin or indyl; And corticosteroid, it is selected from beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, methylprednisolone, Mometasone, metacortandracin and triamcinolone, comprises any its pharmaceutically acceptable salt, ester, isomer or solvate.
12. 1 kinds according to the method described in claim 1 to 11 any one, wherein gives described in patient the FEV that suspension altogether makes patient 1there is the remarkable increase on clinical meaning.
13. methods according to claim 12, wherein give described in patient suspension altogether and within a period of time, make FEV 1increase at least 150mL, described a period of time is selected from 0.5 hour or shorter time, 1 hour or shorter time and 1.5 hours or shorter time.
14. methods according to claim 13, wherein give described in patient suspension altogether and within a period of time, make FEV 1increase at least 200mL, described a period of time is selected from 0.5 hour or shorter time, 1 hour or shorter time and 1.5 hours or shorter time.
15. methods according to claim 14, wherein give described in patient suspension altogether and within a period of time, make FEV 1increase at least 250mL, described a period of time is selected from 0.5 hour or shorter time, 1 hour or shorter time and 1.5 hours or shorter time.
16. methods according to claim 15, wherein give described in patient suspension altogether and within a period of time, make FEV 1increase at least 300mL, described a period of time is selected from 0.5 hour or shorter time, 1 hour or shorter time and 1.5 hours or shorter time.
17. methods according to claim 16, wherein give described in patient suspension altogether and within a period of time, make FEV 1increase at least 350mL, described a period of time be selected from 0.5 hour or shorter, 1 hour or shorter and 1.5 hours or shorter.
18. 1 kinds according to the method described in claim 1 to 17 any one, wherein by giving to be total to the FEV that suspension makes patient described in patient 1being significantly increased on clinical meaning occurs and in a period of time, maintain the significance on clinical meaning, wherein said a period of time is selected from up to 4 hours, up to 6 hours, up to 8 hours, up to 10 hours with up to 12 hours or longer.
19. 1 kinds according to the method described in claim 1 to 17 any one, wherein gives described in patient suspension altogether and makes 50% or more patient FEV within a period of time 1increase by 10% or more than, wherein said a period of time be selected from 0.5 hour or shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours.
20. 1 kinds according to the method described in claim 1 to 17 any one, wherein gives described in patient suspension altogether and makes 60% or more patient FEV within a period of time 1increase by 10% or more than, wherein said a period of time be selected from 0.5 hour or shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours.
21. 1 kinds according to the method described in claim 1 to 17 any one, wherein gives described in patient altogether suspension and makes in 70% or more patient FEV within a period of time 1increase by 10% or more than, wherein said a period of time be selected from 0.5 hour or shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours.
22. 1 kinds according to the method described in claim 1 to 17 any one, wherein gives described in patient altogether suspension and makes in 80% or more patient FEV within a period of time 1increase by 10% or more than, wherein said a period of time be selected from 0.5 hour or shorter, 1 hour or shorter, 1.5 hours or shorter and 2 hours.
23. 1 kinds according to the method described in claim 1 to 11 any one, wherein gives described in patient the FEV that suspension altogether makes patient 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least.
24. 1 kinds according to the method described in claim 1 to 11 any one, wherein gives described in patient the FEV that suspension altogether makes patient within a period of time 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least, wherein said a period of time be selected from 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter.
25. methods according to claim 24, wherein at least 50% patient's FEV within a period of time 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least, wherein said a period of time be selected from 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter.
26. methods according to claim 25, wherein at least 60% patient's FEV within a period of time 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least, wherein said a period of time be selected from 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter.
27. methods according to claim 24, wherein at least 70% patient's FEV within a period of time 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least, wherein said a period of time be selected from 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter.
28. methods according to claim 24, wherein at least 80% patient's FEV within a period of time 1from basic value increase 200ml at least, or from basic value, increase by 12% or more and FEV 1total recruitment 150ml at least, wherein said a period of time be selected from 1 hour or shorter, 1.5 hours or shorter, 2 hours or shorter and 2.5 hours or shorter.
29. 1 kinds according to the method described in claim 1 to 28 any one, wherein by giving to be total to the FEV that suspension makes patient described in patient 1there is the remarkable increase on clinical meaning, and the FEV significantly increasing on described clinical meaning 1it is the remarkable improvement of only sending beyond the increase that the composition of one of described two or more activating agents provides.
30. methods according to claim 29, wherein said FEV 1be significantly improved as 70ml or higher.
31. methods according to claim 30, wherein said FEV 1be significantly improved as 80ml or higher.
32. methods according to claim 31, wherein said FEV 1be significantly improved as 90ml or higher.
33. 1 kinds according to the method described in claim 30 to 32 any one, and wherein said remarkable improvement is according to peak F EV 1improvement measure.
34. 1 kinds according to the method described in claim 30 to 32 any one, and wherein said remarkable improvement is according to FEV 1aUC 0-12improvement measure.
35. 1 kinds according to the method described in claims 1 to 34 any one, wherein gives described in patient suspension altogether and makes gulp capacity (IC) that the remarkable increase on clinical meaning occur.
36. methods according to claim 35, significantly increasing on clinical meaning occurs wherein said IC increases 100ml or more.
37. methods according to claim 36, significantly increasing on clinical meaning occurs wherein said IC increases 200ml or more.
38. according to the method described in claim 37, and significantly increasing on clinical meaning occurs wherein said IC increases 300ml or more.
39. according to the method described in claim 38, and significantly increasing on clinical meaning occurs wherein said IC increases 350ml or more.
40. according to the method described in claim 35 to 39 any one, wherein said IC occur on clinical meaning be significantly increased in 2 hours or shorter time reaches.
41. according to the method described in claim 35 to 40 any one, wherein said IC occur on clinical meaning be significantly increased in 1 hour or shorter time reaches.
42. 1 kinds according to the method described in aforementioned any one claim, wherein with what comprise propellant, can inhalation aerosol form provide and be included in the described suspension media in described suspension altogether, described propellant is selected from HFA propellant, PFC propellant and combination thereof, and described propellant does not basically contain other compositions.
43. 1 kinds according to the method described in aforementioned any one claim, wherein with what substantially formed by propellant, can inhalation aerosol form provide and be included in the described suspension media in described suspension altogether, described propellant is selected from HFA propellant, PFC propellant and combination thereof, and described propellant does not basically contain other compositions.
44. 1 kinds according to the method described in aforementioned any one claim, wherein can inhalation aerosol form providing and be included in described two or more activating agents in described suspension altogether, described activating agent is selected from LAMA activating agent, it is selected from Glycopyrrolate, enlightening Xipi sieve Nimes, Tiotropium Bromide, trospium chloride, aclidinium bromide and Da Tuoping, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate, with LABA activating agent, it is selected from bambuterol, clenbuterol, Formoterol, salmeterol, Carmoxirole, rice water sieve, QAB-149, and containing the derivative β of adamantyl of saligenin or indyl 2activator, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate, and with what comprise excipient, can inhalation aerosol form provide and be included in the described respirable suspended particulate in described suspension altogether, described excipient is selected from least one in lipid, phosphatide, nonionic detergent, polymer, non-ionic block copolymer, surfactant, non-ionic surface active agent, biocompatible fluorinated surfactant, carbohydrate and combination thereof.
45. according to the method described in claim 44, and the wherein said suspended particulate that sucks comprises porous microstructure.
46. according to the method one of claim 44 and 45 Suo Shu, and the wherein said suspended particulate that sucks comprises DSPC and calcium chloride.
47. according to the method described in claim 42 to 46 any one, wherein can inhalation aerosol form to provide and at least 50% the active agent particle being by volume included in described suspension altogether that gives has 5 μ m or less optical diameter.
48. 1 kinds according to the method described in aforementioned any one claim, wherein, can inhalation aerosol form to provide and the described suspended particulate that sucks being included in described suspension altogether that gives is included in described suspension media, the concentration of described suspended particulate in described suspension media is selected from about 1mg/ml to about 15mg/ml, about 3mg/ml to about 10mg/ml, about 5mg/ml to about 8mg/ml and about 6mg/ml.
49. 1 kinds according to the method described in aforementioned any one claim, wherein can inhalation aerosol form to provide and the described MMAD that sucks suspended particulate being included in described suspension altogether that gives is selected from approximately 10 μ m to about 500nm, approximately 5 μ m to about 750nm, approximately 1 μ m to approximately 3 μ m.
50. 1 kinds according to the method described in aforementioned any one claim, wherein can inhalation aerosol form to provide and the described volume intermediate value optical diameter that sucks suspended particulate in described suspension altogether of being included in that gives is selected from approximately 0.2 μ m to approximately 50 μ m, approximately 0.5 μ m to approximately 15 μ m, approximately 1.5 μ m to approximately 10 μ m and approximately 2 μ m to approximately 5 μ m.
51. 1 kinds according to the method described in aforementioned any one claim, and the ratio that wherein can suck the gross mass of suspended particulate and the gross mass of at least one type active agent particle is selected from higher than approximately 1.5, up to approximately 5, up to approximately 10, up to approximately 15, up to approximately 17, up to approximately 20, up to approximately 30, up to approximately 40, up to approximately 50, up to approximately 60, up to approximately 75, up to approximately 100, up to approximately 150 with up to approximately 200.
52. 1 kinds according to the method described in aforementioned any one claim, and the ratio of the gross mass of the gross mass of wherein said at least one type suspended particulate and at least one type active agent particle is selected from about 3:1 to about 15:1 and about 2:1 to 8:1.
53. 1 kinds according to the method described in aforementioned any one claim, even if be wherein subject to being selected from 1g at least, at least 10g, 50g and at least during centrifugal the amplified buoyancy of the acceleration of 100g acceleration at least, with can inhalation aerosol form provide and being included in of giving described in described suspension altogether sucks suspended particulate and active agent particle still can maintain and mutually combine.
54. 1 kinds according to the method described in aforementioned any one claim, wherein with can inhalation aerosol form provide and give be included in the active agent particle that described active agent particle in described suspension altogether comprises the first type and the second type, the active agent particle of described the first type comprises Glycopyrrolate, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate, and the active agent particle of described the second type comprises Formoterol, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate.
55. according to the method described in claim 54, and the active agent particle of wherein said the first type comprises that the active agent particle of Glycopyrrolate crystal and described the second type comprises Formoterol crystal.
56. according to the method described in claim 54, wherein with can inhalation aerosol form provide and the described suspension altogether that gives substantially by the HFA propellant that does not basically contain other compositions, two kinds of activating agents that provide with the active agent particle of the first and the second type and the sucked suspended particulate being formed by phosphatide excipient form, wherein said two kinds of activating agents provide with the active agent particle of the first and the second type, the active agent particle of described the first type comprises Glycopyrrolate crystal, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate, and the active agent particle of described the second type comprises Formoterol, comprise any its pharmaceutically acceptable salt, ester, isomer or solvate.
57. 1 kinds according to the method described in aforementioned any one claim, wherein by MDI, is provided and give described pharmaceutically acceptable suspension altogether.
58. 1 kinds according to the method described in claim 44 to 57 any one, wherein by described altogether suspension can inhalation aerosol form giving patient, comprise that giving described in patient suspension altogether reaches every day twice, and comprise at every turn and send the LAMA activating agent that is no more than 150 μ g and the LABA activating agent that is no more than 12 μ g.
59. 1 kinds according to the method described in claim 44 to 58 any one, wherein by described altogether suspension can inhalation aerosol form giving patient, comprise that giving described in patient suspension altogether reaches every day twice, and each administration comprises and sends the LAMA activating agent that is no more than 100 μ g and the LABA activating agent that is no more than 12 μ g.
60. 1 kinds according to the method described in claim 44 to 59 any one, wherein using described suspension altogether as giving patient by inhalation aerosol, comprise that giving described in patient suspension altogether reaches every day twice, and comprise at every turn and send the LAMA activating agent that is no more than 80 μ g and the LABA activating agent that is no more than 12 μ g.
61. 1 kinds according to the method described in claim 44 to 60 any one, wherein using described suspension altogether as giving patient by inhalation aerosol, comprise that giving described in patient suspension altogether reaches every day twice, and comprise at every turn and send the LAMA activating agent that is no more than 50 μ g and the LABA activating agent that is no more than 12 μ g.
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