CN101336118B - Manifold for use in medicament dispenser - Google Patents

Abstract

There is provided a manifold (450) for use in a medicament dispenser device for the delivery of medicament powder from an open blister pocket (404a,b) of a blister pack (400a,b). The manifold comprises a body, said body defining a chimney (452) having a chimney inlet (453) and a chimney exit (454a,b) for directing airflow (485) from said chimney inlet to said chimney exit; the body further defining a chamber (460) having a chamber inlet (473a,b) and a chamber exit (474). The chimney exit and said chamber inlet lie side-by-side each other such that when said open blister pocket of said blister pack is positioned adjacent thereto said airflow (485) may be directed from the chimney exit to the chamber inlet via the open blister pocket to entrain said medicament powder and enable transport thereof in the airflow from the chamber inlet to said chamber exit. One or more bleed holes are provided between the chimney and the chamber such that bleed airflow may be directed into the chamber to disruptively impact the airflow that transports the entrained medicament powder.

Description

For the manifold of pill dispenser

Related application

The application requires the priority of the UK patent application No.0525237.4 of December in 2005 submission on the 12nd and the UK patent application No.0 623 405.8 of submission on November 23rd, 2006, and its full content is incorporated herein by reference.

Technical field

The present invention relates to a kind of manifold (manifold) being suitable in pill dispenser, it is for distributing for example dry medication powder from the pharmaceutical carrier of blister package (blister pack) form.This manifold helps effectively to discharge the drug powder sucking for patient, and for example, the interface (mouthpiece) from the blister pouch (blister pocket) of opening to allotter, thus for patient's suction.

Background of invention

It is well-known in drug administration, using suction apparatus, for example, in bronchiectasic treatment.This device generally comprises a housing (body) or shell (housing), and pharmaceutical carrier position in the inner.Known suction apparatus comprise those wherein pharmaceutical carrier be to contain a lot of blister pouch to surround the blister package of medicine of dry powder form.This device generally comprises a kind of machinery that takes out drug dose by opening one or more blister pouch.This machinery for example comprises perforating tool or exfoliation tool, to peel off cover plate (lidsheet) from the substrate (base sheet) of blister package.Then the medicine of powdered is discharged for patient and sucks transmission from the blister pouch of opening.

The suction apparatus of the above-mentioned type comprises the element that is commonly referred to manifold, the powder that it is wherein comprised with release for air-flow being directed to the blister pouch of one or more opening, the interface that the powder that then guiding discharges sucks to patient.Should be clear that the feature of manifold is for guaranteeing that it is important effectively discharging powder and guiding powder to the interface discharging subsequently.

The applicant knows that the shape of manifold can affect the character of the particle volume of discharged drug powder at present, and known these character are very important to medicine.Specifically, the applicant understands fine particle mark and can be subject to the impact of the shape of manifold.As known in the art, " fine particle mark " or FP mark are often referred to the percentage ratio of the particle of " absorbable " volume in the atomization medicine of given dose.The shape of wishing manifold can be brought into play such as the effect of FP mark that increases the powder discharging, and makes to be easy to suck into patient at seam.

The applicant now also knows the impact that the performance (the FP mark of the drug powder that for example distributed) of manifold can be arranged by chamber, and the drug powder discharging is transported (in air-flow, being transported) to seam by this chamber.More particularly, the clear chamber that arranges of existing the applicant for example, to promote that the fragmentation (disaggregation or de-agglomerate) that is delivered to this drug powder being discharged by it is useful.

According to an aspect of the present invention, provide a kind of manifold, it has the chimney with chimney (chimney) air inlet and chimney gas outlet, and with the chamber of chamber air inlet and chamber gas outlet.In use, all air-flows that enter manifold all pass through chimney air inlet.The gas outlet of chimney and the import of chamber are adjacent to each other, thereby while making the adjacent place, open blister bag position of the blister package that contains drug powder, at least part of air-flow can be passed through to open blister bag from chimney gas outlet guiding chamber air inlet, to produce described drug powder and to make medicine be transported to chamber gas outlet from chamber air inlet in air-flow.For promoting the fragmentation of drug powder, one or more steam vent can be provided between chimney and chamber, make by indoor the air-flow introduction chamber of discharging, with disruptiveness, to clash into the air-flow that transports the drug powder being transmitted.

Therefore, be understandable that in use, the total air flow " separation " entering in the chimney of manifold can be become be directed to open blister bag to transport the part of drug powder and to be directed to the part by one or more steam vent as air-out.An advantage of manifold of the present invention is that it can be regulated the percentage ratio of determining the total air flow that forms these " separation " each several parts well, therefore can regulate preferably the performance of manifold.

The manifold in the previous field of having described (comprises early stage patent open WO98/30262, WO98/11929, WO02/102,444, US-A-2,587,215, US-A-5,383,850, EP-A-1,106,196, WO94/08552, WO94/11044, US-A-5,590, those that describe in 645 and US-A-5,113,855) comprise the steam vent to chamber or interface element.The manifold in these previous fields is designed to discharge the air of emitting by air intlet, and this air intlet directly communicate with external environment (directly communicating with extraneous air).

Summary of the invention

According to an aspect of the present invention, it provides a kind of manifold for drugs distribution apparatus, and it is for transmitting the drug powder of open blister bag of blister package, and this manifold comprises

A kind of housing (body),

This housing limits a kind of chimney with chimney air inlet and chimney gas outlet, and it is for guiding air-flow to flow to chimney gas outlet from described chimney air inlet;

This housing also limits a kind of chamber with chamber air inlet and chamber gas outlet,

Wherein said chimney gas outlet and chamber air inlet are each other side by side, thereby make when the open blister bag of described blister package is positioned at place located adjacent one another, chamber air inlet can lead by open blister bag air-flow from chimney gas outlet, with by drug powder transmission and make medicine be transported to chamber gas outlet from chamber air inlet in air-flow

And one or more steam vent is wherein provided between chimney and chamber, makes by indoor the air-flow introduction chamber of discharging, with disruptiveness, to clash into the air-flow that transports the drug powder being transmitted.

The invention provides a kind of manifold being suitable in drugs distribution apparatus, this device is used for the drug powder of the open blister bag that transmits blister package.

Therefore, the present invention also provides the drugs distribution apparatus of the drug powder in a kind of open blister bag that is suitable for transmitting blister package, this distributor comprises a kind of shell, a kind of distribution machinery in this shell, this machinery is for distributing the drug powder in the open blister bag of received blister package, and manifold as above.

Described manifold comprises a housing, and it generally determines size and shape by drugs distribution apparatus, and it generally comprises a kind of componentry.Manifold itself can be used as single, complete element or is included as accessory (sub-assembly) or part adjacent element (adjacent component), and is generally formed as a kind of molded parts.

In every respect, manifold and drugs distribution apparatus or the parts that separate that combine or respectively do for oneself.On the one hand, manifold is provided as the discerptible buckle of one (snap-fit) element of drugs distribution apparatus, and the manifold providing and/or drugs distribution apparatus have the snap features (being for example positioned on this distributor housing) that can adjust this pattern.

Centre position between applicable interface and the opening that manifold is arranged in to the medicine for transmitting patient's suction, make to be accepted by drugs distribution apparatus, the open blister bag (at this place, can extract and transport medicine) of blister package is provided to manifold in this position.Be applicable to providing a kind of manifold with buckle characteristic, make buckle can be applicable to interface, to form a kind of buckle-type manifold and interface auxiliary device (mouthpiece sub-assembly).

Manifold body limits a kind of chimney with chimney air inlet and chimney gas outlet.In use, air is passed chimney air inlet suction (result for example sucking as patient), produces therein air-flow.The effect of chimney is by the air-flow guiding chimney gas outlet of chimney air inlet.

Manifold body also limits a kind of chamber with chamber air inlet and chamber gas outlet.The drug powder (see below) of air and wherein delivery can be drawn into chamber gas outlet by chamber air inlet.Interface is generally positioned near chamber gas outlet.In one embodiment, the manifold body part of restriction chamber gas outlet and interface comprises a kind of shared element.

Chimney gas outlet and chamber air inlet position be adjacent to each other (contiguous or close), make when the open blister bag of this blister package is positioned at its vicinity, air-flow can be passed through to the blister pouch of opening from the import of chimney gas outlet guiding chamber, to transport its drug powder.Therefore, can, in air-flow, from the chamber gas outlet of chamber air inlet, transmit the drug particles producing like this.

Manifold can limit more than one chimney gas outlet and chamber air inlet, does like this and generally makes designed manifold use together with drugs distribution apparatus, to divide medicine from more than one open blister bag simultaneously.Generally provide a chimney gas outlet and a chamber air inlet of position adjacency to distribute the powder in each open blister bag.

On the one hand, manifold is suitable in drugs distribution apparatus herein, this drugs distribution apparatus is for transmitting from the drug powder of open blister bag of each of multiple blister packages, this manifold comprises multipair chimney gas outlet and chamber air inlet, described each to being associated with the open blister bag of one of described multiple blister packages.Therefore, for example, at the preferred drugs distribution apparatus herein arranging for distributing the powder in pair of openings blister pouch, this is associated with single long band shape blister pouch to each, provides and has a pair of manifold of the chimney gas outlet of adjacency and relevant chamber air inlet separately each other.

In every respect, the geometry of design manifold makes the total air flow that only has part to enter manifold by chimney air inlet be conducted through chimney gas outlet to the blister pouch of opening.Be applicable to 3-50%, preferably 5-25%, more preferably the total air flow of 15-25% (for example approximately 20%) is conducted through chimney gas outlet to the blister pouch of opening, thus, by chamber air inlet, enters chamber.Be 97-50%, preferably 95-75%, more preferably the total air flow of 85-75% (for example approximately 80%) is conducted through one or more steam vent and enters chamber.

In an embodiment of the present invention, wherein manifold and two blister packages are used, as those described in reference to the following drawings, in use, 80% or approximately 80% the total air flow that enters manifold chimney (by chimney air inlet) is through steam vent, and all the other are by the blister pouch of opening.

Manifold is applicable in drugs distribution apparatus herein, wherein the air-breathing generation air-flow of patient air-flow is emitted and passed through manifold.Design manifold is herein used with the patient's (as asthma) who is applicable to have relative poor respiration capability with drugs distribution apparatus.Typical asthmatic patient can reach an about 30-100 liter/min flow velocity and pass through drugs distribution apparatus.

Described manifold is to entering the general air-flow of 60 liters/min of chimney, and the gas-flow resistance generally providing is 1-5kPa (for example 2-3kPa), and under this flow velocity, about 10% air-flow is directed to and passes through open-bag.The air-flow that enters chimney also can change, and is generally 30-100 liter/min.

Should be clear that in use, the achievable pressure drop of patient and flow velocity depend on the level of gas-flow resistance and patient's the respiration capability (Repiration power) of manifold and/or drugs distribution apparatus.As from understanding following description, especially can control with one or more steam vent wherein providing the gas-flow resistance of whole manifold.

The gas-flow resistance of concrete manifold and/or drugs distribution apparatus can by flow velocity (liter/min) square root that removes pressure drop (kPa) finds.The low-flow resistance of general preferred manifold and/or drugs distribution apparatus, reason is that it can make patient deeply breathe, thus by drug particles transmission (as transmitted from distributor) in lung.

Should be clear that being accurately oriented in to a certain extent of chimney gas outlet and chamber air inlet determined by the shape of blister pouch, and determined by the desired function of transmission (function) of the drug powder granule in the air-flow in guiding blister pouch.On the one hand, described open blister bag generally has a kind of long oval shape, and the position of chimney gas outlet and chamber air inlet side by side, and in use they are positioned on two relative tops of long avette open-bag side (profile).

What will also be understood that is that the shape and size of chimney gas outlet and chamber air inlet are determined by the shape of blister pouch to a certain extent, and is determined by the desired function of transmission of the drug particles in the air-flow by blister pouch.Found that the cross sectional area that reduces chimney gas outlet and chamber air inlet can improve FP mark performance, its gas-flow resistance increasing take loss is as cost, and may reduce the emptying performance of bag.On the one hand, chimney gas outlet and chamber air inlet are defined as annular substantially, and diameter 1-7mm, is in particular 2-5mm.Also design the shape of the other side of chimney gas outlet and chamber air inlet, comprise ovum shape, rectangle, rectangle and crescent with round edge.

Be applicable to that the chimney of manifold of the present invention is arranged in to open blister bag and sentence just generation turbulent flow in air-flow.That is, arrange chimney, make in use at open blister bag place, to occur turbulent airflow.Found that the air flow energy of this turbulent flow helps to transmit the drug powder content of open blister bag, thereby and helped the drug powder content in emptying bag.

On the one hand, turbulent flow produces the result of the creation that is shear stress, and its help transmits drug powder by air-flow.Shear stress is generally defined as the normal average velocity gradient to airflow direction.Therefore, shearing force region (" shearing force ") is the region wherein in relatively short distance with relatively large velocity gradient.

The applicant thinks that the existence of this turbulent flow may be particularly useful for wherein the situation that comprises non-sticky powdery components (being for example non-sticky or only loose combination, i.e. non-poly-attached property component) in drug powder.Can use the Carr index of knowing quantitatively by the cohesiveness of the particular powder that manifold and drugs distribution apparatus transmit herein.Measure the method for Carr index describes in following list of references: Carr, R L (1965) Chem Eng 72 (1) p 162, Carr, R L (1965) Chem Eng72 (2) p 69 and pharmaceutics: dosage form science (Pharmaceutics:The Science of DosageForm) (1988) Ed.Aulton, M E, Churchill Livingstone, New York.

In one aspect of the invention, turbulent flow is at open blister bag place by provide multiple chimneys gas outlet to produce to this chimney, and each outlet is all directed to air-flow the blister pouch place of opening.One concrete aspect, described multiple chimneys gas outlet is positioned at and is made in original place, multiple jet-impingement mouths guiding for example can be produced, on turbulent flow (shearing force) interactive position each other in use.Be suitable for that described multiple chimneys gas outlet (and multiple air-flow spouts) is thus placed in to an angle respect to one another (θ) and locate, wherein θ is generally 150 °-30 °, preferably 120 °-60 °.

In another aspect of this invention, by the moulding of chimney and/or chimney gas outlet, at open blister bag place, create turbulent flow, to produce non-linear air-flow.One concrete aspect, by chimney and/or the moulding of chimney gas outlet, to produce, there is fixing turbulent helical form (as swirl shape) air-flow.

In another aspect of this invention, within barrier is positioned to chimney and/or place, chimney gas outlet, creates non-linear air-flow with breaking property.In another aspect of this invention, within chimney and/or place, chimney gas outlet crosspiece (cross-piece) or separator (for example edge of a knife shape) are provided, to rupture air-flow the regions of turbulent flow of shearing force is provided.

Applicable arrangement is the chimney of manifold herein, makes to create acceleration or deceleration region in the air-flow at open blister bag place.That is, arrange chimney to make in use, at open blister bag place, occur the air-flow of acceleration or deceleration.The air-flow (no matter whether turbulent) of these acceleration or decelerations helps to transmit the drug powder content of open blister bag, and helps thus the drug powder content in emptying bag.

Chimney gas outlet and chamber air inlet can comprise one or more simple opening (being hole) or optionally separately, in some aspects, can provide some feature to it, be included in its one or two opening parts a kind of " crosspiece (cross-piece) " (for example cross) is provided.

Be applicable to by the chimney of manifold and chamber each other side by side or each other the crown arrange, to help to meet, following demand (i) chimney gas outlet and chamber air inlet are settled each other side by side and (ii) between chimney and chamber, provide one or more steam vent, as more described in detail at this.

Manifold of the present invention provides and by chamber, through air-flow, from chamber air inlet to chamber gas outlet, transmits the drug powder transmitting.Between chimney and chamber, provide one or more to get rid of hole (or passage/path), make by indoor the air-flow introduction chamber of discharging, with disruptiveness, to clash into the air-flow that transports the drug powder being transmitted.The existence of one or more steam vent of this location improves whole performance (for example FP mark performance) of this manifold.

The air-flow of emitting specifically, is of value to and promotes to pulverize the interior drug powder transmitting of (for example disaggregation or desorb collection) chamber.Specifically, transmitted drug powder is exposed to the region by the different pressures that introducing exhaust stream produces from chimney to chamber, can helps to promote that in chamber, desired drug powder is pulverized.

Drug powder for example comprises, in cohesive powders composition (comprising the granule that is easy to combine with one another, wherein particle agglomeration) therein, and the facilitation of this fragmentation may be useful especially.

On common (and as between separator (divider)) wall of chimney and chamber, be applicable to providing one or more steam vent.Chimney and chamber are applicable to sharing a partition, and on this total wall, provide in one or more steam vent at least one or all.

Described one or more steam vent generally has 1-35mm ²total area of section (cross-sectional area that all steam vents are added together), preferably 10-30mm ², most preferably 15-25mm ².Described one or more steam vent can limit any applicable shape, comprises ellipse, annular, D-shape and long trough (elongate slot).

On the one hand, described one or more steam vent is annular or oval, and each steam vent has the diameter of 1-7mm, particularly 2-5mm.On the other hand, described one or more steam vent is D-shape, and has the maximum gauge of 1-10mm, preferably 3-7mm.On the other hand, described one or more steam vent comprises or consists of elongate slots, has the length of 1-20mm, preferably 3-10mm, the width of 0.5-3mm, preferably 0.7-2mm.

One concrete aspect, two rectangular flute profile steam vents arranging with parallel mode are provided between chimney and chamber.Preferably described parallel rectangular flute profile steam vent and chamber indoor air stream are arranged in parallel.

On the one hand, one or more steam vent providing is close to (approaching) in chimney gas outlet and/or chamber air inlet.

On the other hand, described one or more steam vent separates with chimney gas outlet and/or chamber air inlet.Usually, the spacing of one or more steam vent and chamber air inlet be chamber air inlet at least 10% of the measured chamber length in chamber gas outlet, preferably at least 20%, more preferably at least 30%.

On the one hand, described one or more steam vent is directed to chamber wall, and therefore, contiguous this wall produces the region of this shearing force, and causes particle and the collision of this wall.Preferably the whole geometry of chamber is arranged, make lead these shearing force regions and/or cause and the collision of wall of air-flow.By lead another advantage of menifold wall of evacuating air, be that prophylactic agent granule deposits thereon.

When multiple steam vent is provided, be applicable to them lead each other, the aerofluxus that obtains is sprayed interact with each other, creation shearing force region.Preferably, arranging the overall geometry of chamber makes air-flow these shearing force regions of leading.

In use, be applicable to described one or more steam vent to lead one or more air port to clash at least one inner surface of chamber, under the air draught flow velocity of 60 liters/min to enter chimney, produce there the shearing force region that at least one is greater than 3Pa.

In use, be applicable to by described at least one shearing force region indoor the drug powder directed cavity in bag, to break the particulate component of any agglomeration.

In use, at least one region of described shearing force is suitable for reducing the deposition of powder on the inner surface of described at least one chamber.

Be understood that and provide these one or more steam vents can also make gas-flow resistance reduce, reason is that a certain proportion of air-flow (as being originally sucked into chimney) is not sucked into the blister pouch of crossing opening.Therefore the steam vent, providing can affect the emptying effect of the open blister bag of its drug substance contents potentially.Therefore must clash into by one or more steam vent (broken useful in chamber on powder) being provided and reducing gas-flow resistance (and it is emptying to affect bag) and produce the relief area (compromise) of accelerating between flow area.As universal law, manifold gas-flow resistance should be reduced to wherein to the level of the emptying level of weakening bag under 30 liters/min of minimum flow velocities that enter chimney.

The manifold of the present invention of generally arranging makes to enter the 3-50% of chimney air inlet, preferably 5-25%, and more preferably the air-flow of 15-25% (for example approximately 20%) is guided through chimney gas outlet in open blister bag.Therefore, remaining air-flow (for example approximately 80%) is not directed in open blister bag, but enters in chamber by one or more steam vent.In general, for the weak powder of viscosity, require powder that specific viscosity is stronger to import in bag air-flow still less.

In this paper each side, regulate the size of manifold and/or the position of any entrance, outlet and/or one or more steam vent, in use to reach desired by flow level and/or gas-flow resistance and/or the shear stress level in manifold of bag.Be understood that these adjustings should consider caking property or other character of the drug powder of passed through manifold.

In addition, if arrange geometric position and the shape of chamber, make it the region that can create high difference power (for example shearing force) own, also can further promote the fragmentation of powder in chamber.If the diameter of chamber and/or shape with its length adaptability change the approach of definite air-flow (along) and make air-flow and the powder that flows through this that transmits is easy to collide chamber wall, can create applicable shearing force region.The collision of these and wall is shearing force region (being that high velocity air is to low speed flow) all the time, reason be the speed of air-flow at wall place actual be zero.

On the other hand, if arrangement chamber makes to produce therein the flow area of acceleration or deceleration, also can in chamber, further promote the fragmentation of powder.That is,, if the powder of air-flow and transmission experience flows through the region of the acceleration or deceleration air-flow of chamber, can promote the fragmentation of powder.Preferably the whole geometry position of chamber is arranged, make the air-flow of the delivery particle that transmits be directed to the region of these acceleration air-flows.

Be understood that in use, in manifold, whether the existence of acceleration or deceleration air-flow can be determined according to the geometry of patient's suction or manifold.Therefore, patient's suction, relates to the variation from being drawn onto slowly fast suction, will cause accelerating " patient creates " region of air-flow.On the other hand, cause obtaining desirable acceleration flow area in the contiguous geometry of the manifold of mobile flow area (for any patient's suction) at a slow speed that produces of flow area of fast moving.In addition, the manifold having such as the feature of air flap (flaps) or valve can be provided, it opens under particular airflow pressure, creates thus from (being that air flap or valve are closed) of 0 air-flow to " acceleration " that allow air-flow (being that air flap or valve are opened).

In use, be applicable to arranging manifold to improve the effect of user suction, thus the acceleration of experiencing while increasing the interior powder aerosolization of blister pouch.

In use, be applicable to arranging manifold to improve the effect of user suction, thus the acceleration of powder experience when increase powder moves from blister pouch to patient by chamber.

For example, if the cross fault area of chamber (diameter) reduces in the flow direction, can suitably create the tendency for the enhancing of given patient's suction, to produce acceleration flow area.Be understood that: less cross-sectional area will mean that, for given flow velocity, air has higher speed.Therefore, for the acceleration of given suction, will correspondingly increase.

For example, if the arrangement of the cross fault area of chamber (diameter) changes with diameter, (along the air flow path limiting) for example narrows along its length, make to flow through this air-flow and the powder of delivery runs into narrower cross section, or along its length broaden (along limit air flow path), make to flow through this air-flow and the powder of delivery runs into wider cross section, the suitable region of acceleration or deceleration air-flow also can produce at manifold place so.

Any this reduction that is understood that chamber cross-sectional area also will cause the increase of gas-flow resistance, therefore, can affect potentially the emptying efficiency of drug substance contents in open blister bag.Therefore must clash into by reducing chamber cross-sectional area (being of value to powder pulverizes) and increasing gas-flow resistance (and impact bag is emptying effectively) and produce the relief area between the region of accelerating air-flow.

On the one hand, the diameter of annular compartment narrows to the approximately 5-8mm of chamber gas outlet end at the approximately 14-16mm of chamber air inlet end.

On the other hand, the diameter of chamber is the approximately 5-7mm (with respect to the approximately 14-16mm of normal dia) that crosses over whole length.

On the other hand, if arrange chamber, make to set up therein mechanical obstacles, also can further promote that the powder in chamber is pulverized.That is,, if the powder of air-flow/delivery experiences mechanical obstacles when flowing through chamber, promote powder to pulverize.

The applicable mechanical obstacles that can offer chamber comprises or is comprised of dividing plate, stirring vane, oar, wheel blade and venturi baffle plate (venturi) form.In addition, chamber itself can be fixed to the shape (for example, with the surperficial indentation limiting or outstanding) of the feature that mechanical obstacles can be provided.

If arrange manifold, make to postpone the emptying of the interior drug powder content of blister pouch, can further strengthen the performance of manifold.

On the one hand, the amount that this delay can be flow through the air of open blister bag by reduction reaches.But this reduction must be too unobvious, reason is being emptied completely of drug substance contents that can hinder open blister bag by the air-flow of blister pouch deficiency.This reduction of the air-flow by open blister bag can, by providing being positioned on the position that makes " shunting " open-bag air-flow, provide with the manifold of one or more steam vent and realize.

When arranging manifold to make to postpone the emptying of drug powder content in blister pouch, for example, until create in the region of the difference power (shearing force/acceleration air) that can cause that powder pulverizes, can strengthen the performance of manifold in chamber.If bag is emptying too early, pulverized powder will pass through this region before setting up completely in high difference power region, and therefore, by guaranteeing more powder experience shearing force region, postponing emptying blister pouch will improve the performance of manifold.

Applicable arrangement manifold herein makes to postpone the emptying of the interior drug powder content of blister pouch, until realize the predetermined flow velocity through air pressure in manifold chamber (just not passing through blister pouch) by the patient who sucks.When by the valve accurate adjustment of predetermined flow velocity, the value of General Requirements between 5-45 liter/min, preferably 20-30 liter/min.

Herein manifold ideally all effect be to take this for strengthening the uniformity of drug dose transmitted.

Ideally, manifold all acts on as strengthening the discharging amount (ED) for the made drug powder that patient sucks, chamber gas outlet/seam provides herein.ED is generally by for example collecting total quantitative determination of the medicated powder of emitting in described distributor, and for example using dosage sampler, as dosage uniform sampling device (DUSA).Also ED can be expressed as in the concrete blister pouch that therefrom discharges medicated powder, contain the percentage ratio (%ED) of the dosage of measuring (MD).Therefore, in this case, %ED is calculated as to (ED/MD) × 100%.Require %ED to be at least 95% weight, preferably exceed 98% weight.

Ideally, manifold effect is herein still for strengthening the FP mark of the made drug powder that suck, that chamber gas outlet/seam provides for patient.

Term " the fine particle mark of institute's releasing dosage " or FP mark (ED) refer to compare with always emitting dosage, have the percentage ratio of the particle of " can suck " big or small aerosolized medicaments in given releasing dosage.Particle size scope that it is generally acknowledged 1-6 μ m has " can suck " size.Therefore, FP mark (ED) can be calculated as to the percentage ratio of institute's discharging amount (ED).Therefore, in this case, FP mark (ED) is calculated as to (FPF/ED) × 100%.Require FP mark (ED) that 25% weight of the discharging amount of the made particle providing at chamber gas outlet/seam is provided, preferably exceed 30% weight.

Also FP mark can be defined as in the concrete blister pouch that therefrom discharges medicated powder, contain the percentage ratio of the dosage of measuring (MD).Therefore, in this case, FP mark (MD) is calculated as to (FPF/MD) × 100%.Require FP mark (MD) to be at least 25% weight, preferably exceed 30% weight.

Manifold of the present invention generally provides (as its componentry) to drugs distribution apparatus, and it is arranged to receive the blister package with one or more blister pouch that contains dry powder form medicine.

Described drugs distribution apparatus is applicable to comprising a kind of shell can with any applicable shape or profile.A kind of preferred form is to have shell-like shell, and it is by two and half shell Matching installations are formed, and it can or hinge in together or optionally half is completely separation with second half.This shell can be formed by any applicable material, but the most typically comprises a kind of plastic polymer material, and this material is relatively solid, but is also easy to manufacture by volume manufacture process.

Suitably, on shell, provide air intake.It generally takes the form that is applicable to shape and big or small hole to offer on the wall of this shell.Be applicable to air intake to be positioned in certain position place, this position is not generally covered or seals by the finger of user and/or thumb in its normal use procedure.Grid or other style that air intake is applicable to protected property at least partly cover, and its effect is pre-anti-blocking and/or entering of undesirable dust and other fume minimized.

Suitably, provide a kind of by the distribution medication device of shell enclosure, it is for distributing from the drug powder of the open blister bag of inferior at least one blister package accepted of mat.The details of applicable distributor is provided by description subsequently.Relevant to described distributor and exchange (be fluid/air stream exchange) with air intake, a kind of manifold of the present invention is provided.

Suitably, provide drugs distribution apparatus, so that air-flow, by the air intake on shell, is attracted separately in the chimney of manifold.That is, all air-flows that enter manifold all so carry out by air intake and the chimney of manifold.

Therefore, in this use procedure, patient sucks by interface, in menifold, produce negative pressure, it makes air suck by air intake from the outside of distributor, and by chimney air inlet, enter in the chimney of menifold, described chimney air inlet and air intake are linked up (for example arranged side by side) in mobility.Then, air-flow is directed to chamber air inlet by open blister bag from chimney gas outlet at least partly, to transport the drug powder content in blister pouch.

Patient, use in the suction process of this distributor, unique entrance that air intake preferably provides air flow to enter drugs distribution apparatus, particularly enters in the open blister bag of described blister package.Therefore, be suitable for no longer providing other air intake or other air intlet point on described shell, shell itself wherein provides a kind of relative aeroseal barrier for extraneous air enters by any other method.

The cross-sectional area that offers the air intake of the shell of described drugs distribution apparatus is applicable to being greater than the cross-sectional area of (for example at least 1.5 times, preferably 2 times) manifold any part, and the air of coming in will experience (catchment) in manifold.Therefore, the cross-sectional area of air intake is applicable to being greater than any cross-sectional area of described chimney; Total cross-sectional area of chimney gas outlet and one or more steam vent; And the cross-sectional area of chamber.This principle is that air intake can not be compressed, otherwise the character of the air flow of impact by described distributor, therefore all controls of air flow (and air pressure etc.) all come from geometry and the layout (comprising the cross-sectional area of selecting any manifold part) of manifold.

In one aspect, multiple blister pouch that described blister package comprises the medicine for containing (containment) dry powder form.Generally blister pouch is arranged in to the rule format that is easy to therefrom discharge medicine.Blister pouch can have any applicable shape, comprises square, circular, ellipse or rectangle.

The concrete form of blister pouch, comprises shape and cross-sectional area, affects the character of air-flow, and especially air-flow resistance and when patient sucks by manifold the pressure decreased of open-bag place experience.

For example, in blister pouch, the exemplary dosage of drug powder is 17 μ l.If this bag is balled form, for adapting to this dosage, it should have 1.7mm radius and 8.0mm ²cross-sectional area.

Pass through 8.0mm ²the 60l/min flow rate of area is equal to the Mean Speed of 125m/s.The pressure drop that this flow rate causes will be approximately equal to:

$\mathrm{\ΔP}=\frac{{\mathrm{K\ρ\υ}}^2}{2}$

(wherein ρ=atmospheric density=1.3kg/m ³, V=average speed=125m/s and K=geometrical factor).

For the cross-sectional area sudden contraction from large to 8.0mm ², K=0.5 (approximately), this pressure drop will be 5.1kP.For from 8.0mm ²sudden enlargement is to large cross-sectional area K=1 (approximately), and this pressure drop will be 10.2kPa.

Therefore, there is 8.0mm ²entrance and 8.0mm ²the geometry of the bag of outlet will have the resistance of 15.3kPa under 60 liters/min.

Resistance=√ (the 15.3)/60=0.065 (kPa) of bag ^0.5min/l, for the pressure drop of 2kPa, flow rate=√ (2)/0.065=22l/min, this is total flow rate about 1/3.

The blister pouch of Diskus (trade mark) equipment of selling at the GlaxoSmithKline PIc that is suitable for knowing and the equipment of following detailed description, medicated powder is stretched (not being spherical) by more, and the cross-sectional area of bag is 4mm ²region, the Mean Speed under 60 liters/min is 250m/s.

For a simple import-outlet system (as implied above), at 60 liters/min, locating pressure drop is 61.2kPa, and resistance is 0.130 (kPa) ^0.5minute/liter, the flow rate of 2kPa pressure drop is 11 liters/min (flows of 18%).For the blister pouch of the Diskus that is applicable to know (trade mark) equipment, resistance will be approximately 0.15 (kPa) ^0.5minute/liter, the flow rate of 2kPa pressure drop is 9.4 liters/min (60 liters/min of flows 16%).

On the one hand, multiple dose blister package is included in multiple blister pouch of generally arranging with ring form in dish-like blister package.An example that is suitable for the drugs distribution apparatus that distributes the drug powder in this dish-like blister package is famous Diskhaler (trade mark) equipment of being sold by GlaxoSmithKline PIc.

On the other hand, blister package is microscler, for example, comprise bar shaped or band shape.Preferably blister package is limited between two parts can peeling off safely each other.The United States Patent(USP) Nos. 5,860,419,5,873,360 and 5,590 of Ge Lan element company limited, 645 have described the drug packages of this universal class.In aspect this, this device has the operating board of an opening conventionally, and it comprises the exfoliation tool of each several part being peeled off to obtain each drug dose.

Suitably, it is microscler lamella situation that described drugs distribution apparatus is suitable for working as peelable part, and it limits the multiple medicament reservoirs that are spaced along its length, and the index instrument for the each container of index successively (indexing) is provided on this device.More preferably, it is to have therein the substrate of multiple bags that described drugs distribution apparatus is suitable for a wherein lamella, and another layer is cover plate, each bag and closing on of cover plate define a described container separately, and this drugs distribution apparatus comprises the manipulation tool that cover plate and substrate are pulled open on open operating board.An example of such drugs distribution apparatus is Diskus (trade mark) equipment that the GlaxoSmithKline PIc. that knows sells.

On the one hand, the drug packages of bubble-cap form comprises

(a) substrate, wherein forms bubble-cap to limit wherein each bag, and each bag comprises a kind of powdery pharmaceutical preparation sucking;

(b) cover plate, it seals the substrate except bubble-cap region, and can be from the strip off of substrate mechanicalness to can discharge the described powdery pharmaceutical preparation that can suck,

Wherein said substrate and/or described cover plate have the structure of layering, and it comprises (a) ground floor aluminum paper tinsel; (b) polymeric material of second layer 10-60 micron thick.

The generally sealing each other on its whole width by substrate and cover plate, except fore-end, does not generally seal them each other completely at front end.Therefore, at the end of band, present substrate and the cover plate of the separation of forward end part.

Polymeric material is applicable to having the 0.6g/ of being less than (100 inches at 25 ℃ ²) water vapour permeability of (24 hours) (milliliter).This vapor permeation sexual compatibility is measured by ASTM experimental technique no.ASTM E96-635 (E).

Suitably, described polymeric material comprises and is selected from following material: polypropylene (for example orientation or cast form; Standard or metallocene); Polyethylene (for example high and low or middle density form); Polrvinyl chloride (PVC); Polyvinylidene chloride (PVDC); Polytrifluorochloroethylene (PCTFE); Cyclic olefine copolymer (COC); And cyclic olefin polymer (COP).

Cover plate is applicable to comprising at least following pantostrat: (a) ply of paper; It is connected in (b) plastic sheeting; It is connected in (c) aluminium foil.

Aluminium foil is generally used to one deck (for example heat-sealing paint of combined base; Thin film or extruding cover) cover.

The thickness of each layer of cover plate can character as requested be selected, but is generally 5-200 micron, particularly 10-50 micron.

In one aspect, plastic layer is applicable to being selected from polyester (astaticism, single shaft or biaxially oriented), polyamide, polypropylene or PVC.On the other hand, plastic foil is a kind of oriented plastic thin film, is applicable to being selected from oriented polyamide (OPA); Oriented polyester (OPET); And oriented polypropylene (OPP).The thickness of plastic layer is generally 5-40 μ m, especially 10-30 μ m.

The thickness of aluminium lamination is generally 10-60 μ m, and especially 15-50 μ m, as 20-30 μ m.

In every respect, described ply of paper comprises paper/extruded layer, and optional lamination (laminated) is on aluminum.

One concrete aspect in, cover plate comprises at least following pantostrat: (a) ply of paper; It is connected in (b) polyester layer; It is connected in (c) aluminum paper tinsel; Its heat-sealing enamelled coating that is used to combined base applies.The thickness of each layer can character as requested be selected, but is generally 5-200 micron, particularly 10-50 micron.

In every respect, described combination for example can be cohesiveness, in conjunction with (bonding based on solvent, wherein solvent is organic or water-based solvent); Solvent-free cohesiveness combination; The combination of extruding laminarity; Or hot calender.

Substrate is applicable to comprising at least following pantostrat: (a) oriented polyamide (OPA); Its adhesiveness is connected in (b) aluminum paper tinsel; It is the 3rd layer of 10-60 micron that its adhesiveness is connected in thickness that (c) comprise a kind of polymeric material.Polymeric material preferably has (100 inches of the 0.6g/ of being less than at 25 ℃ ²) water vapour permeability of (24 hours) (milliliter).Be combined with cover plate for the 3rd layer, it is processed with heat-sealing paint conventionally.

The thickness of the each non-polymeric layer of substrate can be selected according to desired character, but is generally 5-200 micron, particularly 20-60 micron.In the present invention, the thickness of selective polymerization layer enters to reduce dampness, thereby is 10-60 micron, particularly 25-45 micron, preferably 30-40 micron.

Described polymeric material is applicable to being selected from: polypropylene (for example orientation or casting type (cast form); Standard or metallocene); Polrvinyl chloride (PVC); Polyethylene (for example high and low or middle density form); Polyvinylidene chloride (PVDC); Polytrifluorochloroethylene (PCTFE); Cyclic olefine copolymer (COC); With cycloolefin polymer (COP).Optionally also there is other layer material.

Can use various known technology to connect cover plate and substrate, thus sealed blister.These methods comprise adhesive bond, the welding of radiation frequency, ultra-sonic welded and hot bar sealing (hot barsealing).

Substrate is particularly useful for forming by " cold form " method herein, and it carries out under than the low temperature of conventional method (for example, close to room temperature).The medicine that this " cold form " method comprises in described bubble-cap or pharmaceutical preparation have special purposes in the situation that of having thermal sensitivity (heat sensitive) (as degraded or degeneration under heating).

Described blister package is suitable for the pill dispenser of involved manifold of the present invention to be accepted, and described manifold also comprises a kind of shell of accepting this packing.On the one hand, pill dispenser has overall form, and shell is wherein integrated.On the other hand, configuration pill dispenser receives one and fills up cassette (cassette) again, and shell forms the part of filling up again cassette.

Be applicable to the inside sizing of shell or optionally provide specifically instructing feature, suitably to guide the drug packages of bubble-cap form to enter in this shell.Specifically, this guidance should be able to guarantee by blister package fitness the position of be positioned to interact with the internal mechanical of shell (for example index and open machinery).

Described drugs distribution apparatus fitness has a kind of internal mechanical device, its different dry-powder medicament dosage for distributing the blister pouch of the blister package that gives patient's (for example, by sucking) to deliver.Described machinery is applicable to comprising:

A) the reception operating board of reception blister package;

B) releasing device, it is for discharging the different drug dose in the blister pouch of the blister package receiving by this reception operating board; With

C) for the index table top of the different drug dose of single index blister package,

Wherein manifold of the present invention is positioned on the position that can communicate with the drug dose discharging by described releasing device.

Device comprises the receiving tool (for example receiving platform) for receiving blister package.

Device also comprises releasing tool, and it is for discharging the different drug dose in the bubble-cap of the blister package receiving by this reception operating board.Described releasing tool generally comprises the instrument that bubble-cap band mechanicalness is peeled off.

Manifold of the present invention is positioned on the position that can link up from the different powder doses discharging by described releasing tool.The drug delivery of this release is preferably passed through to a kind of delivery outlet separately to the patient who sucks, and this delivery outlet communicates with manifold or forms with manifold the part of integrating.This delivery outlet can have any applicable form.On the one hand, it has for the interface shape inserting in patient's mouth, and in addition, it has for the form of nozzle that is inserted into patient's nasal cavity.

This device also comprises index instrument, and it is for the bubble-cap that contains clear and definite drug dose of the drug packages of bubble-cap form described in index respectively.This index generally occurs in a continuous manner, for example, obtains along the continuously arranged dosage part of length of the drug packages of bubble-cap form.

Described pill dispenser also optionally comprises count tool, and it is for calculate the clear and definite drug dose of finding the drug packages of described bubble-cap form by described descriptor index method at every turn.

In one aspect, arrange count tool in order to calculate the clear and definite drug dose of finding described pharmaceutical carrier by described descriptor index method at every turn.Be applicable to index instrument being directly or indirectly connected each other to (for example passing through adapter) with count tool, to each index can be counted.

Be suitable for providing a kind of count tool with (or being connected with) display, for patient shows the quantity of the dosage of taking the quantity of remaining each dosage or got.

One preferably aspect in, pill dispenser takes to use the allotter form of bubble-cap form drug packages, described drug packages has multiple independently blister pouch that contain inhalable drug dosage, wherein said each bag is spaced along length, and be limited between two strippable lamellas that are sealed each other, this allotter has a kind of for distributing the internal mechanical device of the drug dose that described drug packages contains, and this machinery comprises:

A) receive the open operation platform that pharmaceutical pack packs;

B) a kind of detacher, it is positioned to connect substrate and the cover plate of the packaging bag having received on described open operation platform, be used for peeling away this substrate and cover plate to open the package, described exfoliation tool comprises a kind of cover plate driver, in order to pull open substrate and the cover plate of the packaging bag having received on described open operation platform; With

C) for the index device of the Different Package bag of drug packages described in index respectively,

Wherein manifold of the present invention is positioned on the position that can communicate with open package bag, by its drug dose, can from this open package bag, discharge.

Described index instrument is applicable to comprising one and has therein the rotatable index wheel of groove (recesses), this index wheel can with use in pill dispenser in drug packages is connected (engageable), make described each groove receive each bag of substrate of bubble-cap band in the described pill dispenser in use.

According to a further aspect in the invention, provide a kind of pill dispenser, it comprises the blister package that (for example loading) contains at least one dry-powder medicament.

Manifold is herein described hereinbefore, in use, is suitable for distributing the drugs distribution apparatus of the medicine in the open blister bag of blister package.It should be understood that and also manifold can be applied to any drugs distribution apparatus that is applicable to the medicine in dispense aperture hole, the opening capsule that wherein hole can for example be packed by capsule-type provides.

Therefore, according to another aspect of the invention, provide a kind of manifold for drugs distribution apparatus, this device is for transmitting from the drug powder in the opening hole of drug packages, and this manifold comprises:

Housing,

This housing limits a kind of chimney with chimney air inlet and chimney gas outlet, and it is for guiding air-flow to flow to chimney gas outlet from described chimney air inlet;

This housing also limits a kind of chamber with chamber air inlet and chamber gas outlet,

Wherein said chimney gas outlet and chamber air inlet are arranged side by side, thereby make when described opening hole is positioned at its adjacent place, chamber air inlet can lead by opening hole described air-flow from chimney gas outlet, with by drug powder transmission and make medicine be transported to chamber gas outlet from chamber air inlet in air-flow

And one or more escape orifice is wherein provided between chimney and chamber, makes by indoor the air-flow introduction chamber of discharging, with disruptiveness, to clash into the air-flow that transports the drug powder being transmitted.

Be applicable to pill dispenser to be herein packaged in a kind of packing (, a kind of outer package, for example, with a kind of outer package form), it comprises a kind of being designed for and reduces ambient moisture and enter the packaging material of packaged this allotter (and drug packages).

Described packing be suitable for not moisture-inhibiting gas or substantially any material of not moisture-inhibiting gas make.These packaging material are energy permeating volatile thing preferably, and this volatile matter can be formed object and escape out from the plastics of inhaler and/or bubble-cap form drug packages by disperse or alternate manner, prevents thus the formation of pressure.

Further aspect of the present invention and feature are at appending claims and open in the exemplary of the accompanying drawing referring to describing in detail.

Accompanying drawing summary

Fig. 1 represents the perspective view of the pharmaceutical carrier of the strip blister package form that is applicable to drugs distribution apparatus of the present invention;

Fig. 2 represents the sectional view of the drugs distribution apparatus that comprises Fig. 1 pharmaceutical carrier, and this distributor is applicable to the present invention;

The height summary sectional view that Fig. 3 a represents to comprise a pair of Fig. 1 pharmaceutical carrier and is applicable to the elementary cell of the second drugs distribution apparatus of the present invention;

The height general perspective of the details of the elementary cell of Fig. 3 b presentation graphs 3a;

Fig. 4 a-4c represents the perspective view of the continuous production step of the third drugs distribution apparatus making up a prescription for patient, the pharmaceutical carrier that this device comprises a pair of Fig. 1;

Fig. 5 a-5c represents the side view of the continuous production step of the third drugs distribution apparatus using, and this distributor wherein showing lacks the part of its shell;

Fig. 6 represents the expansion perspective view of the gear mechanism of the third drugs distribution apparatus;

Fig. 7 a-7c represents when preparation at those consecutive steps for corresponding to Fig. 4 a-4c and 5a-5c, the side view detail of described gear mechanism;

Fig. 8 represents the perspective side figure of ratchet-gear wheel " anti-returning " mechanical detail of the third drugs distribution apparatus;

Fig. 9 represents the distributor of the third pill dispenser and the perspective side figure of pharmaceutical carrier;

Figure 10 represents the part expanded view of the third drugs distribution apparatus that lacks interface;

Figure 11 represents thereon the side view with a half-shells of the third drugs distribution apparatus of manifold;

Figure 12 represents the sectional drawing of the third drugs distribution apparatus;

Figure 13 represents the sectional drawing of the interface of the third drugs distribution apparatus and the installation of the first manifold;

Figure 14 a represents the side view of the first manifold in Figure 13;

Figure 14 b is illustrated in the cross-sectional side view of the first manifold obtaining on Figure 15 b center line XIVb, represents the relation of " in the use " of the pharmaceutical carrier of itself and the third drugs distribution apparatus;

Figure 15 a and 15b are illustrated in the cross fault plane graph of the first manifold obtaining on Figure 14 a center line XVa and XVb, and it shows to suck by patient at the seam of the third drugs distribution apparatus separately, through flowing of initial air herein and deaeration;

Figure 15 c is illustrated in the summary cross-sectional side view of the first manifold obtaining on Figure 14 b center line XVc, shows to suck the seam patient of the third drugs distribution apparatus, through flowing of initial air herein and deaeration;

Figure 16 a represents the side view of the another kind of manifold that is applicable to the interface of Figure 13 and the installation of manifold;

Figure 16 b is illustrated in the cross-sectional side view of the another kind of manifold obtaining on Figure 17 b center line XVIb, represents the relation of " in the use " of the pharmaceutical carrier of itself and the third drugs distribution apparatus;

Figure 17 a represents the sectional drawing of the interface of the third pill dispenser and the installation of another manifold; With

Figure 17 b and 17c are illustrated in the cross-sectional side view of another manifold obtaining on Figure 16 b center line XVIIb and XVIIc, and it shows to suck by patient at the seam of the third drugs distribution apparatus separately, through flowing of initial air herein and deaeration.

Diagram describes in detail

Fig. 1 represents the pharmaceutical carrier 100 with rectangular band forms.Pharmaceutical carrier 100 has the DISKUS at GlaxoSmithKline PIc

aDVAI R

the type of using in Diskus, it comprises a kind of pliability band 102, and it limits multiple bags 104, each bag of inhalable drug powder that comprises doses (or its part).Band 102 has enough pliabilities of the curling rolling of energy, as shown in fig. 1.

Band 102 comprises a substrate 110, and wherein bubble-cap 106 forms to limit each bag 104 by cold formation or dark traction, and a cover plate 112, and cover plate is the substrate 110 except the region of bubble-cap 106 by air sealing cover, with each bag 104 of airtight covering.By hermetic closed to substrate and cover plate 110,112, substrate and cover plate 110,112 can be stripped from and open bag 104, to obtain drug powder.By each layer 110,112 sealing each other on whole width, except fore-end 114,116, preferably not by they sealings completely each other.

The each free plastic/aluminium paper tinsel of cover plate 112 and substrate 110 forms, and adhering to each other by heat-sealing.Cover plate 112 comprises at least following pantostrat: (a) ply of paper; Its adhesive bond is in (b) polyester layer; Its adhesive bond is in (c) aluminum paper tinsel; It is used to a heat-sealing enamelled coating coating of combined base.Substrate 110 comprises at least following pantostrat: (a) oriented polyamide (OPA); Its adhesiveness is connected in (b) aluminum paper tinsel; Its adhesiveness is connected in the 3rd layer that (c) comprises a kind of polymer (as polrvinyl chloride).

In addition, described in the international patent application No.PCT/US06/37438 that cover plate 112 can be submitted to by JIUYUE, 2006 on the 26th, make, the full content of this international application and copy US country phase application thereof is incorporated herein by reference.

Each bag 104 mutually the same, except snellen test 108, is positioned at along on the position of described band length equal intervals.Bag 104 is microscler, along the length horizontal spreading of band 102.This facilitates the bag 104 that can provide a large amount of on given band length.For example, can on band 102, provide 30,60 or 100 bags 104, but should be clear that band 102 can have the bag 104 of any applicable quantity.

About the details of band 102 can be found in the U.S. Patent No. 5,590,645 being incorporated herein by reference in full.

In the each embodiment of the present invention, following example can be used multiple this bands 102 in single medicine distributor, and wherein each band provides a kind of each composition drug dose part of composition of medicine product.This band 102 can have separately identical size and/or comprise same dose (for example volume or quality), or in another embodiment, can use in conjunction different size and/or the band that comprises various dose.

Fig. 2 illustrates handheld, the manually operated drugs distribution apparatus of the first of the present invention, its form that is Diskus, and it is suitable for comprising menifold of the present invention.It is DISKUS that inhaler 220 has trade mark

the universal class sold of GlaxoSmithKline PIc, its details is disclosed in above U.S. Patent No. 5,590,645, especially with reference to its Figure 13-16.Inhaler 220 comprises the pharmaceutical carrier of Fig. 1, is referenced herein as 202, and it is with other band feature that is endowed similar numeral.

More particularly, arrange inhaler 220 to distribute the drug powder of the unit dose in each bag 204 of rectangular bubble-cap band 202.This inhaler is comprised of a kind of overcoat around medicine band 202 in housing 222 (outer casing) 221.Patient by control this device 220 to its mouthful, compacting control stick (lever) 224, then by interface 226, suck and use this inhaler.Compacting control stick 224 activates the internal mechanical device of this inhaler, owing to drawing effect before cover plate reel (take-up wheel) 230, the cover plate 212 of curling medicine bubble-cap band 202 and substrate 210 are stripped from separately by indicator wheel (index wheel) 228.Should be clear that, once peeling away, cover plate 212 is crimped onto on reel 230.Then, the substrate 210 of separation is crimped onto on substrate reel 232.The powdered medicine of open blister bag 204 interior unit dose is released in open operation platform 238, and can by manifold hole 240 and final interface 226, be inhaled into through patient.The accurate form that offers the manifold in menifold hole 240 be can't see in Fig. 2, but has form of the present invention and shown in figure subsequently.

Fig. 3 a and 3b are that the second of the present invention is handheld, the height skeleton diagram of manually operated drugs distribution apparatus, its form that is Diskus also has disclosed type in US-A-2005/0154491 (Anderson etc.), and this patent full content is incorporated herein by reference.

That is to say, the second drugs distribution apparatus is provided as two pharmaceutical carrier 300a, 300b of the form of flexible bubble-cap band 302a, 302b, with reference to (similar with the reference number that is used to indicate its feature) described in above Fig. 1.Flexible bubble-cap band 302a, 302b are identical, and each bag has same shape with size and have equal interval along band length.

Wherein Article 1 band 302a comprises identical drug powder in its each bag, and the amount of its active component is also identical with the amount in each bag of this band.Another band 302b comprises equally identical drug powder in its each bag, also contains separately the active component of same amount in such bag.Drug powder in each band can contain single active component or the mixture of active component.But the drug powder in a band comprises at least one not active component in another band.As described in detail further below, in operation the second drugs distribution apparatus, the bag of each bubble-cap band 302a, 302b is peeled away to expose wherein different drug powders.Then patient sucks the powder in open-bag 304a, the 304b to suck band 300a, 300b simultaneously at seam.Therefore, patient can receive the powder doses of the fixing metering of each dosage part of the different pharmaceutical powder formation of each open-bag 304a, 304b.

An elementary cell 319 of Fig. 3 a explanation the second pill dispenser.First and second bubble-cap band 302a, 302b that comprise medicine are arranged in left and right chamber 323a, the 323b separately of elementary cell 319.Each bubble-cap band 302a, 302b connect respectively many bags of indicator wheel 328a, 328b, and guide thus continuous each bag to the open operation platform 333 on rotine positioning.Indicator wheel 328a, 328b match rotation.On open operation platform 333, respectively aluminium foil cover plate 312a, the 312b with 302a, 302b and aluminium foil substrate 310a, 310b part is through prominent (beaks) 336a of point separately, and 336b is stripped from and comes.Empty aluminium foil substrate 310a, the 310b obtaining is coiled in chamber 332a, the 332b of reception substrate separately.Aluminium foil cover plate 312a, 312b used is transported to the prominent 336a of its point separately, and 336b place, is then coiled on wireline reel 330a, 330b at chamber 331a, the 331b of reception cover plate separately.

The release of the powder type medicine in open-bag 304a, the 304b of the one 302a and the 2nd 302b band can enter by menifold 350, menifold 350 is only summary demonstration in Fig. 3 b, but in this embodiment, what it was taked is a kind of form in menifold 450,550 shown in Figure 14 a or Figure 16 a, and it describes in detail in the third drugs distribution apparatus of relevant Fig. 4-17.Menifold 350 is positioned at organ receiving platform 341 places.

In use, the powder of release is sucked in mobile transmission and is moved to interface (not shown) from menifold 350 by patient.Menifold 350 defines specific geometry, mixes before being delivered to interface by the powder in this release.The elementary cell 319 of Fig. 3 a can be stored in different drug types respectively in each band 302a, 302b, but suck product as " mixing " multiple-active combination, discharges simultaneously and is delivered in patient.

Fig. 3 b represents open-bag 304a, 304b in more detail, and (Fig. 3 is the release of Chinese medicine a).Patient breathes by interface (not shown), the open-bag 304a, the 304b that make negative pressure be passed menifold 350 to be delivered to band 302a, the 302b at open operation platform 333 places (Fig. 3 a) in.It generally causes producing Venturi effect, and the powder comprising in each open-bag 302a, 302b is attracted by menifold 350, thereby by patient's inhalation interface.

Fig. 4-15 provide the present invention the third various views hand-held, manually operated drugs distribution apparatus.The third drugs distribution apparatus is Diskus type, and as technical staff to understand, it is similar to above the second drugs distribution apparatus in function and general operation principle.

That is, the third drugs distribution apparatus is provided as can curling bubble-cap band 402a, two kinds of pharmaceutical carrier 400a, 400b of 402b form, described in relevant Fig. 1 above, similar with the reference number that is used to indicate feature.But in band 402a, 402b, snellen test forms bag 404a, the uniformly-spaced part of series of 404b, rather than interval is far away.In each band 402a, 402b, the number of bag 404a, 404b equates, number depends on the treatment how many days of expection and dosage regimen and determines accurately.For example, band 402a, 402b will have 31 bags, every day respectively once, each one bag, the treatment plan of 30 days.That extra bag is snellen test.

Bubble-cap band 402a, 402b that can be curling be identical, and each bag of 404a, 404b are identical separately in shape and size, and along band length equidistant intervals.Wherein Article 1 band 402a comprises identical drug powder in its each bag, and the amount of its active component is also identical with the amount in each bag of this band.Another band 402b comprises equally identical drug powder in its each bag, also contains the active component of same amount in each bag.Drug powder in each band can contain single active component or the mixture of active component.But the drug powder in a band comprises at least one not active component in another band.As detailed below, when preparing described device and patient in the suction of interface 426 places of this device, patient sucks the powder in single opening bag 404a, the 404b of each band 400a, 400b simultaneously, to receive the powder doses of fixing metering of each dosage part that the different pharmaceutical powder of each open-bag forms.

Fig. 4 a-4c and Fig. 5 a-5c represent the corresponding consecutive steps of the third drugs distribution apparatus of preparation use separately.As shown in the figure, the third drugs distribution apparatus comprises a shell 420, wherein has interface 426 and for covering the access flap 438 of interface 426.Window 424 is also provided in shell 420, by this, can be observed the dose counting indicated number 425 of dose counter (not shown).As described in more detail below and as Fig. 6 with in 9-15, understand the same, interface 426 interacts with the menifold 450 that is positioned at open operation platform 427 places, the menifold 450 arranging is in use used to be directed at the respectively drug powder in the single open-bag with 400a, 400b of open operation platform 427 places, for patient, sucks.

As can be from finding out Fig. 5 a, access flap 438 has an arm 434 with bore fixture 436, to fix and the interaction of the ratchet 446 of complicated gear machinery 440.In use, the axle that access flap 438 limits around the rotating shaft of ratchet 446 is in rotary moving.

In Fig. 4 a and 5a, access flap 438 is positioned on first position that wherein interface 426 is capped.

In Fig. 4 b and 5b, access flap 438 has been rotated on second position, and wherein interface 426 and air intlet barrier 470 parts are not capped, but wherein gear mechanism 440 and relevant distributor, what describe in detail below, do not start, therefore there is no drug dose for suction.In addition, dose counter (not shown) does not start, and therefore counting indicator 425 keeps identical.Counting indicator 425 in this particular is indicated the number of the bag 404a, the 404b that do not open on each band 402a, 402b.

In Fig. 4 c and 5c, access flap 438 has been further rotated on the 3rd position, exposes completely or opens interface 426 and air intlet barrier 470.The part of lid 438 almost extends to the bottom 421 of the shell 420 in this position.As the result that further moves to the 3rd position from second position, gear mechanism (illustrating in greater detail in following Fig. 6 and Fig. 7 a-7c) and dispense machine (illustrating in greater detail in following Fig. 9) are activated in this distributor, offer for the drug dose sucking.In other words, described drugs distribution apparatus is now activated stand-by.The startup that this moves the dose counter (device does not show) that also causes drugs distribution apparatus, makes dose counting indicator 425 reduce by a unit to new reading " 29 "

After use, access flap 438 turns back to primary importance (being shown in Fig. 4 a and 5a).Its correspondence storage (" protected the interface ") position of distributor.

Now referring to Fig. 6, at this, present the planar graph of gear mechanism 440.In more detail, on shell 420, provide as seen the internal backplane 428 for outside receiving portion gear mechanism 440.In base plate 428, referring to Fig. 9, can find out better, mirror for dispersion medicine-as (" left side " and " right side " hands) distribution machinery 448a, 448b is provided.Gear mechanism 440 can be thought to forming is the part of distribution machinery 448a, 448b.

See more detailed Fig. 9, the first and second bubble-cap band 400a, the 400b that comprises medicine is positioned at left and right chamber 403a, the 403b separately of base plate 428.Each bubble-cap band 400a, 400b engage respectively the DISKUS of GlaxoSmithKline

many bags of indicator wheel 430a of the type of using in inhaler, 430b, see described in US-A-2005/0126568 (Davies etc.) and shown in-referring to Figure 16, " biobelt " suction apparatus (Anderson etc.) in indicator wheel 416-and US-A-2005/0154491, continuous each bag is directed to open center operating board 427 thus.In open operation platform 427, aluminium foil cover plate 412a, the 412b of each band 400a, 400b and aluminium foil egative film 410a, 410b part are peeled off by point prominent 409a, 409b respectively.Empty aluminium foil egative film 410a, the 410b obtaining receives in chamber (take-up chambers) 415a, 415b and coils in substrate respectively.Rotatable substrate wireline reel (take-up spindle) 413a, 413b hitch the end 414a of other aluminium foil egative film of each point 410a, 410b in chamber 415a, 415b, 414b.The surrounding that the rotation of the progression of other egative film wireline reel of each point 413a, 413b causes " giving up " aluminium foil egative film 410a, 410b to be wound onto axle becomes volume closely.Rotation and each indicator wheel 430a, the 430b of each substrate axle 413a, 413b match.

Aluminium foil cover plate 412a, 412b used is respectively through its point prominent 409a, 409b, and edge lid reel 417a, 417b winding separately, and reel also rotates to be rolled up aluminium foil cover plate 412a, 412b thereon.Each cover plate reel 417a, 417b comprise a center hub (central hub), it is connected on end 416a, the 416b of cover plate 412a, 412b, and make cover plate wound on it, central shaft (not shown) on described wheel hub is rotatable, and a torsionspring (not shown) is installed thereon.Details is described in WO-A-2006/018261 (Glaxo GroupLimited), especially the embodiment of describing about Fig. 1-4, this international application is incorporated herein by reference together with the American National stage patent application that wherein draw in source.The function of torsionspring is to guarantee in the process of each band total length, offers the propelling tension force substantially constant of each band 400a, 400b through its cover plate reel 417a, 417b.At length say, the effect of each torsionspring is that compensation drives the variation of tension force, this tension variation with when cover plate 412a, 412b used gradually looping its when upper, effective coiling diameter increase of each cover plate reel 417a, 417b is correlated with.Therefore, the consistent index of each band 400a, 400b can keep in band total length.

In use, described dispensation apparatus starts as shown in Fig. 4 a-4c and 5a-5c, by covering 438, from second position (seeing shown in Fig. 4 b and 5b), move to the 3rd position (seeing shown in Fig. 4 c and 5c) with driven nature rotation indicator wheel 430a, 430b and cover plate reel 417a, 417b, and each bubble- cap band 400a, 400b are forwarded, thereby causing that its leading bag of not opening is stripped from comes.For obtaining out the content of bag, then patient breathes by interface 426.As described in more detail in Figure 10-15, this causes producing negative pressure, and this negative pressure is passed on the open-bag of each band 400a, 400b on open operation platform 427 by menifold 450.Then it cause the drug powder comprising in each open-bag by conventional menifold 450, to be sucked into interface 426 places simultaneously, arrives in patient thus with inhalation group composite medicine dosage.

Referring to Fig. 6, visible gear mechanism 440 comprises the ratchet gear 442 being arranged on driving shaft 431 again.Ratchet gear 442 is similar to other gear, is that one has in antagonism and outer surface 441,443 (with respect to the outside of described dispensation apparatus) and have therebetween the gear forms of an external peripheral surface 445a.Outer surface 443 is recessed into, to limit the inner circumferential surface 445b relative with external peripheral surface 445a.As finding, described outer and inner circumferential surface 445a, 445b provide with stepped-style, have provided and ratchet 446 ratchetizations interactional each outer and inner ratchet feature 444a, 444b, and described interaction will be described in more detail in Fig. 7 a-7c.Ratchet feature 444a, 444b are the ratchets that equal angles space separates, and in this embodiment, have 5 teeth in each circumferential surface 445a, 445b.Tooth 444a on external peripheral surface 445a (" external tooth 444a ") offsets the tooth 444b from inner circumferential surface 445b (" internal tooth 444b ").In other words, without internal tooth 444b be positioned at leave gear 442 rotating shaft with external tooth 444a same radius on.

As visible in Fig. 7 a, inner circumferential surface 445b comprises the surperficial fragment 449 that internal tooth 444b is connected of each vicinity.Each surperficial fragment 449 is comprised of the first and second part 449a, 449b, its opposite ends from fragment 449 extends internally, Part I 449a extends inwardly to Part II 449b from an internal tooth 444b, and Part II 449b extends inwardly to Part I 449a from the contiguous internal tooth 444b of the next one.The bending radius of Part I 449a is larger than Part II 449b's, and therefore Part II 449b forms a slope (ramp) part with respect to Part I 449a.

Referring to Fig. 6, be understood that substrate wireline reel 413a, 413b and the axle (not shown) of cover plate reel 417a, 417b are connected respectively substrate coiling gear 462a, 462b and cover plate coiling gear 461a, 461b.Gear also provides indicator wheel 430a, 430b.The inner surface 441 of ratchet gear 442 provide for the interact driving teeth 447:(i of (engagement) of following driving) gear of first indicator wheel 430a, and (ii) first idler gear 464.The gear of first indicator wheel 430a is meshed with first gear of cover plate reel gear 461a and the gear of second indicator wheel 430b, and then it be meshed with second cover plate coiling gear 461b.First idler gear 464 is meshed with first gear of substrate wireline reel gear 462b and the gear of second free pulley 465, and then it be meshed with second substrate wireline reel gear 462a.This gear train arrange the index of pharmaceutical carrier 400a, 400b is provided and at access flap 438 from the movement of three positions, second position to the, substrate and cover plate 410a, b, 412a, b's is curling.

The WO-A-2005/079727 (Glaxo Group Limited) that is described in greater detail in that is used for the applicable counter device of described dispensation apparatus provides, it is together with the American National stage patent application No.10/597 that wherein draw in source, and 551 are incorporated herein by reference together.Can be by driving wheel/speed increasing gear be engaged, with substrate wireline reel, 413b drives this counter device.

As shown in Fig. 6-8, ratchet 446 comprises a center-wheel arbor 446a from excircle, and it is depending on multiple equal angles space intervals, ring-type orientation, reverting bar (resilient legs) 446b.This ratchet wheel shaft 446a also comprises a boss (boss) 446c, as shown in Fig. 5 a, within it is installed on the constant aperture 436 of access flap arm (cover arm) 434, for the direct driving of setting up between access flap 438 and ratchet 446, connect, access flap 438 ratchet 446 in rotary moving in its first and the 3rd in rotary moving between position causes ratchet gear 442 thus, this will describe after a while in more detail.In this particular, 5 ratchet lower limb 446b depend on apart from the distance of ratchet wheel shaft 446a.In other words, select the number of ratchet lower limb 446b with the number of the internal tooth 444b of coupling ratchet gear 442.

With reference to Fig. 7 a-7c, can understand better the interaction between ratchet gear 442 and ratchet 446, it shows when in those consecutive steps for the preparation of corresponding to Fig. 4 a-4c, the motion of gear mechanism 440 parts of the third drugs distribution apparatus.

The resting position of Fig. 7 a while closing (be interface cover plate 438), ratchet 446 is arranged among ratchet gear 442 at a certain angle, make ratchet gear 442 internal tooth 444b circumference from the free end space of ratchet lower limb 446b, separate.In second position of Fig. 7 b (being that interface cover plate 438 partially opens), ratchet 446 is around ratchet gear 442 circumference rotations, by the neighbouring surface sections 449 of inner circumferential surface 445b in ratchet lower limb 446b cunning, to engage internal tooth 444b.Therefore, be understood that in second position, ratchet gear 442 warm-ups, but not yet motion, so whole gear mechanism 440 and dispense machine 448a, 448b not yet advance.In the 3rd position of Fig. 7 c (being that interface cover plate 438 is opened completely), (through as directed 72 °) are rotated in ratchet 446 intermeshing effect by ratchet lower limb 446b and internal tooth 444b together with ratchet gear 442, make so whole gear mechanism 440 and dispense machine 448a, 448b advance, make indication and advance each pharmaceutical carrier 400a, 400b, to open independent each bag, and thus by the drug powder comprising in the each open-bag on open operation platform 427 place's menifolds 450, for patient, suck by opening interface 426 time.

Referring to Fig. 8, described dispensation apparatus also comprises the interior support plate 481 for covering gear mechanism 440.This support plate 481 has an arc canopy (shelf) 483, and it is positioned on ratchet gear 442 and ratchet 446.

One end of canopy 483 is configured to pointer 484 springy, a recess 485 is wherein provided.Ratchet 446 comprises an outstanding 446d, when ratchet (and access flap 438) in Fig. 7 a first, during resting position, outstanding (protrusion) 446d engages in described recess, as shown in Figure 8.The effect of a kind of brake of this intermeshing performance (detent) of the outstanding 446d of ratchet and support plate recess 485, to lock the access flap 438 in " down interface " or the resting position of Fig. 4 a, 5a, 7a and 8.

Support plate 481 also comprises a kind of ratchet lower limb (pawl leg) 487 fixing, that can rebound, and it,, for interacting with the external tooth 444a of ratchet gear 442, forms " anti-returning " feature of ratchet gear 442.When access flap 438 is opened, once ratchet lower limb 446b engagement internal tooth 444b, cause that ratchet 446 and ratchet gear subsequently 442 rotate, when ratchet lower limb 487 is ridden external tooth 444a, it is moving that ratchet lower limb 487 does not hinder revolving of ratchet gear 442 to transmit, and reason is orientation and the elasticity of ratchet lower limb 487.But when access flap 438 turns back to the position that it closes, it rotates back to its resting position by ratchet 446 again in turn, by ratchet lower limb 487 and engaging of an external tooth 444a wherein, keep ratchet gear 442 to prevent revolution.Therefore, the ratchet 446 in access flap 438 closures can reverse rotation do not passed to gear mechanism 440.So in the various situations of access flap 438 complete opening and closing, ratchet gear 442 only increases in a direction of rotation.

When access flap 438 return to its first cover position (a) (Fig. 7 be a) time the ratchet in ratchet gear 442 446 rotation is got back to its resting guard for Fig. 4, reverting bar 446b slips back in the space after different internal tooth 444b on inner circumferential surface 445b, prepares against unlock interface lid 438 next time.

In Fig. 7 a, show as seen the zoomed-in view of the profile of one of them gear teeth of indicator wheel 430a.Cogged gear teeth in this gear mechanism is all this profile.

Reel, moving by patient's hands, access flap 438 (as moving to it, Fig. 4 first position a) is opened to interface 426 (as Fig. 4 the 3rd position c) completely from its down interface 426, cause ratchet 446 driven wheels and dispense machine 440, 448a, 448b, make the each bubble-cap band 402a in dispensation apparatus described in index, 402b, to cause each band 402a, the single blister pouch 404a of 402b, 404b opens, and be presented on the menifold 450 of open operation platform 427, in order to patient, suck each new open-bag 404a simultaneously, powder contents in 404b, and therefore accept the combination of the different activities medicine of fixed dosage.Patient sucks after the powder contents in each new open-bag, and patient manually rotates back into access flap 438 its first position in order to using next time.While using next time, bag 404a, 404b that the next one of opening on each band 402a, 402b is closed, and the described drug regimen that makes patient can suck next fixed dosage is sentenced in index to menifold 450.Then for example, according to the prescription of described drug regimen (once a day, every day two inferior), arrange, proceed to open and close circulation, until the marsupial 404a of institute, 404b are emptying, as shown in enumerator labelling 425.As mentioned above, (for example Fig. 4 b) does not make the index of blister pouch 404a, 404b/open in second position of access flap 438 in the middle of moving to from its first position.

Now in conjunction with Figure 10-15, the menifold 450 of the third drugs distribution apparatus is explained in more detail.

Figure 10 shows the third drugs distribution apparatus that does not have interface 426.More particularly, shell 420 comprises first 420a and second 420b shell cover plate part is matched, the effect that its dispense machine device cover is got up in its combination performance.Menifold 450 is received by first casing cover part 420a, and the cover that import 453 is limited to chimney 452 places is received in the inwall 472 of first casing cover part 420a that limits air intlet barrier 470.

As mentioned above and as shown in Fig. 4 a-4c, air intlet barrier 470 in the first casing cover part 420a is when it is in first or (Fig. 4 is a) time in closed position, by access flap 438, covered, when access flap 438 is in second or partially open position (Fig. 4 is b) time, partly covered, when access flap 438 in the 3rd or open position (Fig. 4 c) time, is exposed completely.

As the diagram of arrow in Figure 12 483, in use, when replying patient and suck by interface 426, air intlet barrier 470 makes air pass through chimney import 453 to chimney gas outlet 452, from the outside of described the third drugs distribution apparatus, enters menifold 450.It should be noted that when patient is when interface 426 sucks, this air intlet barrier 470 provides air from outside, to enter the unique predetermined inlet point in described drugs distribution apparatus.More particularly, when patient is when interface 426 sucks, air intlet barrier 470 provides air from distributor outside, to enter unique inlet point of menifold 450.

Menifold 450 also receives by second port lid part 420b, makes within its outstanding bottom 455 is positioned at the hole 475 that receives menifold.A pair of wing 456a, 456b are provided in menifold 450, and it has and menifold 450 can be advanced to the assembly features on interface 426.

From Figure 12-15, also can see, menifold 450 has a kind of specific internal structure, wherein chimney 452 is positioned on chamber 460, and the total wall 459 of partial sharing one, and total wall 459 has formed the part of the bottom of chimney 452 and the top wall of chamber 460.Term " on ", " bottom " and " top " only relative seat feature in menifold 450 for the orientation that is described in the menifold 450 shown in Figure 12 and 13.

Chimney 452 has chimney air inlet 453 and a pair of chimney air vent 454a, 454b.In use, chimney 452 by internal gas flow (when patient sucks at interface 426 places, while receiving separately by air intake barrier 470) from chimney air inlet 453 lead a pair of chimney air vent 454a, 454b.Chamber 460 has a pair of chamber air inlet 473a, 473b and a chamber gas outlet 474.A pair of chimney gas outlet 454a, 454b and a pair of chamber air inlet 473a, 473b limit by a pair of round hole that diameter is about 3mm in this specific embodiment, and each hole provides with decussation formula 451,461.By by they location located adjacent one another, each chimney air vent 454a, 454b and one of them chamber air inlet 473a, 473b pairing.Interface 426 is arranged on chamber gas outlet 474, and by interim installing component 476, (snap-mounts) is installed temporarily.

As detailed above, when access flap 438 being opened at completely to its 3rd position, start gear and dispense machine 440,448a, 448b march forward to cause each bubble- cap band 400a, 400b, and single bag of 404a, the 404b of the each band that will peel off open.As understood in Figure 14 b and 15c, the open blister bag 404a being stripped from of each bubble- cap band 400a, 400b, 404b is in being respectively adjacent to one of them right chimney air vent 454a, 454b and chamber air inlet 473a, 473b place.

Specifically, the open blister bag 404a of the first bubble-cap band 402a is positioned at contiguous the first chimney gas outlet 454a and the first chamber air inlet 473a place (as shown in Figure 15 c), and the open blister bag 404b of the second bubble-cap band 402b is positioned at contiguous another chimney gas outlet 454b and chamber air inlet 473b place equally.As with reference to described in above Fig. 1, blister pouch 404a, 404b with respect to the major axis of band 402a, 402b be microscler, to side, extend.Therefore, each bag of 404a, 404b can be thought at the offside of band longitudinal axis, have first and second sides.When open-bag 404a, 404b are presented on 427 manifold 450 of open operation platform, by each bag of 404a, 404b orientation, make its oriented sideways be calibrated in the direction between each chimney gas outlet 454a, b and chamber air inlet 473a, b.Therefore, as shown in Figure 15 c, chimney gas outlet 454a, b and chamber air inlet 473a, 473b are positioned on the not ipsilateral of blister pouch 404a, 404b, therefore in use, air flows through each bag of 404a, 404b in its side direction, with respect to the side of the longitudinal axis (or length direction) of band 402a, 402b.

As shown in Figure 12,13 and 15, when patient is at interface 426 places when air-breathing, air-flow 483 only enters chimney 452 by air intake barrier 470 by chimney air inlet 453 from the outside of distributor, flows in manifold 450, and chimney air inlet and air intake barrier 470 are in relation located adjacent one another.As shown in Figure 13,15a and 15c, first (or elementary) part 485 of air-flow 483 flows to by each chimney gas outlet 454a, 454b in open blister bag 404a, the 404b of each band 400a, 400b on open operation platform 427, therefore in air-flow, drive the drug powder comprising in each bag, thereby take the medicine powder of each bag of 404a, 404b out of, by chamber air inlet 473a, 473b, enter chamber 460.Then with the air flow stream outgoing interface 426 that transmits drug powder, enter patients with respiratory tract.

As shown in Figure 12-15, on separated wall 459, providing single D-shape steam vent 480 by chimney 452 from chamber 460.The position of this D-shape steam vent 480 is adjacent to chimney gas outlet 454a, 454b and chamber air inlet 473a, 473b.As shown in Figure 13,15b and 15c, in use, the effect of steam vent 480 is that guiding directly enters chamber 460 from the Part II 486 (" discharge portion ") of the air-flow 483 in chimney 452, with disruptiveness, clash into entrained drug powder is transferred to the Part I 485 of the air-flow 483 in chamber 460, thereby pulverize its any dust agglomeration composition.

It should be noted, for being easy to explanation, Figure 15 a and 15b only optionally represent the Part I 485 of air-flow 483 and the flow path of Part II 486.Technical staff is by clear, and when patient sucks at interface 426 places, the first and second parts 485,486 produce in manifold 450 simultaneously, as shown in Figure 13 and 15c.

Figure 16 and Figure 17 show the second manifold 550 of the third drugs distribution apparatus, and it is with a variant of the manifold 450 of " D-hole " type steam vent 480 (selecting with another).Like reference class, numbering name is corresponding to those features in the second manifold 550 of the feature in the first manifold 450.

Be understood that the global shape of the second manifold 550 and form are corresponding to " D-hole " type manifold 450, make in the third drugs distribution apparatus one to be easy to replace another.But, replacing " D-hole " type steam vent 480, the second manifold 550, by wall 559 places separation with chamber 560 chimney 552, has two long trough steam vent 580a, 580b.

More particularly, the second manifold 550 has a kind of internal structure, and wherein chimney 552 is positioned on chamber 560, and partial sharing wall 559, and wall 559 forms the base wall of chimney 552 and the part top wall of chamber 560.Term " more than ", " bottom " and " top " only for illustrating the relative position of the each feature orientation of manifold 550, manifold 550 is as shown in Figure 17 a.Wing 556a, 556b are provided on manifold as previously shown.

Chimney 552 has a chimney air inlet 553 and two chimney gas outlet 554a, 554b.In use, chimney 552 guides internal gas flow 583 (again when receiving separately by air intake barrier 470, as shown in Figure 17 a) from chimney air inlet 553 to chimney gas outlet 554a, 554b.Chamber 560 has two chamber air inlet 573a, 573b and chamber gas outlet 564. Chimney gas outlet 554a, 554b and chamber air inlet 573a, 573b are about the round hole restriction of 3mm by diameter, provide separately with decussation formula 551,561.

As shown in Figure 17 a and 17b, chimney gas outlet 554a, 554b and chamber air inlet 573a, 573b are positioned at adjacent locations each other, for example make, when open blister bag 404a, 404b (seeing Figure 16 b and 17a) are when being close in open operation platform 427 (Figure 11), the Part I 585 of internal gas flow 583 is by open- bag 404a, 404b, from chimney gas outlet 554a, 554b, be directed to chamber air inlet 573a, 573b, enters chamber 560.Open blister bag 404a, this air-flow in 404b place drive the powder contents of each bag of 404a, 404b, and make to carry out from chamber air inlet 573a in the air-flow 583 sucking, 573b is to the delivery of chamber gas outlet 564, thereby arrives in the patient who is sucking by interface 426.

On wall 559, provide rectangular flute profile steam vent 580a, 580b, wall 559 separates chimney 552 and chamber 560.Described rectangular flute profile steam vent 580a, 580b are positioned at away from chimney gas outlet 554a, 554b and chamber air inlet 573a, 573b place.As presented in Figure 17 a and 17c figure, in use, steam vent 580a, 580b effect are that the Part II of air-flow 583 586 (" discharge section ") is directly directed to chamber 560 from chimney 552, with destructiveness, clash into the Part I 585 of the air-flow 583 that transmits the drug powder being transmitted, smash thus its any powders component.

Referring to Figure 16 a, each steam vent 580a, 580b are 1.32mm (± 0.15mm) at the width at 574 places, the nearest chamber of its first end gas outlet, relative the second end width at nearest chimney gas outlet 554a, 554b is 1.11mm (± 0.15mm), and the length of first end to the second end is 6.465mm (± 0.1mm).The cross-sectional area of each steam vent 580a, 580b is 7.8mm ².Therefore, steam vent 580a, 580b have a kind of tapered shape, from first end to the second end, narrow.Certainly, according to the medicine transmitting, can change these diameters from bubble-cap band 402a, 402b.

Will be appreciated that the suction due to interface 426 patients of place, the first and second parts 585,586 of air-flow 583 are simultaneously in the interior generation of menifold 550.

As also will observed from Figure 17 c, configuration and arrange steam vent 580a, 580b, makes the Part II 586 of air-flow 583 mobile the border surface 591 of chamber 560 around again, forms a kind of sheath sample air blanket closing on 591 places, interface.When powder is brought to interface 426 place, this helps to relax the deposition of drug powder on interface 591.

Should observe manifold 450; 550 internal structure is from chimney air inlet 453; 553 extend to divider wall 459; Chimney 452 on 559; 552 the longitudinal axis is vertical or be basically perpendicular to from chamber air inlet 473a, b; 573a, b extend to chamber gas outlet 474; 574 chamber 460; 560 the longitudinal axis.Therefore, suck air-flow 483; 583 discharge portion 486; 586 collide right angle wherein or are generally the chamber 460 at place, right angle; The medicine 485 of the Part I of 560 interior deliveries; 585.

Also will observe manifold 450; 550 need all air-flows by chimney air inlet 453; 553 enter into manifold, then by total air flow 483; 583 " separation " one-tenth " open blister bag guiding " air part 485; 585 (by chimney gas outlet 454a, b; 554a, b and chamber air inlet 473a, b; 573a, b) and chamber 460; " aerofluxus " air part 486 of 560; 586 (by one or more steam vent 480; 580a, b).Therefore, to air-out 486; 586 amount, especially its percentage ratio are (with respect to passing through chimney air inlet 453; 553 enter manifold 450; 550 total air flow) good control may use the manifold with this arrangement.For the third drugs distribution apparatus with a pair of medicine carrier (carriers) 400a, 400b, total air flow 483; 583 Exhaust Gas ratio 486; 586 are desirably 80%; Or be 80% substantially, remaining open-bag 404a, the 404b of passing through.

Be understood that when patient sucks at interface 426 places, may exist some escape of airs to manifold 450; 550, especially by chimney gas outlet 454a, b; 554a, b, and may more particularly pass through chamber air inlet 473a, b; 573a, b, reason is that bubble-cap band 402a, 402b do not form manifold 450 at these opening parts; 550 sealing completely.However, with by air intake barrier 470, through chimney air inlet 453; 553 are inhaled into manifold 450; Total suction air-flow 483 of 550 expection; 583 compare, and any this type of escape of air is all negligible.

In above-mentioned each embodiment, manifold 450; The 550th, the plastic components of monolithic, injection-molding.More particularly, manifold 450; 550 are made by high density polyethylene (HDPE) (HDPE), and reason is that this material is suitable for injection moulding manifold 450; 550, especially high speed injection molding has enough low surface energy simultaneously, to minimize or to suppress medicated powder deposition thereon.But, can use other material and manufacture or moulding process.As other possible material, can be the fluoropolymer polymer that has of mentioning, the ethylene-propylene of for example fluoridizing (FEP) and other non-fluorinated polymer, for example polypropylene (PP).

Be understandable that with any part and any assembly thereof of the equipment of medicament contact and can form or be coated with by the material of such as the fluoropolymer polymer (as PTFE or FEP) etc. that can reduce medicine and its adhesion.Also can on any movably parts, be coated with, increase its desired mobility.Therefore, can apply that friction coatings strengthens CONTACT WITH FRICTION and if desired for example, for reducing the lubricant (silicone oil) of CONTACT WITH FRICTION.

At length say, manifold itself can be all or part of form or is coated with to the material that adheres to trend on it by reducing medicine.Such material can for example reduce the surface energy about manifold surface.Be applicable to using fluoropolymer material.Acetal (acetal) material of high density polyethylene (HDPE) (HDPE) and/or modification is also applicable to using.

Applicable fluoropolymer material comprises those the multiple materials that are selected from one or more following monomeric unit: tetrafluoroethene (PTFE), PEP (FEP), perfluorinate alcoxyl base alkane (PFA), ETFE (ETFE), polyvinylidene fluoride (vinyldienefluoride) are (PVDF) and ethlyene dichloride tetrafluoroethene.Particularly suitable is fluorinated polymer, and it has relatively high fluorine carbon ratio, as perfluocarbon polymer, as PTFE, PFA and FEP.Especially when using making coatings, optionally by fluoropolymer polymer with such as following nonfluorinated polymers, mix, as polyamide, polyimides, polyamide-imide, polyether sulfone, polyphenylene sulfide and amine-formaldehyde thermosetting resin.These polymer that add generally improve the adhesion of polymer coating to substrate.Preferred polymeric blends is PTFE/FEP/ polyamide-imide, PTFE/ polyether sulfone (PES) and FEP-benzo guanamine.

What it should also be clear that is other details, change and the change that " summary of the invention " part discloses illustrative drug distributor, pharmaceutical carrier and the manifold described for relevant accompanying drawing.

When stating, the element of drugs distribution apparatus of the present invention can be manufactured by conventional engineering material, especially conventional engineering plastic materials, and more preferably those allow the material of element casting.

Manifold of the present invention is applicable to the drugs distribution apparatus for dispense powders pharmaceutical preparation, especially treats respiratory system disease, as asthma and chronic obstructive pulmonary disease (COPD), bronchitis and chest infection.

Described manifold especially can be used for transmitting take one or more following listed medicine as basic drug powder agent.When manifold is used for only having single blister package, the pharmaceutical preparation in this packing can comprise only one of listed medicine (monotherapy) or multiple listed medicine (conjoint therapy).When manifold is used for multiple (especially two kinds) blister package, each packing can contain the drug powder preparation that comprises one or more listed medicine, at least one of the medicine that packing contains at least one medicine of not finding in other packing or comprises other packing.When manifold is used for two blister packages, the drug powder preparation in a packing comprises a kind of medicine of not finding in another packing.Usually, each packing is packed different medicines by comprising from another.

Therefore, applicable medicine can be selected from, and for example analgesic, as codeine, paramorphan (dihydromorphine), Ergotamine, fentanyl or morphine, angina pectoris medicine, as diltiazem

, antiallergic agent, for example, for example, as cromoglycate (sodium salt), ketotifen or Nedocromil (its sodium salt), anti-infective, as cephalosporins, penicillins, streptomycin, sulfonamides, Tetracyclines and Pentamidine, antihistaminic, as methapyrilene, anti-inflammatory agent, for example, for example, for example, for example, as beclometasone (its dipropionate), Fluticasone (its propionic ester), flunisolide, budesonide, rofleponide, mometasone (its furoate), ciclesonide, omcilon (its acetonide) or 6 α, α-propionyloxy-androstane-Isosorbide-5-Nitrae-diene-17,9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 β-thiocarboxylic acid S-(2-oxo-tetrahydrochysene-furan-3-yl) ester, cough medicine, as narcotine, bronchodilator, as albuterol (for example, as free alkali or sulfate), salmaterol (for example, as xinafoate), ephedrine, epinephrine, fenoterol (for example, as hydrobromate), Salmefamol, carbuterol, Mabuterol, etanterol, naminterol, clenbuterol, flerobuterol, bambuterol, QAB-149 (indacaterol), formoterol (for example, as fumarate), isoproterenol, metaproterenol (metaproterenol), phyenlephrinium, phenylpropanolamine, pirbuterol (for example, as acetate), D-1959 (for example, as hydrochlorate), asmaten, terbutaline (for example, as sulfate), isoetarine, tulobuterol or 4-hydroxyl-7-[2-[[2-[[3-(2-benzene ethyoxyl) propyl group] sulfonyl] ethyl] amino] ethyl-2 (3H)-benzothiazolone, adenosine 2a agonist, for example (2R, 3R, 4S, 5R)-2-[6-amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purine-9-yl]-5-(2-ethyl-2H-tetrazolium-5-yl)-tetrahydrochysene-furan-3,4-glycol (for example, as maleate), α 4 integrin inhibitors, as (2S)-3-[4-({ [4-(amino carbonyl)-piperidino] carbonyl } oxygen base) phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl group] amino } valeryl) amino] propanoic acid (for example, as free acid or potassium salt), diuretic, as amiloride, anticholinergic, as Atem (as its bromide), tiotropium, atropine or oxitropium bromide, hormone, as cortisone, hydrocortisone or andrographolide, xanthine, as aminophylline, Oxtriphylline, theophylline-lysine or theophylline, human cytokines and peptide class, for example insulin or glucagon, vaccine, diagnostic agent and gene therapy.Those skilled in the art are very clear, when applicable, for activity and/or the stability of optimization medicine, can use the form of salt (for example alkali metal salt or amine salt or acid-addition salts) or ester (for example lower alkyl esters) or the solvate (as hydrate) of medicine.

Described pharmaceutical preparation product can be monotherapy (containing a kind of active medicine) product on the one hand, or can be conjoint therapy (containing various active medicine) product.

The applicable medicine of conjoint therapy product or drug component are generally selected from antiinflammatory (for example 17-hydroxy-11-dehydrocorticosterone or NSAID), anticholinergic agents (for example M ₁, M ₂, M ₁/ M ₂or M ₃receptor antagonist), other β ₂-adrenoceptor agonists, anti-infective (for example antibiotic or antiviral agents) and hydryllin.Comprise all applicable combinations.

Applicable antiinflammatory comprises 17-hydroxy-11-dehydrocorticosterone and NSAIDs.The applicable 17-hydroxy-11-dehydrocorticosterone that can be used for combining with the compounds of this invention use is that those have the oral of anti-inflammatory activity and suck 17-hydroxy-11-dehydrocorticosterone and prodrug thereof.Example comprises medrat, andrographolide, dexamethasone, fluticasone propionate, 6 α, fluoro-17 α of 9 α-bis--[(2-furyl carbonyl) oxygen base]-11 Alpha-Methyl-3-oxo-androstane-1, beta-hydroxy-16, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, α-propionyloxy-androstane-1,9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17, 4-diene-17 β-thiocarboxylic acid S-(2-oxo-tetrahydrochysene-furan-3S-yl) ester, beclomethasone ester (for example its 17-propionic ester or 17, 21-dipropionate), budesonide, flunisolide, mometasone ester (as furoate), triamcinolone acetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541 and ST-126.Preferred 17-hydroxy-11-dehydrocorticosterone comprises fluticasone propionate, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androstane-1, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, fluoro-17 α of 9 α-bis--[(2-furyl carbonyl) oxo]-11 Alpha-Methyl-3-oxo-androstane-1, beta-hydroxy-16, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-3-oxo-17 α-(2, 2, 3, 3-tetramethyl cyclopropyl carbonyl) oxygen base-androstane-1, 4-diene-17 β-thiocarboxylic acid S-cyano methyl ester, 6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-(1-methyl cyclopropyl carbonyl) oxygen base-3-oxo-androstane-1, 4-diene-17 β-thiocarboxylic acid S-methyl fluoride ester and 9 α, chloro-11 β of 21-bis-, 17 alpha-alpha-dimethyl-1, 4-pregnen diethylene-3, 20-diketone-17-[2 '] furoate (mometasone furoate).

Other 17-hydroxy-11-dehydrocorticosterone is shown in described in WO02/088167, WO02/100879, WO02/12265, WO02/12266, WO05/005451, WO05/005452, WO06/072599 and WO06/072600.

To shifting activation, can there is selectivity trans-repression and can in following patent, disclose WO03/082827 by manifold described herein available nonsteroidal compound with glucocorticoid agonism in conjoint therapy, WO98/54159, WO04/005229, WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280, WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO00/66590, WO03/086294, WO04/026248, WO03/061651, WO03/08277, WO06/000401, WO06/000398 and WO06/015870.

Applicable NSAIDs comprises sodium cromoglicate, sodium nedocromil, phosphodiesterase (PDE) inhibitor is (as theophylline, the PDE3/PDE4 inhibitor of PDE4 inhibitor or mixing), leukotriene antagonist, leukotriene synthetic inhibitor, iNOS inhibitor, trypsinlike enzyme and elastase inhibitor, Beta 2 integrin antagonist and adenosine receptor agonist or antagonist (for example adenosine 2a agonist), cytokine antagonist (for example chemokine antagonists), cytokine synthetic inhibitor or 5-fat oxidation enzyme inhibitor.The example of iNOS inhibitor comprise all in WO93/13055, WO98/30537, WO02/50021, WO95/34534 and WO99/62875 disclosed those.The example of CCR3 inhibitor be included in WO02/26722 disclosed those.

Applicable bronchodilator is β ₂-adrenoceptor agonists, comprise that (it can be racemic modification or single enantiomer to salmaterol, as R-enantiomer), (it can be racemic modification or single enantiomer for for example salmeterol xinafoate, albuterol, as R-enantiomer), (it can be racemic modification or single diastereomer, as R for for example salbutamol sulfate or its free alkali, formoterol, R-diastereomer), for example formoterol fumarate or terbutaline and its esters.The β that other is applicable ₂-adrenoceptor agonists is 3-(4-{[6-({ (2R)-2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) hexyl] oxygen base } butyl) benzsulfamide, 3-(3-{[7-((2R)-2-hydroxyl-2-[4-hydroxyl-3-methylol) and phenyl] ethyl }-amino) heptyl] oxygen base } propyl group) benzsulfamide, 4-{ (1R)-2-[(6-{2-[(2, 6-dichloro benzyl) oxygen base] ethyoxyl } hexyl) amino]-1-hydroxyethyl }-2-(hydroxymethyl) phenol, 4-{ (1R)-2-[(6-{4-[3-(cyclopenta sulfonyl) phenyl] butoxy } hexyl) amino]-1-ethoxy }-2-(methylol) phenol, N-[2-hydroxyl-5-[(1R)-1-hydroxyl-2-[[2-4-[[(2R)-2-hydroxyl-2-phenethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] Methanamide, N-2{2-[4-(3-phenyl-4-methoxyphenyl) aminophenyl] ethyl }-2-hydroxyl-2-(8-hydroxyl-2 (1H)-quinoline-5-yl) ethamine and 5-[(R)-2-(2-{4-[4-(2-amino-2-methyl-propoxyl group)-phenyl amino]-phenyl }-ethylamino)-1-hydroxyl-ethyl]-8-hydroxyl-1H-quinoline-2-one-.β ₂-adrenoceptor agonists is the β of long action time preferably ₂-adrenoceptor agonists (LABA), for example, provide effective bronchiectasis approximately 12 hours or above compound.

Other β ₂-adrenoceptor agonists is included in those disclosed in following patent: WO02/066422, WO02/070490, WO 02/076933, WO 03/024439, WO03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01/42193 and WO03/042160.

Applicable phosphodiesterase 4 (PDE4) inhibitor comprises the known compound that can suppress PDE4 enzyme or discovery and act as PDE4 inhibitor, and they are only PDE4 inhibitor, is not the compound that suppresses other member of PDE family and PDE4.Conventionally preferably use and there is IC ₅₀ratio is approximately 0.1 or above PDE4 inhibitor, and this ratio is considered to the IC of high-affinity in conjunction with the PDE4 catalysis form of rolipram ₅₀iC divided by low affinity in conjunction with the form of rolipram ₅₀.For object of the present disclosure, low affinity is called as " low affinity " binding site (LPDE 4) in conjunction with the cAMP catalytic site of R and S rolipram, and high-affinity is called as " high-affinity " catalytic site (HPDE 4) in conjunction with other form of this catalytic site of rolipram.Term " HPDE4 " and the term " hPDE4 " for representing people PDE4 should not obscured mutually.

Measure IC ₅₀the method of ratio is at United States Patent (USP) 5,998, provides in 428, and this patent is incorporated herein by reference by reference of text.For another description of this method of testing, also can apply for WO 00/51599 referring to PCT.

Applicable PDE4 inhibitor comprises that those have the compound of useful treatment ratio, the i.e. preferential compound that suppresses cAMP catalytic activity, wherein this enzyme is the form of low-affinity in conjunction with rolipram, therefore reduces the side effect that obvious form of being combined rolipram with inhibition high-affinity is associated.The another kind of method that those compounds are called to preferred compound is that described compound has 0.1 or above IC ₅₀ratio, this ratio is considered to the IC of high-affinity in conjunction with the PDE4 catalysis form of rolipram ₅₀iC divided by low affinity in conjunction with the form of rolipram ₅₀.

The improvement of another exquisiteness of this standard is that wherein PDE4 inhibitor has approximately 0.1 or above IC ₅₀ratio; This ratio is to adopt 1 μ M[ ³h]-cAMP is substrate, with 1nM[ ³h] R-rolipram competition combination, form high-affinity and be combined the IC of PDE4 catalytic activity of rolipram form with the low affinity of inhibition in conjunction with the PDE4 form of rolipram ₅₀the IC that value is compared ₅₀ratio.

Optimal is that those have IC ₅₀the PDE4 inhibitor that ratio is greater than 0.5, especially has those compounds that are greater than 1.0 ratios.Preferred compound is cis 4-cyano group-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexane extraction-1-carboxylic acid, 2-carbonyl methoxyl group-4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane extraction-1-ketone and cis-[4-cyano group-4-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl) cyclohexane extraction-1-alcohol]; These are preferential examples in conjunction with the compound of low-affinity binding site, and it has 0.1 or above IC ₅₀ratio.

Other applicable medical compounds comprises: at United States Patent (USP) 5, disclosed cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl in 552,438] cyclohexane extraction-1-carboxylic acid (also referred to as cilomilast) and salt, ester, prodrug or physical form; (Abst P.98 for Hofgen, N.et al.15th EFMC lnt Symp Med Chem (Sept 6-10, Edinburgh) 1998 for the AWD-12-281 of elbion; CAS reference No.247584020-9); A kind of 9-benzyladenine derivant of NCS-613 (INSERM) by name; The D-4418 of Chiroscience and Schering-Plough; A kind of benzodiazepine

class PDE4 inhibitor, belongs to the CI-1018 (PD-168787) of Pfizer; Kyowa Hakko is disclosed a kind of benzo benzodioxole derivatives in WO99/16766; The K-34 of Kyowa Hakko; The V-11294A of Napp (Landells, L.J.et al.Eur Resp J[Annu Cong Eur Resp Soc (Sept 19-23, Geneva) 1998] 1998,12 (Suppl.28): Abst P2393); The phthalazone (WO99/47505, the disclosure content is incorporated herein by reference) of roflumilast (CAS searching number 162401-32-3) and Byk-Gulden; Pumafentrine, (-)-p-[(4aR ^*, 10bS ^*)-9-ethyoxyl-1,2,3,4,4a, 10b-six hydrogen-8-methoxyl group-2-methyl benzo [c] [1,6] naphthyridines-6-yl]-N, N-diisopropyl Benzoylamide, it is the PDE3/PDE4 inhibitor mixing, by Byk-Gulden, existing Altana preparation and open; The arofylline of Almirall-Prodesfarma research and development; The VM554/UM565 of Vernalis; Or T-440 (Tanabe Seiyaku; Fuji, 162) and T2585 K.et al.JPharmacol Exp Ther, 1998,284 (1):.

Other compound is open in WO04/024728, WO04/056823 and WO04/103998, is the application of Glaxo Group Limited.

Applicable anticholinergic agents is those compounds that are used as muscarinic receptor antagonist, and especially those are M ₁or M ₃the antagonist of receptor, M ₁/ M ₃or M ₂/ M ₃the dual antagonist of receptor, M ₁/ M ₂/ M ₃the full antagonist of receptor.Exemplary compounds comprises the alkaloids of Semen daturae plant, for example atropine, scopolamine, melyltropeine, hyoscyamine; These compounds as tertiary amine generally with the form administration of salt.

Other applicable anticholinergic agents is muscarine antagonist, as (in 3-)-3-(2, 2-bis--2-thienyl vinyl)-8, 8-dimethyl-8-azepine (azonia) dicyclo [3.2.1] octane iodide, (in 3-)-3-(2-cyano group-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azabicyclo [3.2.1] octane bromide, 4-[hydroxyl (diphenyl) methyl]-1-{2-[(phenyl methyl) oxygen base] ethyl }-1-azabicyclo [2.2.2] octane bromide, (1R, 5S)-3-(2-cyano group-2, 2-diphenyl-ethyl)-8-methyl-8-{2-[(phenyl methyl) oxygen base] ethyl }-8-azabicyclo [3.2.1] octane bromide, (interior)-3-(2-methoxyl group-2, 2-bis--thiophene-2-base-ethyl)-8, 8-dimethyl-8-azabicyclo [3.2.1] octane iodide, (interior)-3-(2-cyano group-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azabicyclo [3.2.1] octane iodide, (interior)-3-(2-carbamoyl-2, 2-diphenyl-ethyl)-8, 8-dimethyl-8-azabicyclo [3.2.1] octane iodide, (interior)-3-(2-cyano group-2, 2-bis--thiophene-2-base-ethyl)-8, 8-dimethyl-8-azabicyclo [3.2.1] octane iodide and (interior)-3-{2, 2-diphenyl-3-[(1-phenyl-methoxyl group)-amino]-propyl group }-8, 8-dimethyl-8-azabicyclo [3.2.1] octane bromide.

Particularly suitable anticholinergic agents comprises ipratropium (for example, as its bromide), and trade name is liked complete happy (Atrovent) (atrovent), oxitropium bromide (oxitropium) (for example, as its bromide) and tiotropium (for example, as its bromide) (CAS-139404-48-1).Also have: methantheline (CAS-53-46-3), Propantheline (CAS-50-34-9), Anisotropine MB or Valpin 50 (CAS-80-50-2), clidinium bromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), Isopropamide Iodide (CAS-71-81-8), Cantil (United States Patent (USP) 2,918,408), Tridihexethyl Chloride (Pathilon, CAS-4310-35-4) and tralin (Tral, CAS-115-63-9).Also can be referring to cyclogyl hydrochloride (CAS-5870-29-1), N-ethyl-N-(.gamma.-picolyl)tropamide (CAS-1508-75-4), benzhexol hydrochloride (CAS-144-11-6), pirenzepine (CAS-29868-97-1), Telenzepine (CAS-80880-90-9), AF-DX 116 or Methoctramine and those disclosed compound in WO01/04118.Also has Revatropate (for example its hydrobromate, CAS 262586-79-8) and WO01/04118 in disclosed LAS-34273, darifenacin (CAS 133099-04-4 or CAS 133099-07-7, commodity are called Enablex, for its hydrobromate), oxibutynin (CAS5633-20-5, commodity are called Ditropan (Ditropan XL)), terodiline (CAS15793-40-5), tolterodine (CAS 124937-51-5 or CAS 124937-52-6, for tartrate, trade name Detrol), otilonium Bromide (otilonium) (for example its bromide, CAS26095-59-0, commodity are called Spasmomen (Spasmomen)), spasmex (CAS10405-02-4) and solifenacin (solifenacin) (CAS 242478-37-1 or CAS242478-38-2, for succinate, also referred to as YM-905, trade name Vesicare).

Other anticholinergic agents is included in those disclosed in USSN 60/487,981 and USSN 60/511,009.

Applicable antihistaminic is (also referred to as H ₁-receptor antagonist) comprise any one or more known inhibition H ₁-receptor is also used safe numerous antagonisies to people.All is all histamine and H ₁reversible, the competitive inhibitor of-acceptor interaction.Example comprises ethanolamines, ethylenediamines and alkyl amine.In addition, other first generation antihistaminic comprises that those are characterized as the compound based on piperazine and phenothiazine.Second filial generation antihistaminic as non-sedating has similar structure activity relationship because their retain parent nucleus ethylidene (alkylamine) or intend with piperazine or piperidines like tertiary amine group.

The example of H1 antagonist includes but not limited to amelexanox, astemizole, azatadine, nitrogen

si Ting, acrivastine, brompheniramine, alerlisin, levocetirizine, Efletirizine, chlorphenamine, Clemastime Fumartis, marezine, carebastine, Cyproheptadine, Polistin, desloratadine, doxylamine, Dimethindene, ebastine, Epinastine, Efletirizine, fexofenadine, atarax, ketotifen, loratadine, Levocabastine, mizolastine, mequitazine, mianserin, Noberastine, meclizine, norastemizole, olopatadine, Picumast, neo-antergan, promethazine, terfenadine, tripelennamine, temelastine, alimemazine and triprolidine, especially alerlisin, levocetirizine, Efletirizine and fexofenadine.

Exemplary H1 antagonist is as follows:

Ethanolamines: the bright and dimenhydrinate of carbinoxamine maleate, tavehil, Diphenylammonium chloride..

Ethylenediamines: Pyrilamine, tripelennamine hydrochloride and tripelennamine citrate.

Alkyl amine: chlorphenamine and its esters, as maleate, and Acrivastine.

Piperazines: hydroxyzine hydrochloride, hydroxyzine pamoate, Cyclizine, cyclizine lactate, bornamine and hydrochloric acid cetirizine HCl.

Piperidines: astemizole, Levocabastine Hydrochloride, loratadine or its decarbonylation base oxethyl analog, and terfenadine and fexofenadine hydrochloride or another pharmaceutically acceptable salt.

But, hydrochloric acid nitrogen this fourth is another H1 receptor antagonist, and it can be used for and PDE4 inhibitor drug combination.

Described medicine or wherein a kind of medicine can be H ₃antagonist (and/or inverse agonist).H ₃the example of antagonist comprises for example those disclosed compounds in WO2004/035556 and WO2006/045416.

Spendable other histamine receptor antagonists comprises H4 receptor antagonist (and/or inverse agonist), the disclosed compound in J.Med.Chem.46:3957-3960 (2003) such as such as Jablonowski.

Aspect combination drug, generally by known method, according to experiment basis, determine preparation (co-formulation) compatibility altogether, and depend on the type of selected drugs distribution apparatus effect.

The ingredient of combination drug is applicable to being selected from antiinflammatory (for example 17-hydroxy-11-dehydrocorticosterone or NSAID), anticholinergic agents (for example M ₁, M ₂, M ₁/ M ₂or M ₃receptor antagonist), other β ₂-adrenoceptor agonists, anti-infective (for example antibiotic or antiviral agents) and hydryllin.Comprise all applicable combinations.

Described preparation compatibility component is altogether applicable to comprising β ₂-adrenoceptor agonists and 17-hydroxy-11-dehydrocorticosterone; And the described component that is incompatible of preparation altogether comprises PDE-4 inhibitor, anticholinergic agents or its mixture.β ₂-adrenoceptor agonists can be for example albuterol (for example its free alkali or sulfate) or salmaterol (for example its xinafoate) or formoterol (for example its fumarate).17-hydroxy-11-dehydrocorticosterone can be for example a kind of beclomethasone ester (for example dipropionate) or Fluticasone ester (for example propionic ester) or budesonide.

In one example, described altogether preparation compatibility component comprises fluticasone propionate and salmaterol or its salt (especially xinafoate), and the described preparation altogether component that is incompatible comprises PDE-4 inhibitor, anticholinergic agents (for example ipratropium bromide or tiotropium bromide) or its mixture.

In another example, the described component of preparation adaptation altogether comprises budesonide and formoterol (for example its fumarate), and the described not adaptive component of preparation altogether comprises PDE-4 inhibitor, anticholinergic agent (for example ipratropium bromide or tiotropium bromide) or its mixture.

The powdery drug particle that is applicable to the alveolar region that is passed to bronchus or lung generally has the aerodynamic diameter that is less than 10 microns, preferably 1-6 micron.If need to be delivered to the other parts of respiratory tract, as nasal cavity, mouth or throat, can use the particle of other volume.Described medicine can, with pure medicament forms transmission, still more suitably, preferably transmit medicine together with the excipient (carrier) that is applicable to sucking.Applicable excipient comprises organic excipients, as polysaccharide (being starch, cellulose etc.), lactose, glucose, mannitol, aminoacid and maltodextrin, and inorganic excipients, as calcium carbonate or sodium chloride.Lactose is preferred excipient.

The granule of powdery medicine and/or excipient can be produced by routine techniques, for example by micronization, mill or sieve.In addition, medicine and/or excipient powders Design and Machining can be had to special density, volume range or characteristic.Granule can comprise active medicine, surfactant, wall and form material or persons skilled in the art and think other compositions of needs.

By the method for knowing, for example, by mixing, co-precipitation etc., excipient can be included in medicine.Generally the admixture of excipient and medicine is made to preparation to allow accurate-metering, and admixture is distributed in dosage form.The admixture of standard for example comprises 13000 microgram lactose with 50 microgram medicament mixed, and the ratio that obtains excipient and medicine is 260: 1.Can use the excipient of 100: 1 to 1: 1 and the dosage admixture of medicine ratio.But extremely low at excipient and medicine ratio, drug dose repeatability may be easy to change.

On the one hand, drugs distribution apparatus as herein described is suitable for distributing the medicine for the treatment of respiratory system disease, and for example pneumonopathy and disease of bronchus, comprise asthma and chronic obstructive pulmonary disease (COPD).On the other hand, the present invention is suitable for distributing that be used for the treatment of need to for example, for example, by the circulate medicine of disease (migraine, diabetes, analgesia) of Drug therapy of body, the morphine sucking.

Therefore, the invention provides drugs distribution apparatus in treatment respiratory system disease, as the purposes in asthma and COPD.In addition, the method that the invention provides one and treat respiratory system disease (as asthma and COPD), the method comprises the drug products that gives effective dose as herein described by sucking from this paper drugs distribution apparatus.

Certainly, requiring to reach any concrete medical compounds of therapeutic effect or the amount of its pharmaceutically acceptable salt, solvate or its physiological functional deriv changes the patient of the approach with affiliated specific compound, administration, treatment and the particular disorder for the treatment of or disease.The medicine of the present invention for the treatment of respiratory disorder can be by for example sucking and give, and its dosage is 0.0005mg-10mg, preferably 0.005mg-0.5mg.Adult's dosage range is generally 0.0005mg-100mg every day, preferably every day 0.01mg-1.5mg.

Should be clear that proposed disclosure is only for the object of explanation, the present invention expands to its change, changes and improvements.

Can use the application of this description and the formation of claims part as any basis of the priority of application afterwards.The claim that these were applied for afterwards requires to relate to the combination of any feature as herein described or feature.The form that they can take product, method or purposes to require, and can comprising, for example but be not limited to one or more of following claim.

Claims (61)

1. for the manifold of drugs distribution apparatus, this device is for transmitting each the drug powder of open blister bag of many blister packages, and this manifold comprises

Housing,

This housing limits the chimney with chimney air inlet and multiple chimneys gas outlet, and it is for guiding air-flow to flow to described chimney gas outlet from described chimney air inlet;

This housing also limits the chamber with multiple chamber air inlets and chamber gas outlet,

Wherein this manifold comprises multipair chimney gas outlet and chimney air inlet,

Wherein said chimney gas outlet and described chamber air inlet are each other side by side, thereby make when the described open blister bag of described blister package is positioned at its adjacent place, described air-flow is directed to chamber air inlet from chimney gas outlet by open blister bag, to carry described drug powder and to make it be sent to described chamber gas outlet from chamber air inlet in air-flow

And it is described each to being in use associated from the open blister bag of one of different described multiple blister packages,

And one or more steam vent is wherein provided between chimney and chamber, makes by indoor the air-flow introduction chamber of discharging, with disruptiveness, clash into and to transport the air-flow that carries drug powder,

And the air entry point that wherein only enters chimney is chimney air inlet, one or more steam vent and one or more chimneys gas outlet.

2. the manifold of claim 1, wherein said chamber only has 1 chamber gas outlet.

3. the manifold of claim 1, the arrangement of wherein said manifold makes in use, can be by the total air flow of 3-50% that enters this manifold by chimney air inlet by described chimney gas outlet or each chimney gas outlet guide openings blister pouch, and the total air flow of 97-50% is led in described chamber by one or more steam vents.

4. the manifold of claim 3, the arrangement of wherein said manifold makes in use, can be by the total air flow of 5-25% that enters this manifold by chimney air inlet by described chimney gas outlet or each chimney gas outlet guide openings blister pouch, and the total air flow of 95-75% is led in described chamber by one or more steam vents.

5. according to the manifold of any one in claim 1-4, the total air flow that wherein this manifold enters manifold for the speed with 60 liters/min by chimney air inlet provides the gas-flow resistance of 1-5kPa.

6. according to the manifold of any one in claim 1-4, wherein said chimney gas outlet and/or chamber air inlet limit the basic circular section that a kind of optional diameter is 1-7mm.

7. according to the manifold of any one in claim 1-4, wherein said chimney gas outlet and/or chamber air inlet are equipped with the crosspiece of crossing over it.

8. the manifold of claim 7, wherein this crosspiece is shaped as cross.

9. according to the manifold of any one in claim 1-4, wherein said chimney and chamber are settled each other side by side.

10. according to the manifold of any one in claim 1-4, wherein said chimney and chamber are positioned in one of top each other.

11. according to the manifold of any one in claim 1-4, and wherein said chimney and chamber are shared common wall, and at least one of one or more steam vents is provided for described common wall.

The manifold of 12. claim 11, wherein all one or more steam vents are all provided for described common wall.

13. according to the manifold of any one in claim 1-4, and total area of section of wherein said one or more steam vents is 1-35mm ².

14. according to the manifold of claim 13, and total area of section of wherein said one or more steam vents is 10-30mm ².

15. according to the manifold of any one in claim 1-4, and wherein said one or more steam vents limit a kind of profile that is selected from avette, ring-type, D-shape and long trough longitudinal section.

The manifold of 16. claim 15, wherein said one or more steam vents limit a kind of ring-type or ovoid in cross-section, and have separately the diameter of 1-7mm.

The manifold of 17. claim 16, wherein said one or more steam vents limit a kind of ring-type or ovoid in cross-section, and have separately the diameter of 2-5mm.

The manifold of 18. claim 15, wherein said one or more steam vents limit a kind of D-shape section, and maximum gauge is separately 1-10mm.

The manifold of 19. claim 18, wherein said one or more steam vents limit a kind of D-shape section, and maximum gauge is separately 3-7mm.

The manifold of 20. claim 15, wherein said one or more steam vents limit a kind of long trough section, and have separately the length of 1-20mm, and the width of 0.5-3mm.

The manifold of 21. claim 20, wherein said one or more steam vents limit a kind of long trough section, and have separately the length of 3-10mm, and the width of 0.7-2mm.

22. according to the manifold of any one in claim 1-4, and it comprises two long trough steam vents that are arranged in parallel with each other.

23. according to the manifold of any one in claim 1-4, and the one or more steam vents that wherein provide are adjacent to chimney gas outlet and/or chamber air inlet.

24. according to the manifold of any one in claim 1-4, and wherein one or more steam vents separate with chimney gas outlet and/or chamber air inlet.

25. according to the manifold of claim 24, and the spacing of wherein one or more steam vents and chamber air inlet is from chamber air inlet at least 10% of the measured chamber length in chamber gas outlet.

26. according to the manifold of claim 25, and the spacing of wherein one or more steam vents and chamber air inlet is from chamber air inlet at least 20% of the measured chamber length in chamber gas outlet.

27. according to the manifold of claim 26, and the spacing of wherein one or more steam vents and chamber air inlet is from chamber air inlet at least 30% of the measured chamber length in chamber gas outlet.

28. according to the manifold of any one in claim 1-4, and at least one of wherein one or more steam vents is directed to the inwall of chamber.

29. according to the manifold of any one in claim 1-4, and wherein said manifold is made by high density polyethylene (HDPE).

30. according to the manifold of any one in claim 1-4, and wherein said manifold is all or part of to be formed and/or is applied by fluoropolymer material.

31. according to the manifold of claim 30, and wherein said fluoropolymer material comprises multiple one or more the following monomeric units that are selected from: tetrafluoroethene (PTFE), PEP (FEP), perfluorinate alcoxyl base alkane (PFA), ETFE (ETFE), vinylidene fluoride (PVDF), ethlyene dichloride tetrafluoroethene and any mixture thereof.

32. according to the manifold of any one in claim 1-4, and wherein said chimney and chamber are conventionally oriented perpendicular to each other.

33. according to the manifold of any one in claim 1-4, and wherein the air-flow of transmission and exhaust airstream are the each air-flow parts that sucks air-flow, and when applying suction in chamber gas outlet, described air-flow is inhaled in manifold by chimney air inlet.

34. according to the manifold of any one in claim 1-4, and when it is suitable for applying a kind of suction at place, chamber gas outlet, exhaust airstream is greater than the air-flow of transmission.

35. according to the manifold of any one in claim 1-4, and the air entry point that wherein only enters chamber is one or more chamber air inlets, one or more steam vent and chamber gas outlet.

36. according to the manifold of any one in claim 1-4, and it is single object.

37. according to the manifold of any one in claim 1-4, and it is molded object.

38. according to the manifold of claim 22, and wherein elongate slots has a kind of tapered shape, and it is from first end that approaches most chamber outlet to second end constriction gradually that approaches most chimney breast.

39. according to the manifold of claim 38, and when wherein configuring and arranging steam vent it being used, the air-flow of Part II also flows around chamber boundary, thereby adjacent cavity boundary forms sheath sample layer.

40. manifolds and interface auxiliary device, it comprises according to the manifold of any one in claim 1-39 and the interface coordinating with it, described interface and chamber gas outlet link up to make the suction guiding air-flow of seam to enter manifold by chimney air inlet.

41. according to the device of claim 40, and wherein said interface is removably installed on manifold.

42. according to the device of claim 40 or 41, and wherein said manifold and interface are buckle-type engagement.

43. drugs distribution apparatus, it is suitable for transmitting the drug powder in each open blister bag of multiple blister packages simultaneously, and described distributor comprises according to the manifold of any one in claim 1-39.

44. according to the drugs distribution apparatus of claim 43, and it also comprises the interface that offers described manifold.

45. according to the drugs distribution apparatus of claim 44, and wherein manifold is positioned at shell, and this shell is at described interface and be used at least one open blister bag of described many blister packages that place, the centre position between place is provided.

46. according to the drugs distribution apparatus of claim 43-44 any one, it also comprises shell, and a kind of machinery in this shell, this machinery is for opening at least one each blister pouch of described many blister packages, and the blister pouch of described opening is offered to chimney gas outlet and chamber air inlet.

47. according to the drugs distribution apparatus of claim 46, and wherein said machinery comprises index device, and it is for guide a blister pouch into manifold at every turn.

48. according to the drugs distribution apparatus of claim 47, and it uses from least one blister package in described multiple blister packages strip and that have the multiple different blister pouch that comprise different pharmaceutical dosage, and wherein said bag is separated continuously along the length of band.

49. according to the drugs distribution apparatus of claim 43, and it comprises the blister package that at least one contains powder type medicine.

50. according to the drugs distribution apparatus of claim 49, and wherein said at least one blister package comprises multiple bubble-caps that contain drug powder.

51. according to the drugs distribution apparatus of claim 49, and wherein said at least one blister package comprises multiple bubble-caps that contain drug powder, and it is arranged in strip blister package in a continuous manner.

52. according to the drugs distribution apparatus of claim 51, and wherein said strip blister package comprises

(a) substrate, wherein forms bubble-cap to limit multiple blister pouch wherein, and each bag comprises drug powder;

(b) cover plate, it seals the substrate except bubble-cap region, and can be from the strip off of substrate mechanicalness to can discharge described drug powder.

53. according to the drugs distribution apparatus of claim 49, and it comprises blister package, and the drug powder that wherein comprised comprises as the bronchodilator of its active medicine component and anti-inflammatory agent.

54. according to the drugs distribution apparatus of claim 49, it comprises first and second kinds of blister packages, the drug powder being wherein included in described the first blister package comprises the bronchodilator as active medicine component, and the drug powder being included in described the second blister package comprises the anti-inflammatory agent as active medicine component.

55. according to the drugs distribution apparatus of claim 53 or 54, and wherein said bronchodilator is beta-2-agonists, and described anti-inflammatory agent is corticosteroid.

56. according to the drugs distribution apparatus of claim 51, and wherein at least one blister package has and is suitable in use longitudinally separating to open the part of this bubble-cap from least one blister package.

57. according to the drugs distribution apparatus of claim 56, wherein said separable part is the Part I of at least one blister package, and described at least one blister package also has the therefrom Part II of separable Part I, described bubble-cap is defined between described the first and second parts.

58. according to the drugs distribution apparatus of claim 57, and wherein Part II is formed by a series of grooves along its length, and wherein drug powder is contained in wherein, and Part I provides lid for each groove.

59. according to claim 56,57 or 58 drugs distribution apparatus, wherein said separable part has the first and second ends, it longitudinally separates each other, and can towards at least one blister package of the second end, draw the first end by longitudinal edge, by separation with at least one blister package described separable part.

60. according to the drugs distribution apparatus of any one in claim 49-52 and 56-58, it comprises first and second kinds of blister packages, each packing has the bag of at least one each self-contained inhalable drug powder, wherein at least one bag of the first packing comprises at least one medicine, and this medicine is not at least one bag in described the second packing.

61. according to the drugs distribution apparatus of claim 60, and wherein the inhalable drug powder in each packing is used for the treatment of respiratory system disease.

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