Abstract:
A medicament dispenser including a medicament container having a dispensing outlet; an agitator for agitating the contents; and a driver for driving the agitator independent of any container movement. The medicament container may be a metered dose inhaler or delivering a suitable inhalable medicament.

Description:
The instant application is filed under 35 U.S.C. § 371 as the United States National Phase Application of International Application No. PCT/EP00/09641 filed 28 Sep. 2000 claiming priority from GB 9924808.0 filed 21 Oct. 1999. 
     TECHNICAL FIELD 
     This invention relates to a medicament dispenser including an agitator for agitating the medicament contents thereof. The dispenser is particularly suitable for use as an inhalation device. 
     BACKGROUND TO THE INVENTION 
     Known medicament dispensers comprise a medicament container having a dispensing outlet for dispensing of the medicament therefrom. Such medicament dispensers often require the patient to agitate the contents thereof prior to dispensing to ensure ready and uniform dispensing of the medicament. The agitation involves a manual shaking action. 
     Agitation is particularly required where the dispenser comprises medicament as a suspension in a propellant formulation. A well-known example of this type is the metered dose inhaler for dispensing of respiratory medicament which comprises an aerosol container having a dispensing valve. The medicament is comprised within the aerosol container in the form of a suspension comprising propellant and optionally other additives such as solvents or surfactants. Such suspensions have a tendency to settle out, sediment or cream. A pre-dispensing agitation step is necessary to re-establish a uniform suspension so that uniform dispensing of medicament may be achieved. 
     Agitation can also be required where the medicament is in powder form. It is known that powders can tend to settle out, agglomerate or even cake on storage. The agitation therefore performs the function of breaking up any agglomerates or cakes that may have formed, and thereby ensures that the powder is readily dispensable. 
     Various suggestions have been made to enhance manual shaking action to maximise the effect of agitation. 
     PCT Patent Application No. WO95/30607 describes a metered dose dispensing valve including a movable agitator in the metering chamber. Manual shaking of the valve causes movement of the agitator therein which is stated to assist mixing of the drug suspension in the metering chamber. 
     PCT Patent Application No. WO96/08284 describes an inhalation device for dispensing powder form medicament including a movable weight which is configured to strike an anvil upon manual shaking of the device. The striking action causes a jolt which acts such as to assist transfer of the powder from a reservoir container to a metering recess formed in a dosing member. 
     Whilst manual shaking is a generally effective means for providing agitation it is sometimes inconvenient for the patient. In social situations, the patient often wishes to administer their medicament discretely and without drawing attention to themselves. Manual shaking of the dispenser is difficult to perform in a discrete fashion. This can lead to patient embarrassment. There is also always the possibility that the patient forgets to shake the dispenser, or does so inadequately, thereby affecting the medicament dose deliverable. 
     The Applicants have now developed a medicament dispenser which requires little or no manual shaking. The dispenser comprises a medicament container and an agitator for agitating the contents of the medicament container. A drive is provided for driving the agitator independently of any movement of the container. The dispenser therefore provides for agitation of the medicament container and contents thereof without requiring shaking by the patient. 
     SUMMARY OF INVENTION 
     According to one aspect of the present invention there is provided a medicament dispenser comprising a medicament container having a dispensing outlet; an agitator for agitating the contents of the container; and a driver for driving the agitator independently of any movement of the container, wherein the driver comprises an energy store for storing energy which energy is releasable to drive the agitator. 
     Preferably, the agitator comprises a movable element within said container. More preferably, the movable element is freely movable within the container. 
     In one aspect, the movable element is magnetically coupled to the driver. Preferably, either or both of the movable element or the driver comprises magnetic material or material which is magnetically inductive, that is to say material into which magnetism can be induced. The material may be permanently or non-permanently magnetisable. 
     In another aspect, the movable element is mechanically coupled to the driver. 
     In a preferred aspect, the container includes a rim defining an access hole, the movable element comprises a flexible sheath protruding through said access hole, and the driver comprises a rod insertable within said flexible sheath for agitation thereof. Preferably, the flexible sheath is in sealing contact with the rim. 
     In another aspect, the movable element is pneumatically drivable. 
     In another aspect, the movable element is hydraulically drivable. 
     In another aspect, the movable element is electrically drivable. Preferably, the movable element comprises a multi-component strip or wire which is deformable in response to electrical current flow. 
     Suitable multi-component strips typically comprise a plurality of layers of material, each material having a different coefficient of thermal expansion. Preferred examples of multi-component strips include strips comprising multiple layers of different metals (e.g. bimetallic strips) and strips comprising at least one piezoelectric or piezoresistive material. Suitable piezoelectric materials include piezoelectric ceramics, such as compounds of lead zirconate and lead titanate, and piezoelectric crystals which are generally polycrystalline ferroelectric materials with the perovskite structure. 
     Suitable multi-component wires typically comprise alloys of two or more metals wherein one or more of the metals undergoes a temperature induced phase change in response to electrical current flow. Preferred examples of multi-component wires include those comprised of alloys of titanium and nickel which contract when electric current is applied. 
     Preferably, the movable element is shaped to create turbulence within the container when agitated. 
     In one aspect, the agitator creates regions of pressure difference within the container. Preferably, the agitator comprises a piston mechanism within the container. More preferably, the piston mechanism is mechanically drivable by the driver. Most preferably, the drive comprises a plunger for moving the piston. 
     In another aspect, the agitator provides wave energy to the interior of the container. Preferably, the agitator is an acoustic wave energy generator or a resonant wave energy generator. 
     In one aspect, the driver is associable with the container. The driver may be external to, or internal to, the container and may be permanently or reversibly attached to the container. 
     In another aspect, the medicament dispenser additionally comprises a housing. Preferably the driver is associable with the housing. The driver may be external to, or internal to, the housing and may be permanently or reversibly attached to the housing. 
     In one aspect, the energy store comprises a biasable resilient member. Preferably, the biasable resilient member is a spring. 
     In another aspect, the energy store comprises a clockwork mechanism. 
     In another aspect, the energy store comprises a battery. 
     Preferably, the driver is responsive to a patient-actuable trigger. The trigger may comprise a button, switch or lever arrangement. More preferably, the trigger comprises a sensor which senses the breath of a patient. 
     In one aspect, the sensor comprises a breath-movable element which is movable in response to the breath of a patient. Preferably, the breath-movable element is selected from the group consisting of a vane, a sail, a piston and an impeller. 
     In another aspect, the sensor comprises a pressure sensor for sensing the pressure profile associated with the breath of a patient. 
     In another aspect, the sensor comprises an airflow sensor for sensing the airflow profile associated with the breath of a patient. 
     In another aspect, the sensor comprises a temperature sensor for sensing the temperature profile associated with the breath of a patient. 
     In another aspect, the sensor comprises a moisture sensor for sensing the moisture profile associated with the breath of a patient. 
     In another aspect, the sensor comprises a gas sensor for sensing the oxygen or carbon dioxide profile associated with the breath of a patient. 
     Preferably, dispensing from the dispensing outlet is responsive to a second patient-actuable trigger. More preferably, the patient-actuable triggers are coupled such that agitation and dispensing occurs in a sequential fashion. 
     In one preferred aspect, the container is an aerosol container, preferably comprising a metering valve at the dispensing outlet. Preferably, the aerosol container comprises a suspension of a medicament in a propellant. 
     The propellant preferably comprises liquefied HFA134a, HFA-227 or carbon dioxide. 
     The medicament is preferably selected from the group consisting of albuterol, salmeterol, fluticasone propionate, beclomethasone dipropionate, salts or solvates thereof and any mixtures thereof. 
    
    
     
       BRIEF DESCRIPTION OF THE INVENTION 
       The invention will now be described further with reference to the accompanying drawings in which: 
         FIG. 1  is a cut-away perspective view of a first medicament dispenser in accord with the present invention; 
         FIG. 2  is a sectional view of a second medicament dispenser in accord with the present invention; 
         FIG. 3  is a sectional view of a third medicament dispenser in accord with the present invention; 
         FIGS. 4   a  and  4   b  are sectional views of a fourth medicament dispenser in accord with the present invention; 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       FIG. 1 . shows a medicament dispenser suitable for use in a metered dose inhaler (MDI) for delivery of inhalable medicament. The dispenser comprises an aerosol can  10  having a dispenser outlet in the form of a metering valve  12 . The valve gasket  14  is fixedly attached (typically by crimping) to the aerosol can body  10 . The can  10  comprises a suspension  20  of medicament in a propellant. 
     Within the can  10  there are provided four vibratable flippers  30  mounted on cross-mounting  32 . Each vibratable flipper  30  is comprised of a bimetallic strip which flexes on application of electrical current. In alternative embodiments, the flippers may also comprise piezoelectric materials. The cross-mounting  32 , and hence each flipper  30 , is connected to external electric power source  40  which may be in the form of a battery or a capacitor. On application of electric power the flippers  30  vibrate thereby resulting in agitation of the suspension  20 . 
       FIG. 2 . also shows a medicament dispenser suitable for use in a metered dose inhaler (MDI) for delivery of inhalable medicament. The dispenser comprises an aerosol can  110  having a dispenser outlet in the form of a metering valve  112 . The valve gasket  114  is fixedly attached (typically by crimping) to the aerosol can body  110 . The can  110  comprises a suspension  120  of medicament in a propellant. 
     It may be seen that an access hole  116  is provided in the base  118  of the aerosol can  110  for receipt of flexible elongate sheath  132 . The sheath  132  typically comprises a latex, rubber or elastomeric material and may be seen to protrude well into the interior of the can  110 . Within the sheath  132  there is provided drive rod  130  which comprises a resiliently flexible material. The drive rod  130  connects to drive motor  140  which may for example, be an electric or clockwork motor. The drive motor  140  may in embodiments be configured to provide oscillatory or rotatory drive motion to the drive rod  130 . On application of the drive energy the drive rod  130  moves within the sheath  132  thereby resulting in agitation of the suspension  120 . 
     In an alternative embodiment, the electric or clockwork drive motor  140  is replaced by a mechanical push-drive which is capable of translating a push motion (e.g. at the top  142  of the drive) into a rotatory drive motion. Such a push-drive could incorporate a suitably configured gear train or worm and helix drive mechanism. In known metered dose inhalers wherein the can  110  sits within an actuator housing, the dispensing action typically requires the user to push down on the base  118  of the can  110  such that the valve  112  is released. It may be appreciated that the use of the push-drive will facilitate a agitation-dispensing sequence in which a first user pushing action on the push-drive results in agitation of the suspension  120  and a second user pushing action (which may be a continuation of the first) results in dispensing of the suspension  120 . 
       FIG. 3 . shows a further medicament dispenser suitable for use in a metered dose inhaler (MDI) for delivery of inhalable medicament. The dispenser comprises an aerosol can  210  having a dispenser outlet in the form of a metering valve  212 . The valve gasket  214  is fixedly attached (typically by crimping) to the aerosol can body  210 . The can  210  comprises a suspension  220  of medicament in a propellant. 
     It may be seen that an access hole  216  is provided in the base  218  of the aerosol can  210  for receipt of dynamic seal  232 . The dynamic seal  232  typically comprises a rigid elastomeric material and may be seen to form a liner to the access hole  216 . Protruding through the dynamic seal  232  there is provided piston drive shaft  230 . Piston drive shaft  230  has a shaped plunger head  234  which may in embodiments, be connected to a drive motor (not shown) such as an electric or clockwork motor. Piston  236  is received by cylinder  250  within which it is drivable. It may be seen that cylinder  250  includes entry hole  252  and narrows at its lower end to form tube  254  having exit hole  256 . 
     Agitation of the suspension  220  within the can  210  is achieved by a driving movement of the piston  236  within the cylinder  250 . In more detail, it can be seen that when the piston  236  is in the withdrawn position (as shown in  FIG. 3 ) gas may enter cylinder  250  through entry hole  252 . As the piston  236  is moved downwards the gas is initially trapped in the cylinder  250 , then pushed through tube  254  and finally expelled through exit hole  256 . Expulsion of the gas results in formation of bubbles  222  and flow agitation in the suspension  220 . 
       FIG. 4   a  shows a medicament dispenser suitable for use in a metered dose inhaler for delivery of inhalable medicament. The dispenser comprises an aerosol canister  310  having a dispenser outlet  312  in the form of a metering valve. The canister  310  has an external  315  and internal  317  wall with cavity  319  therebetween. A suspension  320  of a medicament in a propellant is contained within internal wall  317  of the canister. A magnetic impeller  365  is located within canister  310  and is free to rotate around axis  333  on shaft  335 . 
     Within cavity  319  there is provided an electric or clockwork motor  340  which connects via drive shaft  330  to magnet  360 . The electric motor may be powered by any suitable means, such as a battery (not shown). The magnet  360  may be rotated or oscillated on arm  331 , connecting to drive shaft  330 , around internal wall  317  when powered by the motor  340 . It may be appreciated that rotation or oscillation of arm  331  and of magnet  360  will result in rotation or oscillation of magnetic impeller  365 . 
     Agitation of the suspension  320  within the aerosol canister  310  is achievable by the following steps. The motor  340  is actuated by means of a pressure switch (not shown) to rotate drive shaft  330  and arm  331 , thereby rotating magnet  360  within cavity  319 . The magnet  360  on arm  331  acts magnetically on the magnetic impeller  365  within the can  310  such that the impeller  365  is also rotated. Rotation of the magnetic impeller  365  agitates the suspension  320 . 
       FIG. 4   b  shows a variation of the dispenser of  FIG. 4   a . In the metered dose inhalation device of  FIG. 4   b  an aerosol canister  310  is located within housing  370  such that dispenser outlet  312  is positioned within passage  377  of support  375 . A second passage  378  is provided within support  375  and is directed towards the interior of outlet  379 . 
     Aerosol canister  310  contains a suspension  320  of a medicament in a propellant. Magnetic impeller  365  is located within canister  310  and is free to rotate on shaft  335  about axis  333 . Detachable cap  380  encloses aerosol canister  310  within housing  370 . The cylindrical housing  370  divides into an internal  371  and external  372  wall with cavity  373  therebetween. In the position shown, magnet  360  is suspended from arm  331 , connected to drive shaft  330 , and is free to rotate or oscillate within the cavity  373  when powered by electric or clockwise motor  340 . It will be appreciated that rotation of magnet  360  leads to rotation of magnetic impeller  365  and thus agitation of suspension  320 . 
     To use the device, cap  380  is compressed thereby activating a pressure switch (not shown) of motor  340  leading to rotation of magnet  360  within cavity  373 . Magnetic impeller  365  is thus rotated within canister  310  and agitates suspension  320 . Further compression of cap  380  pushes drive shaft  330  against canister block  311 , stopping rotation of the drive shaft and moving canister  310  relative to valve member  312 . This action opens the valve and a dose of medicament contained within the aerosol canister is dispensed through passage  378  into outlet  379  to be inhaled by the patient. On removal of the pressure, resilient material  381  returns cap  380  to its resting position. 
     It may be appreciated that any of the parts of the dispenser which contact the medicament suspension may be coated with materials such as fluoropolymer materials which reduce the tendency of medicament to adhere thereto. Any movable parts may also have coatings applied thereto which enhance their desired movement characteristics. Frictional coatings may therefore be applied to enhance frictional contact and lubricants used to reduce frictional contact as necessary. 
     The medicament dispenser of the invention is suitable for dispensing medicament, particularly for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease. Appropriate medicaments may thus be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate (e.g. s the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. as the propionate ester), flunisolide, budesonide, rofleponide, mometasone e.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or 4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone; adenosine 2a agonists, e.g. 2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol (e.g. as maleate); α4 integrin inhibitors e.g. (2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoic acid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics and gene therapies. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant. Preferred medicaments are selected from albuterol, salmeterol, fluticasone propionate and beclomethasone dipropionate and salts or solvates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol. 
     Medicaments can also be delivered in combinations. Preferred formulations containing combinations of active ingredients contain salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) or formoterol (e.g. as the fumarate salt) in combination with an antiinflammatory steroid such as a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate) or budesonide. A particularly preferred combination is a combination of fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt). A further combination of particular interest is budesonide and formoterol (e.g. as the fumarate salt). 
     It will be understood that the present disclosure is for the purpose of illustration only and the invention extends to modifications, variations and improvements thereto. 
     The application of which this description and claims form part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described therein. They may take the form of product, method or use claims and may include, by way of example and without limitation, one or more of the following claims: