Abstract:
Chain linked capsules comprising multiple capsules interconnected in a chain by chain links. The capsules comprise a sleeve and a piston whereby a powder product can be sealed within the capsule. The capsules are for use in inhalation devices, for example for entraining a dose of an inhalable pharmaceutical powder product to a patient&#39;s respiratory tract.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
   This application is filed pursuant to 35 U.S.C. § 371 as a United States National Phase Application of International Application No. PCT/EP2004/004007 filed Apr. 14, 2004, which claims priority from GB 0308969.5 filed Apr. 17, 2003. 
   FIELD OF THE INVENTION 
   The present invention relates to chain linked capsules and is particularly, although not exclusively, concerned with such capsules which are adapted to contain therein a powder product, for example a medicinal powder product for a person to inhale using a dry powder inhalation device (“DPI” for short). 
   BACKGROUND OF THE INVENTION 
   DPIs are well established for use in treating respiratory diseases. As an example, there is the DISKUS® device of GlaxoSmithKline. In general, the pharmaceutical composition is formulated as a respirable powder product and the powder product is divided into a plurality of unit doses, each dose contained in its own sealed enclosure, for example in blisters on a dosing strip. When using prior art inhalation devices, an enclosure on a dosing strip in the inhalation device is opened by an opening mechanism of the inhalation device and the powder dose in the enclosure can then be entrained into a patient&#39;s respiratory tract by an airflow generated through the device by the patient inhaling at a mouthpiece of the device. 
   Some sealed enclosures used in DPIs are difficult to fill with a unit dose of the pharmaceutical powder product. Therefore there has been a tendency to make the enclosures bigger than they need to be, and adding a filler to the pure drug powder, such as lactose powder, to bulk out the powder product. The filling of larger enclosures is easier. However, GB0227128.6, filed 20 Nov. 2002, and PCT/EP03/13074 claiming priority therefrom, provides a capsule for holding a powder product which has a mechanism for facilitating the filling of it with the powder product. 
   The capsule disclosed in GB0227128.6 and PCT/EP03/13074 will generally be small enough to dispense active ingredients without the need to bulk out the powder with a lactose or other filler as much as before or even at all. Due to its small size, the capsule is referred to as a “microcapsule”. 
   The handling of the capsule, however, can be difficult or fiddly. The present invention facilitates the handling of the capsule, in particular once filled, for example to make it easier to manipulate a number of them when loaded in a DPI. 
   SUMMARY OF THE INVENTION 
   The present invention provides chain linked capsules. Preferably the present invention provides chain linked microcapsules, for example of a length of no more than about 15 mm, preferably no more than about 6 mm, and a width of no more than about 8 mm, preferably no more than about 5 mm. Preferably the chain linked capsules form a loop, e.g. an endless loop like a bicycle chain. 
   By chain linking the capsules (or microcapsules), they are easier to manipulate during filling, or during use in a DPI, than separate capsules or microcapsules. 
   The present invention further provides a capsule and a chain link for the capsule. Preferably the chain link is engageable with the capsule, for example by insertion of a protrusion of the chain link into an opening in the capsule. However it may be integral with the capsule or it may be engaged with the capsule. 
   Preferably the chain link extends from the capsule. Preferably it extends from a base of the capsule. 
   Preferably the capsule is generally cylindrical. 
   Preferably the chain link extends generally radially outward from the capsule. 
   Preferably the capsule comprises a chamber for containing a powder product. 
   Preferably the capsule comprises a sleeve which is provided with an internal chamber for holding a powder product within the capsule. 
   Preferably the sleeve comprises a first opening at a first end thereof and a second opening at an opposite end thereof. 
   Preferably the capsule comprises the sleeve and a piston. 
   Preferably the capsule comprises two chambers separated by a flange portion within the sleeve, the first of the chambers being for containing the powder product. 
   Preferably the sleeve is a single piece component. 
   Preferably the piston is adapted to extend within the sleeve from the first end, through the first chamber and the flange portion, and into the second chamber. 
   Preferably the piston comprises a cap and a rod. Preferably these parts are integrally formed. 
   Preferably the piston can seal the first chamber by forming a seal against the first opening and the flange portion. 
   Preferably the sleeve and the piston are adapted to be displaced between a discharging position or state in which both the chamber of the capsule that is adapted to contain a powder product is open to the outside environment and a vent provided in the base of the chamber is open for allowing powder product from within the chamber to be sucked out of the chamber through the first opening to the outside environment and a sealing state in which both the chamber is sealed from the outside environment and the vent is closed. 
   Preferably the base is the flange portion that separates the two chambers and the vent is provided through the flange portion. 
   Preferably, in the sealing state, the piston closes the vent to isolate the two chambers from each other. 
   Preferably the capsule can be placed into a third state in which the chamber is open to the outside environment at the first opening and there is a partial seal at the vent. This partial seal will be gas pervious but will entrap powder product, thereby enabling a vacuum to be applied at the vent to create an airflow from the first opening, through the chamber, towards the vent for entraining powder product from a powder product cloud in the outside environment into the chamber. The powder product will not pass beyond the vent, thereby filling the chamber with powder product. 
   Preferably the partial seal at the vent is formed with the piston extending through the flange portion between the two chambers. Preferably, the piston has a circumferential array of longitudinal channels formed in the portion of the outer surface of the piston that is within the flange portion. 
   Preferably the second opening of the sleeve is adapted to engage with a correspondingly sized protrusion on a chain link for rotatably connecting the capsule to the chain link. 
   Preferably the protrusion is a tubular portion having a hole therethrough. 
   Preferably the chain link is pivotally connected to the capsule, or another capsule, at one end of the chain link. 
   Preferably the chain link is pivotally connectable to capsules at both ends of the chain link. 
   Preferably a flange extends outwardly from the second end of the sleeve of the capsule. Preferably a tubular portion is provided at an outermost end of the flange. The flange may be integrally formed with the sleeve. 
   Preferably the tubular portion has a diameter that is substantially equal to or slightly greater than the diameter of the second opening of the capsule. 
   Preferably the tubular portion is inserted into an open end of an adjacent, identical, capsule to form chain linked capsules. 
   Preferably the connection is a push fit. However, the connection may be a loose fit. 
   Preferably the inside diameter of the tubular portion is larger than the distal end of the piston. 
   The chain link may be a separately formed component comprising two tubular portions. 
   Preferably the two tubular portions are provided at the ends of a flange. Preferably the flange extends between the bases of the tubular portions. 
   Preferably a first tubular portion is of a first diameter and the second tubular portion is of a second diameter. 
   Preferably both tubular portions are hollow. 
   Preferably the second tubular portion has an internal diameter corresponding generally to the outside diameter of the first tubular portion. 
   Preferably the first tubular portion of a first chain link fits within a second tubular portion of an adjacent, identical, chain link. 
   Preferably the second tubular portion has an outside diameter corresponding generally with the diameter of the second opening of the capsule. 
   Preferably a plurality of capsules and chain links are connected together to form chain linked capsules. 
   Preferably chain linked capsules are provided within a channel. The channel may be a closed channel, i.e. with both a base and a roof, or the like, and/or an endless channel. 
   Preferably the capsules and chain links are made of a plastics material. Preferably they are moulded. 
   The present invention further provides an inhalation device having chain linked, medicinal powder-containing, capsules. Preferably, the capsules are linked in an endless chain. 
   Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings in which: 

   
     BRIEF DESCRIPTION OF THE FIGURES 
       FIG. 1  is a part sectional side view of a capsule for a powder product as disclosed in GB0227128.6 and PCT/EP03/13074 for use in the present invention with the powder product contained in a sealed chamber defined between a piston and a sleeve; 
       FIG. 2  is a cross-sectional view of the capsule of  FIG. 1  in a discharge position relative to the sleeve; 
       FIG. 3  shows a plurality of capsules in accordance with the present invention in an endless channel; 
       FIG. 4  shows a pair of capsules in accordance with the present invention; and 
       FIG. 5  shows an alternative embodiment of the present invention. 
   

   DETAILED DESCRIPTION 
   Referring to  FIGS. 1 and 2  there is shown a generally cylindrical capsule  10  filled with a powder product  12 . The capsule  10  has particular application for dry powder products, more particularly for holding a unit dose of a dry powder pharmaceutical formulation or medicament for inhalation by a patient. The capsule  10  may be used in a dry powder inhalation device (a DPI). 
   The capsule  10  of  FIGS. 1 and 2  is described in detail in GB0227128.6 and PCT/EP03/13074, the entire contents of which are incorporated herein by way of reference. 
   The capsule  10  comprises a piston  14  and a sleeve  16 . 
   The sleeve  16  is a generally tubular or cylindrical member that defines a generally cylindrical passage  18  therethrough. 
   The passage  18  defines two chambers  19   a ,  19   b  separated by a flange portion  21 . The passage  18  has two ends  20 ,  24 . The flange portion  21  is between the two ends  20 ,  24 . 
   The piston  14  can positioned selectively within the sleeve  16  to provide various states for the capsule  10 : a filling state, a sealing state and a dispensing state. 
   A sealing state is shown in  FIG. 1 . The first chamber  19   a  is sealed closed; the first end  20  of the passage  18  and the flange portion  21  are both sealed by the piston  14 . The second end  24  of the passage  18 , however, is open. 
   A dispensing state is shown in  FIG. 2 . The first chamber  19   a  is no longer sealed. The first end  20  is open and a vent  23  between the flange portion  21  and the piston  14  is open. The second end  24  also still is open. Powder  12  contained within the first chamber  19   a  can therefore be vented  22  from within the capsule  10  through the first end  20  to the outside environment. 
   In a filling state, not shown, the piston  14  is positioned halfway between its positions in the dispensing state and the sealing state. In this position, the first end  20  of the passage  18  will still be open, but the vent  23  between the piston  14  flange portion  21  will be partially sealed (see GB0227128.6 and PCT/EP03/13074). The piston  14  has a circumferential array of longitudinal channels  25  formed in the portion of the outer surface of the piston  14  that will lie within the flange portion  21  in the filling state. These channels  25  allow air to pass through the vent  23 , but will not allow powder  12  to pass through the vent  23 . Therefore, the first chamber  19   a  can be filled by drawing air having powder  12  dispersed therein through the passage  18  extending through the capsule  10  from the first end  20  of the passage  18  to the second end  24  of the passage, when the capsule  10  is in its filling state. 
   The piston  14  comprises a cap  27  and a rod  29 . The cap  27  is for sealing the first end  20  of the passage  18  when the piston  14  is pushed fully into the passage  18 , as shown in  FIG. 1 . The rod  29  extends axially through the passage  18  and is for selectively opening the vent  23  in the flange portion  21 . 
   The rod  29  comprises various portions. Starting at its distal end  28  there is a narrowed portion  40 . Then there is the circumferential array of longitudinal channels  25 . Finally there is a smooth sided piston portion  42 . These, when positioned within the flange portion  21 , select the sealing state of the vent  23  in the flange portion  21 : open, partially sealed and sealed, respectively. 
   The length of the rod  29  is such that, in the sealing state, the distal end  28  of the piston  14  does not protrude beyond the second end  24  of the sleeve  16 . 
   The rod and the passage are generally round in shape. Other shapes may, however, be used. For a round shape, the distal end  14  of the rod  29  has an outer diameter D 5  that is much smaller than the inner diameter D 1  of the passage  18  at the second end  24  of the sleeve  16 . This means that there is an annular space  31  at the second end  24  of the sleeve  16  even when the piston  14  is fully pushed into the sealing state shown in  FIG. 1 . This annular space  31 , in accordance with the present invention, allows a chain link to be used to form chain linked capsules. 
     FIG. 3  shows a plurality of chain linked capsules  10  in an endless channel  30  such as one in a DPI, not shown. Such an endless channel  30  may be provided for retaining a plurality of capsules  10  for use, one at a time, by the DPI. 
   Referring to  FIG. 4 , a preferred arrangement for the chain link  32  is shown. 
   The capsule  10  is generally as described with reference to  FIGS. 1 and 2 . However, a flange  34  extends outwardly from the second end  24  of the sleeve  16  of the capsule  10  to a tubular portion  36 . The flange  34  and the tubular portion  36  form the chain link  32 . 
   The flange  34  is integrally formed with the sleeve  16 . Referring to  FIG. 5 , however, the chain link  32  may be a separately formed component comprising a flange  34  and two tubular portions  36 ,  38 . 
   Referring back to  FIG. 4 , the flange  34  has a tubular portion  36  at its outermost end. The tubular portion  36  has an outer diameter D 2  that is substantially equal to the inner diameter D 1  of the annular space  31 , i.e. the passage  18  extending through the sleeve  16  of the capsule  10 . The tubular portion  36  can therefore be inserted into the annular space  31  at the second end  24  of an adjacent capsule  10  to chain link capsules together. 
   By making the connection a push fit between the tubular portion  36  and the annular space  31 , relative rotation will still be achievable but the separation of the two connected capsules  10  will be difficult. Therefore, the chain linked capsules  10  would be able to travel along the endless channel  30  without being retained in the channel  30  from above. 
   Instead of a push fit connection, however, the capsules could be connected with a loose fit connection. This has the advantage of having a reduced resistance to flexing around the curves of the channel  30 . However, there would be an increase in the tendency for adjacent capsules to separate, thereby breaking the chain link. By making the channel  30  a closed channel, i.e. with both a base and a roof, or the like, relative axial movement between adjacent capsules  10  would be eliminated. This would prevent inadvertent separation of adjacent capsules  10 . 
   The tubular portion  36  has a hole  44  extending therethrough so that the distal end  28  of the piston  14  can be fitted therein. The inside diameter D 6  of the hole  44  is larger than the outer diameter D 5  of the distal end  28  of the piston  14  so that relative rotation of adjacent capsules  10  will not cause the piston  14  to be rotated relative to its sleeve  16 . This will help to prevent inadvertent dispensing of the powder  12  from within the capsule  10 . 
   Referring again to  FIG. 5 , a separate chain link  32  is shown. In this embodiment, the chain link  32  has two tubular portions  36 ,  38 . The two tubular portions  36 ,  38  are at opposed ends of a flange  34 . The flange extends between the bases of the two tubular portions  36 ,  38 . 
   The first tubular portion  36  has a first outside diameter D 2 . The second tubular portion  38  has a second outside diameter D 4 . Both tubular portions have holes  44  extending therethrough. 
   The second tubular portion  38  has an internal diameter D 3  corresponding generally to the outside diameter D 2  of the first tubular portion  36 . The first tubular portion  36 , therefore, has a smaller diameter than the second tubular portion  38  and it fits, rotatably, within a second tubular portion  38  of an adjacent chain link  32 . 
   The second tubular portion  38  has an outside diameter D 4  corresponding generally with the inner diameter D 1  of the passage  18  in the sleeve  16  of the capsules  10 . Therefore, the second tubular portion  38  of the chain link  32  will fit, rotatably, within the passage of the capsule  10 . This will allow a plurality of capsules  10  and chain links  32  to be used to form chain linked capsules in accordance with the present invention. 
   The capsules  10  and chain links  32  are preferably made of a plastics material and they can be moulded, e.g. by injection moulding, micro moulding etc. 
   The capsules  10  may have a length L in the range of about 5 mm to about 15 mm, an outer diameter D in the range of about 3 mm to about 8 mm, and the passage  18  extending through the capsule  10  may have an inner diameter D 1  in the range of about 1 mm to about 6 mm. In other words, the capsules  10  may be microcapsules. Such capsules  10  are particularly suited for holding unit doses of pharmaceutical powder in the range of about 2 μg to about 30 mg. The capsules  10  may each contain a unit dose of pure active drug substance, or a blend of pure active drug substances, in the range of about 2 μg to about 250 μg (i.e. no bulk filler), or a bulked-out unit dose of pharmaceutical powder up to about 30 mg. 
   For a small unit dose of pharmaceutical powder, for instance in the range of about 2-250 μg, it is preferable for the capsule length L to be in the range of about 5 mm to about 6 mm, the outer capsule diameter D to be in the range of about 3 mm to about 5 mm, and the inner diameter D 1  of the passage  18  to be in the range of about 1 mm to about 3 mm, more preferably about 2 mm. 
   Appropriate medicaments for the inhalable pharmaceutical powder for use in the present invention may 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. as 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-phenylethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol (e.g. as maleate); α 4  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. 
   Preferred medicaments are an anti-inflammatory agent (for example a corticosteroid or an NSAID), an anticholinergic agent, a β 2 -adrenoreceptor agonists, an antinfective agent (e.g. an antibiotic or an antiviral) and an antihistamine. The medicament may be the sole medicament in the capsule or in combination with another medicament. Preferred combinations are based on the preferred medicament list above. 
   Preferred as a component of a medicament combination in the capsule are albuterol, salmeterol, fluticasone propionate and beclomethasone dipropionate and salts or solvates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol. 
   A particularly preferred medicament combination for use in the capsule of the invention is a bronchodilator in combination with an anti-inflammatory. The bronchodilator is suitably a beta-agonist, particularly a long-acting beta-agonist (LABA). Suitable bronchodilators include salbutamol (e.g., as the free base or the sulphate salt), salmeterol (e.g., as the xinafoate salt) and formoterol (eg as the fumarate salt). The anti-inflammatory is suitably an anti-inflammatory steroid. Suitable anti-inflammatory compounds include a beclomethasone ester (e.g., the dipropionate), a fluticasone ester (e.g., the propionate) or budesonide or any salt or solvate thereof. One preferred combination is fluticasone propionate and salmeterol, or any salt or solvate thereof (particularly the xinafoate salt). A further preferred combination is budesonide and formoterol or any salt or solvate thereof (e.g. formoterol as the fumarate salt). 
   Generally, powdered medicament particles suitable for delivery to the bronchial or alveolar region of the lung have an aerodynamic diameter of less than 10 micrometers, preferably less than 6 micrometers. Other sized particles may be used if delivery to other portions of the respiratory tract is desired, such as the nasal cavity, mouth or throat. The medicament may be delivered as a pure drug or together with excipients (carriers) which are suitable for inhalation. Suitable excipients include organic excipients such as polysaccharides (i.e. starch, cellulose and the like), lactose, glucose, mannitol, amino acids, and maltodextrins, and inorganic excipients such as calcium carbonate or sodium chloride. Lactose is a preferred excipient. The excipient may be included with the medicament via well-known methods, such as by admixing, co-precipitating and the like. 
   Particles of the powdered medicament and/or excipient may be produced by conventional techniques, for example by micronisation, milling or sieving. Additionally, medicament and/or excipient powders may be engineered with particular densities, size ranges, or characteristics. Particles may comprise active agents, surfactants, wall forming materials, or other components considered desirable by those of ordinary skill. 
   It will of course be understood that the present invention has been described above purely by way of example. Modifications and developments may be made within the scope of the invention as defined in the claims appended hereto. 
   Moreover, use of terms such as “about” etc. in relation to values of parameters of the invention is meant to encompass the exact parameter value as well as minor deviations therefrom.