PCT. Figu re 2. (43) International Publication Date. 15 September 2011 ( ) WO 2011/ A9

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date CORRECTED VERSION (10) International Publication Number 15 September 2011 ( ) WO 2011/ A9 PCT (51) International Patent Classification: (72) Inventors; and A61M 15/00 ( ) (75) Inventors/Applicants (for US only): CHOWDHARY, Santanu [IN/IN]; 101, 1st Floor, A-Block, South City - 2, (21) International Application Number: Gurgaon , Haryana (IN). MITRA, Animesh PCT/IB20 11/ [IN/IN]; Flat No.-l/D, Jayshree Coop, Sector-2A, Ul- (22) International Filing Date: laskar Dutta Sarani, Bidhannagar, Durgapur, Burdwan 25 February ( ) , West Bengal (IN). (25) Filing Language: English (74) Common Representative: RANBAXY LABORATO (26) Publication Language: English RIES LIMITED; c/o Vijayaraghavn, B., Intellectual Property Department, 600 College Road East, Suite 2100, (30) Priority Data: Princeton, New Jersey (US). 566/DEL/ March 2010 ( ) IN (81) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): RAN- kind of national protection available): AE, AG, AL, AM, BAXY LABORATORIES LIMITED [IN/IN]; Head AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, Office: 12th Floor, Devika Tower, 06, Nehru Place, New Delhi , Delhi (IN). (54) Title: SINGLE DOSE DRY POWDER INHALER DEVICE CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, [Continued on next page] (57) Abstract: The present invention relates to a single dose dry powder inhaler de vice with improved lung deposition, the inhaler device comprising: - a sliding mouthpiece; - a capsule chamber; - blades which are inserted into slots in the cap sule chamber; - an outer body covering the capsule chamber, and; - a lower cover with an air inlet hole; wherein the capsule chamber has a recess for the insertion of a capsule, and said capsule gets dissected by the blades along its entire length. < Figu re 2 o

2 w o 2011/ A9 1I II III III I1 1 I II I ll ll II II III III II NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, Published: SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. with international search report (Art. 21(3)) with information concerning authorization of rectifi ca (84) Designated States (unless otherwise indicated, for every tion of an obvious mistake under Rule 91.3 (b) (Rule kind of regional protection available): ARIPO (BW, GH, 48.2(1)) GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (48) Date of publication of this corrected version: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 29 March 2012 EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (15) Information about Corrections: LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, see Notice of 29 March 2012 SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Previous Correction: see Notice of 5 January 201 2

3 SINGLE DOSE DRY POWDER INHALER DEVICE Field of the Invention The present invention relates to a single dose dry powder inhaler device that delivers dry powder medication contained in a capsule to the lungs of a patient, wherein the capsule gets dissected by the blades along its entire length thereby providing improved lung deposition of the medication. Background of the Invention The administration of medicaments by inhalation is well known. There are several inhaler devices available for delivering medication to the patients. Presently, the most widely used systems for inhalation therapy are: a) pressurized metered dose inhalers (MDIs) & b) dry powder inhalers (DPIs). Pressurized metered dose inhalers (MDIs) use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract. However, despite their practicality and popularity, MDIs have some disadvantages: i) droplets leaving the actuator orifice could be large or have an extremely high velocity resulting in extensive oropharyngeal deposition reducing the amount of medicament which penetrates into the lungs; ii) the amount of medicament which penetrates the bronchial tree may be further reduced by poor inhalation technique i.e. due to the common difficulty of the patient to synchronise actuation from the device with inspiration; iii) chlorofluorocarbons (CFCs), such as freons commonly used as propellants in MDIs are disadvantageous on environmental grounds as they have a proven damaging effect on the atmospheric ozone layer. Nowadays, potentially more environmentally friendly hydrofluoroalkanes (HFA) are being used as substitute of CFCs in MDIs. Even they cannot be considered completely devoid of environmental impact.

4 iv) HFA inhalers require special maintenance and cleaning. Before use, they must be primed with several sprays, and some require priming every few weeks or so. Dry powder inhalers (DPIs) constitute a viable alternative to MDIs for the administration of medicaments to airways. The main advantages of DPIs are: i) being breath- actuated delivery systems, they do not require co-ordination of actuation, since the release of the medicament is dependent on the patient's own inhalation; ii) they do not contain propellants acting as environmental hazards; iii) the velocity of the delivered particles is the same or lower than that of the flow of inspired air making them more prone to follow the air flow rather than the faster moving MDI particles, thereby reducing upper respiratory tract deposition. DPIs can be divided into two basic types: i) single dose dry powder inhalers, for the administration of pre- subdivided single doses of the active compound in single dose compartments, like capsules or blister packs; ii) multidose dry powder inhalers (MDPIs), either with pre-subdivided single doses or pre-loaded with quantities of active ingredient sufficient for multiple doses; each dose is created by a metering unit within the inhaler. When only a single dose is desired, multiple dose dry powder inhalers are typically too bulky, costly, inefficient, or difficult to use. Several single dose inhalers intended for one-time use have been proposed. However, they have not achieved widespread use. Disadvantages remain with single dose inhalers relating to powder storage, dose uniformity, dispersion performance, ease of use, cost, and other factors. Accordingly, there is a need for an improved inhaler for efficiently providing a single dose of a powdered medicament. Single dose dry powder inhaler devices using capsule are previously known in the art. U.S. Patent No. 4,013,075 teaches a device, comprising a detachably connected mouthpiece and body, for powdered substances contained in a capsule which is longitudinally inserted into the cylindrical bore of a pivotably mounted carrier member for

5 pivoting into a transversely disposed recess in the body of the device. A pair of cutting blades is attached to the body of the device at opposite ends of the recess for severing the ends of the capsule during the pivoting movement. A bore in the mouthpiece and body coincides with the bore of the carrier member and with holes in the blades so that air can be drawn longitudinally through the severed capsule for inhalation or insufflation. U.S. Publication No. 2007/ discloses an inhaler device for powdered medicaments. The device has a body that has a recess for holding a capsule containing a powdered medicament to be inhaled, at least one air passage that is tangentially disposed to the recess, and a mouthpiece that includes a coaxially disposed inhalation passage that communicates with the recess of the body. The body has a pair of opposed spring based push-buttons that each include at least one piercing element for piercing the capsule when loaded in the recess. The medicament is released from the pierced capsule when air is drawn through the air passage(s) into the recess and swirled about therein. The mouthpiece is pivotally attached to the edge of the body so that it is pivotable between an open loading position and a closed dispensing position about an axis that is perpendicular to the longitudinal axis of the inhaler. The single dose capsule using dry powder inhaler devices known in the prior art either have a low resistance to airflow, as a result of which the powder tends to be administered too quickly and a considerable quantity of the powder impinges in the mouth and throat, where it serves no beneficial therapeutic effect. On the other hand many known dry powder inhaler devices have a greater resistance to airflow. In both cases, sufficient quantity of the powder does not reach the lungs. Indeed, the chief objective of the device from a therapeutic aspect is the maximization of the quantity of powder that reaches the lungs. This objective is defeated with both of the devices of the prior art. A further disadvantage of some known dry powder inhaler devices is their mechanical complexity, resulting in an increased production cost and difficult assembly. Unlike in the prior art devices, the capsule in the present invention is neither pierced to release the content with difficulty (greater resistance to air flow), nor made to rotate, vibrate or twist open (means to decrease resistance to air flow after piercing). Nor are the capsule contents released by cutting off both the ends of the capsule (low resistance

6 to air flow). Here, the only movement present is that of the powder within the capsule that is dissected along its entire length that provides better lung deposition of the powder. Accordingly, it is an objective of the present invention to provide an improved single dose dry powder inhaler for constantly delivering a measured dose amount of the dry powder medication into the lungs of a patient resulting in better lung deposition. The inhaler device is small, compact, and easy to operate. Summary of the Invention According to one embodiment, there is provided a single dose dry powder inhaler device with improved lung deposition, the inhaler device comprising: - a sliding mouthpiece; - a capsule chamber; - at least one blade which is inserted into slots in the capsule chamber; - an outer body covering the capsule chamber, and; - a lower cover with an air inlet hole; wherein the capsule chamber has a recess for the insertion of a capsule, and said capsule gets dissected by the blades along its entire length. According to another embodiment, there is provided a single dose dry powder inhaler device with improved lung deposition, the inhaler device comprising: - a removable cover cap with a clip; - a sliding mouthpiece; - a capsule chamber; - two blades which are inserted into slots present at two sides of the capsule chamber; - an outer body with a window covering the capsule chamber, and; - a lower cover with an air inlet hole; wherein the capsule chamber has a recess for the insertion of a capsule, and said capsule gets dissected by the blades along its entire length.

7 Brief Description of the Drawings The single dose dry powder inhaler which constitutes the present invention is shown in the accompanying drawings of the preferred embodiment in which: Figure 1 is a top perspective view of the inhaler. Figure 2 is a cross-sectional perspective view of the inhaler. Figure 3 is a bottom and rear perspective view of the inhaler. Figure 4 is a front perspective view from one side of the inhaler. Figure 5 is a break-up perspective view of the different elements of the inhaler. Figure 6 is a detailed perspective view of Figure 5. Detailed Description of the Invention Referring to the drawings, the single dose dry powder inhaler device of the present invention shown in Fig. 4 is intended to deliver a single dose of a powdered medicament stored in a capsule to the patient through inhalation. The device illustrated in Fig. 5 & 6 comprises a removable cover cap (a) with a clip (a-i), a sliding mouthpiece (b) intended to deliver medication into the lungs, the capsule chamber (c) for housing the capsule, an outer body (d) with a window (d-i) covering the chamber and a lower cover (e) for removal of unused medication and capsule shell from the device. The lower cover (e) contains an air inlet hole (e-i) through which air is drawn into the capsule chamber during inhalation. The removable cover cap (a) has an inbuilt clip (a-i) with a thumb impression. The cap snugly fits into the mouthpiece (b) so as to prevent the device from foreign matter such as dirt, dust, etc. entering into it and thereby contaminating the medication. The sliding mouthpiece (b) has an opening containing a mesh (b-i) on the outside, through which the patient inhales the medication. This portion of the device on the inner side has an inbuilt provision for a plunger, which basically aids in capsule insertion. A screw (b-ii) enables the mouthpiece to slide vertically upwards & downwards. When slided upwards, the mouthpiece reveals open the capsule chamber.

8 Inside the device is a capsule chamber (c) which has slots (c-i) for holding the blades (c-ii) in their position. The chamber has a recess (c-iii) for housing the capsule while it is to be inserted for getting dissected by the blades (c-ii). The outer body (d) covers the capsule chamber (c) and contains a window (d-i) which is placed symmetrically in line with the chamber. This enables the patient to view the capsule contents and also its fate from outside of the device. Finally, the chamber (c) opens to a lower cover (e) containing an air inlet hole (e-i) at the bottom. The lower cover (e) prevents the medication from falling out of the device after it is dissected. Due to its hinge facility, the lower cover (e) cannot be separated from the device; hence can be opened and closed based on the need to dispense the used medication. To use, the user removes the cover cap (a) to expose the mouthpiece (b). The mouthpiece (b) is allowed to slide vertically upwards and the capsule containing the medication is placed on the mouth of the capsule chamber (c). The mouthpiece (b) with the inbuilt plunger is then allowed to slide vertically downwards, resulting in the dissection of the capsule against the blades (c-ii) along the entire length of the capsule body. The dissected capsule thus falls into the chamber (c) and in turn is supported by the lower cover (e). During inhalation, air flows in from the air inlet hole (e-i) at the bottom of the lower cover (e) thus creating turbulence inside the chamber (c). As a result, the powder inside the capsule shell is dissipated in the device and flows out through the mesh (b-i) of the mouthpiece (b) and finally into the oropharyngeal cavity and into the lungs. The inhaler device of the present invention can be made of any suitable material, for example tough plastic materials such as acrylonitrile-butadiene-styrene (ABS), methylmethacrylate-acrylonitrile-butadiene-styrene (MABS) or an anti-static material. If desired, the material is substantially transparent to help the user to more readily see and understand how the device works. This encourages users to use the device in the correct way and continue to use the device in that manner for the full term of their treatment leading to increased patient compliance. The capsule for use in the inhaler device of the present invention contains a single dose of a powdered medicament. The powdered medicament may be suitable for the

9 treatment of respiratory tract diseases, for example - bronchodilators such as salbutamol, salmeterol, formoterol, or pharmaceutically acceptable salts thereof; antimuscarinic agents such as ipratropium, oxitropium, tiotropium, glycopyrrolate, or pharmaceutically acceptable salts thereof; anti-inflammatory drugs including steroids such as budesonide, beclamethasone, fluticasone, ciclesonide, mometasone or pharmaceutically acceptable salts thereof. 'Improved lung deposition' as used herein refers to 20-30% of the total dose of the powdered medicament reaching the lungs of the patient. Determination of lung deposition of the active ingredients from the dry powder inhaler device is done using an in-vitro method, i.e., Twin stage impinger (TSI). The TSI is a two-stage separation device used in the assessment of oral inhalation devices. Stage one of the apparatus including the upper impinger is a simulation of the upper respiratory tract. Stage two which includes the lower impinger is a simulation of the lower respiratory tract. A suitable liquid is used in both the upper and lower impinger. The inhaler is placed in the mouth of the TSI. Air is caused to flow through the apparatus by means of a pump, which is connected to stage two of the TSI. Air is sucked through the apparatus from the mouth, which flows through upper tubing via the upper impinger and the lower tubing to the lower impinger where it bubbles through the liquid and exits the apparatus via outlet pipe. The liquid in the upper impinger traps any particles with a size such that it is unable to reach stage two of the TSI. Fine particles (particles able to penetrate to the lungs in the respiratory tract), are able to pass into stage two of the TSI where they flow into the lower impinger liquid. The percentage of the active material in each stage of the TSI is calculated from the standard response for each test and the mean for the tests is calculated to give an indication of the proportion of the active particles reaching the second stage of the TSI apparatus. The respirable fraction (fine particle fraction) is calculated as the percentage of the total amount of drug emitted from the inhaler device that reaches stage two of the TSI. This value gives an indication of the proportion of active particles which would reach the deep lung in a patient. The unique features of the dry powder inhaler device of the present invention are:

10 1. Simple and easy to use (can be easily used by patients of the age group between 5 y s - 70yrs). 2. Portability due to its compact shape. 3. Multi-compartments with synchronized built-in features. 4. Better lung deposition of the medicament into the lungs (e.g % of the total dose of medicament) The invention is further illustrated by the following non-limiting examples. Example 1 Determination of lung deposition of the active ingredients from the dry powder inhaler device Twin stage impinger was used to assess the efficiency of the delivery of the active particles to the lungs by the inhaler device of the present invention. 30 ml of a mixture of a solution of decane sulphonic acid sodium salt (ph 2.5) and acetonitrile (70:30) was put into the lower impinger and 7ml of a mixture of a solution of decane sulphonic acid sodium salt (ph 2.5) and acetonitrile (70:30) was put into the upper impinger. The pump was adjusted to give an air flow rate of 30 litres per minute and 60 litres per minute in the apparatus, for two different sets of readings. The device was sequentially filled with ten capsules, one at a time, and turned to inhalation position. The mouthpiece end of the device was located and the pump of the apparatus was switched on for 4 seconds. The assembled inhaler was removed from the mouthpiece and the discharge sequence was repeated for further nine times (nine capsules). The apparatus was dismantled after discharging the length delivery. The sections of the apparatus making up stage one of the TSI were washed into a flask and made up to 100 ml with a mixture of a solution of decane sulphonic acid sodium salt (ph 2.5) and acetonitrile (70:30). The sections making up the second stage of the TSI were washed into another flask and made up to 100 ml with a mixture of a solution of decane sulphonic acid sodium salt (ph 2.5) and acetonitrile (70:30). The amount of active substance in each section of the TSI was measured for each test.

11 The contents of the flasks containing the washings from the stages of the TSI were assayed using High Performance Liquid Chromatography (HPLC) analysis (using Hypersil ODS column with dimension of 150mm x 4.6mm x 5µ) using mobile phase [mixture of a solution of decane sulphonic acid sodium salt (ph 2.5) and methanol (45:55)] for the content of the active material and compared against standard solutions containing, for example, 0.5 µg ml - 1 and 1 µg ml - 1 of the active material. The percentage of the active material in each stage of the TSI was calculated from the standard response for each test and the mean for the tests was calculated to give an indication of the proportion of the active particles reaching the second stage of the TSI apparatus. The values of deposition of emitted dose by TSI using the inhaler device of the invention for Avessa 100 Octacaps are detailed in Table 1. Each capsule contains Formoterol Fumarate Dihydrate IP equivalent to Formoterol Fumarate 6 meg and Fluticasone Propionate IP 100 meg. Table I : Lung Deposition Data for Inhaler of the Invention Example 2 The method detailed above was used to determine lung deposition data of marketed dry powder inhaler devices (DPI), namely Turbospin from PH&T, Cyclohaler from PCH (4 pins) and Monodose from Plastiape (4 pins) at a pump air flow rate of 30 litres per minute and a comparison was made with the values obtained for the inhaler device of the present invention. Avessa 100 Octacaps were used as the test capsule dosag form in the devices. The comparative results are presented in Table 2. Table 2: Comparison Between Lung Deposition Values of Marketed DPI Devices to the Device of the Invention

12 Product Capsule Shells Parameter Evaluated Used Evaluated DPI Devices Tested Turbospin from PH&T Fine Particle Fraction Results at 30 1/min % Avessa HPMC based 100 Size 3 Capsules Octacaps from Capsugel Deposition of Cyclohaler from PCH (4 emitted dose pins) % at different Monodose from Plastiape flow rates (4 pins) Device of the present % invention

13 We claim: 1. A single dose dry powder inhaler device with improved lung deposition, the inhaler device comprising: - a sliding mouthpiece, - a capsule chamber, - at least one blade which is inserted into slots in the capsule chamber, - an outer body covering the capsule chamber, and; - a lower cover with an air inlet hole; wherein the capsule chamber has a recess for the insertion of a capsule, and said capsule gets dissected by the blades along its entire length. 2. The single dose dry powder inhaler device of claim 1, wherein the inhaler device further comprises a removable cover cap with a clip. 3. The single dose dry powder inhaler device of claim 2, wherein the said cap snugly fits into the mouthpiece to prevent contamination of the medicament by entry of foreign matter. 4. The single dose dry powder inhaler device of claim 1, wherein the sliding mouthpiece has an opening containing a mesh through which the patient inhales the medicament. 5. The single dose dry powder inhaler device of claim 1, wherein the said device contains two blades. 6. The single dose dry powder inhaler device of claim 1, wherein the capsule comprises a medicament. 7. The single dose dry powder inhaler device of claim 6, wherein the medicament to be dispensed using the device may be selected from those suitable for the treatment of respiratory tract diseases including bronchodilators such as salbutamol, salmeterol, formoterol, or pharmaceutically acceptable salts thereof; antimuscarinic agents such as ipratropium, oxitropium, tiotropium, glycopyrrolate, or pharmaceutically acceptable salts thereof; anti-inflammatory drugs include steroids

14 such as budesonide, beclamethasone, fluticasone, ciclesonide, mometasone or pharmaceutically acceptable salts thereof. 8. The single dose dry powder inhaler device of claim 1, wherein said device is made of a material selected from tough plastic materials like acrylonitrile-butadienestyrene, methyl-methacrylate-butadiene-styrene or an anti-static material. 9. The single dose dry powder inhaler device of claim 1, wherein said device provides lung deposition of 20-30% of the total dose of medicament into the lungs. 10. The single dose dry powder inhaler device of claim 9, wherein lung deposition is measured using a twin stage impinger.

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17 International application No PCT/IB2011/05Q818 A. CLASSIFICATION OF SUBJECT MATTER INV. ADD. A61M15/00 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched A61M (classification system followed by classification symbols Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) EPO-Internal, WPI Data C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. WO 2O09/ Al (PFIZER LTD [GB] ; DI AP 1,5-10 VALERI E [GB] ; ISAACS WARREN [GB] ; MARSH STEPHEN) 8 January 2009 ( ) the whole document 2-4 US 2003/ Al (MYRMAN MATTIAS [SE] ) 16 October 2003 ( ) the whole document W0 2007/ Al (CI PLA LTD [IN] ; TURNER CRAIG ROBERT [GB] ; MALH0TRA GEENA [IN] ; LULLA A) 2 1 December 2007 ( ) page 16, l ine 30 - page 17, l i ne 11; f i gure 3 W0 2004/ Al (SCHUCKMANN ALFRED VON 2, 3 [DE] ) 22 Apri l 2004 ( ) page 7, l i ne 6 - page 7, l ine 9 ; figure 1 / - Further documents are listed in the continuation of Box C. * Special categories of cited documents : "A" document defining the general state of the art which is not considered to be of particular relevance "E" earlier document but published on or after the international filing date "L" document which may throw doubts on priority claim(s) or which is cited to establish the publication date of another citation or other special reason (as specified) "O" document referring to an oral disclosure, use, exhibition or other means "P" document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search See patent family annex. "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand the principle or theory underlying the invention "X" document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive step when the document is taken alone " document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is combined with one or more other such docu ments, such combination being obvious to a person skilled in the art. "&" document member of the same patent family Date of mailing of the international search report 29 June /07/2011 Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B Patentlaan 2 NL HV Rijswijk Tel. (+31-70) , Fax: (+31-70) Val fort, Cyri l

18 International application No PCT/ I B201 1/05Q8 18 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. WO 2009/ Al ( NEKTAR T HERAPEUTI CS 1-10 [US] ; CH EU SCOT [US] ; CHAN LEO [US] ) 18 J une 2009 ( ) abstract ; f i gure s

19 Information on patent family members International application No PCT/IB2011/05Q818 Patent document Publication Patent family Publication cited in search report date member(s) date WO Al NONE US Al AT T AU Al B R A CA Al EP Al HK Al P A U C O08 SE C SE A O03 O Al ZA A O05 W Al AU Al CA Al CN A EP Al J P A KR A MA Bl PE Al RU A US Al UY Al ZA A WO Al AU Al EP Al P B J P A US Al US Al US Al wo Al AU Al CA Al CN A EP Al J P A KR A