FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
SYSTEM FOR DELIVERY OF ERYTHROPOIETIN
2. APPLICANT (S)
(a) NAME: WOCKHARDT RESEARCH CENTRE
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210, India
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a pen device for precise delivery of erythropoietin, analogues and derivatives thereof primarily for self administration by people suffering from anemia.
The following specification particularly describes the invention and the manner in which it is to be performed.


4. Description
The present invention provides a system for delivering erythropoietin, its analogue or derivatives thereof comprising a pen shaped injection device. The device can be used for self administration by people suffering from diseases for which erythropoietin is indicated.
Pen device either with a cartridge or a syringe is used for administration of a drug substance. Typically a fluid delivery pen comprises of a cartridge holder into which a cartridge of fluids, such as a liquid medication, is loaded. The cartridge holder usually has an elongated tubular design, whose distal end is adapted to carry a needle assembly, such that the proximal tip of the needle, carried by the needle assembly, is in direct contact with the fluid inside the cartridge. The proximal end of the cartridge is generally closed with a plunger, whose inner surface is in contact with the fluid. The outer surface of the plunger is in turn connected to a piston rod. A measured movement of the plunger-piston rod in the distal direction results in the delivery of a measured dose of the fluid. The delivery device is calibrated such that the dose delivered is directly related to the movement of the plunger in the distal direction. In addition the delivery device comprises a dose setting means for setting the dose of the fluid to be dispensed, and a driving means for pushing the plunger through a distance determined by the dose setting means. The piston rod, dose setting means and driving means are enclosed, partly or wholly, in a housing.
Erythropoietin is a 165 amino acid glycoprotein manufactured by recombinant DNA technology, has the same biological effects as endogenous erythropoietin. Erythropoietin is formulated as a sterile, colorless liquid in an isotonic sodium chloride/sodium citrate buffered solution or a sodium chloride/sodium phosphate buffered solution for intravenous (IV) or subcutaneous (SC) administration. It is marketed as EPOGEN®/ PROCRIT® (Epoetin alfa).
It is available as single dose preservative-free vial. Each 1 mL solution contains 2000, 3000, 4000 or 10000 units of Epoetin alfa. It is also available as single dose preservative-free vial. Each 1 mL solution contains 40000 units of Epoetin alfa.


It is available as multi dose preserved vial, each 2 mL (20000 units, 10000 units/ mL). Available dosages are in the form vials, which require carrying and storing a large number of them and also difficulty associated with method of administration.
Erythropoietin is widely recommended for
(i) Treatment of anemia for patients suffering from chronic renal failure
patients, (ii) Treatment of anemia in Zidovudine -treated HIV-infected patients, (iii) Reduction of allogenic blood transfusion in surgery patients, and (iv) Treatment of anemia in cancer patients on chemotherapy.
The variation in dosage do vary with respect to the type of disease mentioned above, type of patient such as pediatric or adult, increase or decrease in hemoglobin content, transferring saturation, and ferritin content. Frequency of dose also varies with elapse of period.
Dosage of administration of erythropoietin is expressed in "IU" units. One "IU" is known as one international unit.
As mentioned earlier the requirement of dosages vary widely from 2000 IU, 3000 IU, 4000 IU, 5000IU, 6000IU at a time depending on the ailment, type of patient and other conditions of the patient. A 3mL cartridge can deliver a maximum dose of 6000 IU at one time and it can be used 5 times to deliver 6000 IU each time. Further if the required dosages are smaller, say 2000 IU, 3000 IU, 4000 IU etc, then erythropoietin can be administered many more times.
The erythropoietin is usually administered using conventional syringe. The delivery of erythropoietin from needles attached to syringe is painful, thus patient non¬compliance is often observed. Moreover the syringe can be used for one time delivery. Withdrawal of the fluid from the vial, often leads to the problems associated with sterility of the product filled therein.


US20060204473 and WO2007092537 discloses a reservoir that can be provided in any of a variety of forms, including, but not limited to, a cartridge, a syringe, a reservoir of a continuous delivery device, and the like.
WO2006138181 discloses four pen devices containing preserved formulations of hGH that are currently available on the market. Norditropin® (liquid, Novo Mordisk), Nutropin AQ® (liquid, Genentech) & Genotropin (lyophilized - dual chamber cartridge, Pharmacia & Upjohn) contain phenol while Somatrope® (Eli Lilly).
It was observed by the present inventor while formulating the device for administration of erythropoietin that pen device offers various administration such as dose adjustment, ease of delivery and comfort to the patient.
One of the aspects of the present invention provides a system for delivering erythropoietin, its analogue or derivatives thereof comprising a pen shaped injection device.
In another embodiments of the invention, the pen shaped injection device comprises of a cartridge.
In another embodiments of the invention, the cartridge is reusable or non-reusable.
In another embodiments of the invention, the erythropoietin, its analogue or derivatives is selected from the group consisting of erythropoietin-alfa, erythropoietin-beta, darbepoetin alfa, and pegylated erythropoietin.
In another embodiments of the invention, the pen shaped device is used for delivery of erythropoietin, its analogue or derivatives is erythropoietin alpha.
In another embodiments of the invention, the pen contains 2000- 40000 international units (IU) of erythropoietin.
In another embodiments of the invention, the dose to be delivered at one time can be 2000 IU, 3000IU, 4000IU, 5000IU and 6000IU.


In another embodiments of the invention, the system comprises of a hollow piston rod which delivers the selected dosage.
In another embodiment of the invention, the hollow piston rod has an internal thread that mate with the external thread of the drive shaft.
In another embodiment of the invention, the hollow piston rod is being axially restrained in the proximal direction relative to the housing.
The pen device that can be used for the administration of erythropoietin as detailed
below. The pen used for precise administration of dose is described in detail with
references to the drawing.
Figure 1 shows the delivery pen in its fully assembled and capped form.
Figure 2 is a sectional view along the line that sections through the center of the dose
window of Figure 1.
Figure 3 shows the assembled delivery pen, in accordance to the present invention, in
which certain layers of the pen are "made transparent", or not shown, in order to
expose the underlying components. In Figure 3 the cartridge holder and the outer
housing-tube is made transparent.
In Figures 4A, B and C the outer housing-tube is not shown, and the outer dose-drum
has been made transparent.
Figures 5 and 6 describe the design of disposable delivery devices.
The distal half of the pen comprises the cartridge holder 1 for holding the fluid containing cartridge 2. On the distal end of the cartridge holder 1 is mounted the needle hub 3, that carries the needle 4. The portion of the needle 4 that projects out of the cartridge holder 1 is, in turn, enclosed by a protective cap 5. The proximal end of the needle communicates with the content 6 of the cartridge. The cartridge 2, comprising the fluid 6, is loaded inside the cartridge holder 1 such that the head 7 and neck 8 of the cartridge is snugly fixed into the neck region 9 of the cartridge holder 1. The distal end of the cartridge is sealed, but the proximal portion of the needle traverses through it in order to communicate with cartridge content 6. The proximal end of the cartridge is enclosed by an airtight, but movable, plunger 10, lOd (lOd


being the plunger after all the available medication has been completely ejected). The outer surface of the cartridge holder, on its proximal end, has helical threads 11.
The proximal half of the pen comprises the pen housing which encloses the dose-setting and driving mechanisms. The pen housing comprises two concentrically arranged housing-tubes - the outer housing-tube 12 and the inner housing-tube 13. On the inner side of the outer housing, at its distal end, are helical threads 14. The cartridge holder 1, containing the medication cartridge 2, is mounted into the housing by screwing it into the outer housing-tube 12 by means of mating threads, 11, 14, on the outer surface of the proximal end of the cartridge holder and on the inner surface of the distal end of the outer housing-tube respectively. Concentrically arranged inside the outer housing-tube 12 is the inner housing-tube 13. Portions of distal portion of the inner housing-tube 13, diametrically opposite each other, are molded as two sprung-clips 15 that are deflected inward when the cartridge holder 1 is mounted into outer-housing-tube 12. The two sprung-clips 15 comprise an inner-toothed surface 16. The inner housing-tube 13 is joined to the outer housing-tubes 12 by ultrasonically welding the non-clip distal region 13' of the inner housing-tube 13 to the inner wall of the outer housing-tube 12. The inner housing-tube 13 encloses the piston drive apparatus, while two concentrically arranged dose-drums - the outer dose-drum 17 and the inner dose-drum 18 - are placed between the inner 13 and outer 12 housing-tubes. A not-self-locking thread connection is formed between the inner side of the outer housing-tube 12 and the outer dose-drum 17 by a helical thread 19 on the inner side of the outer housing-tube 12 that engages helical ribs 20 present on the surface of outer dose-drum 17. The proximal portion of the dose-drums project out of the proximal end of the outer housing-tube 12. Thus the proximal portion of the outer dose-drum - the dose-knob 21 - is amenable to rotation by hand. Thus when the dose-knob 21 is rotated, the outer dose-drum 17 is both rotated and axially displaced relative to the housing. The helical thread 19 on inner side of the outer housing-tube 12 has a left-handed orientation. Hence when the dose-knob 21 is rotated in the clockwise direction it results in the displacement of the dose-drum in the proximal (dose-setting) direction. The outer dose-drum 17 also carries on its outer surface, and along a track parallel to the above helical track, the dose-setting numerals. A thumb pad 23 is present at the proximal end of the injection device. The thumb pad 23 is free to rotate on a bearing surface 24 at the proximal end of the inner dose-drum


18. On the outer surface of the inner dose-drum 18, close to its proximal end, are sprung ridge teeth 25 that contact with mating teeth 26 that are arrayed along the inner circumference of dose-knob 21 on the proximal edge. The said sprung ridge teeth 25 and inner mating teeth 26 mate with each other at an angle to the axis of rotation, and thereby have a duel function. One of the functions is that of a bi-directional ratchet which produces tactile and auditory clicks when the dose-knob is rotated to set the dose. The second function is to provide an axial spring force between the inner dose-drum and the outer dose-drum. Present on the outer surface of the inner dose-drum 18, and on its proximal region, are engagement teeth 27 that can lock with corresponding circularly arrayed teeth 28 on the distal edge of the dose-knob 21 to form a dog clutch. The relative location of these two sets of engagement teeth 27, 28 with respect to each other is such that, when the thumb pad 23 is depressed, the said teeth 27, 28 are interlocked to form a dog clutch. But once the thumb pad 23 is released, the axial spring force between the sprung ridge teeth and inner mating teeth, 25 and 26, force the interlock between the latter engagement teeth 27, 28 apart.
The piston drive apparatus comprises a piston rod cap 29, a hollow piston rod 30 and a drive-shaft 31. The piston rod cap 29 is free to rotate on a bearing surface with the piston rod 30, and directly contacts the cartridge plunger 10, lOd. The drive-shaft 31 is located, at least partially, inside the piston rod 30. A flexible locking bush 32, comprising an outer tooth surface 33, is placed between the distal end of the piston rod 30 and the inner housing-tube 13. When the cartridge holder 1 is assembled into the pen, the two inner housing-tube sprung-clips 15 are deflected inwards, so that the teeth 16 on the inner side of the sprung-clip 15 engage the outer surface teeth 33 of the locking bush 32, preventing the locking 32 from rotating. The inner surface of the locking bush 32 has protrusions 34 which mate with the longitudinal channels 30' that traverse the length of outer surface of the piston rod 30. Hence when the cartridge-holder 1 is assembled into the pen, the piston rod 30 is prevented from rotating. On the other hand when the cartridge holder is removed, the teeth 16, 33 on the sprung-clips 15 and on the locking bush 32 respectively become disengaged, thereby allowing rotation of the locking bush 32 and the piston rod 30. The proximal edge of the locking bush 32 has a ridge 35 that is retained within a corresponding groove 15A formed beyond the proximal edge of the two sprung-clips 15 of the inner housing-tube. The distal edge of the two sprung-clips 15 has a raised ramp 15' that locks into a


corresponding champfer on the inner side of the proximal edge of the cartridge-holder pushing the sprung-clips progressively inwards as the cartridge holder is screwed into the outer housing tube. The drive-shaft 31 has an outer threading 36 that mates with the corresponding internal threading 37 on the piston rod, forming a non-self locking thread connection. The helical thread 36 on the outer surface of the drive-shaft 31 has a right-handed orientation, so that when the drive-shaft 31 is rotated in the anti¬clockwise direction, the piston rod 30 is displaced in the distal direction relative to the drive shaft. This displacement of the piston rod in the distal direction pushes the cartridge plunger lOd in the distal direction ejecting the medication. In addition, at the proximal end of the drive shaft threading 36 there is a collar 31'. The proximal face of the drive-shaft collar 31' forms a bearing surface with the corresponding inner face of the proximal end 13A of the inner housing tube. This bearing surface permits the drive-shaft to rotate relative to the inner housing tube, but restraints the drive-shaft from moving axially in the proximal direction.
The proximal portion of the drive-shaft 31 comprises the drive-shaft coupling 38 which is located beyond the drive-shaft collar 31', and which when assembled defines a groove between its distal face and the proximal bearing face of the drive-shaft collar 31'. The distal face of the drive-shaft coupling forms a bearing surface with the outer face of the proximal end 13A of the inner housing tube. Combination of the drive-shaft collar 31' bearing surface and drive-shaft coupling bearing surface acts to retain the drive-shaft in its axial position relative to its inner housing tube.
The drive-shaft coupling 38 is molded as a separate component and then fixed on to the proximal portion of the drive-shaft. However the drive-shaft coupling 38 is functionally an integral component of the drive-shaft. The drive-shaft coupling 38 comprises three components - a ratchet teeth 39, legs 40 and finger clips 41. The drive-shaft 31 is thus coupled to the inner dose-drum 18 by means of the legs 40. The ratchet teeth 39 on the drive-shaft coupling 38 interdigit the teeth of a corresponding ratchet clips 42 on the inner housing-tube 13 to form a one way ratchet. The interdigiting ratchet teeth and ratchet clip 39, 42 are oriented in such a way that they permit the rotation of the drive-shaft 31 in only the anti-clockwise direction. The consequence of the legs 40 of the drive-shaft coupling 38 coupling with the inner dose-drum 18, and the ratchet teeth 39 on the drive-shaft coupling 38 engaging the


ratchet clips 42 of the inner housing-tube 13 is that it results in a one-way coupling between the driving mechanism and the dose-setting assembly, whereby the piston rod can only be displaced in the distal direction, when the pen is fully assembled.
To set the dose the outer dose-knob 21 is rotated in a clockwise direction. This results in the rotation and axial displacement of the outer dose-drum 17 in the proximal direction, thus setting an appropriate dose, which appears in the dose window 43. This in turn displaces the inner dose-drum 18 axially in the proximal direction. The size of the set dose can be seen on the portion of the dose-scale that is presented in the window. If an excess dose has been set the dose-knob 21 can be rotated in the anti¬clockwise direction until the number corresponding to the required dose-size appears in the window 43. To deliver the set dose the thumb pad 23 is depressed. The inner dose-drum 18 is then forced axially inwards, so that the engagement teeth 27 on the proximal region of the outer surface of the inner dose-drum 18, and the circularly arrayed teeth 28 on the distal edge of the dose-knob 21 become interlocked, thus locking together the inner dose-drum 13 and the outer dose-drum 12. When this happens, the two dose setting drums 17, 18 are in rotational assembly so that they spiral in an anti-clockwise rotation in the distal direction all the way back to the "zero setting". This in turn rotates the drive-shaft 31 in an anti-clockwise direction through the legs 40 of the drive shaft coupling 38 and forces the piston rod 30 forward. The forward movement of the piston rod delivers the appropriate dose of the fluid from the fluid cartridge 2. In another embodiment, in the case of the not-self-locking thread connection that is formed between the inner side of the outer housing-tube and the outer dose-drum by the helical thread-helical rib engagement, the helical thread is present on the outer surface of outer dose-drum, while the helical ribs are present on the inner side of the outer housing-tube. The helical thread present on the surface of outer dose-drum has a left-handed helix orientation. Hence in this embodiment as well, when the dose-knob is rotated in the clock-wise direction to set a dose, the outer dose-drum is rotated and axially displaced relative to the housing.
In another embodiment of the present invention, in the case of the not-self-locking thread connection formed between the inner side of the outer housing-tube and the outer dose-drum by the helical thread-helical rib engagement, the helical thread of the helical track has a right-handed orientation, so that rotation of the dose-drum in the


anti-clockwise direction results in its displacement in the proximal (dose-setting) direction. In a sub-embodiment of this embodiment, the helical thread is present on the inner side of the outer housing-tube, while the helical ribs are present on the outer dose-drum. In another sub-embodiment, the helical thread is present on the surface of outer dose-drum, while the helical ribs are present on the inner side of the outer housing-tube. In either sub-embodiments, the outer threading of the drive-shaft has a left-handed orientation, so that rotation of the drive-shaft in the clockwise direction results in the displacement of the piston rod in the distal direction. Furthermore in such a design, the orientation of the ratchet teeth and ratchet clip interdigiting is such that, rotation of the drive-shaft is permitted only in the clockwise direction. Hence in these embodiments the dose is set by rotating the dose-knob in an anti-clockwise direction, so that the dose-drums are rotated and axially displaced in the proximal direction. When the thumb pad is depressed, the engagement teeth on the proximal outer surface of the inner dose-drum and on the distal edge of the dose-knob get interlocked to form a dog clutch. This results in the locking the inner dose-drum and the outer dose-drum, which then travel in a clockwise rotation towards the distal direction. The drive-shaft in turn rotates in a clockwise direction and forces the piston rod forward. The forward movement of the piston rod delivers the appropriate dose of the fluid.
Figures 5 and 6 describe the design of disposable delivery devices, viz. those which are discarded once the cartridge 2 is empty. The same design features described in all the above embodiments are incorporated in the disposable devices as well. The crucial difference is that the distal edge of the inner housing-tube 13 is joined with the proximal edge of the cartridge holder 1 to form a single enclosure that on its distal part encloses the fluid containing cartridge 2 and on its proximal part is the inner housing-tube 13 which encloses the dose-setting and driving mechanisms, and mates with the outer housing-tube 12 by means of the non-locking thread 19 and rib 20 arrangement. In one embodiment, the said two edges are joined by a clip-ridge inter¬locking between said edges of the cartridge. In an alternative embodiment the said edges are joined by chemically bonding or ultrasonically welding together the said edges. At the distal end of either embodiments, the needle 4 is attached after the fluid containing cartridge 2 has been assembled. The needle hub 3 can be fastened by a mechanical clip, chemical bonding or ultrasonic welding.


Further, in the disposable devices of the above embodiments, the locking bush (32) is molded out of the distal region of the inner housing-tube, the inner surface of which has protrusion which mate with the longitudinal channels that traverse the length of the outer surface of the piston rod.
While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.


We claim:
1. A system for delivering erythropoietin, its analogue or derivatives thereof comprising a pen shaped injection device.
2. The system as claimed in claim 1, wherein the pen shaped injection device comprises of a cartridge.
3. The system as claimed in claim 2, wherein the cartridge is reusable or non-reusable.
4. The system as claimed in claim 1, wherein the erythropoietin, its analogue or derivatives is selected from the group consisting of erythropoietin-alfa, erythropoietin-beta, darbepoetin alfa, and pegylated erythropoietin.
5. The system as claimed in claim 1, wherein the erythropoietin, its analogue or derivatives is erythropoietin alpha.
6. The system as claimed in claim 1, wherein the pen contains 2000- 40000 international units (IU) of erythropoietin.
7. The system as claimed in claim 1, wherein the dose to be delivered at one time can be 2000 IU, 3000IU, 4000IU, 5000IU and 6000IU.


8. The system as claimed in claim 1, wherein the system comprises of a hollow piston rod which delivers the selected dosage.
9. The system as claimed in claim 8, wherein the hollow piston rod has an internal thread that mates with the external thread of the drive shaft.
10. The system as claimed in claim 8, wherein the hollow piston rod is being axially restrained in the proximal direction relative to the housing.

ABSTRACT
The present invention provides system for delivering erythropoietin, its analogue or derivatives thereof comprising a pen shaped injection device primarily for self administration by people suffering from diseases for which erythropoietin is indicated.