DESC:FIELD OF INVENTION
The present invention relates to a novel cartridge for delivery of low molecular weight heparin. More particularly, the present invention relates to a novel cartridge for delivery of Fondaparinux and method of delivering the same using the said cartridge.

BACKGROUND OF INVENTION
Heparin is a polysaccharide drug with potent anticoagulant activity and is used in the prevention and treatment of thrombosis. It decreases the rate of coagulation by increasing the rate at which anti-thrombin inhibits activated coagulation factors such as thrombin, one of the key enzyme in the coagulation cascade. Certain Heparinoids, derivatives, analogues, and other compounds that have Heparin like activity act as anticoagulants. Among all heparin and heparinoids, low molecular weight heparin is of particular interest from clinical stand point. Some of the low molecular weight heparins include Enoxaparin, Ardeparin, Dalteparin, or the chemically synthesized heparin like compound- the pentasaccharide, Fondaparinux. Various studies suggests that low molecular weight heparinoids or heparin like compounds may be associated with reduced risk of bleeding complications, have a longer half-life and have reduced incidence of thrombocytopenia.

However, it is still difficult to handle low molecular weight heparinoids or heparin like compounds, since they are fairly large molecules and have prominent negative charges, cannot be administered by oral delivery and involve invasive delivery approaches. Hence it is necessary that the delivery of such drugs should be in such a manner that it is capable of both multidose and unit dose delivery without any risk of contamination or degradation. The delivery needs to be accurate in terms of dose and if capable of self-administration, should be capable of being administered by an untrained person.

Certain prefilled syringes are already available in the market that can be used to deliver such products. When such products are administered as a unit dose, they may not contain preservatives, thus require proper handling to prevent contamination. Such already available pre-filled syringes may not be capable of multidose administration on account of loss of sterility on first use.

Furthermore, it has been noted that the stability of the drug product in itself be it heparin; low molecular weight heparins or such related molecules and their resultant efficacy is highly dependent on the nature of the formulation, primary packing material used and their mutual compatibility. It has been noted that impurity profiles of each of these molecules varies significantly with the change in packaging material. In addition, a change in the packaging material requires extensive studies pertaining to the compatibility of the formulation to that of the packaging material.

Also there is a need for a novel cartridge to accurately deliver unit dose or multiple doses of drugs such as heparins, low molecular weight heparin or such related molecules that when attached to a suitable delivery device conveniently administer the accurate dose, efficient in controlling impurities and microbial contamination thereby maintaining the sterility of the formulations thus making the administration less cumbersome, cost effective, and improving patient acceptance.

OBJECT OF THE INVENTION
An object of the invention is to provide a novel cartridge for delivery of low molecular weight heparin and method of delivering the same using the cartridge of the present invention.

SUMMARY OF THE INVENTION
The present invention describes a novel cartridge for delivery of low molecular weight heparin which supplies a measured and accurate dose of the drug to a patient.
The present invention also discloses a method of delivery of low molecular weight heparin using the cartridge of the present invention.
The cartridge of the present invention may be described to comprise:
a) a housing assembly (400);
b) a mechanical device termed as a plunger (500) for generating force capable of pushing the drug present in the drug reservoir (300);
c) drug reservoir (300) may contain markings such as (350) and (375) which would indicate the dose delivered;
d) upper section of the housing assembly (400) is attached via a neck portion (250) closed by a cap (100) and sealed by metal disc (200).

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 illustrates a cross sectional view of the device of the present invention
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention is drawn to a novel cartridge for delivery of drug.

The drug of the present invention may be low molecular weight heparin, wherein Low molecular weight heparin may be selected from the group comprising Enoxaparin, Ardeparin, Dalteparin, Fondaparinux, more preferably Enoxaparin, and Fondaparinux and most preferably the drug is Fondaparinux.

The novel cartridge of the present invention for delivery of Fondaparinux may be described to comprise:
a) a housing assembly (400);
b) a mechanical device termed as a plunger (500) for generating force capable of pushing a drug present in the drug reservoir (300);
c) drug reservoir (300) may contain markings such as (350) and (375) which would indicate the dose delivered;
d) upper section of the housing assembly (400) is attached via a neck portion (250) closed by a cap (100) and sealed by metal disc (200).

The reduced number of components of the cartridge enhances the ease of administration of the drug by the end user and also reduces the complexity of administration. The small dose size enhances the delivery of an accurate dose and also reduces the pain during drug delivery.

The cartridge may be designed to be fitted into a disposable pen delivery device.

As shown in Figure 1, the various aspects of the cartridge of the present invention may be used within the scope of this invention.

The cartridge has a bottom-side end and lying opposite a top-side end. The top-side end defines the direction "to the top", the bottom-side end the direction "to the bottom". The top part has at its upper end an opening through which the liquid to be dispensed emerges from the cartridge.

As shown in Figure 1, the cartridge includes a housing assembly (400). The bottom section of the housing assembly (400) may be sealed by means of a mechanical device termed as a plunger (500) slidably disposed in the cartridge. The upper section of the housing assembly may be connected to a neck (250) sealed by a cap (100).

Preferably, the cartridge consists of a housing assembly (400). The bottom section of the housing assembly (400) may be sealed by means of a plunger (500) slidably disposed in the cartridge. The upper section of the housing assembly may be connected to a neck (250) sealed by a cap (100).

The housing assembly (400) may be preferably cylindrical in shape with an inner diameter ranging from 12 mm to 16 mm and an outer diameter ranging from 15 mm to 18 mm. The housing assembly length may be in the range of 150 mm to 175 mm, up to the neck having a wall thickness of 0.25 mm to 1.5 mm.

The housing assembly may be composed of material selected from glass or plastic. Most preferably, the housing assembly is constructed of plastic. The plastic of the housing assembly may be selected from the group comprising Polyvinylpyrrolidone (PVP), Polyethylene glycol (PEG), Cyclic Olefin Copolymer (COC), Cyclo-olefin Polymer (COP), more preferably the material of the housing assembly is Cyclo-olefin Polymer (COP).

The cartridge comprises of a housing assembly (400) attached to a mechanical device for applying pressure known as the plunger or a piston (500) and a drug reservoir (300). The plunger may be placed in such a manner that it has a diameter smaller than that of the housing assembly and is freely moveable inside the assembly. A part of the plunger is found outside the assembly and is moveable with respect to the assembly. The protruding end of the plunger is capable of being held by the end user and the end user is capable of conveniently moving the plunger in a parallel direction to the housing assembly, such that the plunger (500) is capable of compressing the drug present inside the drug reservoir (300) thereby generating a pressure sufficient to extrude the drug through the cap (100) and the disc (200). The plunger rod size may be in the range of 0.25 mm to 1.5 mm.

The plunger (500) may be made up of any suitable material that may be selected from the group comprising glass, stainless steel, elastomeric materials such as polypropylene, polycarbonate, polystyrene, polyethylene, acrylic polymers or methacrylic polymers, preferably elastomeric materials.
The plunger may optionally be coated with materials selected from the group comprising silicon, fluoropolymers, parylene and the like. Such a coating may be utilized to minimize any interaction and/or friction that may be caused between different parts of the device or between the device and the drug during storage or during shipping. The novel cartridge of the present invention makes available a mechanism for the exertion of pressure on the drug present in the drug reservoir (300).

The housing assembly comprises of a drug reservoir (300). The drug reservoir comprises of a drug, which is selected from the group comprising Enoxaparin, Ardeparin, Dalteparin or Fondaparinux, preferably Fondaparinux.

The drug reservoir (300) maybe in the form of a column located inside the housing assembly (400) and connected to the plunger (500) at the base such that while using the longitudinal axis of the cartridge is disposed substantially parallel to the skin-contacting surface.

The drug reservoir may comprise of markings as described herein. The marking may be an external marking. The marking may be present either as fluting in the housing assembly or may be present as any indicator lines that may be made by either paint, marker or laser beam or may be a plastic line. The marking is such that it does not infuse into the housing assembly. The markings consist of a lower marking (375) and then upper marking (350). The space between the markings is carefully measured and set out such that the space between the markings has a certain drug holding capacity. The drug holding capacity between the markings is such that it contains the preferred amount of the drug. The preferred amount of the drug is such that it delivers 1.25 mg when the drug is administered.

The drug is present as a liquid. The drug may be filled between two markings. The drug may be presents between the two markings are set to a pre-determined amount and a dose. It is understood that when the drug is administered to a patient between any two giving markings, a pre-determined dose has been administered to the patient, by the use of the said cartridge of the present invention.

It is understood by one skilled in the art that when there are more than several markings present in the cartridge of the present invention, it is possible to have a drug reservoir, which has a filled drug for more than several markings. This indicates that there are several pre-determined doses, which are multiples or the spaces present between the markings.

The housing assembly may be hollow and capable of holding the plunger. The hollow portion of the housing assembly may be in any shape, which includes hexagon, circular, diamond shaped. Preferably, the hollow is circularly shaped. It is understood by a person skilled in the art that the shape of the plunger would be to match the hollow housing assembly.

The top part of the housing assembly (400) is covered by a cap (200) which may be a moveable rubber type bung or stopper. The cap (200) may be further held in place by a crimped annular metal band disc (100) which may be used to hold the rubber seal in place. The cap (100) may be an integral constituent of cartridge or may also represent an element separate from it.

During administration the metal disc (100) and the cap (200) may be removed and replaced by a needle or optionally the cartridge may be fitted into a disposable pen delivery device.

The cartridge of the present invention may be re-usable i.e. it is designed for precise delivery of successive individual dosages. Since the cartridges comprise of a fixed dose of material, these cartridges are amenable to devices which do not have a resettable dose setting mechanism.

Optionally, the cartridge of the present invention may also be amenable to devices which have a dose setting mechanism. In such an instance, the cartridge may be capable of being inserted into the holder and is attached directly to the dose setting mechanism to the selected dose. After the drug is exhausted, the user may detach the cartridge from the dose setting mechanism and replace the empty cartridge with a filled cartridge.

Optionally, the cartridge of the present invention may also be capable of being attached to a double ended needle assembly. The needle assembly may be threaded onto or pushed or snapped on a distal end of the cartridge housing. In this manner, a double ended needle wanted on the assembly penetrated through a pierceable seal at a distal end of the cartridge. After an injection, the needle assembly may be removed and discarded.

The present invention also envisages a method of delivery of Fondaparinux using the cartridge of the present invention. The end user may attach the pre-filled cartridge with a suitable delivery device. It is understood that when the end user delivers the drug between the two markings (350) to (375), which indicates that the user has delivered the drug present in the space (355), one pre-determined dose has been delivered to the patient.

Without being limited by theory, the cartridge of the present invention may be advantageously used to deliver Fondaparinux. The cartridges of the present invention are designed such that it prevents the disadvantages of Fondaparinux locally compounded in the pharmacies. It is envisaged that by providing Fondaparinux in cartridges of the present invention, the product life span of Fondaparinux may be increased and the drug remains stable for period of 6 months when stored at temperature between 15°C to 25°C. The cartridge of the present invention is convenient to use by the end users and eliminates dosing error. Furthermore, the method of delivering Fondaparinux by attaching the cartridge of the present invention to a suitable drug delivery device reduces the medication cost, is economic for the end user, reduces drug waste, minimizes hospital and industrial waste and eliminates risk of microbial contamination.

The foregoing embodiments and advantages are merely exemplary and are not to be construed as limiting the scope of the present invention. The description of the exemplary embodiments of the present invention is intended to be illustrative and not to limit the scope of the invention. Various modifications, alterations and variations, which are apparent to a person skilled in art, are intended to fall within the scope of the invention as defined in the appended claims and their equivalents.

EXAMPLE 1: Sterility Testing
The sterility tests have been conducted to evaluate the microbial contamination of the pharmaceutical formulations of fondaparinux sodium with and without preservatives, stored in cartridges made of Cyclo-olefin Polymer (COP) or glass, upon multiple opening.
The sterility test was conducted in six cartridges made of glass and Cyclo-olefin Polymer (COP) filled with the formulations of fondaparinux sodium stored at appropriate conditions (RT & Fridge) as per (USP 37 (71)) pharmacopeia with testing intervals at ‘0’ hour opening and 24 hour,72 hours,5th day and final 7th day opening. The results of the sterility tests are represented herein below at Table 1.
Table 1: Microbiological examination of Multidose Cartridges under study
S.No Product studied At 0 Hr just after first opening sent for MB-lab At 24 Hrs just after second opening sent for MB-lab At 72 Hrs just after Third opening sent for MB-lab
On 5th day
On 7th Day
S.No MDCs Room (24oC) Fridge
(8oC) Room (24oC) Fridge
(8oC) Room (24oC) Fridge
(8oC) Room (24oC) Fridge
(8oC) Room (24oC) Fridge
(8oC)
1 FP Glass cartridges without preservative
CRS
CFS
24rs
24fs
72rp
72fp
5rp
5fp
7rp
7fp
2 FP Glass cartridges with 1% Benzyl alcohol
CRS
CFS
24rs

24fs
72rs
72fs
5rs
5fs
7rs
7fs
3 FP Glass cartridges with 0.2% m-cresol
CRS
CFS
24rs

24fs
72rs
72fs
5rs
5fs
7rs
7fs
4 FP COP cartridges without preservative
CRS
CFS
24rs
24fs
72rp
72fp
5rp
5fp
7rp
7fp
5 FP-COP cartridges with 1% Benzyl alcohol
CRS
CFS
24rs

24fs
72rs
72fs
5rs
5fs
7rs
7fs
6 FP-COP cartridges with 0.2% M-cresol
CRS
CFS
24rs

24fs
72rs
72fs
5rs
5fs
7rs
7fs
FP = Fondaparinux; MDCs = Multidose cartridges; CRS =control & sterile at room temperature; CFS=control & sterile in fridge; MB = Microbiology lab; fs = sterile in fridge; rs = sterile at room temperature; fp = positive in fridge; rp = positive at room temperature; “24rs, 72rs, 5rs and 7rs = sterile at room temperature after 24, 72hrs and on 5th and 7th day”; “24fs, 72fs, 5fs and 7fs = sterile in fridge after 24, 72hrs and on 5th and 7th day”; “72rp, 5rp, 7rp = positive after 72hrs, 5th day and 7th day”; “72fp, 5fp, 7fp = positive after 72hrs, 5th day and 7th day”.

From the above Table 1, the following results are noted:
1) At ‘0’ hour and ‘24’ hour opening of the Multidose cartridge, all the formulations have control and are sterile, when stored at 24°C & 8°C.
2) On opening the Multidose cartridges at ‘72” hour, 5th and 7th day, formulations comprising a preservative showed control and sterility, when stored at 24°C & 8°C. However, glass and Cyclo-olefin Polymer (COP) cartridges comprising formulations without preservative showed positive control at the same opening intervals.

EXAMPLE 2: Identification of Impurities
Sterile, stable multiple dose composition of fondaparinux sodium was prepared by dissolving weighed quantity of fondaparinux sodium in sufficient volume of 0.9% sodium chloride solution in water for injection, adjust the pH if necessary to about 7.0 to 7.5 using sodium hydroxide or hydrochloric acid, followed by adjusting the final volume using isotonic solution of NaCl in water for injection. The final solution was filtered using nitrogen gas as filtration aid followed by aseptic filling and terminal sterilization.
The impurities present in a particular marketed composition of Fondaparinux were quantitatively identified by high performance liquid chromatography (HPLC) under the conditions (represented in Table 2) and compared with the fondaparinux solution of the present invention. The comparison results are represented in Table 3.
Table 2: Chromatographic conditions
Mobile Phase A 15±10 ppm of DMSO in 5mM PO4 Solution
Mobile Phase B 2 M NaCl in 5mM PO4
Flow rate 1.0 mL/minute
Column Thermo Scientific Carbopac PA1 Column (4*250mm), Guard Column Carbopac PA1 (4*50mm)
Column temperature 25oC
Injection volume 100 µL
Detector wavelength UV 210 nm
Run time 50 minutes
Analytical HPLC Dionex Ultimate 3000
Gradient program
Time (minutes) Solution (A) (%) Solution (B) (%)
0 55 45
5 55 45
25 5 95
30 5 95
35 55 45
50 55 45
Table 3: Comparison result
Impurities analysed in marketed Product Impurities analysed in Fondaparinux (Test composition)**
Impurity Relative % (by HPLC area) Relative % (by HPLC area)
Compound A 0.6