FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
COMPOSITION AND A SYSTEM OF DELIVERY OF INSULIN LISPRO
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210,
(M.S.) INDIA.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides pharmaceutical composition and a system for precise delivery of a composition comprising 60-70% insulin lispro protamine suspension and 30 -40% insulin lispro.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. Description
The present invention provides pharmaceutical composition and a system for precise delivery of the composition comprising 60-70% insulin lispro protamine suspension and 30 -40 % insulin lispro.
Insulin lispro, rDNA origin is a human insulin analog that is a rapid-acting, parenteral blood glucose-lowering agent. Chemically, it is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B -chain are reversed.
Insulin lispro protamine suspension (NPL component) is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation.
US Patent Nos. 5,514,646 and 5,461,031 discloses insulin lispro or a pharmaceutically acceptable salt and parenteral pharmaceutical formulation.
US Patent No. 6.074,372, EP Patent No. 1424984, PCT Application No. 04069314, discloses several pen devices comprising syringes and cartridges containing drugs such as insulin.
When a meal is taken by an individual, there is an initial step increase in the blood glucose sugar level. Slowly the increased blood sugar levels starts decreasing in an exponential manner because of the action of insulin. In patients suffering from diabetes, this type of control is not available, so we need first an agent which immediately decreases the initial step phase of increased blood sugar level and secondly an agent which will be able to maintain this blood sugar level within the normal limits. Mixture of insulin lispro protamine suspension and insulin lispro is believed to serve the above purpose.
Currently these are available in ratio of 75/25 and 50/50. After an heavy breakfast or normal meal, a person requires a sufficient dose of insulin lispro
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which should be able to decrease the step rise in blood sugar level but at the same time should not leave person hyperglycaemic. At the same time, the system containing the requisite composition should be able to precisely deliver the required dose. In the currently available insulin lispro mixtures either the amount of insulin lispro is 25% or 50%. Mixture containing 25% insulin lispro would not be sufficient for a person having heavy breakfast or meal and mixture containing 50% insulin lispro could lead to hypoglycemia.
Presently while working on a system containing a composition of insulin lispro protamine suspension and insulin lispro, it is surprisingly observed that a pharmaceutical composition comprising 60-70% insulin lispro protamine and 40-30% insulin lispro provides a better control of blood sugar.
In one embodiment the pharmaceutical composition may be administered to the patients by syringe or by a pen device.
One of the embodiments of present invention, the insulin lispro to be administered is stored in vial or cartridge.
One of the embodiments of present invention provides a system of pen shaped injection device comprising a cartridge, wherein the cartridge comprises a composition containing 60-70% insulin lispro protamine suspension and 30-40% insulin lispro
Further this system is sufficient to meet the requirements of insulin in patient suffering from diabetes in a manner which mimics the biological rhythm of insulin secretion.
In one of the embodiments of the invention, the hollow piston rod 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.
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In another embodiment of the invention, the hollow piston rod is being axially restrained in the proximal direction relative to the housing.
In another aspect of the invention, a multidose pack of insulin lispro which comprises at least two cartridges each contains a composition containing 60-70% insulin lispro protamine suspension and 30 -40% insulin lispro.
This varying quantity administration requires multi dose pen device. Any pen device that can precisely deliver the dosage strengths with repetitive usage would serve the purpose. The pen device used can be reusable or non reusable.
The following example provide the composition of the insulin lispro 60/40 or insulin lispro 70/30 prepared by combining insulin lispro and protamine sulfate under appropriate conditions.
EXAMPLE -1
UNIT COMPOSITION FORMULA UNIT-1.0 ML
S. No. Ingredient Lispro Mix 60/40
1 Insulin Lispro (recombinant DNA origin ) 100 IU
2 Protamine sulfate 0.228 mg
3 m-Cresol 1.76 mg
4 Phenol 0.8 mg
5 Glycerol 16 mg
6 Zinc Oxide 0.031 mg (0.025 mg as Zinc )
7. Dibasic sodium phosphate 3.78 mg
8 Sodium Hydroxide q. s. to pH
9 Hydrochloric Acid q. s. to pH
10 Water for Injection q. s. to 1.0 ml
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Procedure:
A. Preparation of Insulin Lispro Protamine Zinc Suspension (60/40)
1. Preparation of Solution I:
Water for injection (WFI) was transferred to a pre-sterilized jacketed stainless steel manufacturing vessel equipped with stirrer. The water for injection was cooled to a temperature of 10°C±5°C. Metacresol, Glycerol, Phenol, Disodium hydrogen phosphate and Sodium dihydrogen phosphate were added one by one and dissolved in a freshly prepared 1N hydrochloric acid solution. The pH of the above solution was adjusted by using 1N hydrochloric acid solution. Volume of the solution was made up with pre-cooled water for injection. The prepared solution was filtered through filter cartridges peristaltic pump into pre-sterilized jacketed stainless steel vessel equipped with magnetic stirrer.
2. Preparation of Solution II
To a pre-cooled water of injection 1N hydrochloric acid solution was added. To this solution 60% quantity of insulin lispro was slowly added with stirring till the solution becomes clear. The pH of the solution was adjusted with 1N hydrochloric acid. Weighed quantity of zinc oxide is added to 1N hydrochloric acid and volume was made with water for injection. The zinc oxide solution followed by protamine sulfate solution in water for injection was added to clear solution containing insulin lispro with stirring. The volume of the solution was made with water for injection and pH was adjusted using 1N hydrochloric acid solution. The prepared solution was filtered through filter cartridges peristaltic pump into pre-sterilized jacketed stainless steel vessel equipped with magnetic stirrer while maintaining the temperature with 10°C±5°C.
3. Mixing of solution I and II- Suspension III
To the sterilized suspension II, solution I was added with stirring.
B. Preparation of Insulin Lispro Solution
1. Preparation of buffer solution containing preservative- Solution IV Metacresol, glycerol, phenol, Disodium hydrogen phosphate and Sodium dihydrogen phosphate were dissolved in freshly prepared water for injection. The pH of the solution was adjusted using 1N HCI. Volume of the solution was adjusted using water for injection.
2. Preparation of Insulin Solution- Solution V
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To a pre-cooled water of injection 1N hydrochloric acid solution was added.
To this solution 40% quantity of insulin lispro was slowly added with stirring till
the solution becomes clear. The pH of the solution was adjusted with 1N
hydrochloric acid. Volume of the solution was adjusted using water for
injection.
3. Mixing of buffer solution containing preservative (Solution IV) Insulin
solution (Solution V)- Solution VI
To the sterilized solution IV, solution V was added with stirring. The pH of the
final solution was adjusted with 1N sodium hydroxide solution. The volume of
the solution was adjusted using water for injection. This solution was filtered
through 0.2 µ filter cartridges peristaltic pump into pre-sterilized jacketed
stainless steel vessel equipped with magnetic stirrer while maintaining the
temperature within 10°C±5°C.
C. Mixing of Insulin Lispro protamine zinc suspension with Insulin Lispro
solution
To the suspension III, solution IV was slowly added with stirring. The final
solution was filled in vials/cartridge.
EXAMPLE -2 UNIT COMPOSITION FORMULA
UNIT-1.0 ML
S. No. Ingredient Lispro Mix 70/30
1 Insulin Lispro (recombinant DNA origin ) 100 IU
2 Protamine sulfate 0.266 mg
3 m-Cresol 1.76 mg
4 Phenol 0.8 mg
5 Glycerol 16 mg
6 Zinc Oxide 0.031 mg (0.025 mg as Zinc )
7. Dibasic sodium phosphate 3.78 mg
8 Sodium Hydroxide q. s. to pH
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9 Hydrochloric Acid q. s. to pH
10 Water for Injection q. s. to 1.0 ml
Procedure:
A. Preparation of Insulin Lispro Protamine Zinc Suspension (70%)
1. Preparation of Solution I:
Water for injection (WFI) was transferred to a pre-sterilized jacketed stainless steel manufacturing vessel equipped with stirrer. The water for injection was cooled to a temperature of 10°C±5°C. Metacresol, Glycerol, Phenol, Disodium hydrogen phosphate and Sodium dihydrogen phosphate were added one by one and dissolved in a freshly prepared 1N hydrochloric acid solution. The pH of the above solution was adjusted by using 1N hydrochloric acid solution. Volume of the solution was made up with pre-cooled water for injection. The prepared solution was filtered through filter cartridges peristaltic pump into pre-sterilized jacketed stainless steel vessel equipped with magnetic stirrer.
2. Preparation of Solution II
To a pre-cooled water of injection 1N hydrochloric acid solution was added. To this solution 70% quantity of insulin lispro was slowly added with stirring till the solution becomes clear. The pH of the solution was adjusted with 1N hydrochloric acid. Weighed quantity of zinc oxide is added to 1N hydrochloric acid and volume was made with water for injection. The zinc oxide solution followed by protamine sulfate solution in water for injection was added to clear solution containing insulin lispro with stirring. The volume of the solution was made with water for injection and pH was adjusted using 1N hydrochloric acid solution. The prepared solution was filtered through filter cartridges peristaltic pump into pre-sterilized jacketed stainless steel vessel equipped with magnetic stirrer while maintaining the temperature with 10°C±5°C.
3. Mixing of solution I and II- Suspension III
To the sterilized suspension II, solution I was added with stirring.
B. Preparation of Insulin Lispro Solution
1. Preparation of buffer solution containing preservative- Solution IV
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Metacresol, glycerol, phenol, Disodium hydrogen phosphate and Sodium dihydrogen phosphate were dissolved in freshly prepared water for injection. The pH of the solution was adjusted using 1N HCI. Volume of the solution was adjusted using water for injection.
2. Preparation of Insulin Solution- Solution V
To a pre-cooled water of injection 1N hydrochloric acid solution was added. To this solution 30% quantity of insulin lispro was slowly added with stirring till the solution becomes clear. The pH of the solution was adjusted with 1N hydrochloric acid. Volume of the solution was adjusted using water for injection.
3. Mixing of buffer solution containing preservative (Solution IV) Insulin
solution (Solution V)- Solution VI
To the sterilized solution IV, solution V was added with stirring. The pH of the
final solution was adjusted with 1N sodium hydroxide solution. The volume of
the solution was adjusted using water for injection. This solution was filtered
through 0.2 µ filter cartridges peristaltic pump into pre-sterilized jacketed
stainless steel vessel equipped with magnetic stirrer while maintaining the
temperature within 10°C±5°C.
C. Mixing of Insulin Lispro protamine zinc suspension with Insulin Lispro
solution
To the suspension III, solution IV was slowly added with stirring. The final
solution was filled in vials/cartridge.
A pen device that would be used for the administration of 60-70% insulin lispro protamine and 30-40% insulin lispro mix is detailed below. The pen used for precise administration of dose is described in detail with references to Figure 1 & Figure 2.
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.
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
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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, solid or hollow. 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, hollow or solid, dose setting means and driving means are enclosed, partly or wholly, in a housing.
Piston rod (30) is hollow or solid having internal thread. It mates with external thread of the drive shaft (31).
Proximal half of the pen comprises the pen housing which encloses the dose-setting and piston driving mechanisms. The dose setting mechanism comprises inner dose drum(18) and outer dose drum(17). A thumb pad (23) is present in the proximal end of the injection device. The piston drive apparatus comprises a piston rod cap(29), a hollow or solid piston rod (30) and a drive shaft(31). The proximal portion of the drive-shaft (31) comprises drive-shaft coupling (38). Piston rod, hollow or solid, can only be displaced in the distal direction when the pen is fully assembled. The coupling of the drive-shaft coupling (38) with the inner dose - drum (18) and ratchet teeth (39) on the drive shaft coupling (38) engaging ratchet clips (42) of the inner housing tube (13) is that it results in one-way coupling between the driving mechanism and dose-setting assembly, whereby the piston rod, hollow or solid, can only be displaced in the distal direction.
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.
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We claim:
1 A pharmaceutical composition comprising 60 -70% insulin lispro protamine suspension and 30 - 40% insulin lispro.
2 The pharmaceutical composition as claimed in claim 1, wherein the composition to be administered is stored in vial or cartridge.
3 The pharmaceutical composition as claimed in claim 1, is further administered by a syringe or a pen shaped injection device.
4 A system of pen shaped injection device comprising a cartridge, wherein the cartridge comprises a composition containing 60 - 70% insulin lispro protamine suspension and 30 - 40 % insulin lispro.
5 The system as claimed in claim 4, wherein the hollow or solid piston rod delivers the selected dosage.
6 The system as claimed in claim 5, wherein the hollow or solid piston rod has an internal thread that mates with the external thread of the drive shaft.
7 The system as claimed in claim 6, wherein the hollow or solid piston rod is being axially restrained in the proximal direction relative to the housing.
8A multidose pack of insulin lispro which comprises at least two cartridges each contains a composition containing 60 - 70% insulin lispro protamine suspension and 30 -40 % insulin lispro.
Dated this _™ day of May, 2008
For Wockhardt Limited

(Mandar Kodgule) Authorizea Signatory
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