FIELD OF THE INVENTION

The present invention relates to a multiple packing and vacuum sealed pack comprising Ivabradine Hydrochloride.

BACKGROUND OF THE INVENTION

Ivabradine hydrochloride of formula I  has very valuable pharmacological and therapeutic properties  and is useful in many cardiovascular diseases such as angina pectoris  myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7 8-dimethoxy-3-{3-{N-[(4 5-dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amino)propyl)-l 3 4 5-tetrahydro-2H-3-benzazepin-2-one hydrochloride.

Ivabradine with a pharmaceutically acceptable acid have very valuable pharmacological and therapeutic properties  especially bradycardic properties  making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischemia such as angina pectoris  myocardial infarct and associated rhythm disturbances  and also in various pathologies involving rhythm disturbances  especially supraventricular rhythm disturbances  and in heart failure. Ivabradine hydrochloride is first disclosed in U.S. Patent No. 5 296 482.

The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state  because of changes in humidity or temperature or oxidative degradation conditions.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations  if the process conditions are not opportunistically controlled. Consequently  a stable Ivabradine hydrochloride would be a significant contribution to the art.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations  if the process conditions are not opportunistically controlled. Consequently  a stable Ivabradine Hydrochloride would be a significant contribution to the art.

Ivabradine Hydrochloride solids are usually packed into various kinds of packing under normal conditions according to the prior art. These packing generally use LDPE  HDPE  plastic bags. Plastic bags find widespread use in the prior art.

Ivabradine Hydrochloride is known to occur in various crystalline forms as well as amorphous forms. However  Ivabradine Hydrochloride can be susceptible to oxidation  heat  light  moisture  low pH  and change to other crystalline forms. Impurities generated upon degradation of active substances can reduce the therapeutic effects of an active substance and unnecessarily burden the body with degradation products. For examples  oxidative degradation of Ivabradine Hydrochloride can lead to impurities such as which are unwanted.

There have been various attempts to stabilize the Ivabradine Hydrochloride.

During our research on Ivabradine Hydrochloride it was observed that this class of compounds is not stable during stability tastings. Long term stability was performed at 25ºC and 60% RH and 30ºC and 65% RH. Accelerated stability was performed at 40ºC and 75% RH. The Ivabradine hydrochloride has a tendency to change its polymorph and it appears that some different polymorph by-products are produced with time. The stability under nitrogen is known for Ivabradine Hydrochloride from the European Pharmacopoeia and the US Pharmacopoeia. It was observed that these conditions are not sufficient for Ivabradine Hydrochloride. In order to overcome this problem it was found that the packaging of Ivabradine Hydrochloride should be done in special conditions

OBJECT OF THE INVENTION:

Therefore  it is an object of the invention to provide packaging system for Ivabradine Hydrochloride so as to enhance their stability.

SUMMARY OF THE INVENTION

In one aspect of the present invention provides a packaging system for Ivabradine Hydrochloride so as to enhance their stability. This can be provided by multiple packing and applying a vacuum  which provides additional benefits. Vacuum packed systems require a minimum of space (as compared to inflated bags produced by introduction of inert gases). Vacuum packaged systems are less prone to leakage and any leakage can be easily detected.

In another aspect of the present invention provides a method of stabilizing Ivabradine Hydrochloride using a multiple sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient.

In another aspect of the present invention provides a method of stabilizing Ivabradine Hydrochloride using a vacuum sealed pack comprising Ivabradine Hydrochloride and optionally pharmaceutically acceptable carrier or excipient.

In another aspect of the present invention provides a vacuum sealed pack wherein the pack comprises three layers.

In another aspect of the present invention provides a vacuum sealed pack wherein the innermost layer is a special plastic bag of (HM  HDPE) high molecular high-density poly ethylene comprises moisture absorber and vacuum sealed using heat induction.

In another aspect of the present invention provides a vacuum sealed pack wherein the Middle layer is a special plastic bag of (HM  HDPE) high molecular high-density poly ethylene or Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.

In another aspect of the present invention provides a vacuum sealed pack wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.

In another aspect of the present invention provides a vacuum sealed pack wherein the moisture absorber is selected from the group consisting of canister desiccant  desiccant  activated carbon  silicas  zeolites  molecular sieves  hydrogels  calcium oxide and diatomaceous earth.

In another aspect of the present invention provides a vacuum sealed pack wherein the bag is put in rigid container.

In another aspect of the present invention provides a vacuum sealed pack wherein the rigid container is non-airtight/air-tight plastic/metal drums  HDPE (high density polyethylene)  PP (polypropylene)  LDPE (low density polyethylene)  PET  PVC (polyvinyl chloride) drum.

In another aspect of the present invention provides an improved packing condition for Ivabradine Hydrochloride comprises layers as
a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed.
c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed  then packed in HDPE drum.

DETAILED DESCRIPTION OF THE INVENTION

The packaging material for package system refer to the substances (e.g.  glass  Polyethylene (PE)  bi-axially oriented polypropylene (BOPP)  PET (polyethylene terpthalate)  oriented polyamide (OPA)  aluminum foil  resin  metal) used to manufacture a packaging component.

The term “desiccant” is a hygroscopic substance that induces or sustains a state of dryness (desiccation) in its local vicinity in a moderately well-sealed container. Commonly encountered pre-packaged desiccants are solids  and work through absorption or adsorption of water  or a combination of the two. Desiccants for specialized purposes may be in forms other than solid  and may work through other principles  such as chemical bonding of water molecules.

Pre-packaged desiccant is most commonly used to remove excessive humidity that would normally degrade or even destroy products sensitive to moisture. Some commonly used desiccants are: silica gel  activated charcoal  calcium sulfate  calcium chloride  montmorillonite clay  and molecular sieves. Silica gel is often used in musical instrument cases.

A specific usage of a desiccant would be in insulated windows where it is placed inside the spacer between the air space and window edge. This prevents moisture condensation between the panes

The desiccant includes activated carbon  silicas  zeolites  molecular sieves  hydrogels  calcium oxide and diatomaceous earth. The particular moisture-retaining materials used will depend upon the humidity level of the environment  for example  in a very low-humidity environment  a moisture-carrying material such as a hydrogel that partially binds water may be preferred. The desiccant can be supplied in the form of a sachet  cartridge or canister. A preferred form is a canister of silica gel  such as SorBit™ (commercially supplied by Sud-Chemie Corporation). Multisorb provides variety of desiccant under trade name of Natrasorb M  Natrasorb S  Natrasorb C  and Hi-dry  which comprise diatomaceous earth  silica gel  calcium oxide and molecular sieve  respectively.

The size and number of desiccant can depend on the amount of residual moisture after vacuum has been applied  hence would mainly depend on package system such as HDPE bottle or permeable/impermeable bags. The desiccant may be in the form of packet  sachet  strips or canisters. The packet  sachet  strips or canisters may additionally comprise a moisture-indicating card.

The packaging material for package system could comprise air as well as moisture-impermeable material so that vacuum created during packaging is maintained throughout the shelf life of the drug. It can be chosen from Polyethylene (PE)  bi-axially oriented polypropylene (BOPP)  PET (polyethylene terpthalate)  oriented polyamide (OPA)  aluminum foil  or a blend of these polymers or a laminated structure of these polymers. Possible structures of the laminate are PET/aluminum foil/PE  or OPA/PET/PE  or Triple Laminate Sunlight Barrier (TLSB) or quad laminate ultra barrier (QLUB) bag and various other permutations and combinations are possible. The laminate structure would primarily depend on moisture/light or gas barrier required by the drug or the composition.

As the polyethylene-based resin  there can be enlisted but are not limited to linear low density polyethylene (LLDPE)  high density polyethylene (HDPE)  low density polyethylene (LDPE)  High Molecular High Density Polyethyene (HMHDPE) polypropylene  acrylonitrile  polyamide  polyvinylidinefluoride (PVDF)  ethylene acrylic acid  ethylene/methacrylic acid (E/MAA) copolymer  polypropylene lacquer  polyacetal and copolymers thereof.

The rigid container as used herein include non-airtight/air-tight plastic/metal drums  corrugated shipper or fiberboard drum for drug packaging and HDPE (high density polyethylene)  PP (polypropylene)  LDPE (low density polyethylene)  PET  PVC (polyvinyl chloride) bottle for composition packaging.

In one of the embodiment of the present invention is to provide a vacuum sealed pack wherein the pack comprises three layers.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the innermost layer is a special plastic bag of (HM  HDPE) high molecular high-density poly ethylene bag comprises moisture absorber and vacuum sealed using heat induction.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the Middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and vacuum sealed using heat induction.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and vacuum sealed using heat induction.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the moisture absorber is selected from the group consisting of canister desiccant  desiccant  activated carbon  silicas  zeolites  molecular sieves  hydrogels  calcium oxide and diatomaceous earth.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the bag is put in rigid container.

In another embodiment of the present invention is to provide a vacuum sealed pack wherein the rigid container is non-airtight/air-tight plastic/metal drums  HDPE (high density polyethylene)  PP (polypropylene)  LDPE (low density polyethylene)  PET  PVC (polyvinyl chloride) drum.

In another embodiment of the present invention is to provide an improved packing condition for Ivabradine Hydrochloride API comprises layers as
a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed.
c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed  then packed in HDPE drum.

Packaging conditions
To avoid degradation during stability  following is the recommended packing condition for Ivabradine Hydrochloride:

Innermost: HMHDPE bag vaccumised and heat sealed.
Middle: TLSB bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed.
Outermost: QLUB bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed  then packed in HDPE drum.
Material should be packed at 25°C+/-2°C 35%+/-5% RH

Example
Ivabradine Hydrochloride drug substance was packaged for long term use or transporting according to various packaging options as described below:

Ivabradine Hydrochloride was packaged in a HMHDPE bag and vacuum was applied the bag was heat sealed. This bag was put into a TSLB bag along with canister desiccant and vacuum was applied to TSLB bag and heat sealed. The sealed TSLB bag was packaged into a QLUB bag along with canister desiccant and vacuum was applied to the QLUB bag and heat sealed. The sealed QLUB bag then packed in HDPE drum.

We Claim 

1. A vacuum sealed pack comprising Ivabradine Hydrochloride wherein the Ivabradine Hydrochloride is packaged in oxygen and moisture impermeable package.

2. A vacuum sealed pack according to claim 1 wherein the pack comprises three layers.

3. A vacuum sealed pack according to claim 2 wherein the Innermost layer comprises the (HM  HDPE) high molecular high-density poly ethylene which is vacuum sealed and sealed using heat induction.

4. A vacuum sealed pack according to claim 2 wherein the Middle layer is a Triple Laminate Sunlight Barrier (TLSB) bag comprises moisture absorber and nitrogen gas purged and sealed using heat induction.

5. A vacuum sealed pack according to claim 2 wherein the Outermost layer is triple laminated aluminum bag inside black coated or quad laminate ultra barrier (QLUB) bag comprises moisture absorber and nitrogen gas purged and sealed using heat induction.

6. A vacuum sealed pack according to claim 4 and 5 wherein the moisture absorber is selected from the group consisting of canister desiccant   desiccant  activated carbon  silicas  zeolites  molecular sieves  hydrogels  calcium oxide and diatomaceous earth.

7. A vacuum sealed pack according to claim 4 wherein the bag is put in rigid container.

8. A vacuum sealed pack according to claim 7 wherein the rigid container is non-airtight/air-tight plastic/metal drums  HDPE (high density polyethylene)  PP (polypropylene)  LDPE (low density polyethylene)  PET  PVC (polyvinyl chloride) drum.

9. An improved packing condition for Ivabradine Hydrochloride comprises layers as
a. Innermost: HMHDPE bag vaccumised and heat sealed.
b. Middle: Triple Laminate Sunlight Barrier (TLSB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed.
c. Outermost: quad laminate ultra barrier (QLUB) bag having canister desiccant  nitrogen gas purged with vacuum and heat sealed  then packed in HDPE drum.

Dated this 3rd day of August 2012

Dr. Alpesh Pathak
Applicant’s Agent