PACKAGING FOR AMORPHOUS STATINS AND COMPOSITIONS THEREOF

Abstract

The present publication relates to a vacuum-sealed pack comprising an amorphous statin or a pharmaceutical composition thereof and at least one stabilizer such as, for example, an oxygen absorber, a moisture absorber or a combination thereof.

Description

FIELD OF THE INVENTION

The present invention relates to a vacuum sealed pack comprising an amorphous statin and at least one stabilizer such as, for example, an oxygen absorber, a moisture absorber or a combination thereof.

BACKGROUND OF THE INVENTION

Statins are currently among the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. Statins are also known to raise HDL cholesterol levels and decrease total triglyceride levels. The mechanism of action of statins has been elucidated in some detail. It is believed that statins disrupt the biosynthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme (“HMG-CoA reductase”). HMG-CoA reductase catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. Consequently, its inhibition leads to a reduction in the rate of formation of cholesterol in the liver.

The main statins currently used in therapeutics are: pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and rosuvastatin. Lovastatin, simvastatin and pravastatin are fully or partially fermentation based products, whereas fluvastatin, rosuvastatin and atorvastatin are entirely synthetic. Simvastatin is a clinically modified 2,2-dimethyl-butyrate analogue of lovastatin. Pravastatin is a purified active metabolite of mevastatin with an open hydroxyacid instead of a lactone ring. All the statins are relatively unstable, and their degradation is catalyzed by several parameters like oxygen, humidity, acidity and temperature.

These statins are known to occur in various crystalline forms as well as amorphous forms. However, amorphous forms can be susceptible to oxidation, heat, light, moisture and low pH, as compared to 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 atorvastatin can lead to impurities such as Atorvastatin diepoxide, dihydroxy epoxide and diketoepoxide.

There have been various attempts to stabilize the amorphous statins.

International Patent Publication WO 2004/032920 describes storage of amorphous atorvastatin calcium solid dosage forms in an inert atmosphere and packaging the dosage form in a material that is not permeable to gases. In one example, tablets containing the drug were packaged in aluminum foil blisters, the blisters having an argon atmosphere.

Another U.S. application 2004/0077708 describes stabilization of a pharmaceutical formulation of an amorphous active substance by packing into gas exchange non-permeable package under an inert gas atmosphere.

SUMMARY OF THE INVENTION

There is still a need for providing a packaging system for amorphous statin so as to enhance their stability. This can be provided by 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 one general aspect, there is provided a vacuum sealed pack comprising an amorphous statin and at least one stabilizer such as, for example, an oxygen absorber, a moisture absorber or a combination thereof.

In another general aspect, there is provided a method of stabilizing an amorphous statin using a vacuum sealed pack comprising an amorphous statin and at least one stabilizer such as, for example, an oxygen absorber or moisture absorber.

In yet another general aspect, there is provided a vacuum sealed pack comprising an amorphous statin and at least one stabilizer such as, for example, an oxygen absorber or moisture absorber wherein the amorphous statin is packaged in a first impermeable bag under vacuum, the first impermeable bag and stabilizer are put into a second bag, then vacuum sealed. These bags may be then put into a rigid container.

In still another general aspect, there is provided a vacuum sealed pack comprising a solid pharmaceutical composition comprising an amorphous statin wherein the pack comprises at least one stabilizer such as, for example, an oxygen absorber or moisture absorber.

In a further general aspect, there is provided a method of stabilizing an amorphous statin using a vacuum sealed pack comprising a solid pharmaceutical composition comprising an amorphous statin wherein the pack comprises at least one stabilizer such as, for example, an oxygen absorber or moisture absorber.

In yet a further general aspect, there is provided a vacuum sealed pack comprising a solid pharmaceutical composition comprising an amorphous statin wherein the pack comprises at least one stabilizer such as, for example, an oxygen absorber or moisture absorber, wherein the composition and stabilizer are packaged in a first impermeable bag under vacuum, the first impermeable bag and stabilizer are put into a second bag, and then vacuum sealed. These bags may be then put into rigid container.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the term “statin” refers to pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin. Pharmaceutically acceptable base addition salts of atorvastatin are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N-1-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

The term “oxygen absorbers” as used herein, means agents used to trap oxygen that is present in the overhead space of closed container. Concerning the chemical and physical mechanisms of active oxygen absorbers, they can be classified into the following categories:

• • inorganic, metal based oxygen absorber
  • ascorbic acid based absorber
  • enzymatic absorber
  • polymer based oxygen absorber

Inorganic, metal-based oxygen absorbers are inexpensive, available with different O₂-scavenging capacities in sachets and common for food and beverages. The broadest range of iron-based products are offered by Mitsubishi Gas Chemicals Ageless™. Similar products are also offered by Multisorb under the trade name Fresh Pax™. The reaction is based on the well-known corrosion of iron. The main drawback of metal based systems is that the absorption of oxygen is only effective with humidity. Due to need for water, metal-based oxygen scavengers are not suitable for dry applications. To overcome this problem, self-activated oxygen absorbers have been produced, which involve combining moisture-retaining additives to metals such as iron. Another modification of metal absorbers is “stealth absorbers”, which is also based on corrosion of iron but the metal is embedded in an extrudable plastic. This system suffers from a relatively low absorption capacity.

Ascorbic acid is a well-known preserving agent. But reactivity and absorption capacity are low. Similar to metal-based scavengers, ascorbic acid needs humidity to react with oxygen and may not be used for dry applications.

The best known enzymatic oxygen absorber is based on glucose/glucose oxidase. In general, enzymes are very expensive and only react with oxygen under special, well-defined conditions (pH level, humidity, temperature).

Polymer based scavengers are suitable for moisture protected applications. Polymer-based compounds consist of high molecular weight, ethylenically-unsaturated hydrocarbons. An activation step often enables the user to start the oxygen scavenging when desired.

Commercially available sachets include D Series FreshPax™ (available from Multisorb Technologies Inc), Ageless™ Z (Ageless-Z is designated as Z-100, Z-1000, etc., to indicate the milliliters of oxygen with which a single packet will react), StabilOx D (available from Multisorb Technologies Inc) and ZPTJ™ sachets (both available from Mitsubishi Gas Corporation), O-Buster™ (available from Hsiao Sung Non-Oxygen Chemical Co., Ltd), Bioka™ Oxygen Absorber (available from Bioka Ltd) and the like.

The moisture absorbers include 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 moisture absorber 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 moisture absorbers 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.

Further, there are certain commercially available packets or sachets which comprise a combination of oxygen absorber and moisture absorber such as PharmaKeep oxygen- and moisture-absorbing packets (PharmaKeep KD or KC) (distributed jointly by Süd-Chemie and Mitsubishi Gas Chemical Company).

In addition, combination of oxygen absorber and moisture absorber can be used together in a vacuum-packaged system. Oxygen absorbers usually lead to an increase in moisture levels, hence a combination of moisture absorber and oxygen absorber will regulate moisture levels as well as oxygen levels, and these levels may have impact on stability of the drug substance as well as composition.

The size and number of moisture/oxygen absorbers can depend on the amount of residual moisture or oxygen left after vacuum has been applied, hence would mainly depend on package system such as HDPE bottle or permeable/impermeable bags. The moisture/oxygen absorber 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 oxygen—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, 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.

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 embodiments, a vacuum packed system for an amorphous statin can be obtained by

• • i) putting the amorphous statin into a bag;
  • ii) closing the bag by twisting the mouth of the bag and thereafter securing with a cable tie;
  • iii) putting the bag of step i) into second bag;
  • iv) vacuum sealing the second bag along with an oxygen absorber and/or a moisture absorber; and
  • v) putting the vacuum sealed bag of step iv) into a third bag with an oxygen absorber and/or a moisture absorber and vacuum sealing the third bag.

In another embodiment, a vacuum packed system for an amorphous statin can be obtained by

• • i) putting the amorphous statin into a bag;
  • ii) vacuum sealing the bag of step i);
  • iii) putting the bag of step ii) into second bag;
  • iv) vacuum sealing the second bag along with an oxygen absorber and/or a moisture absorber; and
  • v) putting the vacuum sealed bag of step iv) into a third bag with an oxygen absorber and/or a moisture absorber and vacuum sealing the third bag.

In another embodiment, a vacuum packed system for a solid pharmaceutical composition is obtained by

• • i) putting the composition into a transparent bag along with an oxygen absorber and/or a moisture absorber;
  • ii) vacuum sealing the bag of step i);
  • iii) putting the bag of step ii) into a rigid container along with an oxygen absorber and/or a moisture absorber; and
  • iv) sealing the rigid container using induction.

In another embodiment, a vacuum packed system for a solid pharmaceutical composition can be obtained by

• • i) putting a solid pharmaceutical composition into an aluminum foil-based bag along with an oxygen absorber and/or a moisture absorber;
  • ii) vacuum sealing the bag of step i);
  • iii) putting the bag of step ii) into a rigid container along with an oxygen absorber and/or a moisture absorber; and
  • iv) sealing the rigid container using induction.

In another embodiment, a vacuum packed system for a solid pharmaceutical composition can be obtained by

• • i) putting a solid pharmaceutical composition into a transparent bag, along with an oxygen absorber and/or a moisture absorber;
  • ii) vacuum sealing the bag of step i);
  • iii) putting the bag of step ii) into an aluminum foil-based bag, along with an oxygen absorber and/or a moisture absorber;
  • iv) putting the bag of step iii) into a rigid container along with an oxygen absorber and/or a moisture absorber; and
  • v) sealing the rigid container using induction.

The composition as used herein includes both immediate and extended release compositions. The statin may be present in the composition between 1% to about 50% by weight of the composition. The composition of amorphous statin may be prepared by formula and method given in the PCT application WO 03/068191 Example 2 as follows.

The tablets of Example 2 were formulated with milled amorphous atorvastatin and an alkali metal salt. The amorphous atorvastatin was milled to reduce its mean particle size d₅₀ to approximately 20-50 μm and d₉₀ to approximately 80-100 μm. Butylated hydroxy anisole (0.12 mg/tablet) and butylated hydroxy toluene (0.12 mg/tablet) were dissolved in isopropyl alcohol and applied on to lactose under high shear mixing. The lactose was dried at 40-45° C. in a fluidized bed dryer. Amorphous atorvastatin (80 mg/tablet), microcrystalline cellulose (300 mg/tablet) and lactose (628 mg/tablet) were mixed. Following the mixing, the dry binder, hydroxypropyl cellulose-L, (24 mg/tablet) and disintegrant, croscarmellose sodium, (72 mg/tablet) were added to the mixture. Following this addition, an alkali metal salt, sodium carbonate (52 mg/tablet), surfactant, sodium lauryl sulphate (2 mg/tablet), and colloidal silicon dioxide (24 mg/tablet) were added. Next, the mixture was lubricated with magnesium stearate (12 mg/tablet) and compressed into tablets. The tablets then were coated with Opadry AMB. The values given above are per tablet and can be adjusted appropriately to provide the desired batch size.

The composition may further contain other pharmaceutically acceptable excipients, such as antioxidants, chelating agents, alkali metal salt additives, alkaline earth metal salt additives, binders, diluents, disintegrants, surfactants or lubricants.

Examples of suitable pharmaceutically acceptable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), sodium ascorbate, butylated hydroxytoluene (BHT), sodium sulfite, propyl gallate, tocopherol, citric acid, malic acid, and ascorbic acid.

The chelating agents may be selected from amongst one or more of those suitable chelating agents known in the art. Examples of suitable chelating agents include, but are not limited to, disodium edetate (EDTA). The chelating agents can be present at a concentration of up to approximately 5% by weight of the composition.

Alkali metal salt additives can be, for example, one or more of sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate or other suitable alkali metal salts. In particular, the stabilizing alkali metal salt additive may be, for example, sodium carbonate or disodium hydrogen orthophosphate, although the other alkali metal salt additives may also be selected. Alkaline earth metal salt additives can include one or more of calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, and aluminum magnesium hydroxide.

The binders may be, for example, one or more binders known in the art. Examples of suitable binders include, but are not limited to, starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and carboxymethylcellulose.

The diluents may be, for example, one or more diluents known in the art. Examples of suitable diluents include, but are not limited to, lactose, microcrystalline cellulose, corn starch, sucrose, and silicic anhydride.

The disintegrant may be, for example, one or more disintegrants known in the art. Examples of disintegrants include, but are not limited to, croscarmellose sodium and starch.

The surfactants may be, for example, one or more surfactants known in the art. Examples of surfactants include, but are not limited to, polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxypropylene copolymer, and sodium lauryl sulphate.

The lubricants may be, for example, one or more lubricants known in the art. Examples of lubricants include, but are not limited to, magnesium stearate, stearic acid, palmitic acid and talc.

The glidants may be, for example, one or more glidants known in the art. An example of a pharmaceutically acceptable glidant includes colloidal silicon dioxide.

The pharmaceutical composition may be prepared by a wet or dry granulation technique or by a direct compression technique.

The composition may be optionally coated with film forming polymers and/or coating additives. The coating may be, for example, one or more coating materials known in the art. For example, the coating material can be Opadry or Opadry AMB (aqueous moisture barrier).

EXAMPLES

Atorvastatin API or tablets were packaged in various packaging options as given below.

The following is the list of materials used in examples which may be acquired from same or different source:

Moisture absorber—Molecular sieve Trisorb sachet (SudChemie); Silica gel (Manufactured by Sudchemie; Trade name Minipak);
Oxygen absorber—StabilOx D-100 (Multisorb);
Bag—i) Gusseted triple-laminated bag, made of laminate of clear transparent polyester film, aluminum foil and natural LDPE

• • ii) Gusseted plastic bag, made of double laminate of clear transparent polyester film and natural LDPE
  • iii) Plastic bag made of natural LDPE
    Bottle—Opaque HDPE bottle.

Example 1

Atorvastatin drug substance (amorphous) was packaged for long term use or transporting according to various packaging options as described below:

• • 1. Amorphous atorvastatin was packaged in a LDPE bag and flushed with nitrogen gas; the bag was twisted and tied; the bag was put into a double laminated bag along with oxygen absorber and flushed with nitrogen gas; vacuum was applied to the double laminated bag and heat sealed; the sealed double laminated bag was packaged into a triple laminated bag along with molecular sieve and flushed with nitrogen gas; vacuum was applied to the triple laminated bag and heat sealed.
  • 2. Amorphous atorvastatin was packaged in a LDPE bag and flushed with nitrogen gas; the bag was twisted and tied; the bag was put into a double laminated bag along with oxygen absorber and silica gel; vacuum was applied to the double laminated bag and heat sealed; sealed double laminated bag was packaged into a triple laminated bag along with molecular sieve; vacuum was applied to triple laminated bag and heat sealed.
  • 3. Amorphous atorvastatin was packaged in a LDPE bag and flushed with nitrogen gas; the bag was twisted and tied; the bag was put into a double laminated bag along with two molecular sieve; vacuum was applied to the double laminated bag and heat sealed; sealed double laminated bag was packaged into a triple laminated bag along with two molecular sieve; vacuum was applied to triple laminated bag and heat sealed.
  • 4. Amorphous atorvastatin was packaged in a LDPE bag and flushed with nitrogen gas; the bag was vacuum sealed; the bag was put into a double laminated bag along with oxygen absorber; vacuum was applied to the double laminated bag and heat sealed; sealed double laminated bag was packaged into a triple laminated bag along with molecular sieve and nitrogen flushed; vacuum was applied to triple laminated bag and heat sealed.

Example 1, option 1 and 4 were subjected to stability studies at 40° C. and 75% RH, the results are given in the Table 1:

TABLE 1
The stability data of Atorvastatin tablets as per Example 1, option 1 and
4 at 40° C. and 75% RH.
	1 month	2 month
Impurity type	Initial	Option 1	Option 4	Option 1	Option 4
Epoxide impurity	0.194	0.162	0.217	0.193	0.179
Total oxidative	0.320	0.299	0.359	0.329	0.292
impurity

Example 2

Atorvastatin tablets according to WO 03/068191 were packaged in following packaging options and were subjected to stability studies:

• • 1. Tablets and molecular sieve were packaged in a double laminated bag and vacuum sealed; double laminated bag was packaged into a HDPE bottle containing oxygen absorber,
  • 2. Tablets and molecular sieve were packaged in a triple laminated bag and vacuum sealed; triple laminated bag was packaged into a HDPE bottle containing oxygen absorber,
  • 3. Tablets and molecular sieve were packaged in a double laminated bag and vacuum sealed; vacuum sealed bag was then put in a triple laminated bag containing oxygen absorber; and packaged into a HDPE bottle.

Example 2, option 2 and 3 were subjected to stability studies at 40° C. and 75% RH, the results are given in the Table 2:

TABLE 2
The stability data of Atorvastatin tablets as per Example 2, option 2 and 3
at 40° C. and 75% RH.
	1 month	3 month
Impurity type	Initial	Option 2	Option 3	Option 2	Option 3
Epoxide impurity	0.725	0.69	0.616	0.679	0.69
Total oxidative	1.411	1.53	1.34	1.511	1.483
impurity

Example 3

An exhibit batch was taken for Atorvastatin tablets according to WO 03/068191; and were packaged in following packaging options and subjected to stability studies:

• • 1. A total of 30 tablets were packaged in a triple laminated bag and vacuum sealed; triple laminated bag was packaged into a HDPE bottle containing oxygen absorber and the bottle was sealed using heat induction.
  • 2. A total of 90 tablets were packaged in a triple laminated bag and vacuum sealed; triple laminated bag was packaged into a HDPE bottle containing oxygen absorber and the bottle was sealed using heat induction.
  • 3. A total of 90 tablets were packaged in a triple laminated bag and vacuum sealed; triple laminated bag was packaged into a HDPE bottle containing molecular sieve and the bottle was sealed using heat induction.

Example 3, option 1-3 were subjected to stability studies at 40° C. and 75% RH after 3 months.

TABLE 3
The stability data of Atorvastatin tablets
as per Example 3 at 40° C. and 75% RH after 3 months.
Impurity type	Initial	Option 1	Option 2	Option 3
Epoxide impurity	0.232	0.146	0.146	0.171
Total oxidative impurity	0.404	0.340	0.343	0.406

Claims

1. A vacuum sealed pack comprising an amorphous statin and at least one stabilizer selected from the group consisting of an oxygen absorber or a moisture absorber or a combination thereof.

2. A vacuum sealed pack comprising a solid pharmaceutical composition comprising an amorphous statin wherein the pack comprises at least one stabilizer selected from the group consisting of an oxygen absorber or a moisture absorber or a combination thereof.

3. The vacuum sealed pack according to claim 1 or 2 wherein the statin is selected from the group consisting of pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin and cerivastatin or pharmaceutically acceptable salts thereof.

4. The vacuum sealed pack according to claim 1 or 2 wherein the oxygen absorber is selected from group consisting of inorganic oxygen absorber, ascorbic acid based absorber, enzymatic absorber and polymer based oxygen absorber or combination thereof.

5. The vacuum sealed pack according to claim 1 or 2 wherein the moisture absorber is selected from the group consisting of activated carbon, silicas, zeolites, molecular sieves, hydrogels, calcium oxide and diatomaceous earth.

6. The vacuum sealed pack according to claim 1 or 2 wherein the statin is packaged in oxygen and moisture impermeable package.

7. The vacuum sealed pack according to claim 6 wherein the package is made up of material selected from Polyethylene (PE), bi-axially oriented polypropylene (BOPP) or PET (polyethylene terpthalate) or oriented polyamide (OPA) or aluminum foil, or a blend of thereof or a laminated structure of these polymers.

8. The vacuum sealed pack according to claim 6 wherein the package is bag.

9. The vacuum sealed pack according to claim 8 wherein the package is vacuum sealed in another package.

10. The vacuum sealed pack according to any of the preceding claim wherein the amorphous statin or composition and the stabilizer are packaged in first impermeable bag under vacuum, the first impermeable bag and the stabilizer is put in second bag and vacuum sealed.

11. The vacuum sealed pack according to claim 10 wherein the second bag is put in rigid container and sealed using heat induction.

12. The vacuum sealed pack according to claim 11 wherein the rigid container is non-airtight/air-tight plastic/metal drums, corrugated shipper or fiberboard drum for amorphous statin and HDPE (high density polyethylene), PP (polypropylene), LDPE (low density polyethylene), PET, PVC (polyvinyl chloride) bottle for composition.

13. The vacuum sealed pack according to claim 2 wherein the pharmaceutical composition is tablet, capsule, pills, dry powder, dragees or granulate.