(12) United States Patent
`Liu et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006310094Bl
`US 6,310,094 Bl
`Oct. 30, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) READY-TO-USE ESMOLOL SOLUTION
`
`(56)
`
`References Cited
`
`(75)
`
`Inventors: Jie Liu, Scotch Plains; Satish K.
`Pejaver, Bridgewater; George Owoo,
`North Plainfield, all of NJ (US)
`
`(73) Assignee: Baxter International Inc., Deerfield, IL
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/759,547
`
`(22) Filed:
`
`Jan. 12, 2001
`
`Int. Cl.7 ..................................................... A61K 31/24
`(51)
`(52) U.S. Cl. .............................................................. 514/538
`(58) Field of Search ............................................... 514/538
`
`U.S. PATENT DOCUMENTS
`4,857,552 * 8/1989 Rosenberg et al. .................. 514/538
`* cited by examiner
`
`Primary Examiner-Raymond Henley, III
`(74) Attorney, Agent, or Firm-Kenneth E Jaconetty
`
`(57)
`
`ABSTRACT
`
`A ready-to-use injectable, aqueous pharmaceutical compo(cid:173)
`sition for the treatment of cardiac conditions, comprising
`methyl-3-[ 4-(2-hydroxy-3-isopropylamino) propoxy] phe(cid:173)
`nylpropionate hydrochloride ( esmolol hydrochloride), a
`buffering agent and an osmotic-adjusting agent, as well as a
`method for its manufacture in a container, is disclosed.
`
`9 Claims, No Drawings
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1033 – Page 1
`
`

`

`US 6,310,094 Bl
`
`1
`READY-TO-USE ESMOLOL SOLUTION
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to a ready-to-use injectable,
`aqueous pharmaceutical composition for the treatment of
`cardiac conditions comprising methyl-3-[ 4-(2-hydroxy-3-
`isopropylamino propoxy] phenylpropionate hydrochloride
`( esmolol hydrochloride), a buffering agent and an osmotic(cid:173)
`adjusting agent, and further relates to a method for its
`manufacture in a container.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`2
`biological burden of the formulation. Esmolol hydrochloride
`formulations of the prior art cannot survive autoclaving. The
`present invention is stable against hydrolytic degradation
`and other adverse chemical reactions, and possesses a
`5 pharmaceutically-acceptable shelf-life. The product is a
`ready-to-use infusion which can be used directly without
`requiring any additional procedures for dilution. This avoids
`the inconvenience of diluting a concentrated esmolol small
`volume parenteral formulation into infusion diluents prior to
`infusion along, eliminates the risk of microbiological con(cid:173)
`tamination during aseptic handling and any potential calcu(cid:173)
`lation or dilution error. As a result, the present invention
`enhances patient safety and physician/nurse compliance
`with use of esmolol injection.
`The pH of the composition greatly effects its stability. The
`pH should be between 3.5 and 6.5, preferably between 4.5
`and 5.5, more preferably about 5.0. The pH can be adjusted
`as known in the art by addition of sodium hydroxide or
`hydrochloric acid. Esmolol hydrochloride is present in the
`instant composition in an amount ranging from 0.1-100
`20 mg/ml, preferably 1-10 mg/ml.
`Suitable buffering agents are known in the art, and are
`present in the composition in an amount ranging from
`0.1-5.0 mg/ml, preferably 0.4--3.0 mg/ml. Buffering agents
`include acetate, glutamate, citrate, tartrate, benzoate, lactate,
`25 gluconate, phosphate and glycine. The preferred buffering
`agent is acetate.
`Suitable osmotic-adjusting agents are known in the art,
`and are present in the composition in an amount ranging
`from 1-10 mg/ml. Osmotic-adjusting agents include sodium
`30 chloride, dextrose, sodium bicarbonate, calcium chloride,
`potassium chloride, sodium lactate, Ringer's solution and
`lactated Ringer's solution. Preferred are sodium chloride, in
`an amount ranging from 4--60 mg/ml, more preferably 4-10
`mg/ml, and dextrose, in an amount ranging from 25-60
`35 mg/ml. Dextrose is preferably present in the composition of
`the present invention at a level no greater than 5% (weight
`by weight) in combination with sodium chloride.
`Compositions according to the present invention are pack(cid:173)
`aged in suitable sealed containers, which may be either glass
`or polymer-based. Polymeric containers are preferably
`flexible, and can be contain or be free of polyvinylchloride
`(PVC). Preferred containers are free of PVC, such as those
`disclosed in U.S. Pat. Nos. 5,849,843 and 5,998,019.
`The polymeric containers can further be provided with a
`moisture barrier as a secondary packaging system to prevent
`the loss of water during storage and to further ensure the
`stability of the formulation. A preferred moisture barrier is
`an aluminum overpouch.
`Procedures for filling compositions of the present inven-
`50 tion in containers, and their subsequent processing are
`known in the art. Typical autoclave cycles in the pharma(cid:173)
`ceutical industry to achieve terminal sterilization of the final
`product are 121 ° C. for 15 minutes. The esmolol hydrochlo(cid:173)
`ride composition of the present invention can be autoclaved
`55 at a temperature ranging from 115 to 130° C. for a period of
`time ranging from 5 to 40 minutes with acceptable stability.
`Autoclaving is preferably carried out in the temperature
`range of 119° C. to 122° C. for a period of time ranging from
`20 to 36 minutes.
`
`15
`
`Esmolol hydrochloride is a short-acting beta-blocker used
`for treatment or prophylaxis of cardiac disorders in mam(cid:173)
`mals. Most of the currently available beta-blockers are stable
`drugs which can be administered to cardiac patients over
`relatively long periods of time. However, it is often desirable
`in the critical care setting to quickly reduce heart work or
`improve rhythmicity during a cardiac crisis, e.g., during or
`shortly after a myocardial infarction. Conventional beta(cid:173)
`blocking agents can be employed for such treatment, but
`their long durations of action can cause undesirable side
`effects.
`Esmolol hydrochloride contains an ester functional group
`and possesses the typical beta-adrenergic blocking activity.
`However, it differs from conventional beta-blocking com(cid:173)
`pound in that esmolol hydrochloride has a short duration in
`vivo due to the presence of the ester group. Thus, esmolol
`hydrochloride is advantageous compared to the conven(cid:173)
`tional beta-blockers because of its unique short-acting activ(cid:173)
`ity. However, the ester group in esmolol hydrochloride is
`found to be unstable in an aqueous environment because of
`it extreme susceptibility to hydrolytic degradation.
`The stability of esmolol in water is mediated by the rate
`of acid/base hydrolysis of the labile aliphatic methyl ester
`group. In the past, the rate of degradation of esmolol
`hydrochloride has been reduced by the use of acetate as a
`buffer, maintaining the pH as close to 5.0 as possible,
`minimizing the concentration of esmolol in the solution, and
`minimizing the concentration of buffer used. Prior art for- 40
`mulations maintain a reasonably long shelf-life, however,
`they are packaged in glass vials or ampules, and suffer from
`severe degradation upon autoclaving. As a result, prior art
`formulations are prepared aseptically. C.f. U.S. Pat. No.
`4,857,552. However, terminal sterilization is typically pre-
`ferred by regulatory authorities as a way of reducing micro(cid:173)
`biological burden and to ensure the safety of the finished
`product.
`In addition, the formulation disclosed in U.S. Pat. No.
`4,857,552 is a small volume injectable formulation. For the
`purposes of intravenous infusion, the disclosed formulation
`must be further diluted in pharmaceutically acceptable dilu(cid:173)
`ents prior to use. This creates a potential opportunity for
`calculation or dilution error in a hospital setting.
`Additionally, microbiological contamination of the product
`during dilution/aseptic handling is of primary concern.
`Therefore, there remains a need for a ready-to-use large
`volume parenteral esmolol hydrochloride that is microbio(cid:173)
`logically safe and stable in vitro during storage.
`
`45
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`60
`
`The present invention provides a stable, ready-to-use
`parenteral solution containing esmolol hydrochloride and a
`pharmaceutically acceptable buffering agent and an osmotic
`adjusting agent to adjust the tonicity of the solution. The 65
`solution can be packaged in a sealed container and subjected
`to terminal sterilization via autoclaving to reduce the micro-
`
`EXAMPLES
`
`Example 1
`
`The following describes the preparation of ready-to-use
`infusion bags of the present invention containing 10 mg/ml
`esmolol HCl solution. The concentration of each ingredient
`of the composition is as follows:
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1033 – Page 2
`
`

`

`US 6,310,094 Bl
`
`3
`
`Ingredient
`
`Esmolol HCl
`
`Sodium Chloride (osmotic)
`
`Sodium Acetate Trihydrate (buffer)
`
`Amount/ml Solution
`
`11 mg/ml
`
`5.9 mg/ml
`
`2.8 mg/ml
`
`Glacial Acetic Acid (buffer)
`
`0.546 mg/ml
`
`Sodium Hydroxide/Hydrochloric Acid
`
`pH adjustment to 5.0
`
`Water for Injection, USP
`
`qs
`
`4
`PVC membrane tube, one PL 2409-3 multi-layer plastic
`co-extruded administration port tube, one PL 141 PVC
`blue-tip closure (administration port protector), available
`from Baxter Healthcare Corporation.) These bags are sealed
`in aluminum foil overpouches. The products are then loaded
`into an autoclaving sterilizer and sterilized at 121 ° C. for 36
`minutes.
`The sterilized products are subjected to inspection and
`release tests. The bag products prepared above are selected
`and placed on stability test. At each stability time, one bag
`of each solution are tested for pH, potency, osmolality,
`physical appearance and particulate matter. The concentra(cid:173)
`tion of the drug is determined by a high performance liquid
`chromatographic (HPLC) method. The results are summa(cid:173)
`rized as follows:
`
`5
`
`10
`
`Stability of Bags Stored at Various Temperatures and Times
`
`Particulate Matter
`
`Test
`Time
`
`Potency
`(mg/ml) pH
`
`Osmolality
`(mosm/kg)
`
`Visual
`Inspection
`
`Particles
`"';10µm
`
`Particles
`"';25 µm
`
`25° C./35% RH*
`
`Initial
`3 months
`6 months
`30° C./35% RH*
`
`Initial
`3 months
`6 months
`40° C./15% RH*
`
`Initial
`1 months
`2 months
`3 months
`6 months
`
`10.9
`10.7
`10.6
`
`10.9
`10.6
`10.4
`
`10.9
`10.7
`10.5
`10.4
`9.9
`
`4.9
`4.9
`4.9
`
`4.9
`4.9
`4.8
`
`4.9
`4.9
`4.9
`4.9
`4.8
`
`304
`303
`302
`
`304
`304
`304
`
`304
`304
`304
`306
`308
`
`Pass**
`Pass
`Pass
`
`Pass
`Pass
`Pass
`
`Pass
`Pass
`Pass
`Pass
`Pass
`
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`*The storage temperature and humidity conditions. RH ~ Relative Humidity
`**Pass: clear colorless solution.
`
`The equipment and glassware for compounding, filtering,
`and filling are properly washed and depyrogenated. The
`filter assembly, filling tube assembly, and other parts and
`equipment are sterilized.
`
`45
`
`Eighty percent (80%) of the final volume of cool Water for
`Injection is collected in a calibrated compounding tank.
`Sodium chloride is added to the tank and the solution is
`stirred until sodium chloride is dissolved. Glacial acetic acid 50
`and sodium acetate are then added to the tank. The solution
`is further stirred until all excipients are dissolved. The tank
`is adjusted to 90% of final volume with Water for Injection
`and mixed. Approximately 2 liter of this solution (buffer 55
`solution) is removed for use in preparation of the slurry
`solution. Esmolol hydrochloride is weighed and added to the
`2 liter of the buffer solution to form a slurry solution. This
`slurry is then added to the compounding tank and the
`solution is mixed. The solution is then adjusted to pH 5.0
`with 1 N sodium hydroxide or hydrochloric acid. The
`solution is brought to final volume with Water for Injection
`and mixed.
`
`60
`
`The solution is then filled into 250 ml non-PVC flexible 65
`bags (Intra Via™ flexible plastic container (PL 2408-3 non(cid:173)
`PVC multi-layer plastic film) with one standard PL 146®
`
`Example 2
`
`Example 1 is repeated with the following formulation:
`
`Ingredient
`
`Esmolol HCl
`Dextrose
`Sodium Acetate Trihydrate
`Glacial Acetic Acid
`Sodium Hydroxide/Hydrochloric Acid
`Water for Injection, USP
`
`Amount/ml Solution
`
`11 mg/ml
`50 mg/ml
`2.8 mg/ml
`0.546 mg/ml
`pH adjustment to 5.0
`qs
`
`Example 3
`
`Example 1 is repeated with the following formulation:
`
`Ingredient
`
`Amount/ml Solution
`
`Esmolol HCl
`Dextrose
`Sodium Chloride
`Sodium Acetate Trihydrate
`Glacial Acetic Acid
`
`11 mg/ml
`25 mg/ml
`2.95 mg/ml
`2.8 mg/ml
`0.546 mg/ml
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1033 – Page 3
`
`

`

`US 6,310,094 Bl
`
`5
`
`-continued
`
`Ingredient
`
`Amount/ml Solution
`
`Sodium Hydroxide/Hydrochloric Acid
`Water for Injection, USP
`
`pH adjustment to 5.0
`qs
`
`5
`
`6
`4. A method for preparing a sterile, injectable aqueous
`pharmaceutical composition for the treatment of cardiac
`conditions, comprising forming an aqueous composition
`having a pH between 3.5 and 6.5 comprising methyl-3-[ 4-
`(2-hydroxy-3-isopropylamino )propoxy] phenylpropionate
`hydrochloride ( esmolol hydrochloride), a buffering agent,
`and an osmotic-adjusting agent in a sealed container, and
`autoclaving for a period of time sufficient to render the
`composition sterile.
`5. The method of claim 4 wherein the composition
`comprises 0.1-100 mg/ml methyl-3-[ 4-(2-hydroxy-3-
`isopropylamino) propoxy] phenylpropionate hydrochloride
`(esmolol hydrochloride), 0.1-5.0 mg/ml buffering agent,
`and 1-100 mg/ml osmotic-adjusting agent.
`6. The method of claim 4 wherein the composition is
`autoclaved at a temperature ranging from 115 to 130° C. for
`a period of time ranging from 5 to 40 minutes.
`7. The method of claim 4 wherein the container is a
`flexible polymeric container free from polyvinyl chloride.
`8. The method of claim 4 further comprising providing the
`20 container with a moisture barrier.
`9. The method of claim 8 wherein the moisture barrier is
`an aluminum overpouch.
`
`We claim:
`1. An injectable, aqueous pharmaceutical composition for
`the treatment of cardiac conditions, having a pH between 3.5 10
`and 6.5 and comprising
`a. 0.1-100 mg/ml methyl-3-[4-(2-hydroxy-3-
`isopropylamino) propoxy] phenylpropionate hydro(cid:173)
`chloride ( esmolol hydrochloride),
`b. 0.1-5.0 mg/ml buffering agent, and
`c. 1-100 mg/ml osmotic-adjusting agent.
`2. The composition of claim 1 wherein the buffering agent
`comprises at least one of acetate, glutamate, citrate, tartrate,
`benzoate, lactate, gluconate, phosphate and glycine.
`3. The composition of claim 1 wherein the osmotic(cid:173)
`adjusting agent comprises at least one of sodium chloride,
`dextrose, sodium bicarbonate, calcium chloride, potassium
`chloride, sodium lactate, Ringer's solution and lactated
`Ringer's solution.
`
`15
`
`* * * * *
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1033 – Page 4
`
`