111111111111111111111111111111t111)1111,10B11111111111111111111111111111
`
`(12) United States Patent (cid:9)
`Krishna et al. (cid:9)
`
`(54)
`
`PHARMACEUTICAL FORMULATIONS OF
`BIVALIRUDIN AND PROCESSES OF MAKING
`THE SAME
`
`(75) Inventors: Gopal Krishna, Parsippany, NJ (US);
`Gary Musso, Parsippany, NJ (US)
`
`(73) Assignee: The Medicines Company, Parsippany,
`NJ (US)
`
`(cid:9) (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 7,598,343 B1
`*Oct. 6, 2009
`
`2008/0268032 Al
`2008/0287650 Al
`2009/0062511 Al
`
`10/2008 Maggio
`11/2008 Tovi et al.
`3/2009 Palle et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO (cid:9)
`WO (cid:9)
`
`2006/045503 (cid:9)
`WO 2007/149096 (cid:9)
`
`5/2006
`12/2007
`
`OTHER PUBLICATIONS
`
`EMEA Publication. Scientific Discussion, 2004, p. 1-32 (www.emea.
`europa. eu/humandoc s/PDFs/EPAR/angiox/103304en6 spdf).
`W.M. Davis, M. C. Vinson, Drug Topics 2001, 145:5, p. 89.
`M. Staples, Pharm. Res. 1992, 9:10, Suppl., S79.
`U.S. Appl. No. 12/180,550, filed Jul. 27, 2008, Krishna et al.
`U.S. Appl. No. 12/180,553, filed Jul. 27, 2008, Krishna et al.
`Office Action issued for U.S. Appl. No. 12/180,553 (Oct. 28, 2008).
`Amsberry et al., "Compatibility and Stability of Bivalirudin in IV
`Admixtures" : http://www.aapsj sorg/abstracts/AM 1999/923 shtm.
`(1999).
`Barn Biotech Abstract, titled "Bivalirudin" : http://www.bambio.
`com/show.asp?id=107. (Sep. 27, 2006).
`Angiomax® U.S. Prescribing Information, Dec. 6, 2005.
`
`Primary Examiner (cid:9) Cecilia Tsang
`Julie Ha
`Assistant Examiner (cid:9)
`(74) Attorney, Agent, or Firm (cid:9) Frommer Lawrence & Haug
`LLP; Sandra Kuzmich; Russell A. Garman
`
`(57) (cid:9)
`
`ABSTRACT
`
`Pharmaceutical batch(es) or pharmaceutical formulation(s)
`comprising bivalirudin as the active ingredient, and a method
`of preparing the pharmaceutical batch(es) or pharmaceutical
`formulation(s). The pharmaceutical batch(es) or pharmaceu-
`tical formulation(s) may have a maximum impurity level of
`Asp9-bivalirudin that does not exceed about 0.6%. Also, the
`pharmaceutical batch(es) or pharmaceutical formulation(s)
`may have a reconstitution time that does not exceed about 42
`seconds. The method of preparing the pharmaceutical
`batch(es) or pharmaceutical formulation(s) may comprise
`dissolving bivalirudin in a solvent to form a first solution,
`efficiently mixing a pH-adjusting solution with the first solu-
`tion to form a second solution in which the pH-adjusting
`solution may comprise a pH-adjusting solution solvent, and
`removing the solvent and the pH-adjusting solution solvent
`from the second solution.
`
`20 Claims, No Drawings
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 12/180,551
`
`(22) Filed: (cid:9)
`
`Jul. 27, 2008
`
`(51) Int. Cl.
`A 61K 38/55 (cid:9)
`C07K 7/08 (cid:9)
`C07K 7/64 (cid:9)
`C07K 1/00 (cid:9)
`C07K 1/04 (cid:9)
`C07K 14/00 (cid:9)
`(52) U.S. Cl.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
` 530/325; 530/324; 530/333;
`530/334; 530/335; 514/13
`(58) Field of Classification Search (cid:9) (cid:9)
` None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,196,404 A
`5,240,913 A
`5,425,936 A
`5,433,940 A
`5,691,311 A
`5,786,330 A
`6,274,553 B1
`7,390,788 B2
`7,425,542 B2
`2007/0093423 Al
`2007/0116729 Al
`2008/0051558 Al
`
`3/1993 Maraganore et al.
`8/1993 Maraganore et al.
`6/1995 Maraganore et al.
`7/1995 Maraganore et al.
`11/1997 Maraganore et al.
`7/1998 Fauchere et al.
`8/2001 Furuya et al.
`6/2008 Pert et al.
`9/2008 Maggio
`4/2007 Tovi et al.
`5/2007 Palepu
`2/2008 Zhou
`
`Page 1
`
`RB Ex. 2002
`BDSI v. RB PHARMACEUTICALS LTD.
`IPR2014-00325
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`US 7,598,343 B1
`
`1
`PHARMACEUTICAL FORMULATIONS OF
`BIVALIRUDIN AND PROCESSES OF MAKING
`THE SAME
`
`INCORPORATION BY REFERENCE (cid:9)
`
`5
`
`The foregoing applications, and all documents cited
`therein or during their prosecution ("appin cited documents")
`and all documents cited or referenced in the appin cited docu-
`ments, and all documents cited or referenced herein ("herein 10
`cited documents"), and all documents cited or referenced in
`herein cited documents, together with any manufacturer's
`instructions, descriptions, product specifications, and product
`sheets for any products mentioned herein or in any document
`incorporated by reference herein, are hereby incorporated 15
`herein by reference, and may be employed in the practice of
`the invention.
`
`FIELD OF THE INVENTION
`
`20
`
`Various embodiments of the present invention are gener-
`ally directed towards a method for preparing a pharmaceuti-
`cal batch(es) or a pharmaceutical formulation(s) comprising
`bivalirudin as the active ingredient. Some embodiments of the
`present invention are also directed towards a pharmaceutical 25
`batch(es) or a pharmaceutical formulation(s) comprising
`bivalirudin as the active ingredient. For example, certain
`embodiments of the present invention relate to pharmaceuti-
`cal batch(es) or pharmaceutical formulation(s) of a drug
`product having reduced levels of a major degradation prod- 3o
`uct, i.e., Asp9-bivalirudin, which may contribute to improved
`stability and shelf-life. In some embodiments, the pharma-
`ceutical batch(es) or pharmaceutical formulation(s) is char-
`acterized by a maximum impurity level of Asp9-bivalirudin
`that does not exceed about 0.6%. In various embodiments, the 35
`pharmaceutical batch(es) or pharmaceutical formulation(s)
`of the present invention are characterized by a reconstitution
`time that does not exceed about 42 seconds. Various embodi-
`ments of the invention further generally relate to an injectable
`dosage form comprising a pharmaceutical formulation and a 4o
`vehicle, and methods of administering the injectable dosage
`form.
`
`BACKGROUND OF THE INVENTION
`
`45
`
`Anticoagulants are substances that prevent blood from
`clotting. They are commonly used during percutaneous coro-
`nary intervention (PCI) and other catherization techniques in
`order to reduce bleeding complications. One class of antico-
`agulants is direct thrombin inhibitors that disrupt the activity so
`of thrombin, an important protein in the coagulation cascade.
`In particular, bivalirudin (ANGIOMAX®), which directly
`inhibits thrombin by specifically binding to both its catalytic
`site and to the anion-binding exosite, is regarded as a highly
`effective anticoagulant for use during catherization proce- 55
`dures.
`Bivalirudin, also known as Hirulog-8, is a synthetic con-
`gener of the naturally occurring thrombin peptide inhibitor
`hirudin, which is found in the saliva of the medicinal leech
`Hirudo medicinalis. Hirudin consists of 65 amino acids, 60
`although shorter peptide segments have proven to be effective
`as thrombin inhibitors. U.S. Pat. No. 5,196,404 (incorporated
`herein by reference) discloses bivalirudin among these
`shorter peptides that demonstrate an anticoagulant activity.
`However, in contrast to hirudin, bivalirudin is a reversible 65
`inhibitor, which is ideal for temporary prevention of blood
`clotting during catherization procedures.
`
`2
`In light of the medical and therapeutic applications of
`bivalirudin, it is essential that the bivalirudin formulation
`maintains a high level of purity. The bivalirudin formulation
`is a compounded formulation containing bivalirudin, e.g.,
`bivalirudin undergoes a compounding process following its
`synthesis so that it is usable and stable for medical and thera-
`peutic applications.
`Impurities such as Asp9-bivalirudin (deamidation of aspar-
`agine at position 9 of bivalirudin to aspartic acid) and
`D-Phe'2-bivalirudin (isomerization of L-phenylalanine at
`position 12 of bivalirudin to the D-isomer) may be generated
`during the synthesis of bivalirudin. Consequently, processes
`for synthesizing bivalirudin have been developed to minimize
`the generation of impurities. However, impurities can also be
`produced during the compounding process, i.e., the process to
`generate a formulation of bivalirudin. It has been shown that
`various compounding processes can result in formulations
`that have up to 12% of Asp9-bivalirudin, which may affect
`product stability and shelf-life. Therefore, development of a
`compounding process for formulating bivalirudin that con-
`sistently generates formulations having low levels of impuri-
`ties is desirable.
`Citation or identification of any document in this applica-
`tion is not an admission that such document is available as
`prior art to the present invention.
`
`SUMMARY OF THE INVENTION
`
`Various embodiments of the present invention relates to a
`compounding process for preparing a pharmaceutical
`batch(es) of a drug product or a pharmaceutical
`formulation(s) comprising bivalirudin as an active ingredient.
`In certain embodiments, the compounding process comprises
`(i) dissolving bivalirudin in a solvent to form a first solution;
`(ii) efficiently mixing a pH-adjusting solution with the first
`solution to form a second solution, wherein Asp9-bivalirudin
`in the second solution is minimized; and (iii) removing the
`solvent from the second solution.
`In some embodiments, the pH of the second solution does
`not exceed about 8. In some embodiments, the pH of the
`second solution does not exceed about 7. In further embodi-
`ments, the pH of the second solution does not exceed about 6.
`In certain embodiments, efficient mixing is achieved by
`adding the pH-adjusting solution to the first solution, by
`adding the first solution to the pH-adjusting solution, or a
`combination thereof. In some embodiments, the pH-adjust-
`ing solution is added to the first solution in portions. In further
`embodiments, the pH-adjusting solution is added to the first
`solution at a constant rate.
`In some embodiments, efficient mixing is achieved by
`using one or more mixing devices. In certain embodiments,
`the mixing device is selected from a group consisting of a
`paddle mixer, magnetic stirrer, shaker, re-circulating pump,
`homogenizer, and any combination thereof. In some embodi-
`ments, the mixing device is a homogenizer, a paddle mixer, or
`a combination thereof.
`In further embodiments, the efficient mixing is achieved
`through high shear mixing.
`In certain embodiments, removal of the solvent from the
`second solution is achieved through lyophilization.
`In some embodiments, the compounding process may fur-
`ther comprise sterilization of the second solution before
`removal of the solvent. In certain embodiments, sterilization
`is achieved by aseptic filtration.
`Various embodiments of the present invention also relate to
`a pharmaceutical batch(es) or a pharmaceutical
`formulation(s) prepared by the compounding process of the
`
`Page 2
`
`

`

`US 7,598,343 B1
`
`4
`3
`acterized by a maximum impurity level of Asp9-bivalirudin
`invention. In certain embodiments, a pharmaceutical batch
`(es) or pharmaceutical formulation(s) is characterized by a (cid:9)
`that does not exceed about 0.6%.
`Certain embodiments of the present invention also relate to
`maximum impurity level of Asp9-bivalirudin that does not
`a pharmaceutical batch(es) of a drug product or pharmaceu-
`exceed about 0.6%. In some embodiments, a pharmaceutical
`batch(es) or pharmaceutical formulation(s) is characterized 5
`tical formulation(s) comprising bivalirudin as an active ingre-
`dient for use as an anticoagulant in a subject in need thereof,
`by a maximum total impurity level that does not exceed about
`said pharmaceutical batch(es) or pharmaceutical
`2%. In additional embodiments, a pharmaceutical batch(es)
`or pharmaceutical formulation(s) is characterized by a maxi- (cid:9)
`formulation(s) prepared by a compounding process compris-
`mum reconstitution time that does not exceed about 42 sec- (cid:9)
`ing: (i) dissolving bivalirudin in a solvent to form a first
`onds. (cid:9)
`10 solution; (ii) efficiently mixing a pH-adjusting solution with
`In addition, various embodiments of the present invention (cid:9)
`the first solution to form a second solution; and (iii) removing
`relate to a pharmaceutical batch(es) of a drug product or a (cid:9)
`the solvent from the second solution; wherein the pharma-
`pharmaceutical formulation(s) comprising bivalirudin as an (cid:9)
`ceutical batch(es) or pharmaceutical formulation(s) is char-
`active ingredient for use as an anticoagulant in a subject in (cid:9)
`acterized by a maximum reconstitution time that does not
`need thereof, said pharmaceutical batch(es) or pharmaceuti- 15 exceed about 42 seconds.
`cal formulation(s) prepared by a compounding process com- (cid:9)
`Furthermore, various embodiments of the present inven-
`prising: (i) dissolving bivalirudin in a solvent to form a first
`tion relate to a pharmaceutical batch(es) of a drug product or
`solution; (ii) efficiently mixing a pH-adjusting solution with
`a pharmaceutical formulation(s) comprising bivalirudin as an
`the first solution to form a second solution; and (iii) removing (cid:9)
`active ingredient for use as an anticoagulant in a subject in
`the solvent from the second solution. (cid:9)
`20 need thereof. Some embodiments of the present invention
`In certain embodiments, the pharmaceutical batch(es) or (cid:9)
`also relate to a pharmaceutical batch(es) of a drug product or
`pharmaceutical formulation(s) is characterized by a maxi- (cid:9)
`a pharmaceutical formulation(s) comprising bivalirudin as an
`mum impurity level of Asp9-bivalirudin that does not exceed
`active ingredient for use as an anticoagulant in a subject in
`about 0.6%. In some embodiments, the maximum impurity (cid:9)
`need thereof, wherein the pharmaceutical batch(es) or phar-
`level of Asp9-bivalirudin does not exceed about 0.4%. In 25 maceutical formulation(s) is characterized by a maximum
`further embodiments, the maximum impurity level of Asp9- (cid:9)
`impurity level of Asp9-bivalirudin that does not exceed about
`bivalirudin does not exceed about 0.3%. (cid:9)
`0.6%.
`In some embodiments of the present invention, the phar- (cid:9)
`In some embodiments, the maximum impurity level of
`maceutical batch(es) or pharmaceutical formulation(s) is
`Asp9-bivalirudin does not exceed about 0.4%. In certain
`characterized by a maximum total impurity level that does not 30 embodiments, the maximum impurity level of Asp9-bivaliru-
`exceed about 2%. In certain embodiments, the maximum
`din does not exceed about 0.3%.
`total impurity level does not exceed about 1%. In additional
`In additional embodiments, the pharmaceutical batch(es)
`embodiments, the pharmaceutical batch(es) or pharmaceuti- (cid:9)
`or pharmaceutical formulation(s) is further characterized by a
`cal formulation(s) is characterized by a maximum level of
`maximum total impurity level that does not exceed about 2%.
`D-Phe'2-bivalirudin that does not exceed about 2.5%. (cid:9)
`35 In certain embodiments, the maximum total impurity level
`In other embodiments, the pharmaceutical batch(es) or
`does not exceed about 1%. In some embodiments, the maxi-
`pharmaceutical formulation(s) is characterized by a maxi- (cid:9)
`mum total impurity level does not exceed about 0.5%.
`mum reconstitution time that does not exceed about 42 sec- (cid:9)
`In certain embodiments of the invention, the pharmaceuti-
`onds. In some embodiments, the maximum reconstitution (cid:9)
`cal batch(es) or pharmaceutical formulation(s) is further
`time does not exceed about 30 seconds. In further embodi- 40 characterized by a maximum level of D-Phe12-bivalirudin that
`ments, the maximum reconstitution time does not exceed
`does not exceed about 2.5%.
`about 21 seconds. (cid:9)
`In some embodiments, the pharmaceutically acceptable
`In some embodiments of the present invention, the phar- (cid:9)
`carrier comprises one or more of a bulking agent or a stabi-
`maceutically acceptable carrier comprises one or more of a
`lizing agent. In certain embodiments, the pharmaceutically
`bulking agent or a stabilizing agent. In certain embodiments, 45 acceptable carrier is a bulking agent. In further embodiments,
`the pharmaceutically acceptable carrier is a bulking agent. In (cid:9)
`the bulking agent is a sugar. In yet additional embodiments,
`additional embodiments, the bulking agent is a sugar. In fur- (cid:9)
`the sugar is mannitol
`ther embodiments, the sugar is mannitol
`Some embodiments of the present invention relate to a
`In certain embodiments, efficient mixing is achieved by (cid:9)
`pharmaceutical batch(es) of a drug product or pharmaceutical
`adding the pH-adjusting solution to the first solution, by so formulation(s) comprising bivalirudin as an active ingredient
`adding the first solution to the pH-adjusting solution, or a
`for use as an anticoagulant in a subject in need thereof,
`combination thereof. In some embodiments, the pH-adjust- (cid:9)
`wherein the pharmaceutical batch(es) or pharmaceutical for-
`ing solution is added to the first solution at a constant rate. In (cid:9)
`mulation(s) is characterized by a maximum reconstitution
`further embodiments, efficient mixing is achieved by using (cid:9)
`time that does not exceed about 42 seconds.
`one or more mixing devices. In yet additional embodiments, 55 (cid:9)
`In certain embodiments, the maximum reconstitution time
`the efficient mixing is achieved through high shear mixing. (cid:9)
`does not exceed about 30 seconds. In some embodiments, the
`Moreover, various embodiments of the present invention (cid:9)
`maximum reconstitution time does not exceed about 21 sec-
`relate to a pharmaceutical batch(es) of a drug product or (cid:9)
`onds.
`pharmaceutical formulation(s) comprising bivalirudin as an
`In some embodiments of the invention, the pharmaceuti-
`active ingredient for use as an anticoagulant in a subject in 60 cally acceptable carrier comprises one or more of a bulking
`need thereof, said pharmaceutical batch(es) or pharmaceuti- (cid:9)
`agent or a stabilizing agent. In certain embodiments, the
`cal formulation(s) prepared by a compounding process com- (cid:9)
`pharmaceutically acceptable carrier is a bulking agent. In
`prising: (i) dissolving bivalirudin in a solvent to form a first
`further embodiments, the bulking agent is a sugar. In yet
`solution; (ii) efficiently mixing a pH-adjusting solution with
`additional embodiments, the sugar is mannitol
`the first solution to form a second solution; and (iii) removing 65 (cid:9)
`Also, various embodiments of the present invention relate
`the solvent from the second solution; wherein the pharma- (cid:9)
`to a pharmaceutical batch(es) of a drug product or pharma-
`ceutical batch(es) or pharmaceutical formulation(s) are char- (cid:9)
`ceutical formulation(s) comprising bivalirudin as an active
`
`Page 3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`

`

`US 7,598,343 B1
`
`5
`ingredient for use as an anticoagulant in a subject in need
`thereof, wherein the pharmaceutical batch(es) or pharmaceu-
`tical formulation(s) is characterized by a maximum impurity
`level of Asp9-bivalirudin that does not exceed about 0.6%, a
`maximum total impurity level that does not exceed about 2%,
`and a maximum reconstitution time that does not exceed
`about 42 seconds.
`These and other embodiments are disclosed or are obvious
`from and encompassed by, the following Detailed Descrip-
`tion.
`
`DETAILED DESCRIPTION
`
`Various embodiments of the present invention relate to a
`compounding process for preparing a pharmaceutical
`batch(es) of a drug product, which results in pharmaceutical
`formulations comprising bivalirudin and a pharmaceutically
`acceptable carrier. Certain embodiments of the present inven-
`tion also relate to a pharmaceutical batch(es) of a drug prod-
`uct, resultant pharmaceutical formulation(s) comprising
`bivalirudin and a pharmaceutically acceptable carrier, and an
`injectable dosage form comprising the pharmaceutical for-
`mulation and a vehicle.
`As used here, "batch" or "pharmaceutical batch" refers to
`material produced by a single execution of a compounding
`process of various embodiments of the present invention.
`"Batches" or "pharmaceutical batches" as defined herein may
`include a single batch, wherein the single batch is represen-
`tative of all commercial batches (see generally, Manual of
`Policies and Procedures, Center for Drug Evaluation and
`Research, MAPP 5225.1, Guidance on the Packaging of Test
`Batches at 1), and wherein the levels of, for example, Asp9-
`bivalirudin, total impurities, and largest unknown impurity,
`and the reconstitution time represent levels for all potential
`batches made by said process. "Batches" may also include all
`batches prepared by a same compounding process.
`The term "drug product" herein refers to an active ingre-
`dient and a pharmaceutically acceptable carrier.
`The term "formulation" or "pharmaceutical formulation"
`refers to a unit dose of an active pharmaceutical ingredient
`and a pharmaceutically acceptable carrier, which is prepared
`by the various processes in certain embodiments of the
`present invention. In the case of the present pharmaceutical
`formulation, the active pharmaceutical ingredient is bivaliru-
`din.
`The term "carrier" refers to any component of the pharma-
`ceutical batch(es) or pharmaceutical formulation(s) that, for
`example, serves as a bulking agent or functions as a stabiliz-
`ing agent for the active ingredient. A bulking agent refers to
`any material that fills or provides volume to the active ingre-
`dient. Examples of appropriate bulking agents may include,
`but are not limited to, sugars such as mannitol, sucrose, lac-
`tose, fructose and trehalose.
`A stabilizing agent refers to any material which serves to
`minimize degradation of the active ingredient. Examples of 55
`stabilizing agents may include, but are not limited to, antioxi-
`dants, buffering agents, preservatives, etc.
`Bivalirudin has the chemical name of D-Phenylalanyl-L-
`Prolyl-L-Arginyl-L-Prolyl-Glycyl-Glycyl-Glycyl-Glycyl-L-
`Asparagyl-Glycyl-L-Aspartyl-L-Phenylalanyl-L-Glutamyl-L- 60
`Glutamyl-L-Isoleucyl-L-Prolyl-L-Glutamyl-L-Glutamyl-L-
`Tyrosyl-L-Leucine trifluoroacetate (salt) hydrate and has a
`molecular weight of 2180 daltons. Bivalirudin is made up of
`the amino acid sequence: (D-Phe)-Pro-Arg-Pro-Gly-Gly-
`Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-
`Leu (SEQ ID NO: 1). Methods for the synthesis of bivalirudin
`may include, but are not limited to, solid-phase peptide syn-
`
`6
`thesis, solution-phase peptide synthesis, or a combination of
`solid-phase and solution-phase procedures (e.g., U.S. Pat.
`No. 5,196,404; Okayama et al., Chem. Pharm. Bull. 1996, 44:
`1344-1350; Steinmetzer et al., Eur. J. Biochem. 1999, 265:
`5 (cid:9) 598-605; PCT Patent Application WO 91/02750).
`As described above, Asp9-bivalirudin is formed due to
`deamidation of asparagine at position 9 of bivalirudin to
`aspartic acid. The amino acid sequence ofAsp9-bivalirudin is:
`(D-Phe)-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asp-Gly-Asp-Phe-
`1 o Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (SEQ ID NO: 2). Further,
`D-Phe'2-bivalirudin is generated from isomerization of L-phe-
`nylalanine at position 12 of bivalirudin to the D-isomer. The
`amino acid sequence of D-Phe'2-bivalirudin is (D-Phe)-Pro-
`Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-(D-Phe)-Glu-Glu-
`15 Ile-Pro-Glu-Glu-Tyr-Leu (SEQ ID NO: 3)
`Bivalirudin inhibits blood clotting by binding to thrombin,
`a key serine protease in blood clot formation. This synthetic
`20 amino acid peptide binds to thrombin at the catalytic site
`and at the anion-binding exocite, thereby inhibiting thrombin.
`20 Thrombin plays a central role in hemostasis. The coagulation
`pathway initiates clotting when thrombin, a serine protease,
`converts fibrinogen into fibrin. Additionally, thrombin acti-
`vates Factor XIII into Factor XIIIa (the latter which links
`fibrin polymers covalently), Factors V and VIII (which pro-
`25 mote thrombin generation), and platelets (which help propa-
`gate the thrombus).
`The method of delivery of bivalirudin may be through
`intravenous administration. Bivalirudin may be supplied in
`single-use vials as a white lyophilized sterile cake. Each
`30 single-use vial may contain about 250 mg of bivalirudin.
`When reconstituted with a sterile aqueous solution for injec-
`tion, the product yields a clear to opalescent, colorless to
`slightly yellow, solution. Such a solution has a pH of about
`5-6.
`The pharmaceutical batch(es) or pharmaceutical formula-
`tion(s) according to certain embodiments of the present
`invention may be used in any application which requires
`altered or inhibited thrombin activity. The pharmaceutical
`batch(es) or pharmaceutical formulation(s) may be used to
`40 alter or inhibit the coagulation cascade, for example, as an
`anticoagulant.
`Approved indications include treatment in patients with
`unstable angina undergoing percutaneous translumnial coro-
`nary angioplasty; administration with the provisional use of
`45 glycoprotein IIb/IIIa inhibitor for use as an anticoagulant in
`patients undergoing percutaneous coronary intervention
`(PCI); and treatment in patients with, or at risk of, heparin-
`induced thrombocytopenia (HIT) or heparin-induced throm-
`bocytopenia and thrombosis syndrome (HITTS) undergoing
`so PCI. Also, the pharmaceutical batch(es) or pharmaceutical
`formulation(s) according to various embodiments of the
`present invention can be used for the prevention and treatment
`of venous thromboembolic disease.
`
`35 (cid:9)
`
`Process for Preparing a Pharmaceutical Batch(es) or a Phar-
`maceutical Formulation(s)
`Various embodiments of the present invention relate to a
`compounding process for preparing a pharmaceutical
`batch(es) or pharmaceutical formulation(s) comprising biva-
`lirudin.
`
`1) Dissolving Bivalirudin in a Solvent to Form a Bivalirudin
`Solution
`In the compounding process of various embodiments of the
`present invention, bivalirudin may be dissolved in a solvent to
`65 form a bivalirudin solution. Bivalirudin may be commercially
`purchased or synthesized by various procedures as described
`above. The concentration of bivalirudin in the solvent may be
`
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`US 7,598,343 B1
`
`7
`between about 0.010 g/mL and about 1 g/mL, or between
`about 0.050 g/mL and about 0.1 g/mL. Solvents may include
`aqueous and non-aqueous liquids, including but not limited
`to, mono- and di-alcohols such as methanol, ethanol, isopro-
`pyl alcohol, and propylene glycol; polyhydric alcohols such
`as glycerol and polyethylene glycol; buffers; and water.
`The solvent may comprise carriers such as sugars. For
`example, the sugar may be a monosaccharide such as glucose
`or fructose; a disaccharide such as sucrose, maltose, or treha-
`lose; an oligosaccharide; or a polysaccharide. Alternatively,
`the sugar may be a sugar alcohol, such as sorbitol or mannitol
`The quantity of carrier in the solvent may be adjusted to
`provide a pharmaceutical batch or pharmaceutical formula-
`tion preferably having a ratio of the carrier to the active
`ingredient of between about 5:1 and about 1:10, or between
`about 1:1 and about 1:4, or more preferably about 1:2.
`Bivalirudin can be dissolved in the solvent by methods
`known in the art, preferably by adding the bivalirudin to the
`solvent. For example, bivalirudin may be added to the solvent
`rapidly, slowly, in portions, at a constant rate, at a variable
`rate, or a combination thereof. A mixing device known in the
`art may be used to dissolve bivalirudin. Examples of mixing
`devices may include, but are not limited to, a paddle mixer,
`magnetic stirrer, shaker, re-circulating pump, homogenizer,
`and any combination thereof. The mixing device may be
`applied at a mixing rate between about 100 and about 2000
`rpm, or between about 300 and about 1500 rpm. The solution
`resulting from dissolving the bivalirudin in the solvent is
`referred to here as the "bivalirudin solution" or alternatively
`the "first solution."
`
`2) Mixing a pH-Adjusting Solution with the Bivalirudin Solu-
`tion to Form a Compounding Solution
`The compounding process may comprise mixing a pH-
`adjusting solution with the bivalirudin solution to form a
`compounding solution. The pH-adjusting solution may be
`prepared before, after, or simultaneously with, the bivalirudin
`solution.
`The pH-adjusting solution may comprise a base dissolved
`in a solvent, wherein the solvent is referred to here as the
`"pH-adjusting solution solvent." In other words, the solution
`resulting from the combination of the base with the pH-
`adjusting solution solvent is referred to here as the "pH-
`adjusting solution." The pH-adjusting solution may also com-
`prise a neat base such as pyridine or a volatilizable base such
`as ammonium carbonate.
`The base may be an organic base or an inorganic base. The
`terms "inorganic base" and "organic base," as used herein,
`refer to compounds that react with an acid to form a salt;
`compounds that produce hydroxide ions in an aqueous solu-
`tion (Arrhenius bases); molecules or ions that capture hydro-
`gen ions (Bronsted-Lowry bases); and/or molecules or ions
`that donate an electron pair to form a chemical bond (Lewis
`bases). In certain processes, the inorganic or organic base
`may be an alkaline carbonate, an alkaline bicarbonate, an
`alkaline earth metal carbonate, an alkaline hydroxide, an
`alkaline earth metal hydroxide, an amine, or a phosphine. For
`example, the inorganic or organic base may be an alkaline
`hydroxide such as lithium hydroxide, potassium hydroxide,
`cesium hydroxide, or sodium hydroxide; an alkaline carbon-
`ate such as calcium carbonate or sodium carbonate; or an
`alkaline bicarbonate such as sodium bicarbonate.
`Solvents may include aqueous and non-aqueous liquids,
`including but not limited to, mono- and di-alcohols such as
`methanol, ethanol, isopropyl alcohol, and propylene glycol;
`polyhydric alcohols such as glycerol and polyethylene gly-
`col; buffers; and water. The pH-adjusting solution solvent
`
`8
`may comprise carriers such as dissolved sugars. For instance,
`the sugar may be a monosaccharide such as glucose or fruc-
`tose; a disaccharide such as sucrose, maltose, or trehalose; an
`oligosaccharide; or a polysaccharide. The sugar may also be
`5 (cid:9) a sugar alcohol, such as sorbitol or mannitol The quantity of
`the carrier in the pH-adjusting solution solvent may be
`adjusted to provide the final product as described above.
`The base is mixed or dissolved in the pH-adjusting solution
`solvent. The mixing or dissolution can be performed by meth-
`10 ods known in the art. For instance, the base may be added to
`the pH-adjusting solution solvent rapidly, slowly, in portions,
`at a constant rate, at a variable rate, or a combination thereof.
`Also, a mixing device known in the art may be used to mix the
`base and the pH-adjusting solution solvent. Examples of mix-
`15 ing devices may include, but are not limited to, a paddle
`mixer, magnetic stirrer, shaker, re-circulating pump, homog-
`enizer, and any combination thereof. The mixing device may
`be applied at a mixing rate between about 100 and about 1500
`rpm, or between about 300 and about 1200 rpm. The base is
`20 added/mixed with the pH-adjusting solution solvent in a
`quantity that will result in a pH-adjusting solution that is
`characterized as being between about 0.01 N and about 5 N,
`or between about 0.1 N and 1 N.
`The pH-adjusting solution may then be mixed with the
`25 bivalirudin solution. This mixing may occur by adding the
`pH-adjusting solution to the bivalirudin solution. Alterna-
`tively, the bivalirudin solution may be added to the pH-ad-
`justing solution, or the pH-adjusting solution and the biva-
`lirudin solution may be added simultaneously (into a separate
`30 vessel), or there may be a combination of these addition
`methods thereof. It is important during the adding or mixing
`of the pH-adjusting solution and the bivalirudin solution that
`pH is controlled. See below. The solution resulting from
`mixing the pH-adjusting solution and the bivalirudin solution
`35 is referred to here as the "compounding solution," or the
`"second solution." The compounding solution or the second
`solution can refer to the bivalirudin solution during or after
`the pH-adjusting solution is added, or can refer to the pH-
`adjusting solution during or after the bivalirudin solution is
`40 added, or can refer to the resulting solution formed during or
`after both the pH-adjusting solution and the bivalirudin solu-
`tion are added together.
`The mixing of the pH-adjusting solution and the bivaliru-
`din solution may occur under controlled conditions. For
`45 example, temperat