US008455524B2
`
`(12) United States Patent
`Duncan et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,455,524 B2
`*Jun. 4, 2013
`
`(54) METHODS OF TREATMENT WITH
`PRE-MIXED, READY-TO-USE
`PHARMACEUTICAL COMPOSITIONS
`(75) Inventors: Michelle Renee Duncan, GlenvieW, IL
`(US); Supriya Gupta, Sunnyvale, CA
`(US); David Hartley Haas, Fremont,
`CA (US); NormaV. Stephens, Skokie,
`IL (US); Camellia Zamiri, Fremont, CA
`(Us)
`(73) Assignee: EKR Therapeutics, Inc., Cary, NC (U S)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 254 days.
`This patent is subject to a terminal dis
`claimer.
`(21) App1.No.: 12/971,084
`(22) Filed:
`Dec. 17, 2010
`(65)
`Prior Publication Data
`
`Apr. 14, 2011
`US 2011/0086892 A1
`Related US. Application Data
`
`(60) Continuation of application No. 12/407,557, ?led on
`Mar. 19, 2009, noW Pat. No. 7,659,291, Which is a
`division of application No. 11/788,076, ?led on Apr.
`18, 2007, noW Pat. No. 7,612,102.
`(60) Provisional application No. 60/793,074, ?led on Apr.
`18, 2006.
`
`(2006.01)
`
`(51) Int. Cl.
`A61K 31/44
`(52) US. Cl.
`USPC ......................................... .. 514/354; 424/400
`(58) Field of Classi?cation Search
`None
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3,985,758 A 10/1976 Murakami
`4,711,902 A 12/1987 Serno
`4,880,823 A 11/1989 Ogawa
`4,940,556 A
`7/1990 MacFarlane
`5,079,237 A
`1/1992 Husu et al.
`5,164,405 A 11/1992 McFarlane
`5,198,226 A
`3/1993 MacFarlane
`RE34,618 E
`5/1994 Ogawa
`5,376,645 A 12/1994 Stella
`5,519,012 A
`5/1996 Fercej-Temeljotov
`5,904,929 A
`5/1999 Uekama
`6,595,926 B1
`7/2003 Laragh
`7,612,102 B2 11/2009 Duncan etal.
`7,659,290 B2
`2/2010 Duncan et al.
`7,659,291 B2
`2/2010 Duncan etal.
`2002/0160942 A1
`l0/2002 Larew et al.
`5/2007 Bhowmick
`2007/0112041 A1
`l0/2007 Gupta
`2007/0244166 A1
`l0/2007 Duncan
`2007/0249689 A1
`
`EP
`EP
`EP
`GB
`WO
`
`FOREIGN PATENT DOCUMENTS
`0143305 Al
`6/1985
`0149475 Bl
`7/1985
`0162705 Bl
`ll/l985
`2228412 A
`8/1990
`01/07086
`2/2001
`
`OTHER PUBLICATIONS
`
`VisIV, Dextrose Injection Solution, (Apr. 2007), pp. l-6.*
`Hersey, Shannon et al., Anesth Analg; 84, (1997), pp. 1239-1244.*
`Varonk, Joseph, et al., Internet Scienti?c Publications (Oct. 1996), pp.
`1-12.
`Zeidler, C., Compatibility of various drugs used in intensive care
`medicine in polyethylene, PVC and glass infusion containers, Euro
`pean Hospital Pharmacy, 5(3), (Sep. 1999), pp. 106-110.*
`Kaise, B., et al., “Solutions to Health Care Waste: Life-Cycle Think
`ing and ‘Green’ Purchasing”, Environmental Health Perspectives,
`vol. 109, No. 3, Mar. 2001, pp. l-4.
`Pomponio, R., et al., “Photostability Studies on Nicardipine
`Cyclodextrin Complexes by Capillary Electroporesis”, Journal of
`Pharmaceutical andBiomedical Analysis, vol. 35, 2004, pp. 267-275.
`Baaske, M., et al., “Stability of Nicardipine Hydrochoride in Intra
`venous Solutions”, Am J Health-Syst Pharm, vol. 53, Jul. 15, 1996,
`pp. 1701-1705.
`Kawano, K., et al., “The Effect of the Drip Condition (Container
`Materials, Concentration, Drip Rate) on the Sorption of Nicardipine
`Hydrochloride from Injection to the Intravenous Infusion Set”, Jpn. J.
`Hosp. Pharm., 18(5), 491-495 (1992) With English translation.
`Kawano, K., et al., “The Sorption of Nicardipine Hydrochloride from
`the Solutions into the Administration Set”, Jpn. J. Hosp. Pharm.,
`18(3), 182-186 (1992) With English translation.
`Yang et al., “Nicardipine versus nitroprusside infusion as
`antihypertensive therapy in hypertensive emergencies,” J. Int Med
`Research, vol. 32(2):ll8-l23 (Mar-Apr. 2004).
`Atlee et al., “The use of esmolol, nicardipine, or their combination to
`blunt hemodynamic changes after laryngoscopy and tracheal intuba
`tion,” Anesth Analg, vol. 90:280-285 (Feb. 2000).
`Aya et al., “Intravenous nicardipine for severe hypertension in pre
`eclampsia4effects of an acute treatment on mother and foetus,”
`Intensive Care Med, vol. 25(ll):l277-l28l (Nov. 1999).
`Cheung et al., “Nicardipine intravenous bolus dosing for acutely
`decreasing arterial blood pressure during general anesthesia for car
`diac operations: pharmacokinetics, pharmacodynamics, and associ
`ated effects on left ventricular function,” Anesth Analg, vol. 89:1116
`1123 (Nov. 1999).
`Colson et al., “Haemodynamic heterogeneity and treatment With the
`calcium channel blocker nicardipine during phaeochromocytoma
`surgery,”ActAnaesthesiol Scand., vol. 42(9): 1 1 14-1 1 19 (Oct. 1998).
`Elatrous et al., “Short-term treatment of severe hypertension of preg
`nancy: prospective comparison of nicardipine and labetalol,” Inten
`sive Care Med, vol. 28(9):l28l-l286 (Jul. 26, 2002).
`Fernandes et al., “Physiochemical characterization and in vitro dis
`solution behavior of nicardipine-cyclodextrins inclusion com
`pounds,” Eur. J. of Pharma. Sci. 15: pp. 79-88, 2002.
`Flynn et al., “Intravenous nicardipine for treatment of severe hyper
`tension in children,” J Pediatr, vol. l39(l):38-43 (Jul. 2001).
`Kwak et al., “Comparison of the effects of nicardipine and sodium
`nitroprusside for control of increased blood pressure after coronary
`artery bypass graft surgery,” J Int Med Res, vol. 32:342-350 (Jul.
`Aug. 2004).
`Vincent et al., “Intravenous nicardipine in the treatment of postop
`erative arterial hypertension,” J Cardiothorac Vasc Anesth, vol.
`11(2):160-164 (Apr. 1997).
`International Preliminary Report on Patentability for PCT/US2007/
`066897, issued Jan. 13, 2009.
`International Search Report for PCT/US2007/066897, published
`Feb. 19, 2009.
`Written Opinion of the International Searching Authority for PCT/
`US2007/066897, mailed Nov. 24, 2008.
`International Preliminary Report on Patentability for PCT/US2007/
`009549, issued Oct. 22, 2008.
`International Search Report for PCT/US2007/009549, published
`Jan. 3, 2008.
`
`(Continued)
`Primary Examiner * Scott Long
`Assistant Examiner * Lyndsey Beckhardt
`(74) Attorney, Agent, or Firm * LoWenstein Sandler LLP
`(57)
`ABSTRACT
`Provided herein are ready-to-use premixed pharmaceutical
`compositions of nicardipine or a pharmaceutically acceptable
`salt and methods for use in treating cardiovascular and cere
`brovascular conditions.
`28 Claims, 5 Drawing Sheets
`
`Sandoz Exhibit 1001 Page 1
`
`

`

`US 8,455,524 B2
`Page 2
`
`OTHER PUBLICATIONS
`Written Opinion of the International Searching Authority for PCT/
`US2007/009549 (date not indicated).
`Non Final Of?ce Action for US. Appl. No. 11/737,067, dated Oct.
`29, 2008.
`PDL Biopharma, Inc.; “Cardene IV (nicardipine hydrochloride),”
`Product Insert, Jan. 2006, USA.
`International Search Report and Written Opinion of the International
`Searching Authority from PCT/U S2007/ 009549, dated Nov. 9, 2007.
`Sweetana and Akers, “Solubility principles and practices for
`parenteral drug dosage form development,” PDA J Pharmaceutical
`Science & Technology, 50(5):330-342 (1996).
`Zhang et al., “The use of nicardipine for electroconvulsive therapy: a
`dose-ranging study,” Anesth Analg, vol. 100:378-381 (Feb. 2005).
`Endoh et al.. “Effects of nicardipine-, nitroglycerin-, and
`prostaglandin El-induced hypotension on human cerebrovascular
`carbon dioxide reactivity during propofol-fentanyl anesthesia,” J
`Clin Anesth, vol. 11(7):545-549 (Nov. 1999).
`Bernard et al., “Long-term hypotensive technique With nicardipine
`and nitroprusside during iso?urane anesthesia for spinal surgery,”
`Anesth Analg, vol. 75(2):179-185 (Aug. 1992).
`Chen et al., “The comparative potentcy of intravenous nicardipine
`and verapamil on the cardiovascular response to tracheal intubation,”
`Acta Anaesthesiol Sin., vol. 34(4): 197-202 (Dec. 1996).
`
`Song et al., “Optimal dose of nicardipine for maintenance of
`hemodynamic stability after tracheal intubation and skin incision,”
`Anesth Analg, vol. 85:1247-1251 (Dec. 1997).
`Cheung et al., “Acute pharmacokinetic and hemodynamic effects of
`intravenous bolus dosing of nicardipine,” Am Heart J ., vol. 119(2 Pt
`2):438-442 (Feb. 1990).
`Yalkowsky et al., “Formulation-related problems associated With
`intravenous drug delivery,” J Pharm Sciences, vol. 87(7):787-796
`(Jul. 1998).
`Maurin et al., “SolubiliZation of nicardipine hydrochloride via
`compleXation and salt formation,” J Pharm Sciences, vol.
`83(10):1418-1420 (Oct. 1994).
`US. Appl. No. 12/977,96SiRGSPOIISG/AIHGIICIIHGIII dated Feb. 28,
`2013.
`US. Appl. No. 12/977,965iNon-Final Rejection dated Nov. 30,
`2012.
`US. Appl. No. 12/645,169iResponse/Amendment dated Feb. 6,
`2013.
`US. Appl. No. 12/645,169iNon-Final Rejection dated Sep. 6,
`2012.
`
`* cited by examiner
`
`Sandoz Exhibit 1001 Page 2
`
`

`

`US. Patent
`
`Jun. 4, 2013
`
`Sheet 1 0f 5
`
`US 8,455,524 B2
`
`FIG. 1
`
`l
`
`4
`
`l
`
`l
`
`1
`
`HO
`
`100
`
`90
`
`Ch 0
`
`01 O
`
`U D
`
`N O
`
`O
`
`o _n
`
`l
`
`3
`3. S
`pH After Mixing
`
`
`
`
`
`Pal-cant Remaining at 24hr
`
`Sandoz Exhibit 1001 Page 3
`
`

`

`US. Patent
`
`Jun. 4, 2013
`
`Sheet 2 0f 5
`
`US 8,455,524 B2
`
`Figure 2A
`
`+ pH 3.3
`--El--pH3.6
`—t-pH 4.0
`—O—pH 4.4
`-— éK- - pH 4.7
`
`I
`
`2
`
`I
`
`I
`
`3
`4
`Time (months)
`
`I
`
`5
`
`I
`
`6
`
`Figure 2B
`
`—O——pH 3.3
`
`- - U - - pH 3.6
`—A-pH 4.0
`—-O—pH 4.4
`— ex- -pH 4.7
`
`110
`105_
`
`
`
`% Drug remaining
`
`75 —
`
`70
`
`0
`
`20
`
`
`
`% Total Impurities
`
`Time (months)
`
`Sandoz Exhibit 1001 Page 4
`
`

`

`US. Patent
`
`Jun. 4, 2013
`
`Sheet 3 of5
`
`US 8,455,524 B2
`
`102
`
`Figure 3A
`
`--El--pH 3.6
`+pH4.0
`
`
`
`
`
`mEEmEQ 9.20 .x.
`
`90
`
`0.5
`
`1.5
`Time (months)
`
`2.5
`
`3.5
`
`Figure 3B
`
`3.0
`
`2.5 1
`
`$.53. 58 Q0
`
`1 1
`5. 0.
`
`_ a
`
`0.5 ~
`
`0.0
`
`Time (months)
`
`Sandoz Exhibit 1001 Page 5
`
`

`

`US. Patent
`
`Jun. 4, 2013
`
`Sheet 4 of5
`
`US 8,455,524 B2
`
`Figure 4A
`
`
`
`%Total Impurities 3
`
`3.0
`
`2.5 '
`
`2.0 -
`
`1.0
`
`0.5 -
`
`
`
`% Total impurities
`
`Figure 48
`
`+0.1 mg/mL
`—O—0.2 mg/mL
`
`0.0
`
`.
`
`i
`
`i
`
`i
`
`Sandoz Exhibit 1001 Page 6
`
`

`

`US. Patent
`
`Jun. 4, 2013
`
`Sheet 5 0f 5
`
`US 8,455,524 B2
`
`110
`
`100
`
`90 ~
`
`
`
`% Drug remaining
`
`Figure 5A
`
`—O—Via?ex
`—Ci-— Stedim 71
`+ lntravia
`
`I
`
`a
`
`50
`
`0
`
`I
`
`2
`
`I
`
`4
`
`I
`
`I
`
`6
`8
`Time (weeks)
`
`l
`
`10
`
`I
`
`12
`
`14
`
`Figure 5B
`
`110
`
`100 _,’A_
`
`
`
`% Drug remaining
`
`90 -
`
`80 ~
`
`70 —
`
`60 —
`
`—O— Excel
`—I—Via?o
`—A-—V|S IV
`
`+Galaxy
`
`so
`
`O
`
`I
`
`5
`
`I
`
`10
`
`I
`
`15
`Time (weeks)
`
`l
`
`20
`
`I’
`
`25
`
`30
`
`Sandoz Exhibit 1001 Page 7
`
`

`

`US 8,455,524 B2
`
`1
`METHODS OF TREATMENT WITH
`PRE-MIXED, READY-TO-USE
`PHARMACEUTICAL COMPOSITIONS
`
`1. CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of US. patent applica
`tion Ser. No. 12/645,169, ?led Dec. 22, 2009 Which is a
`continuation ofU.S. Pat. No. 7,659,291, ?led Mar. 19, 2009
`Which is a divisional ofU.S. Pat. No. 7,612,102, ?ledApr. 18,
`2007, and claims bene?t under 35 U.S.C. §119(e) to US.
`Provisional application Ser. No. 60/793,074, ?led Apr. 18,
`2006, the contents of all of Which are incorporated herein by
`reference.
`
`2. BACKGROUND
`
`Nicardipine hydrochloride ((:)-2-(benZyl-methyl amino)
`ethyl methyl 1 ,4-dihydro-2, 6-dimethyl-4-(m-nitrophenyl) -3,
`5-pyridinedicarboxylate monohydrochloride) is a calcium
`ion in?ux inhibitor useful for the treatment of cardiovascular
`and cerebrovascular disorders (see, e.g., US. Pat. No. 3,985,
`758). Nicardipine hydrochloride is currently sold in capsule
`form and in an injectable intravenous form. The capsule form
`is marketed as CARDENE® and is available as an immediate
`release oral capsule and as an extended release oral capsule.
`The inj ectable intravenous form of CARDENE® is marketed
`in glass ampuls suitable for intravenous administration fol
`lowing dilution in a compatible intravenous ?uid, such as
`dextrose or sodium chloride (CARDENE® I.V.). Each milli
`liter of a CARDENE® I.V. ampul contains 2.5 mg nicardipine
`hydrochloride in Water, 48.0 mg sorbitol, buffered to pH 3.5
`With 0.525 mg citric acid monohydrate and 0.09 mg sodium
`hydroxide. For infusion, each milliliter of the diluted formu
`lation contains 0.1 mg of nicardipine hydrochloride, With a
`variable pH due to the diluent selected by the end user. U.S.
`Reissue Pat. No. RE. 34,618 (a reissue of US. Pat. No.
`4,880,823) describes an injectable composition of nicar
`dipine hydrochloride that is stored in a light resistant broWn
`ampul. US. Pat. No. 5,164,405 describes a buffered pharma
`ceutical composition containing nicardipine designed for
`parenteral administration, that is also stored in an ampul.
`The requirement for diluting CARDENE® I.V. before use
`is associated With a number of disadvantages. One disadvan
`tage is that the diluted solution is only stable for 24 hours at
`room temperature. Another disadvantage is that the pH of the
`diluted formulation varies depending on the choice of diluent.
`Since CARDENE® I.V. can be used under emergency con
`ditions to control blood pressure, dilution of the concentrated
`ampul formulation consumes valuable time that could be used
`to treat a patient. Other disadvantages associated With the
`dilution step include the potential for contamination, dosage
`errors, and safety hazards associated With the use of glass
`ampuls.
`The pharmaceutical compositions and methods described
`herein overcome these disadvantages. In particular, the ready
`to-use, injectable formulations described herein are stable,
`alloW medical personal to use prepared containers containing
`an injectable formulation off the shelf Without additional
`preparation, avoid potential contamination problems, and
`eliminate dosage errors.
`
`3. SUMMARY
`
`Described herein are ready-to-use, premixed pharmaceu
`tical compositions of nicardipine or pharmaceutically accept
`
`20
`
`25
`
`30
`
`35
`
`40
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`45
`
`50
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`55
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`60
`
`65
`
`2
`able salts thereof, Which are suitable for continuous intrave
`nous infusion. By providing ready-to-use, premixed
`pharmaceutical compositions With a buffered pH, these phar
`maceutical compositions are stable at room temperature for at
`least one year. When stored at room temperature, the phar
`maceutical compositions exhibit betWeen 0% to about 15%
`loss of drug andbetWeen 0% to about 3% (W/W) total impurity
`formation over an eighteen to tWenty four month period.
`Additional bene?ts of the pre-mixed, ready-to-use, inject
`able pharmaceutical compositions include convenience and
`ease of use as compared to an ampul formulation, improved
`safety for patients due to elimination of dosage errors and
`solution contamination, reduction of medical Waste, and ease
`of administration in emergency situations.
`The present disclosure relates to premixed pharmaceutical
`compositions comprising nicardipine or pharmaceutically
`acceptable salts thereof, one or more tonicity agents, and a
`buffer. In some embodiments, the compositions optionally
`comprise one or more cosolvents. Nicardipine hydrochloride
`can be present at concentrations betWeen about 0.05 mg/ml to
`about 15 mg/ml. Typically, the concentration range for nica
`rdipine hydrochloride is betWeen about 0.1 mg/ml to about
`0.2 mg/ml. Optionally, the pharmaceutical compositions can
`comprise acids and bases.
`The pharmaceutical compositions described herein require
`no dilution prior to administration and typically have a pH
`Within the range from about 3.6 to about 4.7. The composi
`tions can be administered by parenteral routes, including,
`subcutaneous, intramuscular, intravenous, intra-atrial, or
`intra-arterial continuous infusion to a patient. The composi
`tions are suitable for the short-term treatment of hypertension
`When oral therapy is not feasible or desirable.
`Methods for making a premixed nicardipine hydrochloride
`formulation suitable for intravenous administration comprise
`the steps of providing an effective amount of nicardipine
`hydrochloride in a solution comprising one or more tonicity
`agents, a buffer, and optionally, one or more cosolvents. Suf
`?cient Water is added to make up the ?nal volume. If required,
`the pH of the solution can be adjusted using a suitable pH
`adjuster. The compositions are dispensed in pharmaceutically
`acceptable containers for storage and direct administration to
`patients.
`
`4. BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 provides a diagrammatic illustration of the effect of
`various diluents on the pH and stability of an ampul formu
`lation post dilution over a tWenty four hour period at room
`temperature.
`FIGS. 2A and 2B provide a diagrammatic illustration of the
`effect of pH on drug loss (FIG. 2A) and total impurity forma
`tion (FIG. 2B) in a premixed non-sorbitol formulation com
`prising 0.1 mg/ml nicardipine hydrochloride, 0.1 mM citric
`acid and 5% dextrose at 400 C.;
`FIGS. 3A and 3B provide a diagrammatic illustration of the
`effect of pH on drug loss (FIG. 3A) and total impurity forma
`tion (FIG. 3B) in a premixed non-sorbitol formulation com
`prising 0.1 mg/ml nicardipine hydrochloride, 0.1 mM citric
`acid and 0.9% saline at 400 C.;
`FIGS. 4A and 4B provide a diagrammatic illustration of the
`effect of nicardipine concentration on impurity formation in
`non-sorbitol dextrose formulations comprising 0.1 mg/ml
`nicardipine hydrochloride, 0.1 mM citrate, 5% dextrose, or
`0.2 mg/ml nicardipine hydrochloride, 0.2 mM citrate and 5%
`dextrose after six months at 400 C. (FIG. 4A); and, in non
`sorbitol saline formulations comprising 0.1 mg/ml nicar
`dipine hydrochloride, 0.1 mM citrate, 0.9% saline, or 0.2
`
`Sandoz Exhibit 1001 Page 8
`
`

`

`US 8,455,524 B2
`
`3
`mg/ml nicardipine hydrochloride, 0.2 mM citrate and 0.9%
`saline after 3 months at 400 C. (FIG. 4B); and
`FIGS. 5A and 5B provide a diagrammatic illustration of the
`effect of incompatible (FIG. 5A) and compatible (FIG. 5B)
`plastic ?lm composition on product stability at 400 C. in a
`premixed non-sorbitol formulation comprising 0.2 mg/ml
`nicardipine HCL, 0.2 mM citric acid, 5% dextrose, at a pH of
`4.0 to 4.2.
`
`5. DETAILED DESCRIPTION
`
`The premixed pharmaceutical compositions described
`herein comprise nicardipine or a pharmaceutically acceptable
`salt thereof as the active ingredient, at least one tonicity agent
`and a buffer. As used herein, the term “pre-mixed” refers to a
`pharmaceutical composition that does not require reconstitu
`tion or dilution before administration to a patient. In contrast
`to ampul formulations comprising nicardipine hydrochloride
`that must be diluted prior to use in a diluent and container
`selected by hospital personnel, the premixed pharmaceutical
`compositions provided herein are stable at room temperature
`for 6 months or longer due to the inclusion of a buffer capable
`of maintaining the pH Within an optimal pH range, Which is
`typically betWeen 3.6 to about 4.7. In some embodiments,
`suitable pH adjusters and/or cosolvents are added to the phar
`maceutical compositions.
`5.2 Premixed Pharmaceutical Compositions
`The production of stable, ready-to-use, premixed pharma
`ceutical compositions comprising nicardipine and/or its phar
`maceutically acceptable salts as the active ingredient presents
`different development hurdles than does the development of
`the concentrated ampul product sold commercially as
`CARDENE® I.V. As shoWn in FIG. 1, the percent of nicar
`dipine remaining in solution decreases as function of pH over
`a tWenty-four hour period. The percent decrease in nicar
`dipine varies With the diluent and container chosen by the
`hospital staff.
`As described in the Examples, pH (see, also, e.g., FIGS.
`2A, 2B, 3A and 3B), the concentration of the active ingredient
`(see, also, e. g., FIGS. 4A and 4B), and the composition of the
`container material (see, also, e.g., FIGS. 5A and 5B) affect the
`stability of the active ingredient and the formation of impu
`rities. Thus, the development of a stable, ready-to-use pre
`mixed pharmaceutical composition requires simultaneous
`optimiZation of pH and nicardipine hydrochloride concentra
`tion, as Well as selection of a pharmaceutically compatible
`container. The ready-to-use pharmaceutical compositions
`described herein exhibit 0% to 15% drop in drug concentra
`tion and 0% to 3% formation of impurities When maintained
`at room temperature for 6 to at least 24 months. Typically, the
`pharmaceutical compositions are stable When maintained at
`room temperature for at least 6 months, at least 12 months, at
`least 18 months, and at least 24 months. The compositions are
`also stable over extended periods of time When maintained at
`temperatures from about 20 to 80 C. The term “stable”, as used
`herein, means remaining in a state or condition that is suitable
`for administration to a patient.
`Compounds for use according to the compositions and
`methods described herein that can contain one or more asym
`metric centers can occur as racemates, racemic mixtures, and
`as single enantiomers. Accordingly, the compositions and
`methods described herein are meant to comprehend all iso
`meric forms of such compounds.
`The premixed pharmaceutical compositions described
`herein comprise nicardipine and/or its pharmaceutically
`acceptable salts. Nicardipine, its pharmaceutically accept
`able salts, preparation, and use are knoWn in the art (see, e. g.,
`
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`
`4
`Us. Pat. No. 3,985,758, incorporated herein by reference in
`its entirety). Examples of pharmaceutically acceptable salts
`of nicardipine include hydrochlorides, sulfates, phosphates,
`acetates, fumarates, maleates and tartrates.
`Typically, the premixed pharmaceutical compositions
`comprise 0.05-15 mg/ml nicardipine or a pharmaceutically
`acceptable salt thereof. For example, suitable concentrations
`of nicardipine or a pharmaceutically acceptable salt thereof,
`include, but are not limited to: 0.05-0.1 mg/ml, 0.1-15 mg/ml,
`0.1-10 mg/ml, 0.1-5 mg/ml, 0.1-3.0 mg/ml, 0.1-2.0 mg/ml,
`0.1-1.0 mg/ml, 0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml,
`0.5 mg/ml, 0.4 mg/ml, 0.3 mg/ml, 0.2 mg/ml or 0.1 mg/ml.
`In some embodiments, the premixed pharmaceutical com
`positions comprise nicardipine hydrochloride as the active
`ingredient at a concentration su?icient to permit intravenous
`administration at a concentration betWeen 0.1 mg/ml to 0.2
`mg/ml. In some embodiments, the concentration of nicar
`dipine hydrochloride suitable for use in the compositions and
`methods described herein includes, but is not limited to, at
`least about 0.1 mg/ml. In other embodiments, the concentra
`tion of nicardipine hydrochloride suitable for use in the com
`positions and methods described herein includes, but is not
`limited to, at least about 0.2 mg/ml.
`In some embodiments, the premixed formulation com
`prises, in addition to nicardipine and/ or its pharmaceutically
`acceptable salts, a buffer that has su?icient buffering capacity
`to maintain the desired pH range throughout the shelf-life of
`the product. As shoWn in FIGS. 2A and 2B, pH is important
`for the long term stability of nicardipine in the premixed
`pharmaceutical compositions. Although the pH of the pre
`mixed pharmaceutical compositions can range from betWeen
`about 3 .0 to about 7.0, pharmaceutical compositions having a
`pH Within the range of about 3.6 to about 4.7 exhibit a loWer
`percentage of drug degradation and total impurities (See
`FIGS. 2A, 2B, 3A and 3B). Accordingly, suitable pH ranges
`for use in the premixed pharmaceutical compositions include,
`but are not limited to, pH range of at least about 3.0, at least
`about 3.1, at least about 3.2, at least about 3.3, at least about
`3.4, at least about 3.5, at least about 3.6, at least about 3.7, at
`least about 3.8, at least about 3.9, at least about 4.0, at least
`about 4.1, at least about 4.2, at least about 4.3, at least about
`4.4, at least about 4.5, at least about 4.6, at least about 4.7, at
`least about 4.8, at least about 4.9, at least about 5.0, at least
`about 5.2, at least about 5.5, at least about 6.0, at least about
`6.5, at least about 7.0.
`In some embodiments, the pH of the premixed pharmaceu
`tical compositions is betWeen about 3.0 to about 5.0. In other
`embodiments, the pH of the premixed pharmaceutical com
`positions is betWeen about 3.6 to about 4.7. In other embodi
`ments, the pH of the premixed pharmaceutical compositions
`is betWeen about 4.0 to about 4.4. In yet other embodiments,
`the pH of the premixed pharmaceutical compositions is 4.2.
`Buffers suitable for use in the pharmaceutical composi
`tions described herein include, but are not limited to, phar
`maceutically acceptable salts and acids of acetate, glutamate,
`citrate, tartrate, benZoate, lactate, histidine or other amino
`acids, gluconate, phosphate, malate, succinate, formate, pro
`pionate, and carbonate. “Pharmaceutically acceptable” is
`used herein in the sense of being compatible With the other
`ingredients of the formulation and not deleterious to the
`recipient thereof. Accordingly, the term “pharmaceutically
`acceptable salt” references salt forms of the active com
`pounds Which are prepared With counter ions Which are non
`toxic under the conditions of use and are compatible With a
`stable formulation. The concentration of the buffer in the
`formulation can be expressed in mg/ml, g/L or as a molar
`concentration. In typical embodiments, from about 0.0001
`
`Sandoz Exhibit 1001 Page 9
`
`

`

`US 8,455,524 B2
`
`5
`mg/ml to about 100 mg/ ml of a suitable buffer is present in the
`pharmaceutical compositions. Thus, the premixed pharma
`ceutical compositions can comprise from about 0.0001 to
`about 0.001 mg/ml of a suitable buffer, from about 0.001 to
`about 0.01 mg/ml of a suitable buffer, from about 0.01 to
`about 0.1 mg/ml of a suitable buffer, from about 0.1 to 1
`mg/ml of a suitable buffer, from about 1 to about 5 mg/ml of
`a suitable buffer, from about 5 to about 10 mg/ml of a suitable
`buffer, from about 10 to about 15 mg/ml of a suitable buffer,
`from about 15 to about 20 mg/ml of a suitable buffer, from
`about 20 to about 25 mg/ml of a suitable buffer, from about 25
`to about 50 mg/ml of a suitable buffer, from about 50 to about
`75 mg/ml of a suitable buffer, and from about 75 to about 100
`mg/ml of a suitable buffer.
`Alternatively, the buffer concentration can be expressed as
`molar concentrations. In typical embodiments, from about
`0.1 to 100 mM of a suitable buffer is present in the pharma
`ceutical compositions. Thus, the premixed pharmaceutical
`compositions can comprise a suitable buffer having a concen
`tration from about 0.1 to about 100 mM, from about 0.1 to
`about 0.5 mM, from about 0.5 to about 1.0 mM, from about
`1.0 to about 5 mM, from about 5 to about 10 mM, from about
`10 to about 15 mM, from about 15 to about 25 mM, from
`about 25 to about 50 mM, from about 50 to about 75 mM, and
`from about 75 to about 100 mM.
`In some embodiments, the premixed pharmaceutical com
`positions further comprise a pH adjuster. Suitable pH adjust
`ers typically include at least an acid or a salt thereof, and/ or a
`base or a salt thereof. Acids and bases can be added on an as
`needed basis in order to achieve a desired pH. For example, if
`the pH is greater than the desired pH, an acid can be used to
`loWer the pH to the desired pH. Acids suitable for use in
`premixed pharmaceutical compositions include, but are not
`limited to, hydrochloric acid, phosphoric acid, citric acid,
`ascorbic acid, acetic acid, sulphuric acid, carbonic acid and
`nitric acid. In some embodiments, hydrochloric acid is used
`to adjust the pH. By Way of another example, if the pH is less
`than the desired pH, a base can be used to adjust the pH to the
`desired pH. Bases suitable for use in premixed pharmaceuti
`cal compositions include, but are not limited to, sodium
`hydroxide, potassium hydroxide, calcium hydroxide, sodium
`carbonate, sodium citrate, sodium acetate, and magnesium
`hydroxide. In some embodiments, sodium hydroxide is used
`to adjust the pH.
`In some embodiments, the premixed pharmaceutical com
`positions further comprise one or more tonicity agents. Typi
`cally, tonicity agents are used to adjust the osmolality of the
`premixed pharmaceutical compositions to bring it closer to
`the osmotic pressure of body ?uids, such as blood or plasma.
`In some embodiments the tonicity of the premixed formula
`tion can be modi?ed by adjusting the concentration of buffer
`and/or other components present in the premixed formula
`tion.
`Provided that the compositions are physiologically com
`patible, the compositions do not require any particular osmo
`lality. Thus, the compositions can be hypotonic, isotonic or
`hypertonic. Typically the premixed pharmaceutical composi
`tions have a tonicity betWeen about 250 to about 350 mOsm/
`kg.
`Suitable tonicity agents for use in the premixed pharma
`ceutical compositions include, but are not limited to, anhy
`drous or hydrous forms of sodium chloride, dextrose, sucrose,
`xylitol, fructose, glycerol, sorbitol, mannitol, potassium chlo
`ride, mannose, calcium chloride, magnesium chloride and
`other inorganic salts. The quantity of the tonicity agent in the
`formulation can be expressed in mg/ml or in g/L. In typical
`embodiments, the tonicity agent(s) is present from about 1
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`mg/ml to about 90 mg/ml. Thus, the premixed pharmaceutical
`compositions can comprise one or more tonicity agents at
`about 1-5 mg/ml, at about 5-10 mg/ml, at about 10-15 mg/ml,
`at about 15-25 mg/ml, at about 25-50 mg/ml, at about 50-60
`mg/ml, at about 60-70 mg/ml, at about 70-80 mg/ml, and at
`about 80 to 90 mg/ml, as Well as combinations of the above
`ranges.
`Alternatively, the tonicity agent concentration is measured
`in Weight/volume percent. In typical embodiments, the tonic
`ity agent(s) is present from about 0.1% to about 10%. For
`example, suitable tonicity agent concentrations include, but
`are not limited to, from about 0.1% to about 0.2%, from about
`0.2% to about 0.3%, from about 0.3% to about 0.4%, from
`about 0.4% to about 0.5%, from about 0.5% to about 0.6%,
`from about 0.6% to about 0.7%, from about 0.7% to about
`0.8%, from about 0.8% to about 0.9%, from about 0.9% to
`about 1%, from about 1% to about 2%, from about 2% to
`about 3%, from about 3% to about 4%, from about 4% to
`about 5%, from about 5% to about 6%, from about 6% to
`about 7%, from about 7% to about 8%, from about 8% to
`about 9%, and from about 9% to about 10%, as Well as
`combinations of the above ranges.
`In some embodiments, the tonicity agent is dextrose. Typi
`cally, the concentration of dextrose suitable for use in the
`premixed pharmaceutical compositions is betWeen about
`2.5% (W/v) to about 7.5%. By Way of example, suitable
`dextrose concentrations include, but are not limited to, from
`about 2.5% to about 3%, from about 3% to about 3.5%, from
`about 3.5% to about 4% (Which is equivalent to about 40
`mg/ml), from about 4% to about 4.5%, from about 4.5% to
`about 5% (Which is equivalent to about 50 mg/ml), from about
`5% to about 5.5%, from about 5.5% to about 6% (Which is
`equivalent to about 60 mg/ml), from about 6% to about 6.5%,
`from about 6.5% to about 7%, as Well as combinations of the
`above ranges.
`In some embodiments, the tonicity agent is sodium chlo
`ride. Typically, the concentration of sodium chloride suitable
`for use in the premixed pharmaceutical compositions is
`betWeen about 0.1% (W/v) to about 1.8%. By Way of example,
`suitable sodium chloride concentrations include, but are not
`limited to, from about 0.1% to about 0.2%, from about 0.2%
`to about 0.3%, from about 0.3% to about 0.4%, from about
`0.4% to about 0.5%, from about 0.5% to about 0.6%, from
`about 0.6% to about 0.7%, from about 0.7% to about 0.8%
`(Which is equivalent to 8 mg/ml), from out 0.8% to about
`0.9% (Which is equivalent to 9 mg/ml), from about 0.9% to
`about 1.0%, from about 1% to about 1.2%, from 1.2% (Which
`is equivalent to 12 mg/ml) to about 1.4%, from about 1.4% to
`about 1.6%, and from about 1.6% to about 1.8%.
`In some embodiments, the premixed pharmaceutical com
`positions comprise tWo, three, four, or more tonicity agents.
`In these embodiments, the concentration of each tonicity
`agent is typically less than the concentration that is used When
`only a single agent is present in the premixed formulation. For
`example, if the premixed formulation comprises sorbitol at
`1.92 mg/ml, a suitable concentration of sodium chloride is 8.6
`mg/ml. By Way of another example, if the premixed formu
`lation comprises 1.92 mg/ml sorbitol, a suitable concentra
`tion of dextrose is 48 mg/ml.
`In some embodiments, the premixed pharmaceutical com
`positions further comprise one or more cosolvents. A “cosol
`vent” is a solvent Which is added to the aqueous formulation
`in a Weight amount Which is less than that of Water and assists
`in the solu