United States Patent [!9J
`McFarlane et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005164405A
`5,164,405
`[II] Patent Number:
`[45] Date of Patent: Nov. 17, 1992
`
`[54] NICARDIPINE PHARMACEUTICAL
`COMPOSITION FOR P AREI\'TERAL
`ADMINISTRATION
`
`[75]
`
`Inventors: Calum B. McFarlane, Linlithgow;
`Alistair B. Selkirk, Edinburgh;
`Michael J. Dey, East Calder, all of
`Scotland
`
`[73] Assignee: Syntex (U.S.A.) Inc., Palo Alto, Calif.
`
`[21] Appl. No.: 600,277
`
`[22] Filed:
`
`Oct. 22, 1990
`
`Related U.S. Application Data
`[63] Continuation-in-part ofSer. No. 317,171, Feb. 28, 1989,
`abandoned.
`
`Int. CJ.5 .............................................. A61K 31/44
`[51]
`[52] U.S. Cl ..................................................... 514/354
`[58] Field of Search ......................................... 514/354
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3.985,758 10/1976 Murakami et al. .......... 260/295.5 R
`4,711,902 12/1987 Serno .................................. 514/356
`
`FOREIGN PATENT DOCUMENTS
`0162705 11/1985 European Pat. Off ..
`0200068 5/1986 European Pat. Off ..
`3316510 8/1984 Fed. Rep. of Germany.
`3339861 5/1985 Fed. Rep. of Germany .
`
`Primary Examiner-S. J. Friedman
`Attorney, Agent, or Firm-David A. Lowin; Torn M.
`Moran
`
`ABSTRACI'
`[57]
`There is disclosed a stable pharmaceutical composition
`containing nicardipine hydrochloride, a non-chloride
`isotonicity agent, a buffering agent and a pharmaceuti(cid:173)
`cally acceptable aqueous vehicle for parenteral adminis(cid:173)
`tration.
`
`9 Claims, 2 Drawing Sheets
`
`Sandoz Exhibit 1003 Page 1
`
`

`

`U.S. Patent
`
`Nov. 17, 1992
`
`Sheet 1 of 2
`
`5,164,405
`
`Effect of Added Chloride Ion on
`the Solubility of Nicardipine HCI
`at Various pH
`
`•
`
`No Cl
`0
`O.OlM Cl
`0
`0.05M Cl
`
`10
`
`9
`
`8
`
`7
`
`6
`
`5
`
`Q()
`
`3
`
`4 -e ...._
`E -· >. 2
`::
`:E = 0
`
`tl)
`
`0
`
`2
`
`pH
`
`FIGURE 1
`
`Sandoz Exhibit 1003 Page 2
`
`

`

`U.S. Patent
`
`Nov. 17, 1992
`
`Sheet 2 of 2
`
`5,164,405
`
`Effect of Initial pH of Dextrose
`Injection on the Final pH After Mixing
`With Buffered and Unbuffered Injection
`
`7.5~------------------------------------~
`7
`
`•
`Buffered
`[J
`Unbuffered
`
`6
`
`5
`
`4
`
`u.. 3
`
`2. 5 3
`Initial pH
`
`3. s 4
`
`4. 5 5
`
`5. 5 6
`
`6. 5 7
`
`7. 5 8
`
`FIGURE 2
`
`Sandoz Exhibit 1003 Page 3
`
`

`

`5,164,405
`
`1
`
`NICARDIPINE PHARMACEUTICAL
`COMPOSITION FOR P AREI\'TERAL
`ADMINISTRATION
`
`2
`ethylene glycol, and propylene glycol. Such prepara(cid:173)
`tions are usually administered intramuscularly. The
`most important group of nonaqueous vehicles are the
`fixed oils which must be of vegetable origin in order
`5 that they may be metabolized, must be liquid at room
`temperature, and must not become rancid rapidly. They
`are rarely used in intravenous preparations.
`There has been observed the occurrence of visible as
`well as invisible physical, chemical and therapeutic
`10 incompatibilities when certain drugs or vehicle compo(cid:173)
`nents are combined or added to injectable pharmaceuti(cid:173)
`cal compositions or intravenous fluids. Development of
`a precipitate or a color change in an injectable composi(cid:173)
`tion is a warning that an alteration has occurred. Such a
`15 composition should not be administered to a patient
`since in the former case the solid particles may occlude
`the blood vessels, the therapeutic agent may not be
`available for absorption and/or distribution or in the
`latter case the drug may have degraded into undesirable
`20 substances. These incompatibilites in the composition
`may arise due to effects of pH, ionic concentrations or
`chemical reactions. Losses in potency of a drug with
`infusion fluids may also occur due to adsorption onto
`infusion containers or devices.
`In formulating a nicardipine solution for injection, a
`salt of nicardipine is preferred, especially nicardipine
`hydrochloride, as the salts generally are more water
`soluble and do not require the use of solubilizing agents.
`We have found, however, that dissolving ofnicardipine
`hydrochloride in water for injection, as is described in
`the above-mentioned U.S. Pat. No. 3,985,758, is limited
`by nicardipine hydrochloride solubility in an aqueous
`solution and is accompanied by the formation of nicar(cid:173)
`dipine free base which precipitates from solution and
`forms a yellow sticky substance adhering to the stirring
`system. Prolonged stirring is necessary for its removal.
`Thus, there is a need to formulate a stable aqueous phar(cid:173)
`maceutical composition of nicardipine hydrochloride,
`suitable for parenteral administration or administration
`by infusion, which may be diluted in additional water or
`a mixture of water and water-miscible fluids.
`
`This is a continuation of pending application Ser. No.
`07/317,171 filed Feb. 28, 1989, now abandoned incorpo(cid:173)
`rated herein by reference.
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to an aqueous pharmaceutical
`composition containing nicardipine hydrochloride in a
`therapeutically effective amount suitable for parenteral
`administration, especially intraveneous administration.
`2. Description of Related References
`Nicardipine is a member of the class of drugs referred
`to as calcium channel blocking agents (also referred to
`as calcium entry blocking agents).
`The chemical name for nicardipine, which is used
`primarily as its hydrochloride salt, is as follows:
`2-(Benzylmethylamino)ethyl methyl 1,4-dihydro-2,
`6-dimethyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxy-
`late monohydrochloride.
`Nicardipine hydrochloride, its preparation, and its 25
`use are described in U.S. Pat. No. 3,985,758 (Oct. 12,
`1976).
`
`GENERAL BACKGROUND
`Administration of a drug by injecting a pharmaceuti- 30
`cal composition containing such drug-parenteral ad(cid:173)
`ministration-affords a number of advantages includ(cid:173)
`ing, but not necessarily limited to, the following:
`(1) An almost immediate response may be obtained by
`administering by intravenous injection a solution, 35
`usually aqueous, of the drug;
`(2) The therapeutic response by a patient to a drug may
`be more readily controlled by administering the drug
`parenterally; and
`(3) A drug can be administered parenterally to a patient 40
`when it cannot be administered orally because of the
`unconscious or uncooperative state of the patient, or
`because of inactivation or lack of absorption in the
`intestinal tract.
`Since most liquid solutions for injection are quite 45
`dilute, the component present in the highest proportion
`in a pharmaceutical composition is the pharmaceuti(cid:173)
`cally acceptable carrier (also referred to as the vehicle).
`The vehicle normally should have minimal pharmaco(cid:173)
`logical activity and toxicity but, still the vehicle is of 50
`great importance in the formulation since it presents the
`active constituent for absorption and/or distribution by
`the body fluids and tissues.
`Aqueous vehicles for solutions are normally the least
`pharmacologically active and the least toxic over a 55
`wide volume range. They are therefore the primary
`vehicles of choice. Modification of the aqueous vehicle
`by displacing a minor proportion ( 49% or less of total of
`the aqueous vehicle) with a pharmaceutically accept(cid:173)
`able nonaqueous water-miscible solvent can alter ab- 60
`sorption and distribution patterns and normally results
`in a vehicle with more potential, pharmacological prop(cid:173)
`erties, and toxicity in its own right. A number of such
`solvents that are miscible with water have been used as
`a portion of the vehicle in the formulation of parenter- 65
`als. These solvents are used primarily to effect solubility
`of certain drugs and to improve stability. The most
`important solvents in this group are ethyl alcohol, poly-
`
`SUMMARY OF THE INVENTION
`This invention is a pharmaceutical composition suit(cid:173)
`able for parenteral administration to mammals and use(cid:173)
`ful in the treatment of disease conditions that may be
`alleviated by the administration of calcium channel
`blocking agents, including cardiovascular and cerebro(cid:173)
`vascular disease conditions, comprising:
`(a) a therapeutically effective amount of nicardipine
`hydrochloride;
`(b) a physiologically and pharmaceutically acceptable
`non-chloride compound effective to render the phar(cid:173)
`maceutical composition isotonic;
`(c) a physiologically and pharmaceutically acceptable
`buffer in an amount effective to maintain the pH of
`the composition at about 3.0 to about 4.5; and
`(d) a pharmaceutically acceptable aqueous vehicle com(cid:173)
`prising at least a major proportion of water.
`In another aspect, this invention is in a process for
`producing a stable pharmaceutical composition contain(cid:173)
`ing nicardipine hydrochloride suitable for parenteral
`administration and useful in the treatment of disease
`conditions which may be alleviated by the administra(cid:173)
`tion of calcium channel blocking agents, including car(cid:173)
`diovascular and cerebrovascular disease conditions,
`comprising admixing a therapeutically effective amount
`of nicardipine hydrochloride and a pharmaceutically
`
`Sandoz Exhibit 1003 Page 4
`
`

`

`3
`acceptable aqueous vehicle comprising at least a major
`proportion of water,
`the improvement comprising further admixing
`(a) a physiologically and pharmaceutically acceptable
`non-chloride compound effective to render the phar(cid:173)
`maceutical composition isotonic and
`(b) a physiologically and pharmaceutically acceptable
`buffer in an amount effective to maintain the pH of
`the pharmaceutical composition at about 3.0 to about
`4.5.
`
`DESCRIPTION OF THE DRAWING
`FIG. 1 illustrates the effect of added chloride ion on
`the solubility of nicardipine hydrochloride at various
`pH.
`FIG. 2 illustrates the effect of initial pH of dextrose
`injection on the final pH after mixing with buffered and
`unbuffered injection solution.
`
`DETAILED DESCRIPTION OF INVENTION
`The "active ingredient" component in the pharma(cid:173)
`ceutical composition according to this invention is
`nicardipine hydrochloride.
`As is described above, nicardipine and its pharmaceu(cid:173)
`tically acceptable salts and the preparation and use 25
`thereof is known as is disclosed in U.S. Pat. No.
`3,985,758.
`Nicardipine hydrochloride is present in a "therapeuti(cid:173)
`cally effective amount." By "therapeutically effective
`amount" as applied to nicardipine hydrochloride is 30
`meant that amount which when administered to mam(cid:173)
`mals, especially human patients but also, for example,
`cattle, sheep and horses, will have a calcium entry
`blocking effect that will be useful to treat their disease
`conditions, that is, conditions which may be alleviated 35
`by the administration of calcium channel blocking
`agents, especially cardiovascular and cerebrovascular
`disease conditions. By the expressjr>n "disease condi(cid:173)
`tions which may be alleviated by the, administration of
`calcium channel blocking agents" is meant those patho- 40
`logical conditions which may be corrected, either thera(cid:173)
`peutically or prophylactically, by the use of the class of
`compounds known in the pertinent art as "calcium
`channel blocking agents." The therapeutically effective
`amount of the active ingredient nicardipine hydrochlo- 45
`ride, in the aqueous vehicle broadly, i.e preferably, may
`range from about p.5 rng/rnl to about 10 rng/rnl, more
`preferably from about 1 rng/rnl to about 5 rng/rnl, most
`preferably about 1 rng/rnl to about 2.5 rng/rnl based on
`amount of aqueous vehicle. The dose of active ingredi- 50
`ent may range from about 0.01 to about 10 rng/kg of
`body weight based on a 70 kg patient.
`The physiologically and pharmaceutically acceptable
`non-chloride compound used to render the pharmaceu(cid:173)
`tical composition isotonic preferrably may be selected 55
`from monohydric and polyhydric compounds. The
`term "isotonic" is used in its conventional sense, as is
`described in "Remington's Pharmaceutical Sciences,"
`Mack Publishing Company, Easton, Pa., 1985, Chapter
`80, page 1455 et seq., especially page 1456, left column, 60
`lines 24-33, to mean a fluid corresponding to body flu(cid:173)
`ids including blood and lacrimal fluid, normally having
`an osmotic pressure which is often described as corre(cid:173)
`sponding to that of a 0.9% solution of sodium chloride.
`More preferrably the non-chloride compound may be 65
`selected from the group ofpolyhydric compounds com(cid:173)
`prising saccharides and non-saccharide polyhydric
`compounds. Suitable saccharides include sorbitol, man-
`
`5,164,405
`
`4
`nitol, dextrose and glucose. Suitable polyhydric corn(cid:173)
`pounds which are non-sugar compounds include poly(cid:173)
`ethylene glycol (PEG) and glycerol. When glycerol
`issued, care must be taken to avoid haernolysis. Most
`5 preferably, the non-chloride compound, used as an
`compound is a saccharide compound. Especially pre(cid:173)
`ferred as the non-chloride compound, used as an isoto(cid:173)
`nicity agent, is sorbitol in the amount of about 48 rng/rnl
`to about 50 rng/rnl of aqueous vehicle. The non-chlo-
`10 ride compounds are important because their use avoids
`precipitation of nicardipine. Although the precise cause
`for such precipitation of nicardipine is not fully under(cid:173)
`stood, one explanation may be the following: As shown
`in FIG. 1, the use of chloride containing compounds
`15 restricts the solubility ofnicardipine hydrochloride thus
`limiting the dose strengths available for the parenteral
`dose form. This reduction in solubility may be attrib(cid:173)
`uted to a common ion effect between the nicardipine
`hydrochloride and the chloride ions of the vehicle,
`20 inhibiting ionization of the nicardipine hydrochloride
`and thereby reducing its solubility. This effect is well
`described in many standard textbooks of physical chem(cid:173)
`istry such as "Physical Pharmacy", Lea and Febiger
`Publishing Company, Philadelphia, 1970, Chapter 10,
`pages 237-238.
`The control of pH of the formulation is also essential
`to maintain the aqueous solubility of the nicardipine
`salts to a sufficient extent that the therapeutically desir(cid:173)
`able dose strengths can be manufactured and are physi(cid:173)
`cally stable, i.e. do not give evidence of precipitation.
`Maintenance of the necessary pH range can be best
`controlled by the use of a suitable buffer system.
`The pharmaceutically acceptable buffer may be se(cid:173)
`lected from any of the buffers that are effective to main(cid:173)
`tain the pH in the range of about 3.0-4.5, which buffers
`are well-known in the art to which this invention re-
`lates. More preferably, the buffer may be selected from
`citrate, acetate, phosphate and lactate buffers. Most
`preferably, the buffer is a citrate or acetate buffer, for
`example, citric acid plus sodium hydroxide in appropri(cid:173)
`ate proportions which will maintain the pH at about
`3.5-4.5. Use of citrate buffer in an amount sufficient to
`maintain a concentration in the range of 0.002M to
`0.003M has been found to afford advantages in main(cid:173)
`taining the pH of the composition in the range of about
`3.5-4.5.
`Referring to the citrate buffer (citrate buffer system)
`by way of example, i.e. the buffer is essentially a mixture
`of a sodium citrate prepared by the neutralization of.
`citric acid by sodium hydroxide plus residual citric acid.
`The ratio of citric acid to sodium citrate determines the
`pH of the buffer. Such a buffer system is well known to
`those skilled in the art and is described in neary all
`standard textbooks e.g., Physical Pharmacy by A. N.
`Martin, J. Swarbrick and A. Cammarata, Lee and
`Fabiger, 2nd edition, page 237 onwards.
`The buffer system is useful over the desired dose
`range of the composition to provide ease of manufac(cid:173)
`ture of the composition, to maintain pH stability during
`and after manufacture including terminal sterilization
`by autoclaves and thus to render the composition com-
`patible with a range of infusion fluids.
`Although the pharmaceutically acceptable carrier in
`the pharmaceutical composition may be selected from
`100% of water (water for injection) or an aqueous sys(cid:173)
`tem (that is an aqueous vehicle) comprising at least a
`major proportion of water, preferably the vehicle is
`water alone, without any co-solvent. By "major propor-
`
`Sandoz Exhibit 1003 Page 5
`
`

`

`5
`tion" is meant at least 51% of the aqueous vehicle is
`water and the balance comprising one or more pharma(cid:173)
`ceutically acceptable non-aqueous, water-miscible co(cid:173)
`solvents, such as ethanol and glycols.
`With regard to the process for producing the stable
`pharmaceutical composition according to the inven(cid:173)
`tions, preferably the citric acid and sodium hydroxide is
`first dissolved in some water for injection to form a
`solution of the desired pH. The nicardipine HCI and
`sorbitol are then added and dissolved in this solution of 10
`controlled pH and the resulting solution made to vol(cid:173)
`ume with the remainder of the water for injection. The
`important step is to dissolve the nicardipine HCl in the
`buffer solution to maintain the pH of the liquid into
`which the Nicardipine HCl is dissolving to avoid forma- 15
`tion of the free base of nicardipine with its resultant
`sticking and very slow dissolution. If the Nicardipine
`HCl and sorbitol are dissolved in the buffer solution no
`particular temperature or stirring conditions are re(cid:173)
`quired, i.e. if dissolved in buffer the process is very easy; 20
`if dissolved in water, i.e. either before buffer addition or
`in the unbuffered formulation process it is difficult and
`can require elevated temperatures, e.g. to 60-70' C. and
`prolonged mixing.
`The following examples and tables are illustrative of 25
`the invention and are not to be construed as limiting the
`scope of the invention.
`
`EXAMPLE I
`Effect of Added Chlo:r:ide Ion on Solubility of
`Nicardipine Hydrochloride
`In this example, there was demonstrated, as set forth
`in FIG. 1, the aqueous solubility of nicardipine hydro(cid:173)
`chloride as a function of pH and in the presence of a
`range of chloride concentrations in the dissolution me(cid:173)
`dium. The solubilities were equilibrium solubilities mea(cid:173)
`sured by a saturated solution method well known to
`those skilled in the art.
`The results indicated a reduction in the aqueous solu(cid:173)
`bility as the pH increases and as the chloride ion con(cid:173)
`centration increases.
`
`EXAMPLE II
`Nicardipine Hydrochloride Formulations
`In this example, a variety of nicardipine hydrochlo- 45
`ride formulations and pharmaceutical compositions
`were prepared in an effort to obtain a stable pharmaceu(cid:173)
`tical composition containing I mg of nicardipine hydro(cid:173)
`chloride per ml.
`A. In an initial attempt to formulate a pharmaceutical 50
`composition of nicardipine hydrochloride suitable for
`parenteral administration employing conventional tech(cid:173)
`niques well known in the pertinent art, 1 mg of nicardi(cid:173)
`pine hydrochloride was dissolved in water for injection.
`To this was admixed 6 mg of sodium chloride and a 55
`sufficient amount of hydrochloric acid to give a solu(cid:173)
`tion having a pH of 3 5. This solution was then made up
`to volume with water for injection, i.e., to I ml. The
`resulting composition was packaged in an ampule and
`sterilized by autoclaving. This composition is set out in 60
`Table I as Example A. The 6 mg of sodium chloride
`was the maximum amount of sodium chloride which
`could be added to the composition while achieving the
`desired nicardipine concentration. This amount of so(cid:173)
`dium chloride results in a hypotonic solution which is 65
`far less pharmaceutically desirable. Increasing the
`amount of sodium chloride to a level necessary to give
`an isotonic solution results in failure to dissolve suffi-
`
`5,164,405
`
`6
`cient nicardipine hydrochloride to manufacture the
`required dose strength of I mg per mi. This is ascribed
`to the common ion effect previously described. Accord(cid:173)
`ingly the formulation set out in Example A of Table I
`was unsatisfactory.
`B. Then, in a following attempt to formulate a phar(cid:173)
`maceutical composition of nicardipine hydrochloride
`for parenteral administration employing conventional
`techniques well known in the pertinent art, 1 mg of
`nicardipine hydrochloride together with about 50 mg of
`the non-chloride, saccharide compound, sorbitol, were
`dissolved in a portion of water for injection. Sufficient
`amounts of concentrated hydrochloric acid was added
`to produce a solution of pH 3.5 and the composition was
`made to volume with the remainder of the water for
`injection, i.e. to 1 ml. The resulting composition was
`packaged in an ampule and sterilized by autoclaving.
`This composition is set out in Table 1 as Example B.
`The use of sorbitol in amounts to maintain isotonicity
`appeared to produce a stable isotonic solution suitable
`for parenteral use. However, it was found that upon
`autoclaving, the pH of the sorbitol formulation, and also
`the sodium chloride formulation of Example A, were
`subject to pH change in glass ampules from several
`different suppliers. See Table 3. In addition consider-
`able difficulties were found in the manufacture of the
`formulations, given in Examples A and B, due to the
`precipitation of nicardipine free base when the nicardi-
`30 pine hydrochloride was dissolved in the water for injec(cid:173)
`tion prior to pH adjustment with concentrated hydro(cid:173)
`chloric acid. We have found that the precipitation is due
`to a lack of pH control at this stage which allowed the
`pH to rise as the nicardipine hydrochloride is dissolved
`35 until the free base precipitates. This precipitation neces(cid:173)
`sitates very prolonged mixing times to completely dis(cid:173)
`solve the nicardipine and increases the potential for the
`manufacture of sub-potent batches if these prolonged
`mixing times do not result in complete dissolution of the
`40 nicardipine. The formulation set out in Example B was
`also unsatisfactory.
`C. In order to overcome both the manufacturing
`problems and the pH changes, it was conceived to add
`a dilute buffer solution to the sorbitol formulation of
`Example B.
`More specifically, in accordance with the formula(cid:173)
`tion set out as Example I, Table 2, 1 mg of nicardipine
`hydrochloride and 48.9 mg of sorbitol were dissolved in
`a solution of 0.525 mg of citric acid and 0.09 mg of
`sodium hydroxide in a portion of the water for injec(cid:173)
`tion. The solution was made up to volume, i.e 1 ml. with
`the remainder of the water for injection. This solution
`was then filled into ampules and terminally sterilized by
`autoclaving. A similar procedure was adopted for Ex(cid:173)
`ample 2 in Table 2 except 2.5 mg of nicardipine hydro(cid:173)
`chloride was dissolved instead of 1 mg and a· corre-
`sponding lower amount of sorbitol, 48.0 mg, was also
`dissolved to achieve isotonicity. Upon subjection to
`autoclaving, the compositions according to Examples 1
`and 2 remained stable. Thus has been provided and
`produced a stable isotonic solution containing nicardi-
`pine hydrochloride which is suitable for parenteral use
`and which is not affected by the sterilization procedure
`(Table 2, composition of Example 1). The amount of
`buffer, namely citric acid monohydrate and sodium
`hydroxide added (0.0025M citrate equivalent) was suffi-
`cient to maintain the pH in the range of 3.5 to 3.8 after
`autoclaving (Table 3) but was sufficiently dilute to be
`
`Sandoz Exhibit 1003 Page 6
`
`

`

`5,164,405
`
`7
`buffered by body fluids on injection. No detrimental
`effect on product stability with respect to pH was intro(cid:173)
`duced by the addition of citrate buffer over the range
`0.002-0.003M (Table 4). The addition of the sorbitol
`and nicardipine hydrochloride to the buffer solution 5
`resulted in rapid and complete dissolution of both mate(cid:173)
`rials. No precipitation of free base was observed, analy(cid:173)
`sis of the solutions confirmed their potency and no
`prolonged mixing times were necessary.
`From solubility data (Table 5), alternative buffer 10
`concentrations were evaluated. A solution containing
`2.5 mg of nicardipine HCI per ml of solution was pre(cid:173)
`pared (Table 2, composition of Example 2). Stability
`studies indicate results substantially identical to the
`results obtained with the composition of Example 1 15
`which contains nicardipine HCI in the amount of 1
`mg/ml solution. Filtration of the solutions through a
`0.22 micron filter was accomplished easily regardless of
`the formulation or concentration. The aqueous solu(cid:173)
`tions readily passed through the filters used (Millipore 20
`GSWP or Durapore) with no apparent problems. Ter(cid:173)
`minal sterilization by autoclaving was used to insure
`product sterility.
`The use of various excipient limits did not appear to
`affect product quality or stability. Varying the citrate 25
`buffer content from 0.002 to 0.003M citrate did not
`affect the product quality. No significant changes in pH
`or potency were evident on autoclaving (Table 6). Sta(cid:173)
`bility data shows excellent stability for up to 3 years at
`25° C., with no significant loss in potency or change in 30
`solution pH (Table 7).
`TABLE 1
`Unsatisfactory Prior Art Formulations of
`Nicardipine HCI (I mg/m!) for Injection
`Example A
`Example B
`
`35
`
`1.0 mg
`1.0 mg
`Nicardipine HCL
`0
`6.0
`Sodium Chloride
`50.0 mg
`0
`Sorbitol
`Hydrochloric acid
`qs to pH 3.5
`qs to pH 3.5
`--\\-·a_te_r_f_or_Jn..;..je_c_ti_o_n ---'q'-s-to_L_O_m_l ___ t_o_l_.o_m_l ____ 40
`
`8
`TABLE 3
`pH Changes Induced by Autoclaving for Various
`Nicardipine Injection 1 mg/ml formulations
`Initial pH
`(before)
`
`Sample
`Composition
`
`Ampule
`
`Final pH
`(after)
`
`Sodium Chloride
`Formula (Ex. A)
`Sorbitol
`Formula (Ex. B)
`Buffered
`Sorbitol
`(0.0025M
`citrate)
`(Ex. I)
`
`A
`
`A
`B
`A
`B
`
`3.60
`
`3.55
`3.55
`3.51
`3.51
`
`4.82
`
`4.33
`4.20
`3.65
`3.60
`
`Am puis:
`A = FBG Trident: 5 ml Type I amber glass
`B = Epsom Glass 5 ml Type I amber glass
`
`TABLE 4
`Nicardipine HCl Injection Composition
`Effect of Buffer Strength
`Citric Acid/Sodium Hydroxide amount altered: pH 3.5
`Nicardipine HCl
`Content
`o/c Label Strength
`
`Buffer
`Strength (M)
`
`pH at
`Manufacture
`
`pH after
`Autoclaving
`
`0.002
`0.0025
`0.003
`
`3.54
`3.55
`3.50
`
`3.83
`3.85
`3.80
`
`102.7
`101.4
`101.6
`
`TABLE 5
`Equilibrium Solubility Data for
`Nicardipine Hydrochloride
`Solubility
`mg/ml
`
`pH
`
`3.05
`3.45
`4.06
`4.06
`4.24
`4.68
`5.05
`6.21
`
`2.94
`3.28
`2.95
`5.16
`2.35
`0.85
`0.36
`O.D25
`
`4° c.
`
`25° c.
`
`Sterilization
`cycle
`(°C./minute)
`
`TABLE 6
`Nicardipine HCi Content of Buffered Sorbitol Injection
`Formulation After Various Sterilization Processes
`Nicardipine
`pH
`Content (o/c label)
`(Mean+ s.d.)
`Mean+ s.d.
`After1
`Before 1
`Before
`After
`3.64 + 0.057
`3.60 + O.D25
`101.4 + 0.57
`101.4 ± 0.34
`115/30
`3.64 + 0.057
`3.63 + O.D28
`99.7 + 0.34
`101.4 + 0.34
`121/15
`3.60 + 0.007
`3.64 + 0.017
`102.1 + 0.53
`101.2 + 0.93
`115/30
`3.64 + 0.057
`3.60 + 0.012
`101.8 + 0.33
`101.4 + 0.34
`121/15
`3.71 + 0.081
`3.73 + 0.056
`99.4 + 0.35
`100.4 + 0.16
`121/15
`1No degradation products were observed using a stability indicating h.p.J.c. method.
`
`TABLE 2
`Nicardipine Hydrochloride Pharmaceutical Composition
`for Parenteral Administration
`Composition of
`Composition of
`Ex. I
`Ex. 2
`(I mg/m!)
`(2.5 mg/ml)
`
`Nicardipine HCl
`Sorbitol BP
`Sodium Hydroxide
`Citric Acid
`Monohydrate BP
`Water For Injection
`
`I.Omg
`48.9 mg
`0.09 mg
`0.525 mg
`
`2.5 mg
`48.0 mg
`0.09 mg
`0.525 mg
`
`qs ad 1.0 ml
`
`qs ad 1.0 ml
`
`60
`
`Time
`(Months)
`
`Initial
`3
`6
`12
`18
`24
`36
`
`65
`
`TABLE 7
`Stability Data for Nicardipine HCL Injection
`Stored at 25° C.
`Nicardipine HCl
`Content (o/c label) PH
`3.81
`3.78
`4.01
`3.96
`4.02
`4.05
`3.90
`
`Appearance
`
`Clear Pale Yellow Solution
`No change
`No change
`No change
`No change
`No change
`No change
`
`99.4
`98.9
`99.2
`98.5
`96.7
`97.3
`97.0
`
`Sandoz Exhibit 1003 Page 7
`
`

`

`5,164,405
`
`5
`
`15
`
`9
`EXAMPLE III
`Compatibility Testing with Infusion Fluids
`Nicardipine hydrochloride solution for parenteral
`administration was diluted (1: 10) in a range of infusion
`fluids used as received in 500 ml Viaflex ® containers
`from Bextex Healthcare. The solutions were thor(cid:173)
`oughly mixed and stored at room temperature. Samples
`were removed at intervals up to 24 hours for nicardi- 10
`pine hydrochloride determination using a stability indi(cid:173)
`cating method. The pH and appearance were also ob(cid:173)
`served and recorded.
`No changes in appearance were noted and no degra(cid:173)
`dation products observed in any sample.
`No significant losses in potency occurred with the
`majority of fluids (Table 8), but a number of fluids
`showed a decrease in concentration over the test period
`indicating incompatibility. This loss, due to partition
`into and onto the PVC material occurred at pH greater 20
`than about pH 4.5, when the pH was measured immedi(cid:173)
`ately after mixing. The solution showing incompatabil-
`ity showed initial pH values in the region of pH 6-7 and
`this was insufficiently reduced by the presence of the
`dilute citrate buffer in the parenteral formulation. For 25
`other fluids showing compatability, those with pH val(cid:173)
`ues greater than 4-5 (before addition of the nicardipine
`hydrochloride solution for parental use), showed reduc(cid:173)
`tions in pH values to below pH 4.5 (after the addition of
`nicardipine hydrochloride solution for parenteral use). 30
`this being due to the presence of dilute buffer in the
`parenteral formulation. This effect is further illustrated
`in the next Example.
`
`10
`TABLE 9
`Effect of Initial pH of Dextrose 5o/c Injection on the
`Final Solution pH after addition of Nicardipine HCI
`Injection (Buffered Formula) to 100 mg.J- I
`INITIAL pH
`FINAL pH
`APPEARANCE
`(Before
`(After
`(After
`Addition)
`Addition)
`Mixing)
`
`3.01
`3.72
`4.00
`4.55
`4.81
`5.76
`6.50
`7.00
`7.49
`
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Cloudy pale yellow
`solution with precipitation
`initial pH of Ntcardipine HCI Injection = 3.86
`
`3.67
`3.73
`3.82
`4.06
`4.10
`4.14
`4.21
`4.38
`6.24
`
`TABLE 10
`Effect of Initial pH of Dextrose 5o/c Injection on the
`Final Solution of Nicardipine HCl Injection
`(Unbuffered Formula) to 100 mg · 1- I
`INITIAL pH
`FINAL pH
`APPEARANCE
`(Before
`(After
`(After
`Addition)
`Addition)
`Mixing)
`
`3.34
`3.86
`4.12
`4.99
`5.56
`6.14
`6.86
`7.26
`
`3.42
`3.94
`4.02
`4.66
`5.00
`5.83
`5.89
`i.ll
`
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Clear pale yellow solution
`Cloudy pale yellow solution
`Cloudy pale yellow solution
`
`35
`
`EXAMPLE IV
`Improved Compatibility with Buffered Formula
`Comparison of a buffered formula (0.0025M citrate
`equivalent) and unbuffered formula using Dextrose 5%
`Injection solution, of various pH from pH 3-7.5, using a 40
`I: 10 dilution, showed improved compatability for the
`buffered formula since the pH after mixing remained
`below pH 4.5 for Dextrose Injections solutions up to pH
`7, in comparison to the unbuffered formula which
`showed pHs after mixing above pH 4.5 (Tables 9 and 10 45
`and FIG. 2). The higher pH values after mixing were
`also associated with precipitation of nicardipine, thus
`being more prominent for the unbuffered formula.
`TABLE 8
`---------------------------------------so
`Summarized Compatibility for Nicardipine HCI Injection
`Diluted With Various Infusion Fluids
`COMPATIBLE WITH
`INCOMPATIBLE WITH
`
`Compound Sodium
`Lactate
`Half strength Sodium
`Lactate and
`Dextrose 5'7c
`Darrows Solution
`
`Dextrose 5o/c
`
`Sodium Chloride 0.9'7c
`
`Sodium Chloride 0.9'/c
`and Dextrose 5%
`Potassium Chloride 0.3'/c
`and Dextrose 5o/c
`Potassium Chloride 0.3'/c,
`Sodium Chloride 0.18'7c
`and Dextrose 4%
`Potassium Chloride 0.3'/c
`and Sodium Chloride 0.9'/c
`Laevulose 10%
`Laevulose 20o/c
`Ringers Solution
`
`55
`
`60
`
`What is claimed is:
`1. In a process for producing a stable pharmaceutical
`composition containing nicardipine hydrochloride suit(cid:173)
`able for parenteral administration and useful in the treat(cid:173)
`ment of disease conditions which may be alleviated by
`the administration of calcium channel blocking agents,
`which process comprises admixing a therapeutical