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Pre-mixed, ready-to-use iv bolus compositions and methods of useRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Nitrogen Attached Directly To The Six-membered Hetero Ring By Nonionic Bonding, At 3-positionPre-mixed, ready-to-use iv bolus compositions and methods of use description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070244166, Pre-mixed, ready-to-use iv bolus compositions and methods of use. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims priority benefit under 35 U.S.C. .sctn.119(e) to U.S. Provisional Application Ser. No. 60/793,074, filed Apr. 18, 2006, which is incorporated by reference herein in its entirety. STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] NOT APPLICABLE REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK [0003] NOT APPLICABLE BACKGROUND [0004] Dihydropyridine calcium channel blockers are useful in the treatment of cardiovascular and cerebrovascular disorders. These agents act by inhibiting calcium uptake into vascular smooth muscle cells and mobilizing calcium from their intracellular stores. The vascular smooth muscle relaxes leading to vasodilation, decreased peripheral vascular resistance and decreased blood pressure. Examples of dihydropyridine calcium channel blockers include: amlodipine (NORVASC.RTM.), bepridil, diltiazem (CARDIZEM.RTM.), felodipine (PLENDIL.RTM.), isradipine (DYNACIRC.RTM.), mibefradil, nicardipine (CARDENE.RTM.), nifedipine (ADALAT.RTM. AND PROCARDIA.RTM.), nimodipine (NIMOTOP.RTM.), nisoldipine (SULAR.RTM.), verapamil (CALAN.RTM., ISOPTIN.RTM. and VERELAN.RTM.) and nilvadipine. [0005] Nicardipine has a number of pharmaceutically acceptable salts, including the hydrochloride salt (e.g., IUPAC chemical name (.+-.)-2-(benzyl-methyl amino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride). The preparation and use of nicardipine hydrochloride are described in U.S. Pat. No. 3,985,758. CARDENE.RTM. is sold commercially in several forms. For example, nicardipine hydrochloride is available as an immediate release oral capsule, an extended release oral capsule, and as a concentrated preparation provided as an ampule (i.e., CARDENE.RTM. I.V.) that is greatly diluted into a pharmaceutically acceptable diluent before administration to a patient. CARDENE.RTM. I.V. is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable (see, the product insert for CARDENE.RTM. I.V.). [0006] "Injectable" formulations of nicardipine have been described. For example, U.S. Reissue Pat. No. RE. 34,618, a reissue of U.S. Pat. No. 4,880,823, describes an injectable composition of nicardipine hydrochloride that is stored in a light resistant brown ampule and avoids the use of sodium chloride, particularly as a tonicity agent, in the formulation. U.S. Pat. No. 5,164,405 describes a buffered pharmaceutical composition containing nicardipine that is designed for parenteral administration. This composition is also stored in an ampule. A drawback of both these ampule formulations is that they must be greatly diluted into a pharmaceutically acceptable diluent before administration to a patient. [0007] While nicardipine exists in oral and injectable forms, a bolus formulation of nicardipine has not been approved by the FDA. Nevertheless, nicardipine is administered off-label as a bolus injection. Administration requires dilution of the concentrated ampul formulation. See for example, Deanna Cheung, et al., Am Heart J., vol. 119, pp. 438-442 (1990); Albert Cheung et al., Anesth Analg, vol. 89, pp. 1116-1123 (1999); (author), Anesth Analg, vol. 85, pp. 1247-1251 (1997); Yunan Zhang et al., Anesth Analg, vol. 100, pp. 378-381 (2005); ohn L Atlee et al., Anesth Analg, vol. 90, pp. 280-285 (2000); H J Yang et al., J. Int Med Research, (cite); Jean-Louis Vincent et al., J. Cardiothoracic Vasc Anesth, vol. 11, pp. 160-164 (1997); Chia-Chen Chen, et al., Acta Anaesthesiol Sin, vol. 34, pp. 197-202 (1996); Y L Kwak, et al., J. Int Med Research, vol. 32, pp. 342-350 (2004); P Colson et al., Acta Anaesth Scand, vol. 42, pp. 1114-1119 (1998); Jean-Marc Bernard et al., Anesth Analg, vol. 75, pp. 179-85 (1992); Hiroshi Endoh et al., J. Clin Anesthesia vol. 11, pp. 545-549 (1999); AGM Aya et al., Intensive Care Med, vol. 25, pp. 1277-1281 (1999); S. Elatrous et al., Intensive Care Med, vol. 28, pp. 1282-1286 (2002); Joseph Flynn et al., J. Pediatr, vol. 139, pp. 38-43 (2001); and other references. [0008] Pharmaceutical compositions that are supplied in ampules have several important drawbacks. For example, these ampule formulations must be diluted into a pharmaceutically acceptable diluent prior to use. Therefore, they are not immediately available for use, such as in an emergency setting. Ampule compositions that must be diluted before use introduce the possibility of dosing errors in making the dilution; and safety hazards associated with the use of glass ampules. In addition, according to guidelines for administration of admixed (pre-mixed) products in hospital settings, admixed solutions should be used within 24 hours in order to minimize the risk of microbial contamination. See The United States Pharmacopeia, vol. 1, p. 349 (2007). In addition to the concerns generally associated with off-label use of ampule formulations, CARDENE.RTM. I.V. presents two additional challenges. First, the pH of the diluted solution varies widely because the concentrated ampule solution can be diluted into various diluents, as described in the product insert for CARDENE.RTM. I.V. Second, as shown in the product insert for CARDENE.RTM. I.V., the diluted solution is only stable for 24 hours at room temperature. Therefore, the diluted solution must be used relatively quickly or it will expire. [0009] To minimize the possibility of hemolysis, precipitation, phelebitis and pain, drugs which are directly injected into the circulatory system need to have little to no precipitate formed during storage, and upon contact and subsequent dilution in blood following administration (see., e.g., Yalkowsky, et al., 1998, J. Pharmaceutical Sciences, 87(7): 787-796). Nicardipine is a weak organic base, having a pKa of 7.2, and dissolves poorly in water-based formulations, especially at physiological pH. To avoid precipitation of nicardipine when administered in a more concentrated form, its poor aqueous solubility must be overcome. Thus, there is a long-felt need for a low volume, stable aqueous pharmaceutical formulation of nicardipine which can provide a therapeutically effective dosage and which does not appreciably degrade upon storage or precipitate when parenterally administered in a more concentrated, lower volume formulation. [0010] The compositions provided herein address these and other needs by providing a relatively low volume, pre-mixed, ready-to-use, injectable formulation of nicardipine that is stable enough for clinical use, and yet provides a suitable nicardipine concentration for immediate use, without dilution, by parenteral injection. BRIEF SUMMARY [0011] To meet these and other needs, provided herein are pharmaceutical compositions of nicardipine for direct bolus parenteral administration to a subject and methods of using the compositions to prevent or treat acute elevations of blood pressure in a subject. The compositions can be administered by parenteral routes, including, subcutaneous, intramuscular, and intravenous routes, to a patient. [0012] Accordingly a first aspect provides pharmaceutical compositions of nicardipine for direct bolus intravenous administration to a human subject. In this aspect, the pharmaceutical composition comprises 0.25 mg to 5.0 mg/ml, inclusive of nicardipine (as calculated for either nicardipine base or its hydrochloride salt) in an aqueous formulation having one or more buffering agent(s) each in a concentration from 0.1 mM to 100 mM, and a pH from about 3.5 to 5.5, inclusive, and one or more additional pharmaceutically acceptable excipients or carriers. In some embodiments, the buffering agent(s) can be any one or more salts and acids of citrate, malate, formate, succinate, acetate, propionate, histidine, carbonate, tartrate, phosphate, or 2-(N-morpholino)ethanesulfonic acid (MES). Optionally, the composition comprises a tonicity adjusting agent and/or a co-solvent. Suitable tonicity adjusting agents include but are not limited to, dextrose or sodium chloride. Suitable co-solvents include but are not limited to, polyhydric alcohols (e.g., sorbitol, mannitol, xylitol), glycols (e.g., propylene glycol and polyethylene glycol), and ethanol in a concentration range varying from 0.1 to 25% w/v. Typically, the compositions are provided as low volume, pre-mixed, ready-to-use, bolus injectable, aqueous pharmaceutical compositions. Alternatively, the compositions may be lyophilized and reconstituted in water, saline or a pharmaceutically acceptable aqueous carrier to provide the compositions for use as a bolus injection. [0013] In some further embodiments, the use of nicardipine or a pharmaceutically acceptable salt thereof in the manufacture of the above compositions for the prevention or treatment of acute elevations of blood pressure in a human subject in need thereof are provided. [0014] The second aspect provides pharmaceutical compositions formulated for bolus direct intravenous administration to a human subject which comprises an inclusion complex of nicardipine and/or a pharmaceutically acceptable salt thereof with a sulfoalkylated .beta.-cyclodextrin. Typically, the concentration of the sulfoalkylated .beta.-cyclodextrin in the formulation is from 0.1% to 25% (w/v), inclusive. The pharmaceutical composition comprises 0.25 mg to 5.0 mg/ml, inclusive of nicardipine (as calculated for either nicardipine base or its hydrochloride salt) in an aqueous formulation having one or more buffering agent(s) each in a concentration from 0.1 mM to 100 mM, and a pH from about 3.5 to 7.5, inclusive, and one or more additional pharmaceutically acceptable excipients or carriers. In some embodiments, the buffering agent(s) can be any one or more of an acid or salt of citrate, malate, formate, succinate, acetate, propionate, histidine, carbonate, phosphate, tartrate, or MES. Optionally, the composition comprises a tonicity adjusting agent and/or a co-solvent. Suitable tonicity adjusting agents for use in the compositions provided herein include, but are not limited to, dextrose or sodium chloride. Suitable co-solvents for use in the compositions provided herein include, but are not limited to, polyhydric alcohols (e.g., sorbitol, mannitol, xylitol), glycols (e.g., propylene glycol and polyethylene glycol), and ethanol, in a concentration range varying from 0.1 to 25% w/v. Typically, the compositions are provided as low volume, pre-mixed, ready-to-use, bolus injectable, aqueous pharmaceutical compositions. Alternatively, the compositions may be lyophilized and reconstituted in water, saline, or a pharmaceutically acceptable aqueous carrier to provide the compositions for use as a bolus injection. [0015] In some further embodiments, the use of nicardipine and sulfoalkylated .beta.-cyclodextrin derivatives in the manufacture of the above compositions for the prevention or treatment of acute elevations of blood pressure in a human subject in need thereof are provided. [0016] The pharmaceutical compositions in either of the above aspects can be packaged for use in a variety of containers, such as syringes, ampules, or vials. Typically, the compositions are packaged with materials that protect nicardipine from light. [0017] Examples of pharmaceutically acceptable salts of nicardipine are hydrochlorides, sulfates, phosphates, acetates, fumarates, maleates and tartrates. In some embodiments, the pharmaceutically acceptable salt of nicardipine is nicardipine hydrochloride. [0018] In a third aspect, are provided methods of preventing, or treating acute elevations of blood pressure in a human subject in need thereof by intravenously administering a bolus pharmaceutical composition as described above to the subject. The subjects may be volume-restricted due to any number of existing medical conditions, such as, edema, renal failure, ascites, cerebral edema, or other fluid overload, congestive heart failure, liver failure, or a CNS injury. The dosage can be administered over varying lengths of time and is generally administered over a period of less than 30 seconds, including from about 5 seconds to 30 seconds. In some embodiments, the subject has an elevated blood pressure with a systolic value equal to or above 150 mmHg. In other embodiments, the subject has an elevated blood pressure with a diastolic value equal to or above 90 mmHg. Dosages can be individualized depending upon the severity of hypertension and the response of the individual patient during dosing. [0019] In a fourth aspect, are provided methods for inducing hypotension during surgical procedures in a human subject in need thereof by intravenously administering a bolus formulation as described above to the subject. Continue reading about Pre-mixed, ready-to-use iv bolus compositions and methods of use... Full patent description for Pre-mixed, ready-to-use iv bolus compositions and methods of use Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Pre-mixed, ready-to-use iv bolus compositions and methods of use patent application. ###
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