US20100113534A1 - Pharmaceutical Compositions And Methods For Producing Low Impurity Concentrations Of The Same - Google Patents

Pharmaceutical Compositions And Methods For Producing Low Impurity Concentrations Of The Same Download PDF

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US20100113534A1
US20100113534A1 US12/511,631 US51163109A US2010113534A1 US 20100113534 A1 US20100113534 A1 US 20100113534A1 US 51163109 A US51163109 A US 51163109A US 2010113534 A1 US2010113534 A1 US 2010113534A1
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clevidipine
composition
less
substance
approximately equal
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Rajeshwar Motheram
Gopal Krishna
Min Ding
Keith Flood
Kornepati Ramakrishna
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Chiesi Farmaceutici SpA
Hospira Inc
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Assigned to HOSPIRA, INC. reassignment HOSPIRA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FLOOD, KEITH, RAMAKRISHNA, KORNEPATI
Assigned to THE MEDICINES COMPANY reassignment THE MEDICINES COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KRISHNA, GOPAL, MOTHERAM, RAJESHWAR, DING, MIN
Publication of US20100113534A1 publication Critical patent/US20100113534A1/en
Priority to US13/600,056 priority patent/US20120322835A1/en
Priority to US13/919,893 priority patent/US20140005233A1/en
Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THE MEDICINES COMPANY
Priority to US16/197,647 priority patent/US11058672B2/en
Priority to US17/304,216 priority patent/US20220000849A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Definitions

  • the instant invention relates to pharmaceutical compositions, and in particular to compositions of clevidipine having a reduced level of impurities, and a method of maintaining the stability of such pharmaceutical compositions.
  • Clevidipine which is also known as CleviprexTM, is a short-acting, vascular selective calcium antagonist that has been shown to reduce arterial blood pressure with a fast termination of effect due to metabolism by blood and tissue esterases.
  • clevidipine reduces peripheral vascular resistance directly, without dilating the venous capacitance bed.
  • clevidipine is butyroxymethyl methyl 4-(2′,3′-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (C 21 H 23 Cl 2 NO 6 ). Its structure is as follows:
  • Clevidipine is typically formulated as a liquid emulsion suitable for intravenous administration.
  • Lipid emulsions are widely used in parenteral nutrition use for approximately 30 years and in the recent past have been used as drug carriers for insoluble drugs such as propofol (Diprivan®), and diazepam.
  • insoluble drugs such as propofol (Diprivan®)
  • diazepam Apart from their ability to deliver insoluble drugs, emulsions are also suitable dosage forms for drugs like clevidipine that are susceptible to hydrolytic breakdown. Emulsions have also been reported to prevent drugs from adhering to plastic administration sets used during intravenous injection, and reduce local toxicity on infusion.
  • compositions containing clevidipine As a pharmaceutical composition, it is essential that clevidipine maintains its stability. Over the past several years, various impurities have been identified in compositions containing clevidipine as an active ingredient. For example, some impurities arise from the process used in making clevidipine, while others are due to gradual degradation of the active ingredient. As a pharmaceutical composition, it is essential to maintain stability and minimize the amount of impurities regardless of their source or the mechanism of degradation. Therefore, a need exists for compositions of clevidipine having acceptable stability profiles with respect to their ultimate potency and impurity levels. There is also a need for methods for maintaining the stability of compositions having clevidipine as an active ingredient.
  • the first aspect of the present invention describes a number of impurities which may be derived from clevidipine through a hydrolysis, decarboxylation and condensation reaction. It describes the structure of these impurities and methods of detecting and analyzing these impurities.
  • the second aspect of the present invention describes methods of reducing the amount of such impurities in a pharmaceutical compositions having clevidipine as an active ingredient.
  • the third aspect of the present invention describes pharmaceutical compositions prepared or stored using the methods described herein wherein the level of certain impurities is minimized or reduced,
  • the present invention describes pharmaceutical composition having clevidipine as an active ingredient, and having a reduced level of one or more impurities selected from a group consisting of Substance 23, Substance 24, Substance 25 and H168/79.
  • the present invention describes a pharmaceutical composition having clevidipine as an active ingredient, wherein the compositions contains equal or no more than 0.2% of an impurity on a weight-to-weight of impurity to clevidipine and the impurity is selected from a group consisting of Substance 23, 24 and 25.
  • the present invention describes a pharmaceutical composition having clevidipine or any of its pharmaceutically acceptable salt forms, as the active ingredient, wherein the composition contains equal or no more than 0.2% on a weight-to-weight of impurity to clevidipine for each of the purities, Substance 23, 24 and 25.
  • the present invention includes compositions having clevidipine, as an active ingredient, wherein the composition contain a reduced level of an amount of the impurity H168/79 that is no greater than about 1.5% weight-to-weight of impurity to clevidipine basis, or where the ratio of the area under the chromatographic curve between clevidipine and H168/79 is equal or greater than 60 to 0.9.
  • the present invention also includes compositions having clevidipine or any of its pharmaceutical acceptable salt forms, as an active ingredient, wherein the compositions contain a reduced level of an amount of the impurities H168/79, Substance 23, Substance 24, and Substance 25 that the level of H168/79 is no greater than about 1.5% on a weight-to-weight of impurity to clevidipine or where the ratio of the area under the chromatographic curve between clevidipine and each of Substance 23, Substance 24, and/or Substance 25 is equal or greater than 500 to 1, and the ratio the area under the chromatographic curve between clevidipine and H168/79 is equal or greater than 60 to 0.9.
  • the present invention also describes a method of manufacturing compositions having clevidipine as an active ingredient, and an amount of the impurity H168/79 that is no greater than about 1.0% weight-to-weight of impurity to clevidipine, or where the ratio between clevidipine and H168/79 is equal or greater than 100 to 1.
  • the fourth aspect of the present invention is a method of treating or alleviating a disease or condition in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition having clevidipine or any of its pharmaceutical acceptable salt forms as the active ingredient, wherein the level of impurities is reduced or minimized to no more than 0.2% weight-to-weight of impurity to clevidipine for any of Substance 23, Substance 24, and Substance 25, and no more than 1.5% for H168/79 based on a weight-to-weight of impurity to clevidipine.
  • the disease or condition refers to any disease or condition which may be treated using a selective calcium channel block, such as clevidipine.
  • disorders such as hypertension, such as primary hypertension, secondary hypertension, acute hypertension, chronic hypertension, high blood Pressure, chest pain (angina), migraine, brain aneurysm complications, irregular heartbeats (arrhythmia) and Raynaud's disease.
  • hypertension such as primary hypertension, secondary hypertension, acute hypertension, chronic hypertension, high blood Pressure, chest pain (angina), migraine, brain aneurysm complications, irregular heartbeats (arrhythmia) and Raynaud's disease.
  • FIG. 1 illustrates a proposed degradation pathway of clevidipine.
  • clevidipine is a fast acting dihydropyridine calcium channel blocking agent developed for the treatment of various conditions, such as hypertension, including primary hypertension, secondary hypertension, acute hypertension, chronic hypertension and perioperative hypertension in cardiac surgery, high blood pressure, chest pain (angina), migraines, brain aneurysm complications, irregular heartbeats (arrhythmia) and Raynaud's disease.
  • hypertension including primary hypertension, secondary hypertension, acute hypertension, chronic hypertension and perioperative hypertension in cardiac surgery, high blood pressure, chest pain (angina), migraines, brain aneurysm complications, irregular heartbeats (arrhythmia) and Raynaud's disease.
  • clevidipine reduces peripheral vascular resistance directly, without dilating the venous capacitance bed. The end effect can be a reduction in systolic blood pressure. More detailed information on short-acting dihydropyridines and their clinical indications can be found in U.S. Pat. No. 5,856,346, the entire disclosure
  • clevidipine shall mean and include all varieties of forms of clevidipine. Unless otherwise specified, examples of such forms include all pharmaceutically acceptably salts, esters, isomers, stereo isomers, crystalline and amorphous forms.
  • salts shall refer to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • Clevidipine is manufactured by reaction of 4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid with chloromethyl butyrate to obtain clevidipine.
  • This reaction can be done optionally in the presence of a corresponding hydrogen carbonate, such as KHCO 3 , in refluxing acetonitrile.
  • Inorganic salts can be removed by filtration and the product is crystallized by the addition of isopropanol and water with subsequent cooling. It can also be crystallized by exchanging solvent from acetonitrile to a mixture of alcohol, such as ethanol or isopropanol, and water with repeated evaporations.
  • Clevidipine is practically insoluble in water, and thus is typically formulated as a liquid emulsion suitable for intravenous administration.
  • each mL may contain 0.5 mg clevidipine in approximately 20% soybean oil emulsion for intravenous administration.
  • Other ingredients may include glycerin, water, purified egg yolk phospholipids, and sodium hydroxide to adjust pH.
  • Emulsions offer much better solubility, less side effects of the vehicle and better stability than conventional solutions. Oil-in-water emulsions also prevent the compound from adherence to plastic infusion sets that are to be used when administering the compound. These emulsions provide a fast release and decay, and offer much better in vivo solubility properties, fewer side effects of the vehicle and better stability than conventional solutions. Further information regarding the formulation of clevidipine can be found in U.S. Pat. No. 5,739,152, the entire disclosure of which is incorporated by reference herein as if set forth in its entirety.
  • compositions having clevidipine as an active ingredient are heat intolerant and sensitive to water content.
  • the present invention provides compositions that include clevidipine and minimized impurity levels, along with methods of manufacturing and preserving these pharmaceutical compositions.
  • clevidipine degrades under adverse conditions into several impurities that compromise the purity and ultimately the potency of clevidipine.
  • clevidipine metabolizes into H168/79, which is also called methyl 4-(2′,3′-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-pyridine-carboxylate, and is shown in the following formula:
  • FIG. 1 a degradation pathway of clevidipine is proposed, and is shown in FIG. 1 .
  • This pathway includes a number of clevidipine degradation products, such as H324/78, H152/66, H152/81, H168/79, H207/59, and H207/36, for example.
  • the pathway also illustrates the further degradation of H168/79, by way of hydrolysis and condensation, into Substance 23, Substance 24, and/or Substance 25.
  • the composition of Substance 23, Substance 24, and Substance 25 is as follows:
  • H152/81, H168/79 and H207/59 are metabolites of clevidipine.
  • H324/78 is a pyridine analog of the active ingredient and is formed by the oxidation of clevidipine.
  • Degradation product H152/81 is a dihydropyridine carboxylic acid and is formed from the hydrolysis of clevidipine. H152/81 can undergo decarboxylation and oxidation sequentially to form H168/79 and H207/59 respectively.
  • the degradation product H168/79 can undergo hydrolysis to form the diketo ester H207/36 which can further cyclize to form substituted cyclohexenone derivative impurities such as Substance 23 and Substance 25.
  • Substance 24, a diastereomer of Substance 23, may also form during this reaction.
  • the level of impurities in the composition is as low as possible. Therefore, while various exemplary embodiments of pharmaceutical compositions include amounts of impurities within acceptable and effective ranges for the compositions as a whole, the more pure the composition, meaning the higher the percent of clevidipine or any of its acceptable salt forms, the better.
  • Substance 23 is an impurity generated through the degradation of H168/79.
  • the degradation of H168/79 is accelerated when exposed to temperatures in excess of 25° C. as compared to temperatures below 5° C. Therefore, the level of Substance 23 increases at higher temperatures.
  • Substance 25 is an impurity generated through the degradation of H168/79 and may increase in quantity as H168/79 degrades.
  • Substance 24 is also a degradation product of H168/79. Given that Substance 24 is a diastereomer of Substance 23, a separate HPLC method was developed to validate and quantify Substance 24.
  • the present invention further includes a method of identifying and quantifying levels of Substance 24 in pharmaceutical samples having clevidipine as an active ingredient.
  • the method of detecting Substance 24 in pharmaceutical samples having clevidipine as an active ingredient includes the step of isolating the individual chemical compounds making up the degradants or impurities found in the clevidipine degradation pathway. This can be accomplished by column chromatography, such as high pressure liquid chromatography (“HPLC”), for example.
  • HPLC high pressure liquid chromatography
  • the pharmaceutical sample having clevidipine as an active ingredient can introduced in small volume to the column and the resulting analysis of the eluent may illustrate the isolation and identification of peaks representative of Substance 24.
  • any optimization of the HPLC method may be performed to give the best separation of peaks as between the various impurities found in the degradation of clevidipine.
  • Typical HPLC methods useful in the present invention are presented in Examples 1 and 2. Based on this method of detecting Substance 24, the lower limit of detection, or the minimum detectable level of Substance 24, may be approximately 0.01% area of the pharmaceutical composition containing clevidipine as an active ingredient. Alternatively, there could be a lower limit of Substance 24, where the ratio of clevidipine to Substance 24 may be equal or similar to 9000 to 1 which is equal to or similar to 0.01%.
  • the lower limit of Substance 25 or Substance 23 detection may be set forth as a ratio of clevidipine to Substance 25 or Substance 23, where the ratio of clevidipine to Substance 25 or Substance 23 may be equal or similar to 9000 to 1 which is equal to or similar to 0.01%.
  • Clevidipine assay and related substances were tested at each time point by a stability indicating method.
  • This method is an isocratic, normal phase HPLC method with peak detection at 220 nm wavelength.
  • This method is an isocratic, normal phase HPLC method with peak detection at 220 nm wavelength.
  • quantization of the impurity may be accomplished by standard procedures known in the art such as constructing a standard curve or by calculating a relative response factor (RRF).
  • RRF relative response factor
  • the present invention includes pharmaceutical compositions having clevidipine as an active ingredient, wherein the level of impurity H168/79 is no more than 1.5% on a weight-by-weight basis.
  • the pharmaceutical composition includes clevidipine as an active ingredient and an amount of H168/79 that is no greater than about 1.2%.
  • the amount of H168/79 is preferably no greater than about 1.0%, and most preferably no greater than about 0.5%.
  • These compositions may further include other degradants in variable amounts as described herein, provided the required level of potency of clevidipine remains satisfactory and effective for use to treat any indication as described or incorporated by reference herein.
  • the pharmaceutical composition exemplified in Tables 1, 2 and 3 are emulsions.
  • the emulsions comprise: clevidipine 0.5 mg/ml., egg yolk phospholipid 1.2%, soybean oil 20%, glycerol 2.25%. The remainder being water adjusted to a pH between 6 and 8.8.
  • the products were packaged in 100 ml glass type II bottles with 28 mm West compound 1821 black stopper and aluminum seal.
  • the pharmaceutical composition includes clevidipine as an active ingredient and H168/79, where the ratio of areas under the peak from an HPLC chromatogram between clevidipine and H168/79 is equal or above 60 to 0.9.
  • the ratio between clevidipine and H168/79 can be equal to or above 100 to 1, 200 to 1, or 1000 to 1.
  • the ratio between clevidipine and H168/79 can be between 2000 to 1 and 1000 to 1.
  • These compositions may further include other degradants in variable amounts as described herein, provided the required level of potency of clevidipine remains satisfactory and effective for use to treat any indication as described or incorporated by reference herein.
  • H168/79 increases and stabilizes at lower temperatures approaching about 5° C., while it decreased at a temperatures approaching about 25° C. to about 40° C., for example. This trend shows that a higher temperatures, H168/79 undergoes further degradation to Substance 23, Substance 24, and/or Substance 25, by way of intermediary H207/36, as illustrated in FIG. 1 .
  • the lowering of temperature also provides stability for H168/79 and, as a consequence, lowers and inhibits the amount of resulting second order impurities.
  • the above mentioned methods of stabilizing pharmaceutical compounds having clevidipine as an active ingredient provide a shelf life of at least 36 months for the compositions, when stored at about 2° C. to 8° C. After being removed from this refrigerated condition and placed at roughly room temperature (15° C. to 30° C.), the compositions remain stable for up to at least 2 additional months.
  • the present invention also includes a method of maintaining the stability of a pharmaceutical composition having clevidipine as the active ingredient, including the slowing down or otherwise inhibiting of the hydrolysis pathway of clevidipine by reducing or inhibiting the amount of water in the process of manufacturing the composition, as well as the emulsification process in the final formulation.
  • clevidipine is manufactured by reaction of 4-(2′,3′-dichlorophenyl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylic acid with chloromethyl butyrate to obtain clevidipine.
  • This reaction can be done optionally in the presence of a corresponding hydrogen carbonate, such as KHCO 3 , in refluxing acetonitrile.
  • Inorganic salts can be removed by filtration and the product is crystallized by the addition of isopropanol with subsequent cooling.
  • Clevidipine is typically formulated as a liquid emulsion suitable for intravenous administration.
  • Lipid emulsions are widely used in parenteral nutrition use for approximately 30 years and in the recent past have been used as drug carriers for insoluble drugs such as propofol (Diprivan®), and diazepam.
  • insoluble drugs such as propofol (Diprivan®)
  • diazepam Apart from their ability to deliver insoluble drugs, emulsions are also suitable dosage forms for drugs like clevidipine that are susceptible to hydrolytic breakdown. Emulsions have also been reported to prevent drugs from adhering to plastic administration sets used during intravenous injection, and reduce local toxicity on infusion.
  • each mL may contain 0.5 mg clevidipine in approximately 20% soybean oil emulsion for intravenous administration.
  • Other ingredients may include glycerin, purified egg yolk phospholipids and sodium hydroxide to adjust pH.
  • water for injection is dispensed to a mix tank at about 74° C. to about 78° C.
  • Glycerin is added, and the aqueous phase is cooled to about 60° C. to about 70° C. prior to addition of the oil phase.
  • soybean oil is dispensed into a dissolving tank, mixed and heated to about 70° C. to about 82° C.
  • Clevidipine is then added to the soybean oil mixture and heated to about 78° C. to about 82° C.
  • Egg yolk phospholipids are then added to the mixture.
  • the aqueous and oil phases are mixed together to form an emulsion, and the pH is adjusted with 1N sodium hydroxide to a pH of about 6 to about 8.8.
  • the emulsion is then homogenized at a pressure of about 500 to 8000 psi and a temperature of about 50° C. to about 55° C. to a fine particle size.
  • the emulsion is homogenized at about 25° C., More preferably at about 15° C., still more preferably at about 10° C. and most preferably at about 5° C.
  • Emulsions of the present invention comprise an oil-in-water emulsion comprising: a) clevidipine, b) a lipid phase, c) an emulsifier, and d) water or a buffer.
  • the emulsion may also contain co-solvents or other solubility enhancers, antioxidants, stabilizers, pH-adjusting agents or tonicity modifying agents, such as glycerol.
  • clevidipine is present from about 0.4 mg/ml to about 0.6 mg/ml. Preferably clevidipine is present from abut 0.45 mg/ml to about 0.55 mg/ml.
  • the lipid phase is present from about 1% to about 35%, preferably from about 18% to about 22%.
  • the emulsifier is present from about 0.01 to about 2 times the weight of the lipid phase, preferably from about 0.5% to about 4% and more preferably from about 1% to about 1.32%.
  • the remainder of the emulsion is water or buffer. The preferred range of water or buffer is about 75% to about 90%.
  • the pH of the emulsion is adjusted to about 6 to about 8.8, preferably from about 7.5 to about 8.8.
  • glycerol is present from about 2% to about 2.5%. Percentages of the emulsion composition are expressed as weight/weight.
  • Lipid phases in the emulsion are any pharmaceutically acceptable oil, preferably triglycerides such as soy bean oil, safflower seed oil, olive oil, cottonseed oil, sunflower oil, sesame oil, peanut oil, corn oil, medium chain triglycerides (such as Miglyol® 812 or 810) or triacetin.
  • the lipid phase may also be propylene glycol diesters or monoglycerides (such as acetylareal monoglycerides).
  • the lipid phase can also be a mixture of said ingredients.
  • the most preferred lipid phase is soy bean oil.
  • Emulsifiers are any pharmaceutically acceptable emulsifier, preferably phospholipids extracted from egg yolk or soy bean, synthetic phosphatidyl cholines or purified phosphatidyl cholines from vegetable origin. Hydrogenated derivatives can also be used, such as phosphatidyl choline hydrogenated (egg) and phosphatidyl choline hydrogenated (soya). Emulsifiers may also be non-ionic surfactants such as poloxamers (for example Poloxamer 188 and 407 ), poloxamines, polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters or sorbitan fatty acid esters.
  • poloxamers for example Poloxamer 188 and 407
  • poloxamines polyoxyethylene stearates
  • polyoxyethylene sorbitan fatty acid esters polyoxyethylene sorbitan fatty acid esters or sorbitan fatty acid esters.
  • Ionic suffactants may also be used such as cholic acid and deoxycholic acid or surface active deriviatives or salts thereof.
  • the emulsifier can also be a mixture of said ingredients.
  • the most preferred emulsifier is egg yolk phospholipid.

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CN104974043A (zh) * 2014-04-09 2015-10-14 上海信谊金朱药业有限公司 丁酸氯维地平的杂质化合物的制备方法
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CN104458937B (zh) * 2014-11-20 2017-02-22 北京京科泰来科技有限公司 一种丁酸氯维地平脂肪乳有关物质检测方法
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US11058672B2 (en) 2008-08-01 2021-07-13 Chiesi Farmaceutica S.P.A. Pharmaceutical compositions and methods for producing low impurity concentrations of the same
WO2012051116A1 (en) * 2010-10-12 2012-04-19 The Medicines Company Clevidipine emulsion formulations containing antimicrobial agents
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