USRE34618E - Injection of nicardinpine hydrochloride and process for the production thereof - Google Patents

Injection of nicardinpine hydrochloride and process for the production thereof Download PDF

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Publication number
USRE34618E
USRE34618E US07/791,358 US79135891A USRE34618E US RE34618 E USRE34618 E US RE34618E US 79135891 A US79135891 A US 79135891A US RE34618 E USRE34618 E US RE34618E
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Prior art keywords
injectable composition
nicardipine hydrochloride
solution
polyhydric alcohol
sorbitol
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US07/791,358
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Katayasu Ogawa
Go Ohtani
Shoji Yokota
Masayoshi Aruga
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Astellas Pharma Inc
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Yamanouchi Pharmaceutical Co Ltd
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Priority claimed from JP59102991A external-priority patent/JPS60246313A/en
Application filed by Yamanouchi Pharmaceutical Co Ltd filed Critical Yamanouchi Pharmaceutical Co Ltd
Priority to US07/791,358 priority Critical patent/USRE34618E/en
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Publication of USRE34618E publication Critical patent/USRE34618E/en
Assigned to ASTELLAS PHARMA INC. reassignment ASTELLAS PHARMA INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: YAMANOUCHI PHARMACEUTICAL CO., LTD.
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • This invention relates to an injectable composition of nicardipine hydrochloride having a cerebral vascular dilating activity, a coronary dilator activity, and an anti-hypertension activity. Also, the invention relates to a process of producing the injectable composition. More particularly, the invention relates to an injectable composition containing nicardipine hydrochloride and 2 to 7 W/V% of a polyhydric and a process of producing thereof.
  • the inventors have investigated the possibility of obtaining a desired concentration of nicardipine hydrochloride and the stability of an injectable composition thereof by adding various additives for overcoming the above-described difficulties. As the result of the investigation, it has been found that when sodium chloride which is usually used as an isotonizing agent for injections is added, a desired concentration of nicardipine hydrochloride is not obtained and the injectable composition is insufficient in stability.
  • an injectable composition of nicardipine hydrochloride containing 2 to 7 W/V% of a polyhydric alcohol.
  • a process of producing an injectable composition of nicardipine hydrochloride which comprises dissolving nicardipine hydrochloride and a polyhydric alcohol in an amount of 2 to 7 W/V% of the total amount to water and adjusting the pH of the solution to 2.5 to 5.
  • the effect of this invention is greatly increased when the pH of the aqueous solution of nicardipine hydrochloride is adjusted to 2.5 to 5 as described above.
  • the polyhydric alcohol for use in this invention there are sorbitol, mannitol, xylitol, propylene glycol, glycerol, inositol, etc. They may be used individually or as a mixture of them.
  • the amount of the polyhydric alcohol is about 2 to 7 W/V%, preferably about 5 W/V% based on the whole amount of the injectable composition.
  • a certain polyhydric alcohol may show the insufficient isotonization by the use of about 2 W/V% and in such a case, the isotonization of the injectable composition may be controlled by using other isotonizing agent.
  • the pH of the injectable composition is lower than 2, the stability of nicardipine hydrochloride is reduced, while if the pH is higher than 6, the solubility of nicardipine hydrochloride is reduced.
  • nicardipine hydrochloride there is no particular restriction about the concentration of nicardipine hydrochloride in this invention but is, as a matter of course, dependent upon the amount of the polyhydric alcohol and the pH thereof. By selecting a proper condition, a solubility of about 0.6 W/V% can be obtained.
  • the injectable composition of this invention is prepared by dissolving predetermined amounts of nicardipine hydrochloride and a polyhydric alcohol in water at 50 to 60° C., adjusting the pH to about 2.5 to 5, preferably about 3.5, and then adjusting the volume of the solution to a predetermined volume by the addition of water.
  • the pH of the solution can be controlled by a mineral acid such as hydrochloric acid and, as the case may be, by a base such as sodium hydroxide, sodium hydrogencarbonate, etc.
  • the injectable composition of nicardipine hydrochloride thus obtained can maintain its desired concentration (higher than 0.1 W/V%) and can be stored for a long period of time without being accompanied by the change in quality or stability.
  • Control An aqueous solution of nicardipine hydrochloride (0.1 W/V%, pH 3.5) containing no polyhydric alcohol.
  • Quantitative determination The quantitative determination was performed by a high performance chromatography (HPLC).
  • Example 11 The injectable composition of Example 11: Xylitol (2 W/V%)
  • Example 12 The injectable composition of Example 12: Xylitol (4 W/V%)
  • Example 17 pH 5.0
  • Each sample was stored in a chamber maintained at 100° C. and sampled at each definite time.
  • Example 15 By following the same procedure as Example 15 while adjusting the pH of the solution to 5.0 using 0.1N sodium hydroxide in place of 0.1N hydrochloric acid, an injectable composition was obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

An injectable composition of nicardipine hydrochloride comprising an aqueous nicardipine hydrochloride solution containing 2-7 w/v % of polyhydric alcohol. This injectable composition can maintain its desired concentration and can be stably stored for a long period of time.

Description

This application is a continuation, of application Ser. No. 140,901, filed 12/23/87, now abandoned; which is a continuation of U.S. Pat. No. 925,462, filed 10/30/86, now abandoned, which in turn is a continuation of U.S. Pat. No. 735,558, filed 5/15/85, now abandoned.
FIELD OF THE INVENTION
This invention relates to an injectable composition of nicardipine hydrochloride having a cerebral vascular dilating activity, a coronary dilator activity, and an anti-hypertension activity. Also, the invention relates to a process of producing the injectable composition. More particularly, the invention relates to an injectable composition containing nicardipine hydrochloride and 2 to 7 W/V% of a polyhydric and a process of producing thereof.
BACKGROUND OF THE INVENTION
Hitherto, oral administering formulations containing nicardipine hydrochloride have been developed but an injectable composition containing nicardipine hydrochloride has not yet been developed. This is because in the case of using the compound as an injectable composition, the compound shows a reduction in solubility according to the kind of isotonizing agent used and thus an injectable composition having a desired concentration cannot be obtained or the stability of an injectable composition if obtained is insufficient.
The inventors have investigated the possibility of obtaining a desired concentration of nicardipine hydrochloride and the stability of an injectable composition thereof by adding various additives for overcoming the above-described difficulties. As the result of the investigation, it has been found that when sodium chloride which is usually used as an isotonizing agent for injections is added, a desired concentration of nicardipine hydrochloride is not obtained and the injectable composition is insufficient in stability.
As the result of further investigations, it has been discovered that when nicardipine chloride is dissolved in water together with 2 to 7 W/V% of a polyhydric alcohol, a stable aqueous solution of nicardipine hydrochloride is unexpectedly obtained and based on the discovery, the invention has been attained.
SUMMARY OF THE INVENTION
Thus, according to an embodiment of this invention, there is provided an injectable composition of nicardipine hydrochloride containing 2 to 7 W/V% of a polyhydric alcohol.
According to another embodiment of this invention, there is provided a process of producing an injectable composition of nicardipine hydrochloride which comprises dissolving nicardipine hydrochloride and a polyhydric alcohol in an amount of 2 to 7 W/V% of the total amount to water and adjusting the pH of the solution to 2.5 to 5.
The effect of this invention is greatly increased when the pH of the aqueous solution of nicardipine hydrochloride is adjusted to 2.5 to 5 as described above.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Accordingly, the invention will be explained in detail.
As the polyhydric alcohol for use in this invention, there are sorbitol, mannitol, xylitol, propylene glycol, glycerol, inositol, etc. They may be used individually or as a mixture of them. The amount of the polyhydric alcohol is about 2 to 7 W/V%, preferably about 5 W/V% based on the whole amount of the injectable composition. In addition, a certain polyhydric alcohol may show the insufficient isotonization by the use of about 2 W/V% and in such a case, the isotonization of the injectable composition may be controlled by using other isotonizing agent.
Also, if the pH of the injectable composition is lower than 2, the stability of nicardipine hydrochloride is reduced, while if the pH is higher than 6, the solubility of nicardipine hydrochloride is reduced.
There is no particular restriction about the concentration of nicardipine hydrochloride in this invention but is, as a matter of course, dependent upon the amount of the polyhydric alcohol and the pH thereof. By selecting a proper condition, a solubility of about 0.6 W/V% can be obtained.
The injectable composition of this invention is prepared by dissolving predetermined amounts of nicardipine hydrochloride and a polyhydric alcohol in water at 50 to 60° C., adjusting the pH to about 2.5 to 5, preferably about 3.5, and then adjusting the volume of the solution to a predetermined volume by the addition of water. The pH of the solution can be controlled by a mineral acid such as hydrochloric acid and, as the case may be, by a base such as sodium hydroxide, sodium hydrogencarbonate, etc.
The injectable composition of nicardipine hydrochloride thus obtained can maintain its desired concentration (higher than 0.1 W/V%) and can be stored for a long period of time without being accompanied by the change in quality or stability. In addition, it is preferred to use light-resistant ampoules for the injectable composition.
The test relating to the stability of nicardipine hydrochloride and the result thereof are shown below.
A. Effect of polyhydric alcohol
(a) The case of storing at 60° C.
(i) Sample:
The injectable composition of Example 1: Sorbitol (5 W/V%)
The injectable composition of Example 2: Mannitol (5 W/V%)
The injectable composition of Example 3: Xylitol (5 W/V%)
The injectable composition of Example 4: Propylene glycol (5 W/V%)
Control: An aqueous solution of nicardipine hydrochloride (0.1 W/V%, pH 3.5) containing no polyhydric alcohol.
(ii) Storage condition for sample: Each sample was stored in a bath maintained at 60° C. and sampled at each definite period.
Quantitative determination: The quantitative determination was performed by a high performance chromatography (HPLC).
Condition of HPLC:
Column: Nucleosil C18 (150×4 mm)
Column temperature: 40° C.
Eluent: Methanol-0.01M potassium hydrogen-phosphate solution (18:7)
Detection: Ultraviolet absorption detector Wave length 254 n.m.
(iv) Result: The remaining percentage of nicardipine hydrochloride in each sampled solution is shown in the following table.
______________________________________                                    
           Storage period (week)                                          
Sample       0      4          8    12                                    
______________________________________                                    
Example 1    100    96.09      89.57                                      
                                    69.67                                 
Example 2    100    93.08      88.26                                      
                                    71.63                                 
Example 3    100    95.04      85.60                                      
                                    69.24                                 
Example 4    100    97.20      88.03                                      
                                    74.39                                 
Control      100    93.47      77.94                                      
                                    49.13                                 
______________________________________
(b) The case of storing at 100° C.
(i) Sample:
The injectable composition of Example 7: Sorbitol (2 W/V%)
The injectable composition of Example 8: Sorbitol (4 W/V%)
The injectable composition of Example 9: Mannitol (2 W/V%)
The injectable comopsition of Example 10: Mannitol (4 W/V%)
The injectable composition of Example 11: Xylitol (2 W/V%)
The injectable composition of Example 12: Xylitol (4 W/V%)
The injectable composition of Example 13: Propylene glycol (2 W/V%)
The injectable composition of Example 14: Propylene glycol (4 W/V%)
Control: Same as the case (a)
(ii) Storage condition of sample: Each sample was stored in a chamber at 100° C. and sampled at each definite period.
(iii) Quantitative determination: Same as the case (a).
(iv) Result: The remaining percentage of nicardipine hydrochloride in each sampled solution is shown in the following table.
______________________________________                                    
         Storage day                                                      
Sample     1            3      7                                          
______________________________________                                    
Example 7  93.18        75.77  47.45                                      
Example 8  92.98        79.62  49.66                                      
Example 9  90.35        74.35  47.87                                      
Example 10 92.43        78.27  50.03                                      
Example 11 91.76        75.60  48.06                                      
Example 12 94.26        78.43  50.28                                      
Example 13 97.06        79.87  44.58                                      
Example 14 92.39        78.02  45.77                                      
Control    88.69        58.26  20.48                                      
______________________________________
B. Influence of pH
(i) Sample:
The injectable composition of the Comparison example: pH 2.0
The injectable composition of Example 15: pH 3.0
The injectable composition of Example 16: pH 4.0
The injectable composition of Example 17: pH 5.0
(ii) Test condition of sample:
Each sample was stored in a chamber maintained at 100° C. and sampled at each definite time.
(iii) Quantitative determination: Same as the case (a).
(iv) Result: The remaining percentage of nicardipine, hydrochloride in each sampled solution is shown in the following table.
______________________________________                                    
            Storage time (hr.)                                            
Sample        0      2.5        5    10                                   
______________________________________                                    
Comparison    100    92.02      88.10                                     
                                     85.53                                
example (2.0)                                                             
Example 15 (3.0)                                                          
              100    98.87      98.74                                     
                                     95.14                                
Example 16 (4.0)                                                          
              100    99.18      99.68                                     
                                     99.73                                
Example 17 (5.0)                                                          
              100    98.36      97.23                                     
                                     95.40                                
______________________________________
The following examples are intended to illustrate this invention but not to limit it in any way.
EXAMPLE 1
About 2 liters of distilled water was heated to 50° to 60° C. and 2.5 g of nicardipine hydrochloride and 125 g of sorbitol were dissolved therein with stirring. After cooling the solution (pH about 4.5) thus obtained to room temperature, the pH thereof was adjusted to 3.5 using 0.1 N hydrochloric acid. Then, when the whole volume thereof was adjusted to 2.5 liters by the addition of distilled water and after filtering the solution, 5 ml each of the solution was filled in each light-resistant brown ampuol
EXAMPLE 2
By following the same procedure as Example 1 using the same amount of mannitol in place of sorbitol, an injectable composition was obtained.
EXAMPLE 3
By the following the same procedure as Example 1 using the same amount of xylitol in place of sorbitol, an injectable composition was obtained.
EXAMPLE 4
By following the same procedure as Example 1 using the same amount of propylene glycol in place of sorbitol, an injectable composition was obtained.
EXAMPLE 5
By the following the same procedure as Example 1 using the same amount of glycerol in place of sorbitol, an injectable composition was obtained.
EXAMPLE 6
By following the same procedure as Example 1 using the same amount of inositol in place of sorbitol, an injectable composition was obtained.
EXAMPLE 7
By following the same procedure as Example 1 using 50 g of sorbitol, an injectable composition was obtained.
EXAMPLE 8
By following the same procedure as Example 1 using 100 g of sorbitol, an injectable composition was obtained.
EXAMPLE 9
By following the same procedure as Example 2 using 50 g of mannitol, an injectable composition was obtained.
EXAMPLE 10
By following the same procedure as Example 2 using 100 g of mannitol, an injectable composition was obtained.
EXAMPLE 11
By following the same procedure as Example 3 using 50 g of xylitol, an injectable composition was obtained.
EXAMPLE 12
By following the same procedure as Example 3 using 100 g of xylitol, an injectable composition was obtained.
EXAMPLE 13
By following the same procedure as Example 4 using 50 g of propylene glycol, an injectable composition was obtained.
EXAMPLE 14
By following the same procedure as Example 4 using 100 g of propylene glycol, an injectable composition was obtained.
EXAMPLE 15
About 2 liters of distilled water was heated to 50° to 60° C. and 1.0 g of nicardipine hydrochloride and 125 g of sorbitol were dissolved therein with stirring. After cooling the solution (pH about 5.0) to room temperature, the pH of the solution was adjusted to 3.0 using 0.1 N hydrochloric acid. Then, the whole volume of the solution was adjusted to 2.5 liters by the addition of distilled water and after filtering the solution, 5 ml each of the solution was filled in each light-resistant brown ampuol.
EXAMPLE 16
By following the same procedure as Example 15 while adjusting the pH of the solution to 4.0, an injectable composition was obtained.
EXAMPLE 17
By following the same procedure as Example 15 while adjusting the pH of the solution to 5.0 using 0.1N sodium hydroxide in place of 0.1N hydrochloric acid, an injectable composition was obtained.
EXAMPLE 18
By following the same procedure as Example 1 using 62.5 g of sorbitol and 62.5 g of mannitol in place of 125 g of sorbitol, an injectable composition was obtained.
COMPARISON EXAMPLE
By following the same procedure as Example 15 while adjusting the pH of the solution to 2.0, an injectable composition was obtained.

Claims (5)

What is claimed is:
1. A stable, injectable composition of nicardipine hydrochloride .[.in ampoule form.]. comprising an aqueous nicardipine hydrochloride solution containing 0.04 to 0.6 W/V% nicardipine hydrochloride and 2 to 7 W/V% of a polyhydric alcohol and wherein the pH of said solution is from 2.5 to 5, and the percentage of nicardipine hydrochloride remaining in said solution after a 12 week storage period at 60° C. is between 69.24 percent and 74.39 percent.
2. The stable injectable composition as claimed in claim 1, wherein the polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, xylitol, propylene glycol, glycerol, and inositol. .[.3. A process of producing a stable nicardipine hydrochloride injectable composition of claim 8, which process comprises dissolving nicardipine hydrochloride and a polyhydric alcohol in an amount of 2 to 7 W/V% of the whole amount of the injection in water and adjusting the pH of the solution to 2.5 to 5..]. .[.4. The process as claimed in claim 3, wherein the polyhydric alcohol is selected from the group consisting of sorbitol,
mannitol, xylitol, propylene glycol, glycerol and inositol..]. 5. The stable injectable composition of claim 1 wherein the aqueous nicardipine
solution contains 0.1 to 0.6 W/V% nicardipine hydrochloride. 6. A process of producing a stable nicardipine hydrochloride injectable composition of claim 5, which process comprises dissolving nicardipine hydrochloride and a polyhydric alcohol in an amount of 2 to 7 W/V% of the whole amount of the injectable composition in water and adjusting the pH of the solution
to 2.5 to 5. 7. The process as claimed in claim 6 wherein the polyhydric alcohol is selected from the group consisting of sorbitol, mannitol, xylitol, propylene glycol, glycerol, and inositol.
US07/791,358 1984-05-22 1991-11-14 Injection of nicardinpine hydrochloride and process for the production thereof Expired - Lifetime USRE34618E (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/791,358 USRE34618E (en) 1984-05-22 1991-11-14 Injection of nicardinpine hydrochloride and process for the production thereof

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
JP59102991A JPS60246313A (en) 1984-05-22 1984-05-22 Injection of nicardipine hydrochloride and its preparation
JP59-102991 1984-05-22
US73555885A 1985-05-15 1985-05-15
US92546286A 1986-10-30 1986-10-30
US14090187A 1987-12-23 1987-12-23
US07/338,402 US4880823A (en) 1984-05-22 1989-04-12 Injection of nicardinpine hydrochloride and process for the production thereof
US07/791,358 USRE34618E (en) 1984-05-22 1991-11-14 Injection of nicardinpine hydrochloride and process for the production thereof

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US14090187A Continuation 1984-05-22 1987-12-23
US07/338,402 Reissue US4880823A (en) 1984-05-22 1989-04-12 Injection of nicardinpine hydrochloride and process for the production thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070244166A1 (en) * 2006-04-18 2007-10-18 Pdl Biopharma, Inc. Pre-mixed, ready-to-use iv bolus compositions and methods of use

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CA1142937A (en) * 1979-09-01 1983-03-15 Egbert Wehinger Optically active 1,4-dihydropyridine compounds, their production and their medicinal use
US4582840A (en) * 1982-04-06 1986-04-15 Bayer Aktiengesellschaft 1,4-dihydro-2,6-dimethyl-4-nitrophenyl-3,5-pyridinedicarboxylic acid esters useful for treating renal insufficiency

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Publication number Priority date Publication date Assignee Title
CA1142937A (en) * 1979-09-01 1983-03-15 Egbert Wehinger Optically active 1,4-dihydropyridine compounds, their production and their medicinal use
US4582840A (en) * 1982-04-06 1986-04-15 Bayer Aktiengesellschaft 1,4-dihydro-2,6-dimethyl-4-nitrophenyl-3,5-pyridinedicarboxylic acid esters useful for treating renal insufficiency

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Title
Odani et al, C.A. vol. 92 (1980) 92:104,384u. *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070244166A1 (en) * 2006-04-18 2007-10-18 Pdl Biopharma, Inc. Pre-mixed, ready-to-use iv bolus compositions and methods of use
US20070249689A1 (en) * 2006-04-18 2007-10-25 Pdl Biopharma, Inc. Pre-mixed, ready-to-use pharmaceutical compositions
US20090182018A1 (en) * 2006-04-18 2009-07-16 Ekr Therapeutics, Inc. Pre-Mixed, Ready-To-Use Pharmaceutical Compositions
US20090182017A1 (en) * 2006-04-18 2009-07-16 Ekr Therapeutics, Inc. Pre-Mixed, Ready-To-Use Pharmaceutical Compositions
US7612102B2 (en) 2006-04-18 2009-11-03 Ekr Therapeutics, Inc. Pre-mixed, ready-to-use pharmaceutical compositions
US7659291B2 (en) 2006-04-18 2010-02-09 Ekr Therapeutics, Inc. Methods of treatment with pre-mixed, ready-to-use pharmaceutical compositions
US7659290B2 (en) 2006-04-18 2010-02-09 Ekr Therapeutics, Inc. Methods of preparing pre-mixed, ready-to-use pharmaceutical compositions
US20110086892A1 (en) * 2006-04-18 2011-04-14 Ekr Therapeutics, Inc. Pre-Mixed, Ready-To-Use Pharmaceutical Compositions
US20110152327A1 (en) * 2006-04-18 2011-06-23 Ekr Therapeutics, Inc. Pre-Mixed, Ready-To-Use Pharmaceutical Compositions
US8455524B2 (en) 2006-04-18 2013-06-04 Ekr Therapeutics, Inc. Methods of treatment with pre-mixed, ready-to-use pharmaceutical compositions
US9364564B2 (en) 2006-04-18 2016-06-14 Ekr Therapeutics, Inc. Pre-mixed, ready-to-use pharmaceutical compositions
US9370586B2 (en) 2006-04-18 2016-06-21 Ekr Therapeutics, Inc. Methods of preparing pre-mixed, ready-to-use pharmaceutical compositions
US9549994B2 (en) 2006-04-18 2017-01-24 Ekr Therapeutics, Inc. Compositions of nicardipine and sulfoalkylated β-cyclodextrin
US10758616B2 (en) 2006-04-18 2020-09-01 Ekr Therapeutics, Inc. Pre-mixed, ready-to-use pharmaceutical compositions
US11547758B2 (en) 2006-04-18 2023-01-10 Ekr Therapeutics, Llc Pre-mixed, ready-to-use pharmaceutical compositions

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