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WO1993013765A1 - Solutions contenant des lecithines avec du levemopamil - Google Patents

Solutions contenant des lecithines avec du levemopamil Download PDF

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Publication number
WO1993013765A1
WO1993013765A1 PCT/EP1993/000062 EP9300062W WO9313765A1 WO 1993013765 A1 WO1993013765 A1 WO 1993013765A1 EP 9300062 W EP9300062 W EP 9300062W WO 9313765 A1 WO9313765 A1 WO 9313765A1
Authority
WO
WIPO (PCT)
Prior art keywords
levemopamil
solutions
lecithin
phospholipid
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1993/000062
Other languages
German (de)
English (en)
Inventor
Aktiengesellschaft Knoll
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott GmbH and Co KG
Original Assignee
Knoll GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Knoll GmbH filed Critical Knoll GmbH
Publication of WO1993013765A1 publication Critical patent/WO1993013765A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • Levemopamil is one of these active ingredients (EP 147 707). It is known that the local tolerance of levemopamil can be improved with the help of lipids and phospholipids.
  • Levemopamil can, on the one hand, as described in DE-A-4015108.3, be solubilized in a fat emulsion, as a result of which the local tolerance, tested by intravenous application to the rat, is improved compared to the aqueous solution.
  • the invention relates to a process for the preparation of colloidal aqueous levemopamil solutions, characterized in that a mixture of levemopamil salt, a phospholipid and an isotonizing agent is mixed with water and homogenized
  • the active substance (levemopamil) is used in the form of its salts. Levemopamil hydrochloride is preferred.
  • the active ingredient concentration in the finished solution is 1-20 mg / ml, preferably 3-10 mg / ml. Concentrations of about 5 mg / ml are very particularly preferred.
  • the amount of phospholipid added to the active ingredient is decisive for achieving good local tolerance.
  • the weight ratio of active ingredient to phospholipid is 1: 4 to 1:20, preferably 1: 4 to 1:10. Weight ratios of active ingredient to phospholipid of 1: 5 to are very particularly preferred Suitable phospholipids are natural (ie derived from natural products) or synthetic phospholipids. Preference is given to neutral and / or zwitterionic phospholipids such as the lecithins (phosphatidylcholines), in particular those which contain unsaturated fatty acid residues such as oleic acid and / or linoleic acid. Highly purified egg and soy lecithins containing at least 80% phosphatidylcholine are particularly preferred.
  • levemopamil hydrochloride in the lecithin-containing solutions according to the invention leads to pH values in the weakly acidic range (pH approx. 4-4.5). Despite the relatively acidic pH, these solutions are distinguished by a significantly improved local compatibility after intravenous administration compared to aqueous solutions of the same concentration which do not contain any phospholipid.
  • the local tolerance of the levemopamil hydrochloride solution can be easily increased by increasing the pH up to 7.0.
  • the long-term storage stability of the pH-neutral solutions is worse than that of the weakly acidic solutions, so that the pH-neutral solutions should be stored in a cool place.
  • Another method of improving the storage stability is to freeze-dry the solutions according to the invention. As a result of the very careful removal of the water, a dry preparation (lyophilisate) is formed which can be stored at room temperature. Before use, all that needs to be added is the water removed from the water.
  • the buffer solution can compensate for the low pH values (pH 4-5) of the levemopamil solution caused by the active ingredient (hydrochloride). Buffers which allow a pH of 5-7 in the finished solution are preferred. Phosphate buffers are very particularly preferred. Alkaline pH values above pH 7 are less suitable because the stability of the auxiliary (lecithin) is reduced by hydrolysis. Other auxiliary substances, e.g. Antioxidants can be added (2,6-di-tert-butyl-4-methylphenol) and / or heavy metal chelators such as EDTA (ethylenediamine-tetraacetic acid). The quantities used are based on the dosages that can be used in general in other injection preparations.
  • the isotonicization of the solution to achieve blood isotonicity can be carried out with the abovementioned buffer or with sodium chloride, but also with other salts, but preferably with carbohydrates such as sucrose and / or maltose. Glycerin is also suitable.
  • the salts or the carbohydrates become the buffer solution in quantities added, which in the finished application solution give Os olarities of about 280 to 400 mOsmol / kg.
  • the batch is homogenized. Preference is given to processes which bring the particle sizes of the colloidal solution to values below 0.2 micrometers (on average), so that the entire formulation can be sterile filtered (so-called sterilization filtration with a 0.2 micrometer filter).
  • a suspension in which the average particle sizes are still in the range of several micrometers is produced using simple dispersing devices which cause the coarse agglomerates to be broken up by knives running at high speed.
  • This suspension is then further homogenized using suitable methods.
  • High-pressure homogenizers which are widely used for the production of emulsions
  • filtration processes in which the suspension is pressed under suitable pressure through suitable membrane filters (extrusion). Both processes allow a gentle reduction of particle sizes to mean values of less than 0.2 micrometers.
  • the finished solutions can thus be sterile filtered, which means that sterilization filtration can take place, which is very important for a pharmaceutical form which is to be administered parenterally.
  • the reduction in particle sizes is still necessary to achieve adequate storage stability. Colloidal solutions with particle sizes in the micrometer range tend to sedimentation and / or flocculation and, moreover, cannot be administered parenterally because of possible embolisms.
  • the finished colloidal solution can be autoclaved in the final container by known methods (typically 20 min at 120 ° C.) without flocculation in the colloidal solution. This sterilization in the final container ensures that the finished dosage form is sterile.
  • the method according to the invention has the advantage of a significantly lower amount of lipid, which must be used for good local tolerance. While the weight ratio of active substance: lipid in the case of the emulsion is 1:11, this value can be reduced to about 1: 6 in the process according to the invention without differences in local tolerance being detectable in animal experiments. As a result, in the case of the method according to the invention, an unnecessarily high lipid load on the patient can be avoided.
  • the transparent, slightly opalescent colloidal solution was passed through a sterile filter (0.2 micrometer).
  • the ampoules were then sterilized in an autoclave for 20 minutes at 120 ° C.
  • the average particle size after autoclaving was 0.082 micrometers (measured by photon correlation spectroscopy).
  • the pH was 6.32.
  • Example 2 The preparation was carried out as in Example 1, but with egg lecithin E 100 (from Lipoid, FRG; same amount as in Example 1).
  • the mean particle sizes after autoclaving were 0.099 micrometers, the pH was 6.18.
  • Example 4 The preparation was carried out as in Example 2, but with a buffer solution which contained 43.15 g of maltrose monohydrate instead of sucrose. The mean particle sizes after autoclaving were 0.089 micrometers, the pH was 6.05. Example 4
  • the preparation was carried out as in Example 3, but without the addition of the phosphate buffer substances.
  • the mean particle sizes after autoclaving were 0.109 micrometers, the pH was 4.15.
  • the preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances.
  • the mean particle sizes after autoclaving were 0.086 microns, the pH was 4.07.
  • the preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances and with 26.0 g glycerol instead of saccharose.
  • the mean particle sizes after autoclaving were 0.046 micrometers, the pH was 4.17.
  • the preparation was carried out as in Example 2, but only with 2.063 g of egg lecithin E 100.
  • the average particle sizes were 0.063 micrometers, the pH was 6.33.
  • Levemopamil hydrochloride was dissolved in water at a concentration of 5.50 mg / ml.
  • Example 2 The formulations of Examples 2, 7 and 8 were administered intravenously at 6 times a day at a dose of 15 mg levemopamil hydrochloride per kg body weight to 6 rats at a rate of 0.6 ml / min. Formulation 8 was only applicable for 2 days, formulation 7 was applicable for 6 days until the occurrence of local incompatibilities made further application impossible. In contrast, the formulation of Example 2 could be administered to the animals over 28 days without local incompatibility reactions occurring.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

On décrit une solution colloïdale aqueuse de levemopamil obtenue par le fait qu'un mélange contenant de l'hydrochlorure de levemopamil, un phospholipide, un produit d'isotonicité et de l'eau ou une solution tampon est préparé et homogénéisé.
PCT/EP1993/000062 1992-01-21 1993-01-14 Solutions contenant des lecithines avec du levemopamil Ceased WO1993013765A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19924201527 DE4201527A1 (de) 1992-01-21 1992-01-21 Lecithinhaltige loesungen mit levemopamil
DEP4201527.8920121 1992-01-21

Publications (1)

Publication Number Publication Date
WO1993013765A1 true WO1993013765A1 (fr) 1993-07-22

Family

ID=6449954

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/000062 Ceased WO1993013765A1 (fr) 1992-01-21 1993-01-14 Solutions contenant des lecithines avec du levemopamil

Country Status (4)

Country Link
AU (1) AU3349693A (fr)
DE (1) DE4201527A1 (fr)
SI (1) SI9300029A (fr)
WO (1) WO1993013765A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060337A1 (fr) * 2000-02-14 2001-08-23 The Procter & Gamble Company Compositions a oxydation reduite utilisees pour l'administration locale d'un agent actif sur le plan pharmaceutique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI9300468A (en) * 1992-10-14 1994-06-30 Hoffmann La Roche Injectable composition for the sustained release of biologically active compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2949707A1 (de) * 1979-12-11 1981-06-19 A. Nattermann & Cie GmbH, 5000 Köln Parenteral applizierbare waessrige arzneimittelloesungen von diphenylmehtylpiperazin-derivaten
EP0366990A2 (fr) * 1988-10-29 1990-05-09 A. Nattermann & Cie. GmbH Solution stabilisée pour l'administration parentérale à base de 2-phényl-1,2-benzisosélénazol-3(2H)-one et procédé pour la préparer
WO1992001441A1 (fr) * 1990-07-21 1992-02-06 Knoll Aktiengesellschaft Formulation stable de substance active
WO1993001811A1 (fr) * 1991-07-22 1993-02-04 Knoll Aktiengesellschaft Procede de fabrication d'une solution de matiere active filtrable en milieu sterile
EP0456106B1 (fr) * 1990-05-11 1994-12-07 Knoll Ag Emulsion stable pour l'administration pharmaceutique, procédé pour sa préparation et son emploi comme agent pharmaceutique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2949707A1 (de) * 1979-12-11 1981-06-19 A. Nattermann & Cie GmbH, 5000 Köln Parenteral applizierbare waessrige arzneimittelloesungen von diphenylmehtylpiperazin-derivaten
EP0366990A2 (fr) * 1988-10-29 1990-05-09 A. Nattermann & Cie. GmbH Solution stabilisée pour l'administration parentérale à base de 2-phényl-1,2-benzisosélénazol-3(2H)-one et procédé pour la préparer
EP0456106B1 (fr) * 1990-05-11 1994-12-07 Knoll Ag Emulsion stable pour l'administration pharmaceutique, procédé pour sa préparation et son emploi comme agent pharmaceutique
WO1992001441A1 (fr) * 1990-07-21 1992-02-06 Knoll Aktiengesellschaft Formulation stable de substance active
WO1993001811A1 (fr) * 1991-07-22 1993-02-04 Knoll Aktiengesellschaft Procede de fabrication d'une solution de matiere active filtrable en milieu sterile

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060337A1 (fr) * 2000-02-14 2001-08-23 The Procter & Gamble Company Compositions a oxydation reduite utilisees pour l'administration locale d'un agent actif sur le plan pharmaceutique

Also Published As

Publication number Publication date
SI9300029A (en) 1993-09-30
AU3349693A (en) 1993-08-03
DE4201527A1 (de) 1993-07-22

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