WO1996006617A1 - Liposome preparation - Google Patents
Liposome preparation Download PDFInfo
- Publication number
- WO1996006617A1 WO1996006617A1 PCT/JP1995/001707 JP9501707W WO9606617A1 WO 1996006617 A1 WO1996006617 A1 WO 1996006617A1 JP 9501707 W JP9501707 W JP 9501707W WO 9606617 A1 WO9606617 A1 WO 9606617A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- liposome preparation
- liposome
- preparation
- tricyclic compound
- injection
- Prior art date
Links
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
- A61K9/127—Liposomes
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
Definitions
- This invention relates to a pharmaceutical liposome preparation
- a pharmaceutical liposome preparation comprising, as an active ingredient, a tricyclic compound having a potent cholecystokinin antagonism and shown by the general formula (I) represented hereinafter or a pharmaceutically acceptable salt thereof.
- the present invention relates to a liposome preparation comprising the above active ingredient stably entrapped into liposomes and as a consequence capable of maintaining stable solution in various media such as physiological saline, glucose solution for injection, water or juices and, hence, being applicable to various methods of administration including injections such as intravenous injection, intramuscular injection, and topical injections for intraarticular and the like, topical administration such as application to skin, instillation into eye, nasal administration, and inhalation, and further, oral administration and rectal administration etc.
- injections such as intravenous injection, intramuscular injection, and topical injections for intraarticular and the like
- topical administration such as application to skin, instillation into eye, nasal administration, and inhalation
- oral administration and rectal administration etc etc.
- R 1 is an aryl group optionally having at least one suitable substituent therein.
- this tricyclic compound (I) and pharmaceutically acceptable salt thereof have been expected for an efficacy against non-cholinergic miosis (e.g. traumatic iosis, miosis after surgery of eye, etc. ) .
- the tricyclic compound (I) and pharmaceutically acceptable salt thereof are hardly water-soluble and, accordingly, have been hardly used as a pharmaceutical solution, particularly as a solution for injection.
- the object of the present invention is to realize the use of the tricyclic compound (I) or pharmaceutically acceptable salt thereof as a liquid preparation. That is, the present invention discloses a liposome preparation comprising, as an active ingredient, the above tricyclic compound (I) or pharmaceutically acceptable salt thereof entrapped into liposomes.
- the pharmaceutically acceptable salts of the tricyclic compound (I) are conventional non-toxic salts.
- such salts of the compound (I) include metal salts such as alkali metal salts, for example, sodium salt and potassium salt, and alkaline earth metal salts, for example, calcium salt and magnesium salt; ammonium salts; salts with organic bases such as amine salts, for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexyla ine salt and N , ' -dibenzylethylenediamine salt; salts with organic acids, such as acetate, maleate, tartarate, methanesulfonate , benzene- sulfonate, formate, toluenesulfonate and trifluoroacetate ; salts with inorganic acids, such as hydrochloride , hydrobromide , sulfate and phosphate; salts with amino acids such as arginine,
- Preferred examples of the "aryl group" in the tricyclic compound (I) include, for example, phenyl, naphthyl and the like
- Preferred examples of the suitable "substituents" in the "aryl group optionally having at least one suitable substituent” include, for example, halogen, amino group, lower alkoxy group, mono- (or di- or tri-) halo ( lower ) alkyl group and the like.
- halogen and the "halogen moiety" in the "mono- (or di- or tri-) halo ( lower ) alkyl group” include, for example, chlorine, bromine, fluorine, iodine and the 1 ike .
- lower alkoxy group examples include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy , hexyloxy and the like.
- lower alkyl group and the “lower alkyl moiety" in the "mono- (or di- or tri-) halo ( lower )alkyl group” include straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl. hexyl and the like.
- the liposome preparation provided by the present invention will be described.
- the liposome preparation of the present invention essentially comprises the above-described tricyclic compound (I) or pharmaceutically acceptable salt thereof [hereinaf er, simply referred to as "compound (I)"] entrapped into liposomes, and is not subject to other conditions such as the structure and composition of liposomes, method of production of the liposomes. size thereof, the types of additives to be used, etc. , unless such conditions interfere with the stable entrapping of the tricyclic compound (I) into the liposomes.
- the structure of the liposome may be a large unilamellar vesicle (LUV) , a multilamellar vesicle (MLV) or a small unilamellar vesicle (SUV) .
- LUV large unilamellar vesicle
- MLV multilamellar vesicle
- SUV small unilamellar vesicle
- lipids and the like are employed as the liposome-forming substances.
- the lipids include sterols such as cholesterol, glycerides such as triglycerlde, phospholipids and nitrolipids.
- sterols such as cholesterol
- glycerides such as triglycerlde
- phospholipids and nitrolipids.
- generally phosphollpids are preferred.
- natural phosphollpids such as lecithins (phosphatidyl choline; e.g. , egg yolk lecithin, soybean lecithin, etc.
- lysolecithin , sphingomyelin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl glycerol, diphosphatidyl glycerol, cardiolipin, plasmalogen, etc.
- phosphol i ids such as dicetyl phosphate, distearoylphosphatidyl choline, dipalmitoyl- phosphatidyl choline, dipalmitoylphosphatidyl ethanolamine, dipalmi toylphosphatidyl serine, eleostearoylphosphatidyl choline, eleostearoylphosphatidyl ethanolamine.
- dicetyl phosphate distearoylphosphatidyl choline, dipalmitoyl- phosphatidyl choline, dipalmitoylphosphatidyl ethanolamine, dipalmi toylphosphatidyl serine, eleostearoylphosphatidyl choline, eleostearoylphosphatidyl ethanolamine.
- eleostearoylphosphatidyl serine, etc. can be mentioned.
- liposome-forming substances can be used independ ⁇ ently or in combination of two or more of them.
- the compound (I) and the liposome-forming substances described above are dissolved in a non-aqueous solution [for example, an alcohol (e.g. , methanol, ethanol, etc. ) , chloroform, etc. ] , and then water was added thereto.
- a non-aqueous solution for example, an alcohol (e.g. , methanol, ethanol, etc. ) , chloroform, etc. ]
- the resultant is added and dispersed into water or an aqueous solution of a sugar (e.g. , lactose) , to thereby obtain a liposome preparation.
- the liposome preparation thus obtained may be once lyophilized, and re-dispersed in a suitable solvent (e.g. , water, physiological saline, a glucose solution for injection, etc.
- a suitable solvent e.g. , water, physiological saline, a glucose solution for injection, etc.
- the method for producing the liposome preparation of the present invention is not particularly limited to the above process, and may be any of the known methods, a method combining two or more of the known methods, or a modification of any of the known methods.
- the liposome preparation of the present invention may contain suitable additives, including excipient for lyophiliza- tion such as sugars (e.g. , lactose, glucose, mannitol, sorbitol, xylitol, etc. ) , inorganic salts (e.g. , sodium chloride, disodium hydrogenphosphate, sodium dihydrogenphosphate, etc. ) and polymers [dextran, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, etc. l ; antioxidants for enhancement of the stability of the 1 iposome-forming substances and the active ingredient [compound (1)1 , such as tocopherols (e.g. , ⁇ -tocopherol , etc.
- excipient for lyophiliza- tion such as sugars (e.g. , lactose, glucose, mannitol, sorbitol, xylitol, etc. )
- inorganic salts
- the amount ratio of the active ingredient [compound (I)] to the liposome-forming substances to be used in the liposome preparation is no particular limitation on the amount ratio of the active ingredient [compound (I)] to the liposome-forming substances to be used in the liposome preparation, and the amount ratio may be suitably selected depending on the types of the active ingredient and the liposome-forming substances.
- the weight ratio of the active ingredient to the liposome-forming substances is within the range from 1:5 to 1:1000, preferably from 1:10 to 1:500, most preferably 1:30 to 1:300.
- the amount ratio between the active ingredient, liposome-forming substances and the additives in the liposome preparation there is also no particular limitation on the amount ratio between the active ingredient, liposome-forming substances and the additives in the liposome preparation, and the amount ratio is may be suitably selected depending on the types of the active ingredient, the liposome- forming substances and the additives.
- the weight ratio of the liposome-forming substances to the excipient for lyophi lization such as a sugar is usually 2:1 to 1:50, preferably 1:1 to 1:40, most preferably 1:5 to 1:20.
- the weight ratio of the active ingredient to the antioxidant such as a tocopherol is usually 20:1 to 1:10, preferably 10:1 to 1:5, most preferably 6:1 to 1:2.
- the liposome preparation according to the present invention is useful as a cholecystokinin antagonist and, therefore, is useful as a drug for the prevention and treatment of pancreatitis and the like.
- the liposome preparation of the present invention can be administered in any form such as a solid preparation, a semi- solid preparation and a liquid preparation, and may be suitably selected depending on the routes of the administration.
- the liposome preparation can be administered in the form of an injection, an eye drop, a nasal drop, an inhalant, a transdermal dosage, a topical injection and the like, and it is preferred to use the liposome preparation in the form of a liquid preparation, for example, for injection.
- the amount of the active ingredient [compound (I)] in the liposome preparation may be suitably selected depending on the routes of administration or the like.
- the amount of the active ingredient is preferably 0.001 to 2 mg/ml , most preferably 0.01 to 0.5 mg/ml.
- Example 3 a lyophilized liposome preparation obtained in Example 3 below, which comprised compound (I) (FK480) wherein R was a fluorophenyl group as an active ingredient.
- FK480 (3S)-l-(2-fluorophenyl ) -3 , 4 , 6 , 7-tetrahydro-3- (2- indo lylcarbonyl amino )-4-oxopyrrolo [3,2,1- jk] [l,4]benzodiazepine.
- Example 5 a lyophilized liposome preparation obtained in Example 5 below, which comprised FK480 as an active ingredient .
- FK480 (1 mg) and purified egg yolk lecithin (100 mg) were dissolved in ethanol to obtain 1 ml of a mixed solution, and water (0.1 ml) was further added thereto. The resultant was dispersed into water (8.9 ml) while stirring using a stirrer (Politron) to thereby obtain a liposome preparation.
- the content of the active ingredient (FK480) in the obtained liposome preparation was 96 wg/ml (yield: 96%).
- FK480 (10 mg) and purified egg yolk lecithin (1000 mg) were dissolved in ethanol to obtain 10 ml of a mixed solution, and a 5%-aqueous solution of lactose (1 ml) was further added thereto.
- the resultant was dispersed into a 55--aqueous solution of lactose (89 ml) while stirring using a stirrer (Politron) to thereby obtain a liposome preparation.
- the average particle diameter of the liposomes was 79 nm and the content of the active ingredient (FK480) in the liposome preparation was 99.7 ug/ml (yield: 99.7%).
- a liposome preparation was prepared in the same manner as in Example 2. The obtained liposome preparation was then lyophilized. The obtained lyophilized liposome preparation was readily re-dispersed into both water for injection and a glucose solution for injection.
- Example 4 Substantially the same manner as in Example 4 was repeated, except 5 ml of the preparation liquid 1 obtained by the same manner as in Example 4 was charged into a 28 ml-glass vial, to thereby obtain a lyophilized liposome preparation comprising FK480 (0.5 mg) .
- the obtained lyophilized liposome preparation was readily re-dispersed into both water for injection and a glucose solution for injection.
- the liposome preparation of the present invention allows the hardly water-soluble tricyclic compound (I), which has been hardly provided as a solution for injection, to be provided in the form of a stable liquid preparation. Consequently, the liposome preparation can be provided as a stable solution for injection (e.g. , intravenous injection, intramuscular injection, topical injection for intraarticular , etc.) which does not cause crystallization of the active ingredient on contact with the body fluid. Hence, by using the liposome preparation, a stable pharmaceutical preparation being safe and showing high bioavailability can be provided to therapeutic field. Besides solutions for injection, it can assume a broad variety of pharmaceutical preparations such as preparations for topical administration including application to skin, instillation into eye, nasal administration and inhalation, oral administration and rectal administration.
- preparations for topical administration including application to skin, instillation into eye, nasal administration and inhalation, oral administration and rectal administration.
Abstract
Disclosed is a liposome preparation comprising a tricyclic compound or a pharmaceutically acceptable salt thereof having a cholecystokinin antagonism entrapped in liposomes. Since the tricyclic compound, which is hardly water soluble, is entrapped stably and quantitatively into the liposomes, a pharmaceutical preparation having a broad variety of drug forms including solutions for injection and insuring a long duration of efficacy can be provided.
Description
SPECIFICATION
Title of the Invention
Liposome preparation
Field of the invention
This invention relates to a pharmaceutical liposome preparation comprising, as an active ingredient, a tricyclic compound having a potent cholecystokinin antagonism and shown by the general formula (I) represented hereinafter or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a liposome preparation comprising the above active ingredient stably entrapped into liposomes and as a consequence capable of maintaining stable solution in various media such as physiological saline, glucose solution for injection, water or juices and, hence, being applicable to various methods of administration including injections such as intravenous injection, intramuscular injection, and topical injections for intraarticular and the like, topical administration such as application to skin, instillation into eye, nasal administration, and inhalation, and further, oral administration and rectal administration etc.
Prior Art
It has been known that a tricyclic compound represented
by the following general formula (I) and a pharmaceutically acceptable salt thereof have a cholecystokinin antagonism and are useful as a drug for the prevention and treatment of pancreatitis and the like (Japanese Patent Application Laid-open No. HEI 2- 111774) :
wherein R1 is an aryl group optionally having at least one suitable substituent therein.
In addition, this tricyclic compound (I) and pharmaceutically acceptable salt thereof have been expected for an efficacy against non-cholinergic miosis (e.g. traumatic iosis, miosis after surgery of eye, etc. ) .
However, the tricyclic compound (I) and pharmaceutically acceptable salt thereof are hardly water-soluble and, accordingly, have been hardly used as a pharmaceutical solution, particularly as a solution for injection.
Disclosure of the Invention
The object of the present invention is to realize the use of the tricyclic compound (I) or pharmaceutically acceptable salt
thereof as a liquid preparation. That is, the present invention discloses a liposome preparation comprising, as an active ingredient, the above tricyclic compound (I) or pharmaceutically acceptable salt thereof entrapped into liposomes.
Best Mode of Practicing the Invention
Hereinafter, description will be made in detail to the various definitions used in the foregoing description and the description below in this specification, suitable examples and illustrations involved in the scope of the present invention.
The pharmaceutically acceptable salts of the tricyclic compound (I) are conventional non-toxic salts. Examples of such salts of the compound (I) include metal salts such as alkali metal salts, for example, sodium salt and potassium salt, and alkaline earth metal salts, for example, calcium salt and magnesium salt; ammonium salts; salts with organic bases such as amine salts, for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexyla ine salt and N , ' -dibenzylethylenediamine salt; salts with organic acids, such as acetate, maleate, tartarate, methanesulfonate , benzene- sulfonate, formate, toluenesulfonate and trifluoroacetate ; salts with inorganic acids, such as hydrochloride , hydrobromide , sulfate and phosphate; salts with amino acids such as arginine, aspartic acid and glutamic acid; and the like.
Preferred examples of the "aryl group" in the tricyclic compound (I) include, for example, phenyl, naphthyl and the like
Preferred examples of the suitable "substituents" in the "aryl group optionally having at least one suitable substituent" include, for example, halogen, amino group, lower alkoxy group, mono- (or di- or tri-) halo ( lower ) alkyl group and the like.
Preferred examples of the "halogen" and the "halogen moiety" in the "mono- (or di- or tri-) halo ( lower ) alkyl group" include, for example, chlorine, bromine, fluorine, iodine and the 1 ike .
Preferred examples of the "lower alkoxy group" include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy , hexyloxy and the like.
Preferred examples of the "lower alkyl group" and the "lower alkyl moiety" in the "mono- (or di- or tri-) halo ( lower )alkyl group" include straight or branched chain alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl. hexyl and the like.
The liposome preparation provided by the present invention will be described.
The liposome preparation of the present invention essentially comprises the above-described tricyclic compound (I) or pharmaceutically acceptable salt thereof [hereinaf er, simply referred to as "compound (I)"] entrapped into liposomes, and is not subject to other conditions such as the structure and composition of liposomes, method of production of the liposomes.
size thereof, the types of additives to be used, etc. , unless such conditions interfere with the stable entrapping of the tricyclic compound (I) into the liposomes.
Therefore, the structure of the liposome may be a large unilamellar vesicle (LUV) , a multilamellar vesicle (MLV) or a small unilamellar vesicle (SUV) .
As the liposome-forming substances, lipids and the like are employed. Examples of the lipids include sterols such as cholesterol, glycerides such as triglycerlde, phospholipids and nitrolipids. Among these, generally phosphollpids are preferred. For example, natural phosphollpids such as lecithins (phosphatidyl choline; e.g. , egg yolk lecithin, soybean lecithin, etc. ) , lysolecithin , sphingomyelin, phosphatidic acid, phosphatidyl serine, phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl glycerol, diphosphatidyl glycerol, cardiolipin, plasmalogen, etc. or hydrogenation products obtainable from the above natural phosphollpids by the conventional technology, and synthetic phosphol i ids such as dicetyl phosphate, distearoylphosphatidyl choline, dipalmitoyl- phosphatidyl choline, dipalmitoylphosphatidyl ethanolamine, dipalmi toylphosphatidyl serine, eleostearoylphosphatidyl choline, eleostearoylphosphatidyl ethanolamine. eleostearoylphosphatidyl serine, etc. , can be mentioned.
These liposome-forming substances can be used independ¬ ently or in combination of two or more of them.
The representative process for producing the liposome
preparation of the present invention is now described. For example, the compound (I) and the liposome-forming substances described above are dissolved in a non-aqueous solution [for example, an alcohol (e.g. , methanol, ethanol, etc. ) , chloroform, etc. ] , and then water was added thereto. The resultant is added and dispersed into water or an aqueous solution of a sugar (e.g. , lactose) , to thereby obtain a liposome preparation. The liposome preparation thus obtained may be once lyophilized, and re-dispersed in a suitable solvent (e.g. , water, physiological saline, a glucose solution for injection, etc. ) when it is used for therapy. The method for producing the liposome preparation of the present invention is not particularly limited to the above process, and may be any of the known methods, a method combining two or more of the known methods, or a modification of any of the known methods.
The liposome preparation of the present invention may contain suitable additives, including excipient for lyophiliza- tion such as sugars (e.g. , lactose, glucose, mannitol, sorbitol, xylitol, etc. ) , inorganic salts (e.g. , sodium chloride, disodium hydrogenphosphate, sodium dihydrogenphosphate, etc. ) and polymers [dextran, polyvinyl alcohol, polyvinyl pyrrolidone, gelatin, etc. l ; antioxidants for enhancement of the stability of the 1 iposome-forming substances and the active ingredient [compound (1)1 , such as tocopherols (e.g. , α -tocopherol , etc. ) , dibutyl- hydroxytoluene , ascorbic acid, alkali metal pyrosulfites (e.g. sodium pyrosulfite, etc. ) ; and other additives such as agents for
facilitating the formation of the liposome preparations and agents for control of the rate of release of the active compound (I) from the liposomes. There is no particular limitation on the amount ratio of the active ingredient [compound (I)] to the liposome-forming substances to be used in the liposome preparation, and the amount ratio may be suitably selected depending on the types of the active ingredient and the liposome-forming substances. Usually, the weight ratio of the active ingredient to the liposome-forming substances is within the range from 1:5 to 1:1000, preferably from 1:10 to 1:500, most preferably 1:30 to 1:300.
When the liposome preparation contains such suitable additives as described above, there is also no particular limitation on the amount ratio between the active ingredient, liposome-forming substances and the additives in the liposome preparation, and the amount ratio is may be suitably selected depending on the types of the active ingredient, the liposome- forming substances and the additives. For example, the weight ratio of the liposome-forming substances to the excipient for lyophi lization such as a sugar is usually 2:1 to 1:50, preferably 1:1 to 1:40, most preferably 1:5 to 1:20. The weight ratio of the active ingredient to the antioxidant such as a tocopherol is usually 20:1 to 1:10, preferably 10:1 to 1:5, most preferably 6:1 to 1:2.
The liposome preparation according to the present invention is useful as a cholecystokinin antagonist and,
therefore, is useful as a drug for the prevention and treatment of pancreatitis and the like.
The liposome preparation of the present invention can be administered in any form such as a solid preparation, a semi- solid preparation and a liquid preparation, and may be suitably selected depending on the routes of the administration. For example, the liposome preparation can be administered in the form of an injection, an eye drop, a nasal drop, an inhalant, a transdermal dosage, a topical injection and the like, and it is preferred to use the liposome preparation in the form of a liquid preparation, for example, for injection. The amount of the active ingredient [compound (I)] in the liposome preparation may be suitably selected depending on the routes of administration or the like. For example, when the liposome preparation is used as a liquid preparation for injection, the amount of the active ingredient is preferably 0.001 to 2 mg/ml , most preferably 0.01 to 0.5 mg/ml.
For demonstrating that the liposome preparation of the present invention is stable and pharmaceutically useful, the following tests were conducted.
[Test 1]
Test Preparation
In this test, was used a lyophilized liposome preparation obtained in Example 3 below, which comprised compound (I) (FK480) wherein R was a fluorophenyl group as an active ingredient.
FK480: (3S)-l-(2-fluorophenyl ) -3 , 4 , 6 , 7-tetrahydro-3- (2- indo lylcarbonyl amino )-4-oxopyrrolo [3,2,1- jk] [l,4]benzodiazepine.
Test Result
Table 1: Stability of liposome preparation
Items of Stability of : Lyophilized liposome preparation evaluation
Just after After 1 month After 3 months preparation (40βC) (40βC)
Appearance White mass White mass White mass
State of Translucent Translucent Translucent solution* emulsion emulsion emulsion
PH 6.95 6.73 7.13
Particle diameter of 84 96 134 liposome (nm)
Residual percent of active 100 100.2 100.1 ingredient in liposome preparation
(%)
•: The state of a solution in which the lyophilized liposome preparation was re-dispersed into 5 ml of water for injection
[Test 21
Test Preparation
In this test, was used a lyophilized liposome preparation obtained in Example 5 below, which comprised FK480 as an active ingredient .
Te s t Re s u l t
Table 2: Stability of liposome preparation
Items of Stability of lyophilized liposome preparation evaluation
Just after After After 3 months preparation 3 months (40"C; relative
(25°C) humidity of 75%)
Appearance Slightly Slightly Slightly yellowish yellowish yellowish white mass white mass white mass
State of Emulsion Emulsion Emulsion solution' with the with the with the above color above color above color
Time required for 15 15 15 re-dispersion
(sec. )
PH 5.97 5.78 6.65
Particle diameter of 132 126 138 liposome (nm)
Residual percent of ac ive 100 101.0 98.5 ingredient in liposome preparation
(%)
•: The state of a solution in which the lyophilized liposome preparation was re-dispersed into 5 ml of water for injection
As shown in Tables 1 and 2 above, it was found that the liposome preparation of the present invention is stable and useful as a pharmaceutical preparation, especially as a liquid preparation for injection and the like.
Hereinafter, the present invention will be described in more detail with reference to the following Examples, but they should not be construed to be limiting the scope of the present invention.
Example 1
FK480 (1 mg) and purified egg yolk lecithin (100 mg) were dissolved in ethanol to obtain 1 ml of a mixed solution, and water (0.1 ml) was further added thereto. The resultant was dispersed into water (8.9 ml) while stirring using a stirrer (Politron) to thereby obtain a liposome preparation. The content of the active ingredient (FK480) in the obtained liposome preparation was 96 wg/ml (yield: 96%).
Example 2
FK480 (10 mg) and purified egg yolk lecithin (1000 mg) were dissolved in ethanol to obtain 10 ml of a mixed solution, and a 5%-aqueous solution of lactose (1 ml) was further added thereto. The resultant was dispersed into a 55--aqueous solution of lactose (89 ml) while stirring using a stirrer (Politron) to thereby obtain a liposome preparation. The average particle diameter of the liposomes was 79 nm and the content of the active
ingredient (FK480) in the liposome preparation was 99.7 ug/ml (yield: 99.7%).
Example 3
A liposome preparation was prepared in the same manner as in Example 2. The obtained liposome preparation was then lyophilized. The obtained lyophilized liposome preparation was readily re-dispersed into both water for injection and a glucose solution for injection.
Example 4
FK480 (4 g), purified egg yolk lecithin (400 g) and α- tocopherol (2 g) were dissolved in ethanol to obtain 4 liter of a mixed solution. On the other hand, lactose (3.89 kg) was dissolved in water for injection to obtain 35 liter of an aqueous solution of lactose. Into another vessel, 31.5 liter of the resultant lactose aqueous solution was charged, and 3.5 liter of the above lecithin-ethanol solution was dispersed thereinto, to thereby obtain liquid 1.
12.5 ml of the liquid 1 was charged into a 28 ml-glass vial and then subjected to lyophilization , to thereby obtain 1.25 mg of a lyophilized liposome preparation. The content of the active ingredient (FK480) in the obtained liposome preparation was 1.25 to 1.28 mg/vial. The obtained lyophilized liposome preparation was readily re-dispersed into both water for injection and a glucose solution for injection, and the average
particle diameter of the liposomes was 115 to 130 nm.
Example 5
Substantially the same manner as in Example 4 was repeated, except 5 ml of the preparation liquid 1 obtained by the same manner as in Example 4 was charged into a 28 ml-glass vial, to thereby obtain a lyophilized liposome preparation comprising FK480 (0.5 mg) . The obtained lyophilized liposome preparation was readily re-dispersed into both water for injection and a glucose solution for injection.
Effect of the Invention
Having the above-described structure, the liposome preparation of the present invention allows the hardly water-soluble tricyclic compound (I), which has been hardly provided as a solution for injection, to be provided in the form of a stable liquid preparation. Consequently, the liposome preparation can be provided as a stable solution for injection (e.g. , intravenous injection, intramuscular injection, topical injection for intraarticular , etc.) which does not cause crystallization of the active ingredient on contact with the body fluid. Hence, by using the liposome preparation, a stable pharmaceutical preparation being safe and showing high bioavailability can be provided to therapeutic field. Besides solutions for injection, it can assume a broad variety of pharmaceutical preparations such as preparations for topical
administration including application to skin, instillation into eye, nasal administration and inhalation, oral administration and rectal administration.
Moreover, it is possible to enhance the delivery of the tricyclic compound (I) to regions where a high concentration of the compound is required, or to suppress the delivery of the compound to regions where the drug is not necessarily required. As a result, it is expected that practically excellent results such as increase in and extended duration of drug efficacy, and alleviation of adverse reactions would be obtained.
lδ
Claims
1. A liposome preparation characterized by comprising, as an active ingredient, a tricyclic compound of the following general formula (I) or a pharmaceutically acceptable salt thereof entrapped into liposomes:
wherein R represents an aryl group optionally having at least one suitable substituent therein.
2. The liposome preparation as defined in claim 1, wherein R in the tricyclic compound (I) is a phenyl group optionally having at least one halogen atom therein.
3. The liposome preparation as defined in claim 2, wherein R in the tricyclic compound (I) is a phenyl group having a fluorine atom therein.
4. The liposome preparation as defined in claim 3, wherein the tricyclic compound (I) is (3S )-1-(2-fluorophenyl ) - 3,4,6,7-tetrahydro-3-(2-indolylcarbonylamino)-4-oxopyrrolo[3,2,l- jkl [l,4]benzodiazepine.
5. The liposome preparation as defined in any of claims 1 to 4, wherein a phospholipid is used as the liposome-forming substances .
6. The liposome preparation as defined in claim 5, wherein the phospholipid is lecithin.
7. The liposome preparation as defined in any of claims 1 to 6, which contains a sugar as an additive.
8. The liposome preparation as defined in claim 7, wherein the sugar is lactose.
9. The liposome preparation as defined in any of claims 1 to 6, which contains a sugar and a tocopherol as additives.
10. The liposome preparation as defined in claim 9, wherein the sugar is lactose and the tocopherol is α -tocopherol
11. A process for producing the liposome preparation as defined in any of claims 1 to 10, which basically comprises a conventional technique.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU32658/95A AU3265895A (en) | 1994-08-30 | 1995-08-28 | Liposome preparation |
JP7525575A JPH10505818A (en) | 1994-08-30 | 1995-08-28 | Liposome preparation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20563794 | 1994-08-30 | ||
JP6/205637 | 1994-08-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996006617A1 true WO1996006617A1 (en) | 1996-03-07 |
Family
ID=16510196
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1995/001707 WO1996006617A1 (en) | 1994-08-30 | 1995-08-28 | Liposome preparation |
Country Status (5)
Country | Link |
---|---|
JP (1) | JPH10505818A (en) |
AU (1) | AU3265895A (en) |
IL (1) | IL115089A0 (en) |
WO (1) | WO1996006617A1 (en) |
ZA (1) | ZA957201B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6365585B1 (en) * | 1998-03-27 | 2002-04-02 | Warner-Lambert Company | Phosphodiesterase IV-inhibiting diazepinoindoles |
WO2002078673A1 (en) * | 2001-03-29 | 2002-10-10 | Takeda Chemical Industries, Ltd. | Process for producing fine granulate drug |
WO2006050327A2 (en) * | 2004-10-28 | 2006-05-11 | Alza Corporation | Lyophilized liposome formulations and method |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0340064A1 (en) * | 1988-04-25 | 1989-11-02 | Jouveinal S.A. | Benzodiazepines, process and intermediates for their preparation and their use in therapy |
EP0360079A1 (en) * | 1988-09-09 | 1990-03-28 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclic compounds, processes for their preparation and pharmaceutical compositions comprising them |
EP0420716A2 (en) * | 1989-09-28 | 1991-04-03 | Jouveinal S.A. | Benzodiazepines, process and intermediates for their preparation and their therapeutic use |
JPH0748246A (en) * | 1993-08-06 | 1995-02-21 | Fujisawa Pharmaceut Co Ltd | Sustained release injection agent |
-
1995
- 1995-08-28 ZA ZA957201A patent/ZA957201B/en unknown
- 1995-08-28 IL IL11508995A patent/IL115089A0/en unknown
- 1995-08-28 JP JP7525575A patent/JPH10505818A/en active Pending
- 1995-08-28 WO PCT/JP1995/001707 patent/WO1996006617A1/en active Application Filing
- 1995-08-28 AU AU32658/95A patent/AU3265895A/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0340064A1 (en) * | 1988-04-25 | 1989-11-02 | Jouveinal S.A. | Benzodiazepines, process and intermediates for their preparation and their use in therapy |
EP0360079A1 (en) * | 1988-09-09 | 1990-03-28 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclic compounds, processes for their preparation and pharmaceutical compositions comprising them |
EP0420716A2 (en) * | 1989-09-28 | 1991-04-03 | Jouveinal S.A. | Benzodiazepines, process and intermediates for their preparation and their therapeutic use |
JPH0748246A (en) * | 1993-08-06 | 1995-02-21 | Fujisawa Pharmaceut Co Ltd | Sustained release injection agent |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 122, no. 20, 15 May 1995, Columbus, Ohio, US; abstract no. 248356 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6365585B1 (en) * | 1998-03-27 | 2002-04-02 | Warner-Lambert Company | Phosphodiesterase IV-inhibiting diazepinoindoles |
WO2002078673A1 (en) * | 2001-03-29 | 2002-10-10 | Takeda Chemical Industries, Ltd. | Process for producing fine granulate drug |
WO2006050327A2 (en) * | 2004-10-28 | 2006-05-11 | Alza Corporation | Lyophilized liposome formulations and method |
WO2006050327A3 (en) * | 2004-10-28 | 2006-07-20 | Alza Corp | Lyophilized liposome formulations and method |
Also Published As
Publication number | Publication date |
---|---|
JPH10505818A (en) | 1998-06-09 |
AU3265895A (en) | 1996-03-22 |
ZA957201B (en) | 1996-04-01 |
IL115089A0 (en) | 1995-12-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU698441B2 (en) | Injectable liposomal pharmaceutical preparations | |
EP0161445A1 (en) | Water soluble drug complex and method for production of same | |
US7029695B2 (en) | Therapeutic compositions containing glutathione analogs | |
WO1995008986A1 (en) | Camptothecin formulations | |
EP0140085A2 (en) | Drug-containing lipid vesicle preparation and method for preparing them | |
CA2153553A1 (en) | Stable lipid emulsion | |
JPH0811725B2 (en) | Chlorofluorocarbon aerosol propellant formulations containing drug | |
CA2202531C (en) | Lyophilizate of lipid complex of water insoluble camptothecins | |
JP3202999B2 (en) | Hepatic liposome preparation | |
RU2571283C2 (en) | Parenteral formulations of elacytarabine derivatives | |
EP1759699B1 (en) | Liposome preparation containing slightly water-soluble camptothecin | |
US5039527A (en) | Hexamethylmelamine containing parenteral emulsions | |
JP3804452B2 (en) | Hepatitis treatment agent | |
CA2333162C (en) | Process for producing composite preparation containing nucleic acid | |
JP2007326877A (en) | Therapeutic composition containing glutathione analog | |
WO1996006617A1 (en) | Liposome preparation | |
AU718856B2 (en) | Liposome preparations of indolocarbazole derivatives | |
EP1029544A1 (en) | Intra-cancer-cell nuclease activator | |
JP2922017B2 (en) | Oral lipid membrane structure | |
JP3074732B2 (en) | Fat emulsion | |
JPH06183954A (en) | Liposome pharmaceutical preparation | |
SK284247B6 (en) | Liposome formulation of 6,9-bis-[(2-aminoethyl)- amino]benzo[g]isoquinoline-5,10-dione dimaleate | |
EP0767655B1 (en) | Methods of treating hypertension | |
JP2001026544A (en) | Liposome formulation of oil-soluble antitumor agent | |
JPH1171266A (en) | Liposome preparation of xanthin derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA CN HU JP KR MX RU US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |