CA2125408C - Drug formulations for parenteral use - Google Patents
Drug formulations for parenteral use Download PDFInfo
- Publication number
- CA2125408C CA2125408C CA002125408A CA2125408A CA2125408C CA 2125408 C CA2125408 C CA 2125408C CA 002125408 A CA002125408 A CA 002125408A CA 2125408 A CA2125408 A CA 2125408A CA 2125408 C CA2125408 C CA 2125408C
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- Canada
- Prior art keywords
- toremifene
- drug
- cyclodextrin
- liposomes
- tamoxifen
- 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.)
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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
- 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
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
This invention relates to parenteral preparations of antiestrogens such as toremifene, desmethyl toremifene, tamoxifen or desmethyltamoxifen. The preparations can be emulsions, liposomes or aqueous solutions of cyclodextrin-drug complexes.
Particularly the invention relates to a parenteral drug formulation comprising a complex having a 2-hydroxypropyl cyclodextrin component and including an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present either in an aqueous solution or emulsion or loaded into a liposome.
Particularly the invention relates to a parenteral drug formulation comprising a complex having a 2-hydroxypropyl cyclodextrin component and including an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present either in an aqueous solution or emulsion or loaded into a liposome.
Description
WC~ 93/11757 ~ ~ PC'T/FI92/00339 Drug formulations for parenteral use This invention relates to drug formulations of antiestrogens, ~ particularly antiestrogens comprising a triphenylbutene moiety, for use in parenteral administration.
Toremifene, desmethyl toremifene, desmethyl tamoxi~n and tamoxifen are all examples of substituted triphenylbutenes useful in cancer therapy. Reference is made to US 4696949, US 4990538 and US 4356516. They can all be described with the formula OCH2CH~~-CH3 C
~J . ~, i i in which R1 is CH3 or H and R2 is H or C1.
The compounds mentioned above have the following values of R1 and Rz;
toremifene CHI C1 desmethyl toremifene H C1 tamoxifen CH3 H
desmethyl tamoxifen H H
A common feature of these antiestrogens is their poor solubility. in water. Thus, parenteral administration of these drugs cannot be accomplished simply by an aqueous solution ' of the active ingredients.
There is a clear need for parenteral formulations of the anticancer antiestrogens. Injectable high-concentration toremifene formulations will have important clinical benefit 1) in the attempts to reach high concentrations in tissue This is necessary especially when combinations of toremifene with cytotoxic drugs are given to a WO 93/11757 PCT/F~92/00339 21~~~08 2 patient. As shown by DeGregorio et al (J Clinical Oncology, vol 7, 7No 9,1989: 1359 - 1364.) high plasma concentrations are more effective in reversing multidrug resistance than low concentrations. An injectable formulation enables high peak concentrations in blood v and tissues without exposing the patient to long-term treatment;
Toremifene, desmethyl toremifene, desmethyl tamoxi~n and tamoxifen are all examples of substituted triphenylbutenes useful in cancer therapy. Reference is made to US 4696949, US 4990538 and US 4356516. They can all be described with the formula OCH2CH~~-CH3 C
~J . ~, i i in which R1 is CH3 or H and R2 is H or C1.
The compounds mentioned above have the following values of R1 and Rz;
toremifene CHI C1 desmethyl toremifene H C1 tamoxifen CH3 H
desmethyl tamoxifen H H
A common feature of these antiestrogens is their poor solubility. in water. Thus, parenteral administration of these drugs cannot be accomplished simply by an aqueous solution ' of the active ingredients.
There is a clear need for parenteral formulations of the anticancer antiestrogens. Injectable high-concentration toremifene formulations will have important clinical benefit 1) in the attempts to reach high concentrations in tissue This is necessary especially when combinations of toremifene with cytotoxic drugs are given to a WO 93/11757 PCT/F~92/00339 21~~~08 2 patient. As shown by DeGregorio et al (J Clinical Oncology, vol 7, 7No 9,1989: 1359 - 1364.) high plasma concentrations are more effective in reversing multidrug resistance than low concentrations. An injectable formulation enables high peak concentrations in blood v and tissues without exposing the patient to long-term treatment;
2) when given locally into a tumor. This enables a high and efficacious concentration in the tumor to be achieved;
3) when used topically in a benign estrogen-dependent ar.
lesion like cystic mastalgia, where toremifene can be injected directly into a painful cyst;
lesion like cystic mastalgia, where toremifene can be injected directly into a painful cyst;
4) when spreading toremifene topically onto palpable and subcutaneous breast cancer metastases;
5) when an intravesical installation is given for the therapy of superficial bladder cancer. Tn this indication toremifene may well be used together with other anticancer drugs to enhance their efficacy;
6) when an intraperitoneal solution is given for the treatment of certain types of overian cancer;
7) when other topical, estrogen-dependent lesions are treated with an antiestrogen.
'lhe parenteral drug formulations according to this invention include emulsions; aqueous solutions of cyclodextrin - drug complexes and liposomes.
Dissolution properties of drugs can be significantly improved by complexation of the drug substance with cyclodextrins.
Cyclodextrins (including a, j3 and r cyclodextrins and their derivatives) are all cyclic oligomers of glucose. The cyclodextrins can form inclusion complexes with drugs in that the drug molecule is included in the lipophile-seeking cavities of the cyclodextrin molecule. Therefore the cyclodextrins effectively solubilize lipophilic drugs into aqueous media. The use of cyclodextrins in the. pharmaceutical field has been described e.g. in Drug Development and Industrial Pharmacy, 17(11), 1503-1549, 1991.
With respect to the antiestrogens mentioned above, however, no parenteral drug formulations based on complexation of the active drug substance with 2-hydroxypropyl cyclodextrins are known in the art. One object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably ~, r 2-hydroxypropyl j3-cyclodextrin or 2-hydroxypropyl-r--cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyltoremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present in an aqueous solution.
Emulsions of the antiestrogens mentioned above can be made by .
dispersing the drug or a cylodextrin complex of said drug into a pharmaceutically acceptable emulsifier, and optionally -adding a stabilizing agent.
Parenteral administration of the drugs mentioned above may also be accomplished by aqueous solutions of liposomes containing said drug or a salt thereof. Liposomes are spherical particles in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. The lipid surface may be either unilamellar~or multilamellar. The liposomes may be loaded with either hydrophobic or hydrophilic drug substances.
Another object of the invention is a parenteral formulation based on the drug substance as such loaded into liposomes.
Such liposomes can be made by dissolving the drug or drug-cyclodextrin.complex together with a phospholipid component, preferably DMPG (dimyra.stoylphosphatidylglycerol) and/or POPC
(= 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine), in a chloroform - methanol mixture, evaporating the solvent, dissolving the residue into water followed by homogenization.
According to this invention liposomes can be made directly by dissolving the drug or the drug-cyclodextrin complex and phospholipid component directly in water without foregoing dissolving into chloroform - methanol mixture.
Another object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably Z-hydroxypropyl j3-cyclodextrin or 2-hydroxypropyl t-c~rclodextrin, complex including~an active drug substance selected from the ~qroup consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being loaded into a-liposome.
Preparation of the antiestrocren-2-hydroxy~~ropyl cyclodextrin complexes:
A weighed amount of 2-hydroxypropyl cyclodextrin was dissolved into distilled water by shaking with a shaker. The so formed clear solution was equilibrated with a large excess of antiestrogen at the boiling point. After removing the almost clear solution the excess. of antiestrogen started to precigitate. The solution was kept overnight at room temperature and the excess of precipitated antiestrogen was removed by centrifugation.
Measurement by HPLC of the solubility of the anti-estrogen in an aqueous solution of 2-hydroxypropyl cyclodextrin.
The fully automated HPLC apparatus (Hewlett-Packard, USA) consisted of a pump 1090, an autosampler and autoinjector (798~7A) with an injection volume of 10 u1 and a fixed wavelength Uv.detector, 280 nm (7988IA). The chromatograms and peak areas were recorded with an integrator 3393. The separations were carried ouL at room temperature on a 35 WO 93/11757 ~ POf/FI92/00339 4.6 mm stainless steel column (packed with 3-~.zm spherical octadecylsilanebonded silica particles; HS-3 C-18, (Perkin-Elmer, USA) The mobile phase consisted of a mixture of acetonitrile~.
0.05 M aqueous phosphate buffer cpntaining 0.004 M of dimethylactyl amine with a pH of 7.4. The flow rate was 0.8 ml/min.
Preparation of the liposomes:
1) Liposomes based on cyclodextrin - drug complexes and i r ~ ..:.:.
prepared by dissolving the components in an organic solution 2-hydroxypropyl-J3-cyclodextrin (12 mg), POPC (32 mg), choleste-rol (4 mg), DMPG (dimyristoylphosphatidylglycerol) (8 mg) and toremifene citrate (2 mg) were dissolved fn choloroform - met-hanol (2:1) and evaporated. The residue was dissolved in water and homogenized by sonication (Labsonic U, 50 W). The stability of the solution was good; no turbidity was observed after one month in room temperature.
2) Liposomes based on cyclodextrin - drug complexes and prepared by dissolving and homogenizing components directly in water 2-hydroxypropyl-~i-cyclodextrin (24 mg), DMPG (dimyristo-ylphosphatidylglycerol) (16 mg) and toremifene citrate (2 mg) were simultaneously dissolved in 2 ml water and homogenized by sonication '(Labsonic U, SO W). The final solution was as clear as the solution above. The mean particle diameter of these two solutions were about 100 nm (Nicomp 370/HPL high power laser option). The solution was stable after one week storage at room temperature.
3) Liposomes which were not based on cyclodextrin complexes ,., ., "Lf: ! ,...
i T , 1 -:
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f '. k .. :.. ~ .r Z. ,s ':-~~ . ~ ..S. ...,5., t r' t f t. , i '..~ '.-.~,::..
~, Y:,'t .
.~...t ...... ~~7.~..,. .........". ......n...... . ,. ,..
..s..:,.fi..l.l:'..:~.A;. , . ...... ~.fA'l'1.', t~'alV."n.~.~..:..........tv:
. .,.. . . . ... .,...,..v.n . v, o..... , .. ~ ....... ..
WO 93/11757 PCT/Fd92/00339 Preparation of these solutions was attempted by dissolving the components directly into water. The only composition which gave a clear or slightly opalescent solution aas DMPG
(16 or 32 mg), toremifene citrate ~(2 mg) dissolved and homogenized by sonication (50 W) in 2 ml water. The stability of the solutions were not however good enough;
solutions became a bit turbid in one month storage at room temperature, e.g., the composition toremifene citrate (2 mg), DMPG (32 mg) and cholesterol (4 mg) was not able to dissolve and homogenized in 2 ml water.
These results indicate that stable liposomes cannot be ~f'' achieved in the absence of a cyclodextrin component especially if the drug and phosphiolipid are mixed directly into water.
However, cyclodextrin-free liposomes can be made by mixing the ingredients first in chloroform/ethanol (2:1) as w described above for the cyclodextrin-containing liposomes.
WO 93/11757 PCT/F~92100339 ~~ ~5~Q8 Solubilitv results Formulation Toremifene,solubilit~
mQ of toremifene ml of cyclodextrin-water sole.
500 mg ~3-HPC/ml of aqueous soln, g7.7 250 " ' 53.0 125 " 21.7 63 " 14.1 25 " 7.4 0 " 0.3 J3-HPC = 2-hydroxypropyl-j3-cyclodextrin ''S00 mg r-HPC/ml of aqueous soln. 125.4 250 "
125 N 61.1 36.3 r-HPC = 2-hydroxypropyl-t-cyclodextrin Tamoxifen solubility mcr of tamoxifen _ ml of cyclodextrin-water soln.
500 mg ~i-HPC/ml of aqueous soln. 67.4 250 " 43.3 125 " 23.5 63 " 13.3 25 " 6.1 0 ~~ < 1. 0 Desmethyl toremifene solubility mg of desmethyl toremifene ml of cyclodextrin-water soln.~
1,25 mg j3-HPC/ml of aqueous soln . 21. 0 The pharmacokinetics of the toremifene formulations described above, when give intravenously, resemble closely those of perorally given toremifene. However, during the first minutes and 1-2 hours the cancentrations of the intravenously given drug are high, while the drug; when given per os, has not yet bden absorbed completely from the gastrointestinal tract.
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WO 93/1157 ~ ~ ~ ~ L~ Q ~ PCT/F192/00339 Preparation of emulsions:
Emulsions prepared by dissolving the drug in a commercial fat emulsion.
The commercial fat emulsion used was Emulsan~ 20 (manufacturer Leiras°Kabi Infusion Ltd., Finland). Different amounts of toremifene citrate were dissolved in Emulsan solution and homogenized by sonication (Labsonic ZJ, 50 W).
The toremifene concentrations were 10 mg/ml, 14 mg/ml and 20 mg/ml. After the homogenization the samples were filtered through the 0 . 2 [tm, 0 . 45 Eun and 1. 2 [tm filters .
~fihe concentration of toremifene was determined from the filtrate with a spectrofotometric method using the wave length of 278 nm. The samples were dissolved in methanol and diluted in the concentration of 0.02 mg/ml.
The results are presented in the following table:
Concentration Size of Concentration before filtration the filter after filtration [mg/ml] [gym] [mg/ml]
0.2 4.4 0.45 4.0 I.2 4.4 14 0.45 4.3 1.2 3.7 0.45 3.6 1.2 3.6 The results'show that the solubility of toremifene can be increased considerably by encapsulating the toremifene in an emulsion droplet.
'lhe parenteral drug formulations according to this invention include emulsions; aqueous solutions of cyclodextrin - drug complexes and liposomes.
Dissolution properties of drugs can be significantly improved by complexation of the drug substance with cyclodextrins.
Cyclodextrins (including a, j3 and r cyclodextrins and their derivatives) are all cyclic oligomers of glucose. The cyclodextrins can form inclusion complexes with drugs in that the drug molecule is included in the lipophile-seeking cavities of the cyclodextrin molecule. Therefore the cyclodextrins effectively solubilize lipophilic drugs into aqueous media. The use of cyclodextrins in the. pharmaceutical field has been described e.g. in Drug Development and Industrial Pharmacy, 17(11), 1503-1549, 1991.
With respect to the antiestrogens mentioned above, however, no parenteral drug formulations based on complexation of the active drug substance with 2-hydroxypropyl cyclodextrins are known in the art. One object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably ~, r 2-hydroxypropyl j3-cyclodextrin or 2-hydroxypropyl-r--cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyltoremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present in an aqueous solution.
Emulsions of the antiestrogens mentioned above can be made by .
dispersing the drug or a cylodextrin complex of said drug into a pharmaceutically acceptable emulsifier, and optionally -adding a stabilizing agent.
Parenteral administration of the drugs mentioned above may also be accomplished by aqueous solutions of liposomes containing said drug or a salt thereof. Liposomes are spherical particles in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. The lipid surface may be either unilamellar~or multilamellar. The liposomes may be loaded with either hydrophobic or hydrophilic drug substances.
Another object of the invention is a parenteral formulation based on the drug substance as such loaded into liposomes.
Such liposomes can be made by dissolving the drug or drug-cyclodextrin.complex together with a phospholipid component, preferably DMPG (dimyra.stoylphosphatidylglycerol) and/or POPC
(= 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine), in a chloroform - methanol mixture, evaporating the solvent, dissolving the residue into water followed by homogenization.
According to this invention liposomes can be made directly by dissolving the drug or the drug-cyclodextrin complex and phospholipid component directly in water without foregoing dissolving into chloroform - methanol mixture.
Another object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably Z-hydroxypropyl j3-cyclodextrin or 2-hydroxypropyl t-c~rclodextrin, complex including~an active drug substance selected from the ~qroup consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being loaded into a-liposome.
Preparation of the antiestrocren-2-hydroxy~~ropyl cyclodextrin complexes:
A weighed amount of 2-hydroxypropyl cyclodextrin was dissolved into distilled water by shaking with a shaker. The so formed clear solution was equilibrated with a large excess of antiestrogen at the boiling point. After removing the almost clear solution the excess. of antiestrogen started to precigitate. The solution was kept overnight at room temperature and the excess of precipitated antiestrogen was removed by centrifugation.
Measurement by HPLC of the solubility of the anti-estrogen in an aqueous solution of 2-hydroxypropyl cyclodextrin.
The fully automated HPLC apparatus (Hewlett-Packard, USA) consisted of a pump 1090, an autosampler and autoinjector (798~7A) with an injection volume of 10 u1 and a fixed wavelength Uv.detector, 280 nm (7988IA). The chromatograms and peak areas were recorded with an integrator 3393. The separations were carried ouL at room temperature on a 35 WO 93/11757 ~ POf/FI92/00339 4.6 mm stainless steel column (packed with 3-~.zm spherical octadecylsilanebonded silica particles; HS-3 C-18, (Perkin-Elmer, USA) The mobile phase consisted of a mixture of acetonitrile~.
0.05 M aqueous phosphate buffer cpntaining 0.004 M of dimethylactyl amine with a pH of 7.4. The flow rate was 0.8 ml/min.
Preparation of the liposomes:
1) Liposomes based on cyclodextrin - drug complexes and i r ~ ..:.:.
prepared by dissolving the components in an organic solution 2-hydroxypropyl-J3-cyclodextrin (12 mg), POPC (32 mg), choleste-rol (4 mg), DMPG (dimyristoylphosphatidylglycerol) (8 mg) and toremifene citrate (2 mg) were dissolved fn choloroform - met-hanol (2:1) and evaporated. The residue was dissolved in water and homogenized by sonication (Labsonic U, 50 W). The stability of the solution was good; no turbidity was observed after one month in room temperature.
2) Liposomes based on cyclodextrin - drug complexes and prepared by dissolving and homogenizing components directly in water 2-hydroxypropyl-~i-cyclodextrin (24 mg), DMPG (dimyristo-ylphosphatidylglycerol) (16 mg) and toremifene citrate (2 mg) were simultaneously dissolved in 2 ml water and homogenized by sonication '(Labsonic U, SO W). The final solution was as clear as the solution above. The mean particle diameter of these two solutions were about 100 nm (Nicomp 370/HPL high power laser option). The solution was stable after one week storage at room temperature.
3) Liposomes which were not based on cyclodextrin complexes ,., ., "Lf: ! ,...
i T , 1 -:
!:'~" ..$ :' i.. ~ ..
f '. k .. :.. ~ .r Z. ,s ':-~~ . ~ ..S. ...,5., t r' t f t. , i '..~ '.-.~,::..
~, Y:,'t .
.~...t ...... ~~7.~..,. .........". ......n...... . ,. ,..
..s..:,.fi..l.l:'..:~.A;. , . ...... ~.fA'l'1.', t~'alV."n.~.~..:..........tv:
. .,.. . . . ... .,...,..v.n . v, o..... , .. ~ ....... ..
WO 93/11757 PCT/Fd92/00339 Preparation of these solutions was attempted by dissolving the components directly into water. The only composition which gave a clear or slightly opalescent solution aas DMPG
(16 or 32 mg), toremifene citrate ~(2 mg) dissolved and homogenized by sonication (50 W) in 2 ml water. The stability of the solutions were not however good enough;
solutions became a bit turbid in one month storage at room temperature, e.g., the composition toremifene citrate (2 mg), DMPG (32 mg) and cholesterol (4 mg) was not able to dissolve and homogenized in 2 ml water.
These results indicate that stable liposomes cannot be ~f'' achieved in the absence of a cyclodextrin component especially if the drug and phosphiolipid are mixed directly into water.
However, cyclodextrin-free liposomes can be made by mixing the ingredients first in chloroform/ethanol (2:1) as w described above for the cyclodextrin-containing liposomes.
WO 93/11757 PCT/F~92100339 ~~ ~5~Q8 Solubilitv results Formulation Toremifene,solubilit~
mQ of toremifene ml of cyclodextrin-water sole.
500 mg ~3-HPC/ml of aqueous soln, g7.7 250 " ' 53.0 125 " 21.7 63 " 14.1 25 " 7.4 0 " 0.3 J3-HPC = 2-hydroxypropyl-j3-cyclodextrin ''S00 mg r-HPC/ml of aqueous soln. 125.4 250 "
125 N 61.1 36.3 r-HPC = 2-hydroxypropyl-t-cyclodextrin Tamoxifen solubility mcr of tamoxifen _ ml of cyclodextrin-water soln.
500 mg ~i-HPC/ml of aqueous soln. 67.4 250 " 43.3 125 " 23.5 63 " 13.3 25 " 6.1 0 ~~ < 1. 0 Desmethyl toremifene solubility mg of desmethyl toremifene ml of cyclodextrin-water soln.~
1,25 mg j3-HPC/ml of aqueous soln . 21. 0 The pharmacokinetics of the toremifene formulations described above, when give intravenously, resemble closely those of perorally given toremifene. However, during the first minutes and 1-2 hours the cancentrations of the intravenously given drug are high, while the drug; when given per os, has not yet bden absorbed completely from the gastrointestinal tract.
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F . 'Tf.. . '.'5.,....,t~..,::.
S.. r.
L
z: .::f: , f.:,...x:..: .,,I
....,.4 '!z ;ad'... ... .~. s, . , v. 5,-.
-a.? a.~r ...,a.:...
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,.bl.i.,~v; , ..~. a . v1. ... 1: .. Z 4a7~.. ~~ .p,~, t.x.t ,',a' ,~ .et..,,,;;h:. 1v a t .yln -, t d! '- r a t.. ..
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at. '., ...v.e z 1 . 'A : v . , . , . a ~. . a. . v w:1 . .. . , .
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WO 93/1157 ~ ~ ~ ~ L~ Q ~ PCT/F192/00339 Preparation of emulsions:
Emulsions prepared by dissolving the drug in a commercial fat emulsion.
The commercial fat emulsion used was Emulsan~ 20 (manufacturer Leiras°Kabi Infusion Ltd., Finland). Different amounts of toremifene citrate were dissolved in Emulsan solution and homogenized by sonication (Labsonic ZJ, 50 W).
The toremifene concentrations were 10 mg/ml, 14 mg/ml and 20 mg/ml. After the homogenization the samples were filtered through the 0 . 2 [tm, 0 . 45 Eun and 1. 2 [tm filters .
~fihe concentration of toremifene was determined from the filtrate with a spectrofotometric method using the wave length of 278 nm. The samples were dissolved in methanol and diluted in the concentration of 0.02 mg/ml.
The results are presented in the following table:
Concentration Size of Concentration before filtration the filter after filtration [mg/ml] [gym] [mg/ml]
0.2 4.4 0.45 4.0 I.2 4.4 14 0.45 4.3 1.2 3.7 0.45 3.6 1.2 3.6 The results'show that the solubility of toremifene can be increased considerably by encapsulating the toremifene in an emulsion droplet.
Claims (2)
1. A parenteral drug preparation in the form of an emulsion or liposome of an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof.
2. A preparation according to claim 1 where the drug is toremifene or its non-toxic, pharmaceutically acceptable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002456970A CA2456970C (en) | 1991-12-10 | 1992-12-10 | Drug formulations for parenteral use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919126209A GB9126209D0 (en) | 1991-12-10 | 1991-12-10 | Drug formulations for parenteral use |
| GB9126209.7 | 1991-12-10 | ||
| PCT/FI1992/000339 WO1993011757A1 (en) | 1991-12-10 | 1992-12-10 | Drug formulations for parenteral use |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002456970A Division CA2456970C (en) | 1991-12-10 | 1992-12-10 | Drug formulations for parenteral use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2125408A1 CA2125408A1 (en) | 1993-06-23 |
| CA2125408C true CA2125408C (en) | 2004-04-20 |
Family
ID=10706001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002125408A Expired - Lifetime CA2125408C (en) | 1991-12-10 | 1992-12-10 | Drug formulations for parenteral use |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5571534A (en) |
| EP (1) | EP0616529B1 (en) |
| JP (1) | JP3558344B2 (en) |
| AT (1) | ATE149828T1 (en) |
| AU (1) | AU667861B2 (en) |
| CA (1) | CA2125408C (en) |
| DE (1) | DE69218241T2 (en) |
| GB (1) | GB9126209D0 (en) |
| NO (1) | NO308578B1 (en) |
| WO (1) | WO1993011757A1 (en) |
| ZA (1) | ZA929592B (en) |
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| WO1995015746A1 (en) * | 1993-12-10 | 1995-06-15 | The School Of Pharmacy | Liposome delivery systems |
| GB9411115D0 (en) * | 1994-06-03 | 1994-07-27 | Secr Defence | Stabilisation of photosensitive material |
| GB9609171D0 (en) * | 1996-05-02 | 1996-07-03 | Orion Yhtymae Oy | Antioxidant compounds |
| ATE214269T1 (en) * | 1997-06-27 | 2002-03-15 | Akzo Nobel Nv | LIQUID MEDICINAL SOLUTION FOR ORAL APPLICATION |
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| US6413533B1 (en) * | 1998-05-07 | 2002-07-02 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
| US6632447B1 (en) | 1998-05-07 | 2003-10-14 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
| US20030130316A1 (en) * | 2000-03-20 | 2003-07-10 | Steiner Mitchell S. | Method for chemoprevention of prostate cancer |
| US6413534B1 (en) | 1998-05-07 | 2002-07-02 | The University Of Tennessee Research Corporation | Method for chemoprevention of prostate cancer |
| DE1003496T1 (en) * | 1998-05-07 | 2000-11-02 | Univ Tennessee Res Corp | Method of preventing prostate cancer |
| PT1135193E (en) * | 1998-12-04 | 2003-01-31 | Max Delbrueck Centrum | AGENTS FOR THE TREATMENT OF TUMORS BASED ON LIPOSOMES AND COMPREHENDING TAMOXYPHEN |
| FI109332B (en) | 1998-12-17 | 2002-07-15 | Orion Yhtymae Oyj | Soluble compositions of toremifene |
| FI982733A (en) | 1998-12-17 | 2000-06-18 | Orion Yhtymae Oyj | Soluble compositions of triphenylethylene estrogens |
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| US20040029831A1 (en) * | 2000-05-31 | 2004-02-12 | Kava Pharmaceuticals, Inc. | Extracts of kava-kava |
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| US20050239747A1 (en) * | 2004-04-21 | 2005-10-27 | Pharmaceutical Industry Technology And Development Center | Compositions and methods of enhanced transdermal delivery of steroid compounds and preparation methods |
| WO2006001035A2 (en) * | 2004-06-28 | 2006-01-05 | Lifecare Innovations Pvt. Ltd. | Synergistic liposomal tamoxifen composition for topical application and method of preparing thereof. |
| US20060019989A1 (en) * | 2004-07-21 | 2006-01-26 | Steiner Mitchell S | Compositions comprising 5-alpha reductase inhibitors and SERMs and methods of use thereof |
| US20160106717A1 (en) | 2004-09-24 | 2016-04-21 | Gen Pharma Holdings LLC | Cai-based systems and methods for the localized treatment of uveitis |
| CA2581126A1 (en) | 2004-09-24 | 2006-04-06 | Rfe Pharma Llc | Carboxy-amido-triazoles for the localized treatment of ocular diseases |
| US20060105045A1 (en) * | 2004-11-08 | 2006-05-18 | Buchanan Charles M | Cyclodextrin solubilizers for liquid and semi-solid formulations |
| WO2006052922A2 (en) * | 2004-11-08 | 2006-05-18 | Eastman Chemical Company | Pharmaceutical formulations of cyclodextrins and selective estrogen receptor modulator compounds |
| ES2401285T3 (en) | 2004-12-16 | 2013-04-18 | The Regents Of The University Of California | Drugs with lung as target |
| US20060270641A1 (en) * | 2005-05-31 | 2006-11-30 | Steiner Mitchell S | Method for chemoprevention of prostate cancer |
| WO2007005754A2 (en) * | 2005-07-01 | 2007-01-11 | Alza Corporation | Liposomal delivery vehicle for hydrophobic drugs |
| US8998881B2 (en) | 2005-08-10 | 2015-04-07 | Alza Corporation | Method for delivering drugs to tissue under microjet propulsion |
| WO2007078060A1 (en) * | 2005-12-30 | 2007-07-12 | Amorepacific Corporation | Polymer-liposome nano-complexes and the preparation method thereof, and the composition of skin external application containing the same |
| EP2617423A1 (en) | 2006-10-19 | 2013-07-24 | Genzyme Corporation | Purine derivatives for the treatment of cystic diseases |
| PE20120923A1 (en) | 2009-03-30 | 2012-08-27 | Eisai Randd Man Co Ltd | PHARMACEUTICAL COMPOSITIONS INCLUDING LIPOSOMES CONTAINING ERIBULIN OR A SALT OF IT |
| JP5622719B2 (en) * | 2009-03-30 | 2014-11-12 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing liposome composition |
| NZ609420A (en) | 2010-09-16 | 2015-06-26 | Shimoda Biotech Pty Ltd | Fulvestrant compositions and methods of use |
| WO2013008083A1 (en) | 2011-07-13 | 2013-01-17 | National Institute Of Pharmaceutical Education And Research (Niper) | Pharmaceutical composition for enhancing anticancer efficacy of tamoxifen |
| MX346432B (en) | 2011-09-18 | 2017-03-21 | Euro-Celtique S A * | Pharmaceutical compositions. |
| TWI573792B (en) | 2012-02-01 | 2017-03-11 | 歐陸斯迪公司 | Novel therapeutic agents |
| CN107056838A (en) | 2013-03-15 | 2017-08-18 | 加利福尼亚大学董事会 | Acyclic nucleoside phosphonate diester |
| GB201409471D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB201409485D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| GB201409488D0 (en) | 2014-05-28 | 2014-07-09 | Euro Celtique Sa | Pharmaceutical composition |
| HRP20220651T1 (en) | 2014-09-15 | 2022-08-19 | The Regents Of The University Of California | Nucleotide analogs |
| CN105748442B (en) * | 2016-04-07 | 2019-04-12 | 天津中医药大学 | A kind of preparation method of rhodioside and double load medicine anti-breast cancer nanometer formulations of tamoxifen |
| DK3471722T3 (en) | 2016-06-17 | 2023-12-04 | Univ Pennsylvania | Compounds, compositions and methods for preventing and/or treating cancer |
| WO2018068832A1 (en) | 2016-10-11 | 2018-04-19 | Euro-Celtique S.A. | Hodgkin lymphoma therapy |
| GB201709403D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating sarcoma |
| GB201709406D0 (en) | 2017-06-13 | 2017-07-26 | Euro-Cletique S A | Compounds for treating TNBC |
| GB201709402D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating t-pll |
| GB201709405D0 (en) | 2017-06-13 | 2017-07-26 | Euro Celtique Sa | Compounds for treating ovarian cancer |
| CA3068591A1 (en) * | 2017-06-30 | 2019-01-03 | Celgene Corporation | Compositions and methods of use of 2-(4-chlorophenyl)-n-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) methyl)-2,2-difluoroacetamide |
| WO2019118855A1 (en) * | 2017-12-14 | 2019-06-20 | The Trustees Of The University Of Pennsylvania | Compounds and compositions for prevention and/or treatment of cancer |
| US11083705B2 (en) | 2019-07-26 | 2021-08-10 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumor |
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| JPS5793909A (en) * | 1980-12-03 | 1982-06-11 | Sankyo Co Ltd | Carcinostatic pharmaceutical having directivity to specific internal organ and its preparation |
| FR2502951B1 (en) * | 1981-04-06 | 1985-12-06 | Sandoz Sa | TOPICAL PHARMACEUTICAL COMPOSITIONS IN THE FORM OF A MICRO-EMULSION |
| FI67538C (en) * | 1982-05-27 | 1985-04-10 | Farmos Oy | PROCEDURE FOR FRAMSTATION OF AV (Z) -1,2-DIPHENYL-1- (4- (2- (N N-DIMETHYLAMINO) ETHOXY) PHENYL) -1-BUTEN |
| DE3331459A1 (en) * | 1982-08-31 | 1984-03-01 | Martin Dr.med. 6900 Heidelberg Berger | Composition for tumour treatment containing diazoxide, and the use thereof |
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| JPS60208910A (en) * | 1984-03-31 | 1985-10-21 | Green Cross Corp:The | Preparation of composite of hardly water-soluble drug and phospholipid |
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| IE62095B1 (en) * | 1988-03-29 | 1994-12-14 | Univ Florida | Pharmaceutical formulations for parenteral use |
| JP2847783B2 (en) * | 1988-08-11 | 1999-01-20 | 日清製粉株式会社 | Anticancer activity enhancer |
| DE3827974A1 (en) * | 1988-08-18 | 1990-02-22 | Boehringer Mannheim Gmbh | COMBINATION PREPARATIONS OF PROTEINKINASE-C INHIBITORS WITH LIPIDS, LIPID ANALOGS, CYTOSTATICA OR INHIBITORS OF PHOSPHOLIPASES |
| MY106598A (en) * | 1988-08-31 | 1995-06-30 | Australian Commercial Res & Development Ltd | Compositions and methods for drug delivery and chromatography. |
| DE3837596A1 (en) * | 1988-11-05 | 1990-05-10 | Rosink Gmbh & Co Kg | KANNENSTOCK |
| FR2640137A1 (en) * | 1988-12-08 | 1990-06-15 | Texinfine Sa | SYSTEMS CONVEYING LIPOPHILIC ACTIVE INGREDIENTS AND PROCESS FOR OBTAINING SAME |
| CA2084208A1 (en) * | 1990-05-17 | 1991-11-18 | Barry Markaverich | Growth inhibitors and methods of treating cancer and cell proliferative diseases |
-
1991
- 1991-12-10 GB GB919126209A patent/GB9126209D0/en active Pending
-
1992
- 1992-12-10 DE DE69218241T patent/DE69218241T2/en not_active Expired - Fee Related
- 1992-12-10 JP JP51065093A patent/JP3558344B2/en not_active Expired - Lifetime
- 1992-12-10 AT AT93900114T patent/ATE149828T1/en not_active IP Right Cessation
- 1992-12-10 WO PCT/FI1992/000339 patent/WO1993011757A1/en active IP Right Grant
- 1992-12-10 EP EP93900114A patent/EP0616529B1/en not_active Expired - Lifetime
- 1992-12-10 US US08/244,549 patent/US5571534A/en not_active Expired - Lifetime
- 1992-12-10 AU AU31599/93A patent/AU667861B2/en not_active Ceased
- 1992-12-10 CA CA002125408A patent/CA2125408C/en not_active Expired - Lifetime
- 1992-12-10 ZA ZA929592A patent/ZA929592B/en unknown
-
1994
- 1994-06-09 NO NO942155A patent/NO308578B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0616529B1 (en) | 1997-03-12 |
| AU3159993A (en) | 1993-07-19 |
| JP3558344B2 (en) | 2004-08-25 |
| NO308578B1 (en) | 2000-10-02 |
| NO942155D0 (en) | 1994-06-09 |
| ATE149828T1 (en) | 1997-03-15 |
| DE69218241T2 (en) | 1997-06-19 |
| GB9126209D0 (en) | 1992-02-12 |
| ZA929592B (en) | 1993-08-06 |
| CA2125408A1 (en) | 1993-06-23 |
| AU667861B2 (en) | 1996-04-18 |
| NO942155L (en) | 1994-06-10 |
| JPH07501813A (en) | 1995-02-23 |
| US5571534A (en) | 1996-11-05 |
| DE69218241D1 (en) | 1997-04-17 |
| EP0616529A1 (en) | 1994-09-28 |
| WO1993011757A1 (en) | 1993-06-24 |
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