AU680708B2 - Use of amino cyclodextrins for the aqueous solubilisation of dibenzazepines for use as an antiepileptic agent - Google Patents
Use of amino cyclodextrins for the aqueous solubilisation of dibenzazepines for use as an antiepileptic agent Download PDFInfo
- Publication number
- AU680708B2 AU680708B2 AU13200/95A AU1320095A AU680708B2 AU 680708 B2 AU680708 B2 AU 680708B2 AU 13200/95 A AU13200/95 A AU 13200/95A AU 1320095 A AU1320095 A AU 1320095A AU 680708 B2 AU680708 B2 AU 680708B2
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- AU
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- Prior art keywords
- cyclodextrin
- dibenzazepines
- amino
- inclusion complex
- hydrophobic
- 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
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- 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
-
- 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
-
- 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
Description
DESCRIPTIVE ABSTRACT The invention relates to the use of aminocyclodextrins for the aqueous solubilization of hydrophobic compounds chosen from among the group of dibenzazepine usable as an antiepileptic agent.
These aminocyclodextrins comply with the following formula: 1 2 which R is OH or NHR R 2 represents H or an alkyl group and n= 5 6 or Preferably,1 represent OH, R is H and n is equal to 6.
Preferably, all the R represent OH, R is H and n is equal to 6.
The hydrophobic compound can be carbamazepine.
B 11749.3 MDT Clsl~Pr P~k~ USE OF AMINOCYCLODEXTRINS FOR THE AQUEOUS SOLUBILIZATION OF DIBENZAZEPINES USABLE AS AN ANTIEPILEPTIC AGENT
DESCRIPTION
The present invention relates to a process for the solubilization in an aqueous medium of hydrophobic chemical compounds usable as an antiepileptic agent.
More specifically, it relates to a process permitting the solubilization in aqueous media of hydrophobic compounds by the inclusion of these compounds in an appropriate cyclodextrin.
Cyclodextrins or cyclomaltooligosaccharides are compounds having a natural origin forming by a linking of 6, 7 or 8 glucose units bonded in C-1,4.
Numerous works have shown that these cyclodextrins could form inclusion complexes with hydrophobic molecules and thus permit the solubilization of these molecules in aqueous media. Numerous applications have been proposed for taking advantage of this phenomenon, particularly in the pharmaceutical field, as is described by D. Duchene in the work entitled "Cyclodextrins and their industrial uses", chapter 6, pp 213 to 257, Editions de Sante, 1987. Pharmaceutical compositions using these cyclodextrins have also been marketed in Japan and Italy and more recently in France, e.g. by Pierre
(R)
Fabre Medicament for Brexin which is an inclusion complex of Piroxicam in P-cyclodextrin.
Among the usable cyclodextrins, P-cyclodextrin, which has 7 glucose units, is the most appropriate with regards to the size of its cavity and is the least expensive of the three, but its use causes certain problems, because it is less soluble than other cyclodextrins and has a hemolytic character.
Consideration has also been given to the improvement of the properties of p-cyclodextrin by chemically modifying to make it more suitable. Several solutions have been envisaged and have led to the use of methyl derivatives or hydroxyalkyl derivatives.
Methyl derivatives are much more soluble than the original cyclodextrin and they have good properties of solubilizing hydrophobic, organic compounds, B 11749.3 MDT 2 particularly in the case of 2,6-dimethyl-p-cyclodextrin. However, these methyl derivatives, apart from the fact that they are difficult to obtain in the pure state, are unusable for pharmaceutical applications, particularly for injectablE forms, due to their very pronounced hemolytic character.
The hydroxyalkyl derivatives more particularly developed by Janssen, e.g.
hydroxypropyl-cyclodextrins have a very high solubility in water and are only slightly hemolytic. However, their use remains difficult due to their extreme chemical heterogeneity. In addition, substitutions can limit the formation of inclusion complexes by steric hindrance and as yet no pharmaceutical application has been developed with these derivatives.
The present invention relates to a process for solubilizing hydrophobic chemical compounds using amino derivatives of cyclodextrins making it possible to obviate these disadvantages.
According to the invention, the solubilization process in an aqueous medium for a hydrophobic chemical compound chosen from within the group of dibenzazepines consists of combining the hydrophobic chemical compound with an aminocyclodextrin of formula: in
R
2 7, B 1 B 1 which the R which can be the same or different, represent OH or NHR 2 represents a hydrogen atom or an alkyl group and n is equal to 5, 6 or for forming therewith a water-soluble inclusion complex.
1749.3 MDT 3 The use in this process of amino derivatives complying with the aforementioned formula has the advantage of improving the solubility, stability and bioavailability, in various administration forms, of the hydrophobic compound, particularly for pharmaceutical applications.
Preference is given in the invention to the use of a monoaminocyclodextrin derivative, i.e. in the above formula I all the R 1 represent OH. The amino substituent NHR 2 is preferably NH2. However, it is also possible to use as the amino group monoalkylamino groups. Generally, the alkyl groups used for R 2 are lower alkyl groups having 1 to 4 carbon atoms.
Although in the invention preference is given to the use of P-cyclodextrin, i.e. the derivative of formula with n=6, it is also possible to use the amino derivative of -cyclodextrin or the amino derivative of Y-cyclodextrin The hydrophobic chemical compounds which can be solubilized in aqueous media by means of aminocyclodextrins are dibenzazepines, which are antiepileptic agents, useful for the treatment of psychomotor epilepsy. An example of such compounds is carbamazepine.
The invention also relates to inclusion complexes of an aminocyclodextrin according to formula with a hydrophobic chemical compound chosen from among the group of dibenzazepines, in particular anti-epileptic agents.
In these inclusion complexes, preference is given to the cyclodextrin of formula being a monoaminocyclodextrin, in particular the monoamino- P-cyclodextrin.
These inclusion complexes can be prepared by conventional processes, e.g.
by adding to a solution or a suspension of the aminocyclodextrin of formula used, a solution of the hydrophobic compound in an appropriate organic solvent, e.g. acetone. It is then possible to isolate the thus formed inclusion complex by lyophilization.
The invention also relates to a pharmaceutical composition incorporating an S11749.3 DT B 11749.3 MDT a a a ~y 4 inclusion complex of an aminocyclodextrin of formula and a hydrophobic chemical compound chosen from within the group of dibenzazepines, with a pharmaceutically acceptable vehicle.
These pharmaceutical compositions, which can be administered orally or parenterally, are e.g. solutions, powders, suspensions, etc. and in particular injectable solutions.
The aminocyclodextrins used in the process of the invention can be obtained in the form of very high purity hydrochloride from natural cyclodextrins by a three-stage process.
Unlike the hydroxypropyl derivatives of cyclodextrins, these amino derivatives are in the form of a single chemical species, which is perfectly characterized by conventional physicochemical methods.
Compared with methyl derivatives, which have comparable solubilization properties, they have the advantage of being much less hemolytic.
Other features and advantages of the invention can be better gathered from the following illustrative and non-limitative examples with reference to the attached drawings, in which is shown a graph representing the hemolysis percentages induced by different cyclodextrins as a function of their concentration (in mmole/l).
Example 1: Preparation of amino-I-cyclodextrin This cyclodextrin derivative complies with formula with all the R representing OH, R 2 representing a hydrogen atom and n being equal to 6.
Preparation takes place in the following way: Synthesis of mono-6-tosyl-P-cyclodextrin.
g of cyclomaltoheptaose (52.8 mmole) are suspended in 500 ml of distilled water. Dropwise addition takes place of 6.57 g (164 mmole) of caustic soda dissolved in 20 ml of water over a period of 5 minutes and with strong magnetic stirring. To the clear solution obtained are added B 11749.3 MDT I--s 5 10.08 g (52.9 mmole) of p-toluene solphonyl chloride (tosyl chloride) in ml of acetonitrile in dropwise manner over 10 minutes. After stirring for 2 hours at ambient temperature, the precipitate formed is eliminated by filtration and the filtrate is kept for 48 hours at 4°C. The precipitate is isolated by filtration in vacuo, washed with 50 ml of ice water and recrystallized immediately in boiling water. After one night at 4°C, the precipitate is filtered and dried in vacuo at 30°C. This gives 7.5 g (12%) of a pure compound in accordance with the specifications.
Synthesis of mono-6-azido-p-cyclodextrin.
Into a 500 ml flask surmounted with a condenser are introduced 15 g (11.6 mmole) of the previously described tosyl cyclodextrin suspended in 200 ml of distilled water. At ambient temperature and accompanied by stirring addition takes place of 7.65 g of lithium nitride LiN 3 in 40 ml of water.
The mixture is refluxed (the solution becoming clear) for 4 hours and stirring is continued at ambient temperature for 18 hours. The product is precipitated by adding 150 ml of acetone, kept in ice for 2 hours and isolated by filtering and washing with acetone. The white compound is washed with 3 x 20 ml of boiling ethanol to eliminate any traces of lithium nitride and dried in vacuo. This gives 13.5 g of pure monoazido-pcyclodextrin.
Synthesis of mono-6-amino-P-cyclodextrin.
To 10 g (8.6 mmole) of mono-azido-P-cyclodextrin in 120 ml of dimethyl formamide (DMF) are added dropwise and accompanied by stirring at ambient temperature 9.06 g (4 equivalents) of triphenyl phosphine dissolved in ml of DMF. The reaction mixture is kept for one hour under stirring, cooled in ice and treated with 20 ml of 20% ammonia. It is left under stirring for 18 hours at ambient temperature and the solvent is eliminated under reduced pressure at 30°C. The residue is taken up with 50 ml of water, accompanied by stirring. The precipitate of triphenyl phosphine and the corresponding oxide is eliminated by filtration and the solution treated by 150 ml of acetone. After one night at 4°C, the precipitate is isolated, washed with acetone and dried in vacuo at 30"C. This gives 9.6 g of monoamino-P-cyclodextrin.
B 11749.3 MDT -6 Final purification.
The aminocyclodextrin still contains a small proportion of unmodified cyclodextrin coming from the tosylation stage. The latter can easily be eliminated (this purification being very important) by ion exchange resin chromatography in the following way.
A solution of monoamino-P-cyclodextrin (1.5 g) in 10 ml of water is applied to a column containing 140 ml of H SP1080 Lewatit resin (Merck) suspended in water. After washing with 400 ml of water (making it possible to eliminate the unmodified cyclodextrin which is not retained), the monoaminocyclodextrin is eluted by an aqueous 6% ammonia solution. 100 ml of basic eluate are collected and concentrated in vacuo at 30°C. The final traces of ammonia are eliminated by evaporation in vacuo in the presence of 20 ml of water. The residue is taken up in the minimum of water and precipitated by 150 ml of acetone, kept for one night at 4 C, isolated by filtration, washed with acetone and dried in vacuo at 30°C. This gives 1.15 g of the end product completely free from the original cyclodextrin.
After dissolving in water and adjustment to pH 7 by HC1, the solution is lyophilized.
Thus, the amino-S-cyclodextrin is obtained in its hydrochloride form.
The solubility in water of the compound obtained is 200 g/l at 20*C in piace of 18 g/1 for natural P-cyclodextrin, which is comparable with the solubility of T-cyclodextrin. In solution, due to its weak base character, the hydrochloride leads to a pH close to physiological values (pH 6.8 in the case of a 1 wt.% solution of the hydrochloride in water). Thus, it acts as a buffer.
The hemolytic properties of the hydrochloride were tested by contacting 0.4 ml of a suspension of human erythrocytes with 4 ml of the solution of the hydrochloride in 10 mmole of an isotonic phosphate buffer at a pH of 7.4, for 30 minutes at 37°C.
The results obtained, expressed in the form of a hemolysis percentage as a B 11749.3 MDT 7 function of the cyclodextrin concentration of the solution, are given in the attached graph.
In the graph curve 1 relates to amino-P-cyclodextrin hydrochloride. Curves 2, 3 and 4 illustrate in comparative manner the results obtained under the same conditions with a solution of -cyclodextrin (p-CD, curve c4-cyclodextrin OC-CD, curve 3) and Y-cyclodextrin y-CD, cuve On the basis of this drawing, it can be seen that the amino derivative of the P-cyclodextrin has a much lower hemolytic effect than that of P-cyclodextrin and C-cyclodextrin. Thus, the p-cyclodextrin induces 50% hemolysis at a concentration of 5 mmole/l, i.e. approximately 6 g/l, whereas the amino-Pcyclodextrin only reaches such an effect at much higher concentrations of about 30 mmole/l, i.e. 35 g/l.
Example 2: Preparation of an inclusion complex of amino- -cyclodextrin and carbamazepine Carbamazepine is a compound complying with the formula:
CONH
2 It is an anti-epileptic compound (Merck Index 1783) with a very limited solubility in pure water (12 ug/ml at 25°C). The availability of soluble injectable forms could permit the emergency treatment of epilepsy with this compound.
An inclusion complex of this molecule is prepared with the monoaminocyclodextrin of example 1 using the following operating procedure. 10 pmole of amino- -cyclodextrin (hydrochloride prepared in example 1) are dissolved in Cd B 11749.3 MDT I- c t I 8 1 ml of pure water (apyrogenic water for injection) and addition takes place of 5 pmole of carbamazepine in the form of a 50 mmole/l concentrated solution in acetone. The acetone is eliminated by nitrogen passage for minutes and the solution is lyophilized.
In this way an inclusion complex is obtained.
Example 3 In this example evaluation takes place of the solubilization of carbamazepine by different derivatives of cyclodextrins under standard conditions.
The solubility measurements are performed at 25°C in the presence of the cyclodextrin in question at a concentration of 25 mmole/l, the pH of the solution being adjusted in all cases to 7.4 to simulate physiological conditions to the greatest possible extent. The results obtained and the cyclodextrins (CD) used are given in the following table 1.
Table 1 Cyclodextrin (25MM)
OC-CD
P-CD
T -CD
HPBCD
P-CD-NH
2 2) phosphate buffer 7.4 pure water Carbamazepine 8.10- /M 3.6 mM 1.2 mM 1.8 mM 12 mM -5 7Q10 5
M
5.10-5 M 5,10 M 1) The compound HPBCD is hydroxypropyl-,-cyclodextrin.
2) p-CD-NH 2 mono-6-amino-p-cyclodextrin according to example 1.
For comparison purposes this table also gives the solubilities of carbamazepine in pure water and in a phosphate buffer.
The results of this table make it clear that the amino-P-cyclodextrin of example 1 makes it possible to significantly improve the solubility in an B 11749.3 MDT a ILd 9 aqueous medium of carbamazepine.
Acute toxicity, ocular tolerance and mutagenic power studies of the amino 13-CD used in the invention (example 1) also demonstrated that: 1) this cyclodextrin leads to no mortality in the male and female Sprague- Dawley rate, when it is intravenously injected in hydrochloride form at a dosage of 2 g/kg of body weight; 2) this cyclodextrin induces no mutagenic activity in Escherichia Coli and Salmonella typhimurium strains according to the AMES test; and 3) this cyclodextrin is in class 1 of "slightly irritating products" for the acute ocular tolerance evaluated by the PREDISAFE method.
Therefore, the use according to the invention of mono-6-amino-p-cyclodextrin for solubilizing carbamazepine is very interesting, because it constitutes the first means making it possible to condition an antiepileptic in injectable form, which permits emergency care to take place.
I' r q B 11749.3 MDT Sa i I Y.
Claims (10)
1. Process for the solubilization in an aqueous medium of a hydrophobic chemical compound chosen from within the group of dibenzazepines, character- ized in that it consists of combining the hydrophobic chemical compound with an aminocyclodextrin of formula: in S 2 in which the R which can be the same or different, represent represents a hydrogen atom or an alkyl group and n is equal order to form therewith a water-soluble inclusion complex. 2 or NHR 5, 6 or 7,
2. Process according to claim 1, characterized in that all the sent OH. R repre-
3. Process according to either of the claims 1 and 2, characterized in that R 2 is a hydrogen atom.
4. Process according to any one of the claims 1 to 3, characterized in that n is equal to 6. Process according to any one of the claims 1 to 4, characterized in that the hydrophobic compound is carbamazepine.
6. Inclusion complex of an aminocyclodextrin of formula: ,fl~I* b8Us,' B 11749.3 MDT 11 R 0 HO OH ,NHR 2 n O H OH in which the R which can be the same or different, represent OH or 2 2 NHR R represents a hydrogen atom or an alkyl group and n is equal to 6 or 7, with a hydrophobic chemical compound chosen from within the group of dibenzazepines.
7. Inclusion complex according to claim 6, characterized in that all the I R represent OH.
8. Inclusion complex according to claim 7, characterized in that R 2 represents a hydrogen atom.
9. Complex according to any one of the claims 6 to 8, characterized in that n is equal to 6. Complex according to any one of the claims 6 to 9, characterized in that the hydrophobic chemical compound is an anti-epileptic agent.
11. Complex according to claim 10, characterized in that the anti-epileptic agent is carbamazepine.
12. Pharmaceutical composition, characterized in that it comprises an inclusion complex of a cyclodextrin according to any one of the claims 6 to 11 with a pharmaceutically acceptable vehicle. ,r B B 11749.3 MDT -e _II
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9315471 | 1993-12-22 | ||
| FR9315471A FR2713934B1 (en) | 1993-12-22 | 1993-12-22 | Use of amino cyclodextrins for the aqueous solubilization of hydrophobic compounds, in particular of pharmaceutically active molecules. |
| PCT/FR1994/001503 WO1995017191A1 (en) | 1993-12-22 | 1994-12-21 | Use of amino cyclodextrins for the aqueous solubilisation of dibenzazepines for use as an antiepileptic agent. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1320095A AU1320095A (en) | 1995-07-10 |
| AU680708B2 true AU680708B2 (en) | 1997-08-07 |
Family
ID=9454243
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU13200/95A Ceased AU680708B2 (en) | 1993-12-22 | 1994-12-21 | Use of amino cyclodextrins for the aqueous solubilisation of dibenzazepines for use as an antiepileptic agent |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0735879B1 (en) |
| JP (1) | JPH09506889A (en) |
| AU (1) | AU680708B2 (en) |
| DE (1) | DE69432268T2 (en) |
| FR (1) | FR2713934B1 (en) |
| HU (1) | HU219606B (en) |
| WO (1) | WO1995017191A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10223783A1 (en) * | 2002-05-29 | 2003-12-11 | Boehringer Ingelheim Pharma | New formulation for parenteral administration of a Na-channel blocker |
| US6828311B2 (en) | 2002-05-29 | 2004-12-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Formulation for the parenteral application of a sodium channel blocker |
| US7851457B2 (en) | 2004-01-29 | 2010-12-14 | Innovative Biologics, Inc. | β-Cyclodextrin derivatives |
| AU2006211173A1 (en) | 2005-01-28 | 2006-08-10 | Pinnacle Pharmaceuticals, Inc. | Beta-cyclodextrin derivatives as antibacterial agents |
| US20100204178A1 (en) | 2006-10-02 | 2010-08-12 | James Cloyd | Novel parenteral carbamazepine formulation |
| AU2013200204B9 (en) * | 2005-09-30 | 2015-03-05 | Lundbeck Llc | Novel parenteral carbamazepine formulation |
| EP1928464B1 (en) * | 2005-09-30 | 2014-05-14 | Lundbeck Inc. | Novel parenteral carbamazepine formulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002141A1 (en) * | 1988-08-31 | 1990-03-08 | Australian Commercial Research & Development Limited | Compositions and methods for drug delivery and chromatography |
| WO1991004026A1 (en) * | 1989-09-14 | 1991-04-04 | Australian Commercial Research & Development Limited | Drug delivery compositions |
| WO1991013100A1 (en) * | 1990-03-02 | 1991-09-05 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0435826A1 (en) * | 1989-12-27 | 1991-07-03 | Ciba-Geigy Ag | Intravenous solutions for epilepsy |
| US5231089A (en) * | 1991-12-02 | 1993-07-27 | University Of Florida | Method of improving oral bioavailability of carbamazepine |
-
1993
- 1993-12-22 FR FR9315471A patent/FR2713934B1/en not_active Expired - Fee Related
-
1994
- 1994-12-21 HU HU9601737A patent/HU219606B/en not_active IP Right Cessation
- 1994-12-21 DE DE69432268T patent/DE69432268T2/en not_active Expired - Fee Related
- 1994-12-21 AU AU13200/95A patent/AU680708B2/en not_active Ceased
- 1994-12-21 EP EP95904579A patent/EP0735879B1/en not_active Expired - Lifetime
- 1994-12-21 WO PCT/FR1994/001503 patent/WO1995017191A1/en active IP Right Grant
- 1994-12-21 JP JP7517235A patent/JPH09506889A/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990002141A1 (en) * | 1988-08-31 | 1990-03-08 | Australian Commercial Research & Development Limited | Compositions and methods for drug delivery and chromatography |
| WO1991004026A1 (en) * | 1989-09-14 | 1991-04-04 | Australian Commercial Research & Development Limited | Drug delivery compositions |
| WO1991013100A1 (en) * | 1990-03-02 | 1991-09-05 | Australian Commercial Research & Development Limited | Cyclodextrin compositions and methods for pharmaceutical and industrial applications |
Also Published As
| Publication number | Publication date |
|---|---|
| HUT75333A (en) | 1997-05-28 |
| HU9601737D0 (en) | 1996-08-28 |
| DE69432268D1 (en) | 2003-04-17 |
| EP0735879B1 (en) | 2003-03-12 |
| JPH09506889A (en) | 1997-07-08 |
| EP0735879A1 (en) | 1996-10-09 |
| WO1995017191A1 (en) | 1995-06-29 |
| AU1320095A (en) | 1995-07-10 |
| FR2713934B1 (en) | 1996-01-12 |
| DE69432268T2 (en) | 2003-12-04 |
| HU219606B (en) | 2001-05-28 |
| FR2713934A1 (en) | 1995-06-23 |
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