CA2826513A1 - Compositions comprising propofol salt and a cyclodextrin - Google Patents
Compositions comprising propofol salt and a cyclodextrin Download PDFInfo
- Publication number
- CA2826513A1 CA2826513A1 CA2826513A CA2826513A CA2826513A1 CA 2826513 A1 CA2826513 A1 CA 2826513A1 CA 2826513 A CA2826513 A CA 2826513A CA 2826513 A CA2826513 A CA 2826513A CA 2826513 A1 CA2826513 A1 CA 2826513A1
- Authority
- CA
- Canada
- Prior art keywords
- propofol
- formulation
- cyclodextrin
- salt
- further preferably
- 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.)
- Granted
Links
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a pharmaceutical formulation that contains a complex of a propofol salt with a cyclodextrin. The invention makes it possible to provide propofol in a formulation that can be stored and that can be administered intravenously without problems.
Description
Pharmaceutical preparation The invention relates to a pharmaceutical formulation which comprises propofol.
In pharmacy, it is a frequent problem to formulate a pharmaceutical active ingredient such that it is administered at the intended site of action in the desired concentration and as efficiently as possible by means of a specific type of application. Thus, an active ingredient intended for intravenous application must be soluble in water to a certain extent so that a systemic concentration in the blood can be achieved at all. On the other hand, it must generally have a certain lipophilicity in order, if appropriate, to be able to penetrate cell membranes at the intended site of action. A merely readily water-soluble active ingredient can, for example, build up a high systemic concentration in the blood following intravenous application, but, for example in the event of excessively low lipophilicity, it will have low bioavailability since passage through the cell membrane is possibly inadequate at the intended site of action.
Propofol is an intravenous anesthetic tested in clinical practice for the first time in 1977. Propofol is a scarcely water-soluble anesthetic active ingredient which has to be rendered accessible to intravenous administration.
The solution of the anesthetic in a fatty emulsion (trade name Diprivane) was able to reduce the vein pain often observed with i.v. administration, and so propofol was introduced into clinical practice in 1989.
This propofol lipid emulsion comprises soybean oil, glycerol and egg phosphatides. Vein pain upon injection is a problem that continues to arise often. Moreover, , CA 02826513 2013-08-02 =
In pharmacy, it is a frequent problem to formulate a pharmaceutical active ingredient such that it is administered at the intended site of action in the desired concentration and as efficiently as possible by means of a specific type of application. Thus, an active ingredient intended for intravenous application must be soluble in water to a certain extent so that a systemic concentration in the blood can be achieved at all. On the other hand, it must generally have a certain lipophilicity in order, if appropriate, to be able to penetrate cell membranes at the intended site of action. A merely readily water-soluble active ingredient can, for example, build up a high systemic concentration in the blood following intravenous application, but, for example in the event of excessively low lipophilicity, it will have low bioavailability since passage through the cell membrane is possibly inadequate at the intended site of action.
Propofol is an intravenous anesthetic tested in clinical practice for the first time in 1977. Propofol is a scarcely water-soluble anesthetic active ingredient which has to be rendered accessible to intravenous administration.
The solution of the anesthetic in a fatty emulsion (trade name Diprivane) was able to reduce the vein pain often observed with i.v. administration, and so propofol was introduced into clinical practice in 1989.
This propofol lipid emulsion comprises soybean oil, glycerol and egg phosphatides. Vein pain upon injection is a problem that continues to arise often. Moreover, , CA 02826513 2013-08-02 =
- 2 -it can lead to serious allergic reactions. Since the formulation as a fatty emulsion favors microbial growth, contamination of the emulsion can lead, even after short storage times, to sepsis after administration.
The object of the invention is to provide a pharmaceutical formulation of the type mentioned at the start which permits trouble-free intravenous administration and has the specified disadvantages to a lesser extent, if at all.
This object is achieved by complexing propofol as salt with a cyclodextrin. Propofol can be converted to a salt in an alkaline medium. The propofol anion can be complexed by a cyclodextrin. Within the context of the invention, the term propofol salt refers to the anion of propofol (phenolate), which can be complexed by the cyclodextrin. In the complex according to the invention, propofol is thus present in complexed form as an anion.
Surprisingly, it has been found that a stable, injectable, pharmaceutical formulation with a high propofol concentration can be prepared in this way. The pharmaceutical formulation according to the invention can be provided as an aqueous solution suitable for injection. Alternatively, it is possible, after preparing the complex, to draw off the solvent and to provide the complex as a storable solid. Prior to administration, this solid is converted again to an aqueous solution.
The pH of an aqueous solution of the complex is preferably above 7, further preferably above 8, further preferably above 9. Preferred upper limits for the pH
are 11 or 10. Particular preference is given to a pH
The object of the invention is to provide a pharmaceutical formulation of the type mentioned at the start which permits trouble-free intravenous administration and has the specified disadvantages to a lesser extent, if at all.
This object is achieved by complexing propofol as salt with a cyclodextrin. Propofol can be converted to a salt in an alkaline medium. The propofol anion can be complexed by a cyclodextrin. Within the context of the invention, the term propofol salt refers to the anion of propofol (phenolate), which can be complexed by the cyclodextrin. In the complex according to the invention, propofol is thus present in complexed form as an anion.
Surprisingly, it has been found that a stable, injectable, pharmaceutical formulation with a high propofol concentration can be prepared in this way. The pharmaceutical formulation according to the invention can be provided as an aqueous solution suitable for injection. Alternatively, it is possible, after preparing the complex, to draw off the solvent and to provide the complex as a storable solid. Prior to administration, this solid is converted again to an aqueous solution.
The pH of an aqueous solution of the complex is preferably above 7, further preferably above 8, further preferably above 9. Preferred upper limits for the pH
are 11 or 10. Particular preference is given to a pH
- 3 -range of 8-11, further preferably 9-11, further preferably 9-10. If the complex is provided as a storable solid, a pH from the stated ranges is preferably established following resolubilization in water.
According to the invention, the cyclodextrin used for complexing the propofol is particularly preferably 2-hydroxypropyl-beta-cyclodextrin (HPBCD). The propofol salt used is preferably an alkali metal salt, particularly preferably a sodium salt.
The molar ratio of propofol salt and cyclodextrin to one another is preferably 1:2 to 1:6, further preferably 1:2 to 1:4, further preferably about 1:2.
The propofol salt content of the complex is preferably about 4 to 9% by weight.
The invention also provides a process for preparing a pharmaceutical formulation according to the invention.
According to the invention, firstly an alkaline aqueous solution of the cyclodextrin is prepared. Propofol is added to this alkaline solution and mixed, preferably with stirring, to the point of dissolution and complexation. This preferably takes place under an inert gas atmosphere. According to the invention, it is likewise possible to establish alkaline conditions only after the propofol has been added to the cyclodextrin.
The dissolution and complexation of propofol takes place preferably over a period of 2 to 10 h, further preferably 3 to 5 h, further preferably about 4 h.
According to the invention, the dissolution and complexation process takes place essentially more quickly than in the case of the complexation of the phenolic form of propofol. A significantly higher =
According to the invention, the cyclodextrin used for complexing the propofol is particularly preferably 2-hydroxypropyl-beta-cyclodextrin (HPBCD). The propofol salt used is preferably an alkali metal salt, particularly preferably a sodium salt.
The molar ratio of propofol salt and cyclodextrin to one another is preferably 1:2 to 1:6, further preferably 1:2 to 1:4, further preferably about 1:2.
The propofol salt content of the complex is preferably about 4 to 9% by weight.
The invention also provides a process for preparing a pharmaceutical formulation according to the invention.
According to the invention, firstly an alkaline aqueous solution of the cyclodextrin is prepared. Propofol is added to this alkaline solution and mixed, preferably with stirring, to the point of dissolution and complexation. This preferably takes place under an inert gas atmosphere. According to the invention, it is likewise possible to establish alkaline conditions only after the propofol has been added to the cyclodextrin.
The dissolution and complexation of propofol takes place preferably over a period of 2 to 10 h, further preferably 3 to 5 h, further preferably about 4 h.
According to the invention, the dissolution and complexation process takes place essentially more quickly than in the case of the complexation of the phenolic form of propofol. A significantly higher =
- 4 -concentration of the propofol in the complex can also be established.
In a further step, the solution obtained according to the invention can be freed from remaining solids fractions, for example filtered. Of suitability is e.g.
a filtration through a pore filter with the pore size 0.45 pm.
The solvent can be drawn off from the solution prepared according to the invention by known and suitable processes such as, for example, freeze-drying. The complex is provided in this way as a storable and resolubilizable solid.
One working example of the invention is explained below.
The specifications of all of the materials used correspond to the European Pharmacopeia (Ph. Eur.). The following feed substances were used:
- propofol - NaOH
- HPBCD
- water for injection purposes NaOH was prepared with 60 ml of water to give a 0.01 N
NaOH solution. 12 g of HPBCD were added thereto and dissolved with stirring. Then, 0.817 g of propofol were added and the mixture was stirred for a further 4 h at 40-80 min-1 until the evolving propofol salt was dissolved and complexed. The resulting solution has a pH of 9-10.
The solution obtained was filtered through a pore filter with a pore size of 0.45 pm. After the .. . CA 02826513 2013-08-02 =
In a further step, the solution obtained according to the invention can be freed from remaining solids fractions, for example filtered. Of suitability is e.g.
a filtration through a pore filter with the pore size 0.45 pm.
The solvent can be drawn off from the solution prepared according to the invention by known and suitable processes such as, for example, freeze-drying. The complex is provided in this way as a storable and resolubilizable solid.
One working example of the invention is explained below.
The specifications of all of the materials used correspond to the European Pharmacopeia (Ph. Eur.). The following feed substances were used:
- propofol - NaOH
- HPBCD
- water for injection purposes NaOH was prepared with 60 ml of water to give a 0.01 N
NaOH solution. 12 g of HPBCD were added thereto and dissolved with stirring. Then, 0.817 g of propofol were added and the mixture was stirred for a further 4 h at 40-80 min-1 until the evolving propofol salt was dissolved and complexed. The resulting solution has a pH of 9-10.
The solution obtained was filtered through a pore filter with a pore size of 0.45 pm. After the .. . CA 02826513 2013-08-02 =
- 5 -filtration, the solution was lyophilized. This gave a white powder. The complex obtained can be characterized as follows:
Water content: 1.4% by weight pH of a 1% strength aqueous 9.5 solution:
Propofol content (calculated as 6.5% by weight active phenol form):
Solubility of the complex in water: 41% by weight Resolubilization of the complex in water gives an aqueous solution with a content of active propofol of 46 mg/ml.
Water content: 1.4% by weight pH of a 1% strength aqueous 9.5 solution:
Propofol content (calculated as 6.5% by weight active phenol form):
Solubility of the complex in water: 41% by weight Resolubilization of the complex in water gives an aqueous solution with a content of active propofol of 46 mg/ml.
Claims (15)
1. A pharmaceutical formulation which comprises a complex of a propofol salt with a cyclodextrin.
2. The formulation as claimed in claim 1, characterized in that the cyclodextrin is 2-hydroxypropyl-.beta.-cyclodextrin (HPBCD).
3. The formulation as claimed in claim 1 or 2, characterized in that the propofol salt is an alkali metal salt.
4. The formulation as claimed in claim 3, characterized in that the propofol salt is a sodium salt.
5. The formulation as claimed in any one of claims 1 to 4, characterized in that the propofol salt:
cyclodextrin molar ratio is 1:2 to 1:6, preferably 1:2 to 1:4, further preferably about 1:2.
cyclodextrin molar ratio is 1:2 to 1:6, preferably 1:2 to 1:4, further preferably about 1:2.
6. The formulation as claimed in any one of claims 1 to 4, characterized in that the propofol salt content of the complex is 4 to 9% by weight.
7. The formulation as claimed in any one of claims 1 to 6, characterized in that it is an aqueous solution suitable for injection.
8. The formulation as claimed in claim 7, characterized in that the pH is between 7 and 11, preferably between 8 and 11, further preferably between 9 and 11, further preferably between 9 and 10.
9. The formulation as claimed in any one of claims 1 to 6, characterized in that it is a water-soluble solid.
10. The formulation as claimed in any one of claims 1 to 9 for use as an anesthetic.
11. A process for preparing a formulation as claimed in any one of claims 1 to 8, characterized by the steps:
a) preparing an alkaline aqueous solution of the cyclodextrin, b) dissolving propofol in the alkaline aqueous solution.
a) preparing an alkaline aqueous solution of the cyclodextrin, b) dissolving propofol in the alkaline aqueous solution.
12. The process as claimed in claim 11, characterized in that the dissolution of the propofol takes place under an inert gas atmosphere.
13. The process as claimed in claim 11 or 12, characterized in that the dissolution of the propofol takes place over a period of from 2 to 10 h, preferably 3 to 5 h, further preferably about 4 h.
14. The process as claimed in any one of claims 11 to 13, characterized in that the solution obtained in step b) is filtered.
15. The process as claimed in any one of claims 11 to 14, characterized in that water is removed from the optionally filtered solution obtained in step b), preferably by freeze-drying.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2012/000391 WO2012104730A1 (en) | 2011-02-04 | 2012-03-01 | Pharmaceutical preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2826513A1 true CA2826513A1 (en) | 2012-08-09 |
| CA2826513C CA2826513C (en) | 2019-02-05 |
Family
ID=49221649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2826513A Expired - Fee Related CA2826513C (en) | 2012-03-01 | 2012-03-01 | Compositions comprising propofol salt and a cyclodextrin |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101889121B1 (en) |
| CA (1) | CA2826513C (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7034013B2 (en) * | 2001-03-20 | 2006-04-25 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| AU2002254309B2 (en) * | 2001-03-20 | 2006-02-02 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| KR20040091004A (en) * | 2002-02-01 | 2004-10-27 | 쉬모다 바이오테크(피티와이) 리미티드 | Pharmaceutical Composition |
-
2012
- 2012-03-01 KR KR1020137023297A patent/KR101889121B1/en active IP Right Grant
- 2012-03-01 CA CA2826513A patent/CA2826513C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR20140120254A (en) | 2014-10-13 |
| CA2826513C (en) | 2019-02-05 |
| KR101889121B1 (en) | 2018-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9006215B2 (en) | Pharmaceutical preparation comprising propofol salt and cyclodextrin | |
| EP2679227B1 (en) | Nanoparticle containing prostaglandin i2 derivative | |
| US20220370400A1 (en) | Pharmaceutical compositions of furosemide and uses thereof | |
| US20080233196A1 (en) | Injectable sterile pharmaceutical composition with piperacillin sodium and tazobactam sodium as active principles | |
| CN103315948B (en) | Nimodipine polymer blending micelle preparation and preparation method thereof | |
| WO2013003306A1 (en) | Pharmaceutical compositions for parenteral administration | |
| CA2809646C (en) | 5.alpha.-androstane-3.beta.,5,6.beta.-triol injection and preparation method therefor | |
| CA2826513C (en) | Compositions comprising propofol salt and a cyclodextrin | |
| EP3173071B1 (en) | Maropitant formulation | |
| CN108697726A (en) | liquid pharmaceutical formulation | |
| CN102451176A (en) | Docetaxel/steroid composite | |
| JP2010030906A (en) | Chemical preparation of poorly water-soluble medicine, method for producing the medicine chemical preparation and method for producing diluted medicine chemical preparation | |
| CN106176769A (en) | Long-acting veterinary Ursocycline injection and preparation method thereof | |
| CN101590029B (en) | Propofol composition | |
| Apridamayanti et al. | Formulation vitamin C using niosomes system span 80 in gel for increase stability and penetration in vitro | |
| JP4475405B2 (en) | Pharmaceutical composition | |
| JP6189437B2 (en) | Injectable antibiotic preparation and method of use thereof | |
| CN106337077B (en) | Indissoluble fat acid mother liquor of chemically defined high density CHO culture medium and preparation method thereof | |
| WO2008099084A1 (en) | Parenteral pharmaceutical composition and method for preparing the same | |
| CN102697720A (en) | Irinotecan hydrochloride lipid nanoparticles injection | |
| JP5691142B2 (en) | Benzimidazole injection | |
| CN105395490A (en) | Freeze-dried powder injection containing pharmaceutical composition of dextral rabeprazole sodium and preparation method of freeze-dried injection powder |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20170119 |
|
| MKLA | Lapsed |
Effective date: 20210901 |
|
| MKLA | Lapsed |
Effective date: 20200302 |