CA1322170C - Use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations, pharmaceutical formulations, and a process for their preparation - Google Patents
Use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations, pharmaceutical formulations, and a process for their preparationInfo
- Publication number
- CA1322170C CA1322170C CA000538397A CA538397A CA1322170C CA 1322170 C CA1322170 C CA 1322170C CA 000538397 A CA000538397 A CA 000538397A CA 538397 A CA538397 A CA 538397A CA 1322170 C CA1322170 C CA 1322170C
- Authority
- CA
- Canada
- Prior art keywords
- liquid pharmaceutical
- ethylene oxide
- propylene oxide
- pharmaceutical formulations
- concentration
- 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.)
- Expired - Lifetime
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Professional, Industrial, Or Sporting Protective Garments (AREA)
- Cephalosporin Compounds (AREA)
- Display Devices Of Pinball Game Machines (AREA)
- Jib Cranes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Manufacture Of Porous Articles, And Recovery And Treatment Of Waste Products (AREA)
- Polyethers (AREA)
Abstract
Abstract of the disclosure The use of ethylene oxide/propylene oxide block copolymers for controlling foam in pharmaceutical formulations, especially in those for parenteral administration, is described. Also described are liquid pharmaceutical formulations and a process for their preparation.
Description
~ 3 ~
HOECHST AKTIENGESELLSCHAFT Dr.D/gm HOE 86/F 121 The use of ethylene oxide/propylene oxide block copoly-mers for controlling foam in liquid pharmaceutical formu-lations, pharmaceutical formulations, and a process for their preparation - _ The preparation and d;spensing of liquid pharmaceutical formulations for parenteral administration which are prone to foam-for~ation are difficult and always time-consuming~
There is also delay involved in preparation for adminis-tration since it is necessary to await the collapse of the foam.
An injec~ion solution whose surface is covered with foam cannot be adminis~ered.
For toxicological reasons, there are problems with cus-tomary antifoam agents for liquid pharmaceutical formula-tions for oral administration, such as silicone oil or octanol, as additives to formulations for parenteral use.
In addition, these additives may cause turbidity in in-jection solutions. It has been found, surprisingly, thattraces of a surfactant of the ethylene oxide/propylene oxide~block copolymer type effect rapid collapse of the ` foam.
Ethylene oxide/propylene oxide block copolymers are used as weakly foaming raw materials in detergents for dish-washing and laundering. Their properties as emulsifiers, demulsifiers and wetting agents have been described.
However, the possibility of using them as antifoam agents is unknown.
Thus the invention relates to the use of ethylene oxide/
propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations, especially in those for parenteral administration~ :
The particularly preferred ethylene oxide/propylene oxide - block copolymer is polyethylene/polypropylene glycol 1800-~
`` ~ 322~7~
(aLso called PPG 1800). The use in formulations for parenteral administration is particularly preferred~ The antifoam agent must comply with the purity criteria nor-mally required of pharmaceutical auxiliari~s.
In principle, the ethylene oxide/propylene oxide block copolymers are suitable for controlling foam in all liquid formulations, especially aqueous, of pharmaceuti-cals. Of course, the medicinal agents must be compatible with the ethylene oxide/propylene oxide block copolymers used. Examples of suitable medicinal agents are cephalo-sporin derivatives such as cefpirom (HR 810) and penicil-lin derivatives such as procaine benzylpenicillin.
The invention also relates to pharmaceutical formulations containing ethylene oxide/propylene oxide block copolymers for controlling foam, and to a process for their pre-paration.
The liquid formulation contains about 0.1 to 0.00001% by weight of ethylene oxide/propylene oxide block copolymer such as, for example, PPG 1800, preferably 0.01-0.0001%
by ~eight of PPG 1800.
The process for the preparation of the formulations com-prises application of ethylene oxide/propylene oxide block copolymers to the solid active compound, or impreg-nation of the latter with the polymer or addition of the polymer to the solvent.
Example 1 A formulation intended for injections and containing 1.23 9 of HR 810 sulfate and 0~2Z g of Na2C03 (anhydrous) showed, after dissolution in 10 ml of water, a foam which was stable for about 5 minutes.
~' If a 0.0005~ strength aqueous solution of polyethylene/
polypropylene glycol 1800 is used ins~ead of water for .
.~" ~ ' .
: - ..
" ~3~2~ ~
dissolving, the foam collapses virtually immediateLy after the dissolution.
The same effect can be achieved if approximately equiva-lent amounts of PPG 1800 are applied to the solid com-ponents, singly or altogether, for example by precipita-tion in the presence of PPG 1800, by addition of PPG 1800 to the solution used for washing the precipitated solids, or by spraying PPG 1800 solution onto the solids, follswed by drying. It is also possible to achieve the antifoam effect of PPG 1800 by impregnation of the primary packag-ing (for examPle injection vials and/or injection vial stoppers) with PPG 1800.
Example 2 It is difficult to dispense a 300,000 IU/ml procaine benzylpenicillin suspension because foaming is excessive.
The suspension has been increased in volume by the foam and no longer fits in the injection vials intended for primary packaging. Addition of only 0.001% of PPG 1800 counteracts foam formation, as shown by the table below:
Table Suspension Density ~Q/ml]
HOECHST AKTIENGESELLSCHAFT Dr.D/gm HOE 86/F 121 The use of ethylene oxide/propylene oxide block copoly-mers for controlling foam in liquid pharmaceutical formu-lations, pharmaceutical formulations, and a process for their preparation - _ The preparation and d;spensing of liquid pharmaceutical formulations for parenteral administration which are prone to foam-for~ation are difficult and always time-consuming~
There is also delay involved in preparation for adminis-tration since it is necessary to await the collapse of the foam.
An injec~ion solution whose surface is covered with foam cannot be adminis~ered.
For toxicological reasons, there are problems with cus-tomary antifoam agents for liquid pharmaceutical formula-tions for oral administration, such as silicone oil or octanol, as additives to formulations for parenteral use.
In addition, these additives may cause turbidity in in-jection solutions. It has been found, surprisingly, thattraces of a surfactant of the ethylene oxide/propylene oxide~block copolymer type effect rapid collapse of the ` foam.
Ethylene oxide/propylene oxide block copolymers are used as weakly foaming raw materials in detergents for dish-washing and laundering. Their properties as emulsifiers, demulsifiers and wetting agents have been described.
However, the possibility of using them as antifoam agents is unknown.
Thus the invention relates to the use of ethylene oxide/
propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations, especially in those for parenteral administration~ :
The particularly preferred ethylene oxide/propylene oxide - block copolymer is polyethylene/polypropylene glycol 1800-~
`` ~ 322~7~
(aLso called PPG 1800). The use in formulations for parenteral administration is particularly preferred~ The antifoam agent must comply with the purity criteria nor-mally required of pharmaceutical auxiliari~s.
In principle, the ethylene oxide/propylene oxide block copolymers are suitable for controlling foam in all liquid formulations, especially aqueous, of pharmaceuti-cals. Of course, the medicinal agents must be compatible with the ethylene oxide/propylene oxide block copolymers used. Examples of suitable medicinal agents are cephalo-sporin derivatives such as cefpirom (HR 810) and penicil-lin derivatives such as procaine benzylpenicillin.
The invention also relates to pharmaceutical formulations containing ethylene oxide/propylene oxide block copolymers for controlling foam, and to a process for their pre-paration.
The liquid formulation contains about 0.1 to 0.00001% by weight of ethylene oxide/propylene oxide block copolymer such as, for example, PPG 1800, preferably 0.01-0.0001%
by ~eight of PPG 1800.
The process for the preparation of the formulations com-prises application of ethylene oxide/propylene oxide block copolymers to the solid active compound, or impreg-nation of the latter with the polymer or addition of the polymer to the solvent.
Example 1 A formulation intended for injections and containing 1.23 9 of HR 810 sulfate and 0~2Z g of Na2C03 (anhydrous) showed, after dissolution in 10 ml of water, a foam which was stable for about 5 minutes.
~' If a 0.0005~ strength aqueous solution of polyethylene/
polypropylene glycol 1800 is used ins~ead of water for .
.~" ~ ' .
: - ..
" ~3~2~ ~
dissolving, the foam collapses virtually immediateLy after the dissolution.
The same effect can be achieved if approximately equiva-lent amounts of PPG 1800 are applied to the solid com-ponents, singly or altogether, for example by precipita-tion in the presence of PPG 1800, by addition of PPG 1800 to the solution used for washing the precipitated solids, or by spraying PPG 1800 solution onto the solids, follswed by drying. It is also possible to achieve the antifoam effect of PPG 1800 by impregnation of the primary packag-ing (for examPle injection vials and/or injection vial stoppers) with PPG 1800.
Example 2 It is difficult to dispense a 300,000 IU/ml procaine benzylpenicillin suspension because foaming is excessive.
The suspension has been increased in volume by the foam and no longer fits in the injection vials intended for primary packaging. Addition of only 0.001% of PPG 1800 counteracts foam formation, as shown by the table below:
Table Suspension Density ~Q/ml]
2 minutes 60 minutes after shaking after shaking 30 without PPG 1800 1.012 1.00 addition of 0.001% PPG 1800 1.041 1.055 addition of 0.01% PPG 1800 1.053 1.058 .
Claims (22)
1. A liquid pharmaceutical formulation which is capable of being used for parenteral administration which contains ethylene oxide/propylene oxide block copolymers for controlling foam and a cephalosporin derivative or a penicillin derivative.
2. A liquid pharmaceutical formulation which is capable of being used for parenteral administration which contains polyethylene/polypropylene glycol 1800 for controlling foam in liquid pharmaceutical formulations and a caphalosporin derivative or a penicillin derivative.
3. A liquid pharmaceutical formulation as claimed in claim 1 or 2 wherein the formulation contains cefpirom.
4. A liquid pharmaceutical formulation as claimed in claim 1 or 2, wherein the formulation contains procaine benzylpenicillin.
5. A liquid pharmaceutical formulation as claimed in claim 1, wherein the concentration of ethylene oxide/propylene oxide is between 0.1 to 0.00001% by weight.
6. A liquid pharmaceutical formulation as claimed in claim 1, wherein the concentration of ethylene oxide/propylene oxide is between 0.01 to 0.0001% by weight.
7. A liquid pharmaceutical formulation as claimed in claim 2, wherein the concentration of polyethylene/polypropylene glycol 1800 is between 0.1 to 0.00001% by weight.
8. A liquid pharmaceutical formulation as claimed in claim 2, wherein the concentration of polyethylene/polypropylene glycol 1800 is between 0.01 to 0.0001% by weight.
9. A process for the preparation of a liquid pharmaceutical formulation as claimed in claim 1, which comprises application of an ethylene oxide/propylene oxide block copolymer to the solid active compound, or impregnation of the latter with it and subsequent dissolution in a suitable solvent, or comprises dissolution of the active compound in a solvent in the presence of an ethylene oxide/propylene oxide block copolymer.
10. The process as claimed in claim 9, wherein the ethylene oxide/propylene oxide block copolymer is polyethylene/polypropylene glycol 1800.
11. The process as claimed in claim 9 or 10, wherein the pharmaceutical formulations contain cefpirom.
12. The process as claimed in claim 9 or 10, wherein the pharmaceutical formulations contain procaine benzyl-penicillin.
13. The process as claimed in claim 9, wherein the concentration of the ethylene oxide/propylene oxide block copolymer is between 0.1 to 0.00001% by weight.
14. The process as claimed in claim 9, wherein the concentration of ethylene oxide/propylene oxide block polymer is between 0.01 to 0.0001% by weight.
15. The process as claimed in claim 10, wherein the concentration of the polyethylene/polypropylene glycol 1800 is between 0.1 to 0.0001% by weight.
16. The process as claimed in claim 10, wherein the concentration of the polyethylene/polypropylene glycol 1800 is between 0.01 to 0.0001% by weight.
17. The use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations which are capable of being used for parenteral administration and which contain a cephalosporin derivative or a penicillin derivative.
18. The use of polyethylene/polypropylene glycol 1800 for controlling foam in liquid pharmaceutical formulations which are capable of being used for parenteral administration and which contain a cephalosporin derivative or a penicillin derivative.
19. The use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations which are capable of being used for parenteral administration and which contain cefpirom.
20. The use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations which are capable of being used for parenteral administration and which contain procaine benzylpenicillin.
21. The use as claimed in any one of claims 17 to 20, wherein the ethylene oxide/propylene oxide is present in a concentration of 0.1 to 0.00001.
22. The use as claimed in any one of claims 17 to 20 wherein the ethylene oxide/propylene oxide is present in a concentration of 0.01 to 0.0001% by weight.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3618217.6 | 1986-05-30 | ||
| DE3618217A DE3618217C1 (en) | 1986-05-30 | 1986-05-30 | Use of ethylene oxide-propylene oxide block polymers for foam control in liquid medicinal preparations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1322170C true CA1322170C (en) | 1993-09-14 |
Family
ID=6301946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000538397A Expired - Lifetime CA1322170C (en) | 1986-05-30 | 1987-05-29 | Use of ethylene oxide/propylene oxide block copolymers for controlling foam in liquid pharmaceutical formulations, pharmaceutical formulations, and a process for their preparation |
Country Status (24)
| Country | Link |
|---|---|
| EP (1) | EP0247584B1 (en) |
| JP (1) | JPS62289529A (en) |
| KR (1) | KR970005334B1 (en) |
| AT (1) | ATE59783T1 (en) |
| AU (1) | AU599658B2 (en) |
| CA (1) | CA1322170C (en) |
| CS (1) | CS268831B2 (en) |
| DD (1) | DD266026A5 (en) |
| DE (2) | DE3618217C1 (en) |
| DK (1) | DK167211B1 (en) |
| ES (1) | ES2036544T3 (en) |
| FI (1) | FI88871C (en) |
| GR (1) | GR3001614T3 (en) |
| HK (1) | HK86895A (en) |
| HU (1) | HU196311B (en) |
| IE (1) | IE60658B1 (en) |
| IL (1) | IL82700A (en) |
| MA (1) | MA20988A1 (en) |
| MY (1) | MY102448A (en) |
| NO (1) | NO175844C (en) |
| NZ (1) | NZ220479A (en) |
| PH (1) | PH24473A (en) |
| PT (1) | PT84970B (en) |
| ZA (1) | ZA873878B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1475098B1 (en) * | 2002-01-18 | 2015-08-05 | Asahi Kasei Pharma Corporation | High-concentration preparation of soluble thrombomodulin |
| DE102010048948A1 (en) | 2010-10-19 | 2011-12-29 | Clariant International Ltd. | Aqueous defoamer emulsion, useful e.g. as protective colloids, comprises oil phase, emulsifiers, and water-soluble or -swellable, crosslinked copolymers containing e.g. acrylamidoalkylsulfonic acid- and cyclic N-vinylcarboxamide-compounds |
| DE102018220624A1 (en) | 2018-11-29 | 2020-06-04 | B. Braun Melsungen Ag | Aqueous composition, especially for the treatment of mucous membranes and / or wounds |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3142628A (en) * | 1964-07-28 | Process of reducing foam in submerges | ||
| DE925375C (en) * | 1949-08-03 | 1955-03-21 | Upjohn Co | Process for the production of a procaine-penicillin-G preparation |
| US2937104A (en) * | 1958-08-18 | 1960-05-17 | Stephan John Thomas | Polymeric alkylene-oxide defoamer material for alkaline aqueous adhesive solutions and the like |
| JPS5416568B2 (en) * | 1972-09-29 | 1979-06-23 | ||
| US4104033A (en) * | 1975-09-12 | 1978-08-01 | Drew Chemical Corporation | Foam prevention in sodium carbonate crystallization |
| GB2067533B (en) * | 1980-01-15 | 1983-07-13 | Exxon Research Engineering Co | Defoaming acid gas scrubbing solutions |
| US4533542A (en) * | 1983-08-22 | 1985-08-06 | Eli Lilly And Company | Pharmaceutical compositions for storage in plastic containers and process therefor |
-
1986
- 1986-05-30 DE DE3618217A patent/DE3618217C1/en not_active Expired
-
1987
- 1987-05-26 DE DE8787107677T patent/DE3767215D1/en not_active Expired - Lifetime
- 1987-05-26 ES ES198787107677T patent/ES2036544T3/en not_active Expired - Lifetime
- 1987-05-26 EP EP87107677A patent/EP0247584B1/en not_active Expired - Lifetime
- 1987-05-26 AT AT87107677T patent/ATE59783T1/en not_active IP Right Cessation
- 1987-05-27 MY MYPI87000742A patent/MY102448A/en unknown
- 1987-05-28 CS CS873893A patent/CS268831B2/en not_active IP Right Cessation
- 1987-05-28 PH PH35316A patent/PH24473A/en unknown
- 1987-05-28 DD DD87303274A patent/DD266026A5/en not_active IP Right Cessation
- 1987-05-28 MA MA21227A patent/MA20988A1/en unknown
- 1987-05-28 NZ NZ220479A patent/NZ220479A/en unknown
- 1987-05-28 FI FI872381A patent/FI88871C/en not_active IP Right Cessation
- 1987-05-29 AU AU73643/87A patent/AU599658B2/en not_active Expired
- 1987-05-29 IE IE142987A patent/IE60658B1/en not_active IP Right Cessation
- 1987-05-29 CA CA000538397A patent/CA1322170C/en not_active Expired - Lifetime
- 1987-05-29 PT PT84970A patent/PT84970B/en unknown
- 1987-05-29 NO NO872265A patent/NO175844C/en unknown
- 1987-05-29 IL IL82700A patent/IL82700A/en not_active IP Right Cessation
- 1987-05-29 HU HU872489A patent/HU196311B/en unknown
- 1987-05-29 ZA ZA873878A patent/ZA873878B/en unknown
- 1987-05-29 DK DK274787A patent/DK167211B1/en not_active IP Right Cessation
- 1987-05-29 JP JP62131929A patent/JPS62289529A/en active Pending
- 1987-05-29 KR KR1019870005376A patent/KR970005334B1/en not_active IP Right Cessation
-
1991
- 1991-03-15 GR GR91400062T patent/GR3001614T3/en unknown
-
1995
- 1995-06-01 HK HK86895A patent/HK86895A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |
Effective date: 20100914 |