GB2027590A - Parenteral compositions containing tiamulin - Google Patents
Parenteral compositions containing tiamulin Download PDFInfo
- Publication number
- GB2027590A GB2027590A GB7833200A GB7833200A GB2027590A GB 2027590 A GB2027590 A GB 2027590A GB 7833200 A GB7833200 A GB 7833200A GB 7833200 A GB7833200 A GB 7833200A GB 2027590 A GB2027590 A GB 2027590A
- Authority
- GB
- United Kingdom
- Prior art keywords
- tiamulin
- composition
- ethylenediamine
- sesame oil
- oily vehicle
- 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.)
- Withdrawn
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Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Emergency Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Parenteral veterinary compositions comprise the antibiotic Tiamulin (i.e. 14-deoxy-14-(2-diethyl- aminoethyl)mercaptoacetoxy mutilin), or a pharmaceutically acceptable salt thereof, in a parenterally acceptable oily vehicle containing ethylenediamine as a stabilizing agent for the tiamulin.
Description
SPECIFICATION
Tiamulin
Pleuromutilin (also known as pleuromulin) is an antibiotic produced by cultures of the basidiomycete Pleurotus mutilis. This antibiotic has antibacterial activity.
A group of derivatives of pleuromutilin having similar antimicrobial and antibacterial activity is described in United States Patent Specification
No. 3,919,290. One of these derivatdives in particular, 1 4-deoxy-1 4-(2-diethylaminoethyl)mercaptoacetoxy mutilin (known generically as tiamutilin or tiamulin), which is frequently used as the hydrogen fumarate salt, has been found to be very active against certain microorganisms, such as Streptococci, Staphylococci and Mycoplasmas, and is particularly useful in veterinary medicine.
See Antimicrobial Agents and Chemotherapy, May 1975, pages 507-516, 517-521.This substance is, however, subject to difficulties in manufacture, formulation and administration.
It has been found that tiamulin in an oily vehicle degrades by an oxidative process. The degradation products are coloured and therefore lead to significant colour changes in the product while under normal storage conditions. These colour changes are unacceptable from the pharmaceutical point of view.
In an attempt to overcome or reduce this oxidative process, the use of antioxidants has been tried. However, conventional antioxidants, such as ascorbyl palmitate, lecithin, tocopherol, butylated hydroxytoluene, octyl gallate and their combinations or mixtures are only partly successful in controlling the formation of coloured products. Reducing the oxygen headspace, by flushing with nitrogen, to 5% or less, is effective in maintaining an acceptable colour for the product.
However, a low oxygen headspace requires an additional operation in the filling process and adds to the cost of manufacturing the product.
Furthermore, in a multidose container the integrity of the headspace is soon lost, once the container is in use.
We have now found that the use of a suitable chemical stabilizer avoids the need for a reduced oxygen headspace and affords useful protection to the product during its "in use" life.
The present invention, in one of its aspects, provides a parenteral composition comprising tiamulin or a salt thereof in a pharmaceutically acceptable oily vehicle therefor stabilized with ethylenediamine.
A preferred veterinary composition according to the invention comprises 2% to 20% by weight of tiamulin or a physiologically acceptable salt thereof in a natural or synthetic oily vehicle acceptable for parenteral administration and stabilized with about 0.001% to 0.05%, preferably about 0.005% to 0.01%, by weight of ethylenediamine based on the volume of the final product.
The invention, in another of its aspects, provides a veterinary composition comprising tiamulin, ethylenediamine, ethyl alcohol and butyl paraben in an oily vehicle acceptable for parenteral administration.
The invention further provides a veterinary composition containing 4% to 16% tiamulin, 0.005% to 0.01% of ethylenediamine, 0.005% to 0.02% butylparaben and 1% to 5% of ethyl alcohol, by weight, in sesame oil.
The present invention is concerned with the provision of stable parenteral compositions containing the compound 14-deoxy-1 4-(2- diethylaminoethyl)mercaptoacetoxy mutilin or salts thereof in pharmaceutically acceptable natural or synthetic oils suitable for injection.
Reference may be made to Hodgin et al, Eur. J.
Biochem. 47, 527-533 (1974) for information about the structure of this compound and this system of nomenclature. The compound can also be named as the 1 4-(2-diethyl-aminoethyl)thioacetate ester of mutilin. It is known by the generic names tiamutilin or tiamulin, which latter will generally be used in the following description and claims.
Tiamulin forms salts with various inorganic and organic acids, as are described in the above mentioned United States Patent. A salt is frequently used in preparing formulations for use and suitable salts are also within the scope of the invention.
The hydrogen fumarate salt, which contains one mole of fumaric acid and one mole of tiamulin, has been extensively investigated as an antimicrobial agent in veterinary medicine and the present invention includes, inter alia, compositions containing tiamulin as the hydrogen fumarate salt.
It is, however; especially preferred to use tiamulin in the form of a free base.
Tiamulin and its acid acEdition salts are useful as antimicrobial agents, particularly as antibacterial agents in veterinary medicine and especially for the treatment of infections due to pathogenic gram positive bacteria, such as Streptocciand
Staphylococci, as well as Mycoplasma and
Treponema. Some gram positive organism, such as Shigella, Klesbsiella and Escherichia coli, are also responsive to treatment with tiamulin or a suitable salt thereof. These substances are therefore useful for the treatment of such animal infections as swine dysentery (due to Treponema hyodysenteriae), enzootic pneumonia of pigs, atrophic rhinitis in pigs, mycopolasmosis, chronic respiratory disease in poultry (CRD), air sac disease, infectious synovitis, fowl cholera, bovine pneumonia, and respiratory infections of horses, sheep, dogs and cats.
Effective doses generally lie in the range of 1 to 50 mg/kg, preferably from 5 to 20 mg/kg.
Compositions containing tiamulin or a salt thereof, depending on the intended use and type of animal involved, can usually contain from 2% to 20%, preferably 4% to 16%, by weight of the active substance, e.g. 20 to 200 mg/ml and 40 to 1 60 mg/ml, respectively.
A preferred method of administration is by injection, particularly intramuscular injection.
The vehicle used in the composition of the invention containing tiamulin or its salts if, preferably a naturally occurring vegetable oil, e.g., corn oil, sesame oil (which is preferred), soybean oil, fractionated coconut oil, castor ojl, peanut oil, cottonseed oil or the like, or a commercially available derivative of vegetable oils, such as
Neobee Oil, Miglyol, Alembicol D, or the like, or synthetic oils such as ethyl oleate, glyceryl triacetate and benzyl benzoate, to give some examples.
The drug is generally administered utilizing sufficient active material in about 5 to 10 ml. of vehicle to provide active concentration of 2% to 20% (weighI/vol.). The dosage is in general administered 1 to 2 times daily for 5 to 10 days.
In order to avoid the tendency of the oil solution to degrade and discolour, as described above, ethylenediamine is incorporated in the tiamulincontaining composition. The ethylenediamine is incorporated in the oil composition containing the tiamulin or salt in an amount of from about 0.001% to 0.05%, preferably from about 0.005% to 0.01%, by weight, based on the volume of final product.
The ethylenediamine stabilizer is added to the oil containing the active substance and other formulation components and thoroughly admixed until it is completely dissolved. If desired, the bulk product may be purged with nitrogen to remove dissolved oxygen prior to sterilization by filtration through a sterilizing grade membrane filter, prior to filling into sterile containers under aseptic conditions. If desired, the containers may be finally purged with sterile nitrogen prior to being sealed under aseptic conditions.
Other substances can be included in the formulation, as may be required to produce a suitable composition of pharmaceutical elegance.
For example, the composition can include ethyl alcohol, preservatives like phenol, chlorbutanol, methylparaben, propylparaben, butylparaben or benzyl alcohol, and buffering agents, as may be required by conventional pharmaceutical practice in formulating drug compositions, especially for veterinary use.
Preferred compositions according to this invention comprise tiamulin, ethylenediamine and sesame oil as the vehicle. These preferably contain 4% to 16% of tiamulin and 0.005% to 0.01% of ethylenediamine in the sesame oil. Especially preferred are such compositions which also include butylparaben and ethyl alcohol, preferably in amounts of 0.005% to 0.02% and 1% to 5%, respectively.
The development of colour in such formulations containing ethylenediamine is greatly reduced and such formulations remain a pale yellow colour after several months storage under both ambient and elevated temperature conditions.
This is particularly notable for partially filled vials in which the integrity of any protective headspace has been lost once the container is in use.
In comparison, formulations without
ethylenediamine discolour to a pharmaceutically
unacceptable brown colour when exposed to the same conditions.
The following examples are illustrative of the invention.
EXAMPLE 1
A 1 6.22% solution of tiamulin in sesame oil is prepared from the following:
Tiamulin 16.22 kg.
Ethyl alcohol 5.0 kg.
Butyl paraben 20.0 gm.
Ethylenediamine 10.0 gm.
Sesame oil to 1 00 litres The tiamulin, ethyl alcohol, butyl paraben and ethylenediamine are dissolved in sesame oil in a suitable container and made up to volume. The product is sterilized by filtration through a sterilizing grade membrane filter under aseptic conditions, and filled into sterile containers, preferably single dose ampoules each containing 10 ml. (160 mg/ml) or multidose vials each containing 60 ml., and finally sealed under aseptic conditions.
EXAMPLE 2
A 12.16% solution of tiamulin in sesame oil is prepared from the following ingredients:
Tiamulin 12.16 kg.
Ethyl alcohol 3.75 kg.
Butyl paraben 20.0 gm.
Ethylenediamine 10.0 gm.
Sesame oil to 10Q litres
These ingredients are processed as in Example 1 to obtain multidose vials each containing 100 ml. (120 mg/ml.).
EXAMPLE 3
An 8.11% solution of tiamulin in sesame oil is prepared from the following ingredients:
Tiamulin 8.11 kg.
Ethyl alcohol 2.5 kg.
Butylparaben 20.0 gm
Ethylenediamine 10.0 gm.
Sesame oil to 1 00 litres These ingredients are processed as in Example 1 to obtain single dose ampoules each containing 5 ml. (80 mg/ml.).
EXAMPLE 4
A 4.05% solution of tiamulin in sesame oil is prepared from the following ingredients:
Tiamulin 4.05 kg.
Ethyl alcohol 1.25 kg.
Butyl paraben 20.0 gm.
Ethylenediamine 10.0 gm.
Sesame oil to 1 00 litres These ingredients are processed as in Example 1 to obtain single dose ampoules each containing 5 ml. (40 mg/ml).
EXAMPLE 5
By substituting Neobee Oil (coconut oil derivative supplied by PVO Into., Morristown, N.J.,
U.S.A.) for the sesame oil in Example 4, single dose ampoules each containing 5 ml. are obtained.
Claims (2)
1. A parenteral composition comprising tiamulin or a salt thereof in a pharmaceutically acceptable oily vehicle therefor stabilized with ethylenediamine.
2. A method of treating animals against disease which comprises administering to them in dosage form a composition as claimed in any of the preceding claims.
2. A veterinary composition comprising 2% to 20% by weight of tiamulin or a physiologically acceptable salt thereof in a natural or synthetic oily vehicle acceptable for parenteral administration and stabilized with about 0.001% to 0.05% by weight of ethylenediamine, based on the volume of the final product.
3. A composition as claimed in claim 1 or claim 2, wherein the oily vehicle is sesame oil.
4. A composition as claimed in any of the preceding claims which contains from about 0.005% to 0.01% by weight of ethylenediamine, based on the volume of the final product.
5. A composition as claimed in any of the preceding claims, wherein the oily vehicle is sesame oil.
6. A composition as claimed in any of the preceding claims which also contains ethyl alcohol.
7. A composition as claimed in any of the preceding claims which also contains butyl paraben.
8. A veterinary composition comprising tiamulin, ethylenediamine, ethyl alcohol and butyl paraben in an oily vehicle acceptable for parenteral administration.
9. A veterinary composition containing 4% to 16% of tiamulin, about 0.001% to 0.05%, preferably about 0.005% to 0.01% of ethylenediamine, 0.005% to 0.02% of butylparaben and 0.01% of ethyl alcohol, by weight, in sesame oil.
10. A composition as claimed in claim 1, claim 2, claim 8 or claim 9, substantially as herein described, or given in any of the examples.
11. A method of treatment against microorganisms which comprises administering a composition as claimed in any of the preceding -claims.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7833200A GB2027590A (en) | 1978-08-14 | 1978-08-14 | Parenteral compositions containing tiamulin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7833200A GB2027590A (en) | 1978-08-14 | 1978-08-14 | Parenteral compositions containing tiamulin |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2027590A true GB2027590A (en) | 1980-02-27 |
Family
ID=10499028
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB7833200A Withdrawn GB2027590A (en) | 1978-08-14 | 1978-08-14 | Parenteral compositions containing tiamulin |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2027590A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2563432A1 (en) * | 1985-04-26 | 1985-10-31 | Hajdusagi Agraripari Egyesules | New antibacterial and antiprotozoal pharmaceutical compositions comprising tiamulin acid fumarate and process for preparing them |
GB2158353A (en) * | 1984-04-28 | 1985-11-13 | Hajdusagi Agraripari Egyesules | Veterinary preparations |
WO2009066117A1 (en) * | 2007-11-22 | 2009-05-28 | Pharmateka Kiskereskedelmi Bt | Use of edta and its derivatives for prevention and treatment of bacterial intestinal diseases of pigs and for increasing the effects of antibiotics exerted in such diseases |
WO2014033490A1 (en) | 2012-08-30 | 2014-03-06 | PHARMATÉKA Kutató, Fejlesztö és Szolgátató Kft. | Preventive products against pathogenic germs, and method for use thereof |
-
1978
- 1978-08-14 GB GB7833200A patent/GB2027590A/en not_active Withdrawn
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2158353A (en) * | 1984-04-28 | 1985-11-13 | Hajdusagi Agraripari Egyesules | Veterinary preparations |
AT388669B (en) * | 1984-04-28 | 1989-08-10 | Hajdusagi Agraripari Egyesules | METHOD FOR PRODUCING SYNERGISTICALLY ACTIVE ANTIBIOTIC COMBINATIONS |
FR2563432A1 (en) * | 1985-04-26 | 1985-10-31 | Hajdusagi Agraripari Egyesules | New antibacterial and antiprotozoal pharmaceutical compositions comprising tiamulin acid fumarate and process for preparing them |
WO2009066117A1 (en) * | 2007-11-22 | 2009-05-28 | Pharmateka Kiskereskedelmi Bt | Use of edta and its derivatives for prevention and treatment of bacterial intestinal diseases of pigs and for increasing the effects of antibiotics exerted in such diseases |
EA017656B1 (en) * | 2007-11-22 | 2013-02-28 | Фарматека Дьярто Эш Керешкедельми Бт | Composition for prevention and treatment of pig dysentery |
US8425918B2 (en) | 2007-11-22 | 2013-04-23 | Pharmatéka Gyártó´és Kereskedelmi BT | Use of EDTA and its derivatives for prevention and treatment of bacterial intestinal diseases of pigs and for increasing the effects of antibiotics exerted in such diseases |
WO2014033490A1 (en) | 2012-08-30 | 2014-03-06 | PHARMATÉKA Kutató, Fejlesztö és Szolgátató Kft. | Preventive products against pathogenic germs, and method for use thereof |
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Legal Events
Date | Code | Title | Description |
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WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |