GB2232082A - Sustained release amoxycillin preparation - Google Patents
Sustained release amoxycillin preparation Download PDFInfo
- Publication number
- GB2232082A GB2232082A GB9012096A GB9012096A GB2232082A GB 2232082 A GB2232082 A GB 2232082A GB 9012096 A GB9012096 A GB 9012096A GB 9012096 A GB9012096 A GB 9012096A GB 2232082 A GB2232082 A GB 2232082A
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- United Kingdom
- Prior art keywords
- preparation
- agent
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
A veterinary preparation for intramuscular and subcutaneous administration comprises amoxycillin trihydrate e.g. at 15% or 30% by weight and a system to promote sustained release and an agent to promote quick release of the active ingredient. The quick release agent preferably comprises glycerol monodicaprylate in an amount of from 0.5 to 1%, preferably approximately 0.8% by weight. The sustained release system preferably comprises an oily vehicle, preferably a polyethylene glycol diester of saturated fatty acids of 8 to 10 carbon atoms which is present in an amount of from 60 to 85%, preferably approximately 77% by weight. The preparation preferably includes an absorbent or gel forming agent, typically aluminium stearate which is present in an amount of from 1 to 3% by weight.
Description
A Veterinary Preparation
The invention relates to a veterinary preparation and in particular to a veterinary preparation for intramuscular and subcutaneous administration of amoxycillin.
Amoxycillin is a beta-}actam antibiotic with activity against a wide range of gram positive and gram negative organisms which are of importance in veterinary medicine.
Various injectable amoxycillin preparations have been proposed however there is need for an improved formulation for injection which will have minimum irritancy at the inection site and which will produce both a quick action and a sustained release of amoxycillin over a period of days and which may be readily administered to a range of large and small animals.
this invention is directed towards providing such a preparation.
According to the invention there is provided a veterinary preparation for intramuscular and subcutaneous administration comprising amoxycillin trihydrate, a system to promote sustained release of the active ingredient and an agent to promote quick release of the active ingredient at the injection site.
In a particularly preferred embodiment to the invention the agent to promote quick release comprises a medium chain glyceride, preferably a medium chain partial glyceride.
In a preferred embodiment to the invention the agent comprises glycerol mono8icaprylate.
Preferably the agent is that sold under the name Imwitor.
In one embodiment of the invention the agent is present in an amount of from 0.5 to 1%, most preferably approximately 0.8% by weight.
ln a particularly preferred embodiment the invention the system for promoting sustained release comprises an oily vehicle containing an aluminium salt of a fatty acid as an absorbent or gel-forming agent.
Preferably the oily vehicle is a low viscosity medium chain triglyceride or a mixture of medium chain triglycerides.
Most preferably the vehicle is a polyethylene glycol diester of saturated fatty acids having a chain length of 8 to 10 carbon atoms, preferably that sold under the trade name
Miglyol, especially Miglyol grade 840.
In a preferred embodiment of the invention the vehicle is present in an amount of from 60 to 85%, most preferably approximately 77% by weight.
In a particularly preferred embodiment of the invention the absorbent or gel-forming agent is aluminium stearate.
Preferably the aluminium stearate is present in amount of from 1 to 3%, most preferably approximately 1.878 by weight.
Preferably amoxycillin trihydrate is present in an amount of from 10 to 35, most preferably either approximately 158 by weight per unit volume or approximately 30% by weight per unit volume.
Zt is preferred that the active ingredient is present in e micronised form, at least 908 of the amoxycillin trihydrate having a major dimension of less than 25 microns.
The invention also provides a process for preparing a veterinary preparation for intramuscular and uubcutaneous administration as hereinbefore defined comprising the steps of:
suspending amoxycillin trihydrate in a micronised form
in a low viscosity oily vehicle.
In a preferred embodiment of this aspect of the invention the vehicle is previously sterilised and an agent for sustained release is added to the vehicle and the mixture is allowed to cool to form a gel base.
Preferably the amoxycillin trihydrate is suspended in the gel base.
In a preferred embodiment of the invention the agent to promote quick release which also acts as a dual wetting and dispersing agent is added to the gel base prior to the addition of amoxycillin trihydrate.
The invention will be more clearly understood from the following description thereof given by way of example only.
Example quantity
gram litre) Miglyol 823,75 Aluminium Stearate 18.65
Imwitor 908 8.00
Amoxycillin (as its Trihydrate) B.P, 150
The Miglyol is placed in a stainless steel pressure process vessel. The contents of the vessel are then heated to 1600C and this temperature is maintained for two hours to sterilise the contents of the vessel. The Miglyol is allowed to cool to 7OcC. Aluminium Stearate is added with gentle stirring until a solution is formed. The contents are re-heated to 140to while mixing. On reaching 1400C the mixer is stopped and the contents are allowed to cool without further stirxing. The
Imwitor is added to the cooled gel when the temperature has dropped to 50tC and mixed for 5 to 10 minutes.Finally, when the gel has cooled to ambient temperature, the amoxycillin trihydrate is added and suspended aseptically.
The final product is a stable, off-white suspension.
The product is used for the treatment and control of diseases in cattle, sheep, pigs, dogs and cats caused by or associated with organisms sensitive to Amoxycillin.
Generally the product is administered by intramuscular injection in an amount of approximately 1 ml per 10 kg of bodyweight to a maximum dosage at a single injection site of approximately 20ml. A second dose may be administered after 24-48 hours.
The concentration of amoxycillin at approximately 150 mg per ml is chosen to allow therapeutic doses of amoxycillin in volumes suitable for administration to a range of both small and large animals and to achieve and maintain therapeutic plasma level of amoxycillin over a period of at least 36 to 48 hours.
Amoxycillin trihydrate is not soluble in water and considerable research was carried out into the selection of a vehicle which is stable against oxidation and is well tolerated with minimum irritation at the site of intramuscular injection. After considerable experimentation esters of medium-chain fatty acids, also known as fractionated coconut oil and medium-chain triglycerides were chosen. In particular, the vehicle used is Miglyol 840 which is a propylene glycol diester of saturated fatty acids of chain length C8 to Cl. It has a low viscosity and is therefore suitable for administration by injection.
Aluminium stearate is intended, in association with the oily vehicle, to assist in sustained release of the amoxycillin at the injection site. The addition of aluminum stearate to the vehicle and the process of heating the two and allowing the product to cool produces a stable, thixotropic gel which is capable of retaining amoxycillin in suspenslon and which, on re-suspension, allows accurate dosage measurement. The amount of aluminum stearate used is chosen to allow for formation of the suspension while still facilitating syringeability of the product.
Zmwitor 908 is a medium change partial glyceride, glycerol monodicaprylate and acts to promote a quick release of active ingredient at the injection site. It also acts, both as a wetting agent and a dispersing agent.
The particle size range of the amoxycillin trihydrate used is also of critical importance. It is important that the amoxycillin trihydrate is in a micronised form, 908 of the amoxycillin trihydrate used having an average major dimension of less than 25 microns to prevent compaction and to facilitate re-suspension of the product, in use.
The tolerance of calves to the preparation according to the invention when administered by intramuscular injection at a dosage level of 15 mg of amoxycillin per kilo gram body weight has been investigated in detail. No signs of inflammation at the site of injection in any animals at any observation point was noted. All animals observed were eating and drinking normally during the 48 hour period following the injection and there were no other signs of systemic toxicity.
The bioavailability of amoxycillin using the veterinary preparation of Example 1 was evaluated by measuring the concentration of amoxycillin (Mg/l) in bovine plasma following intramuscular injection over a time period of 48 hours. The results are summarised in Table 1 and plotted in Fig 1.
It will be noted that the mean plasma concentration increased over the first hour to a peak value of 3.49 mg/i after 1.0 hours indicating the initial quick action of the product. The level then declined rapidly up to 5 hours and then more slowly, indicating the prolonged nature of the product.
It will be noted that the product combines the effect of both a quick release and long acting or sustained release product in a single dose. The plasma concentration increases rapidly over the first hour to a peak value of 3,49 mg/l at 1 hour giving an initial quick action. The level then declines rapidly up to 5 hours but does not decline to a low level.
Rather, the level declines slowly after 5 hours giving a product with a long acting effect. Thus, the product provides the combined benefit of quick release and long action in a single dose.
The combined effect of an oily vehicle and a thickener and a combined wetting and dispersing agent is to provide a product which in a single dose provides not one or other benefit of a quick release or long acting product but rather, most unexpectedly, the synergistic effect of both quick release and long action in a single dose.
It is believed that the oily vehicle in combination with an absorbent or gel-forming agent, particularly a polyethylene glycol diester of saturated fatty acids having a chain length of 8-10 carbon atoms, particularly that sold under the Trade name Miglyol as the oily vehicle in combination with an aluminium salt of a fatty acid, especially aluminium stearate contributes to the long acting effect of the product.
It is also believed that the use of a combined wetting and dispersing agent, particularly a medium chain partial glyceride, glycerol monodicaprylate, particularly that sold under the Trade name Xmwitor contributes to the quick release property of the product.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (26)
1. A veterinary preparation for intramuscular and subcutaneous administration comprising amoxycillin trihydrate, a system to promote sustained release of the active ingredient and an agent to promote quick release of the active ingredient at the injection site.
2. A preparation as claimed in claim 1 wherein the agent to promote quick release comprises a medium chain glyceride, preferably a medium chain partial glyceride.
3. A preparation as claimed in claim 2 wherein the agent comprises glycerol monodicaprylate.
4. A preparation as claimed in any of claims 1 to 3 wherein the agent is that sold under the trade name Smwitor.
5. A preparation as claimed in any of claims 1 to 4 wherein the agent is present in an amount of from 0.5 to 1% by weight.
6. A preparation as claimed in claim 5 wherein the agent is present in an amount of approximately 0.88 by weight.
7, A preparation as claimed in claim 1 wherein the system to promote sustained release comprises an oily vehicle containing an aluminium salt of a fatty acid as an absorbent or gel-forming agent.
8. A preparation as claimed in claim 7 wherein the oily vehicle is a low viscosity medium chain triglyceride or a mixture of medium chain triglyceridea.
9. A preparation as claimed in claim 8 wherein the vehicle is a polyethylene glycol diester of saturated fatty acids having a chain length of 8 to 10 carbon atoms.
10. A preparation as claimed in claim 9 wherein the vehicle is that sold under the trade name Miglyol.
11. A preparation as claimed in claim 10 wherein the xiglyol is grade 840.
12. A preparation as claimed in any of claims 7 to 11 wherein the vehicle is present in an amount of from 60 to 85% by weight.
13. A preparation as claimed in claim 12 wherein the vehicle is present in an amount of approximately 77% by weight.
14. A preparation as claimed in claim 8 wherein the absorbent or gel-forming agent is aluminium stearate.
15. A preparation as claimed in claim 14 wherein the aluminum stearate is present in an amount of 1 to 3% by weight.
16. A preparation as claimed in claim 15 wherein the aluminum stearate is present in an amount of approximately 1.878 by weight.
17. A preparation as claimed in any preceding claim wherein amoxycillin as its trihydrate is present in an amount of from 10 to 35% by weight per unit volume.
18. A preparation as claimed in claim 17 wherein the amoxycillin as its trihydrate is present in an amount of approximately 15% by weight or 30% by weight.
19. A preparation as claimed in any preceding claim wherein the active ingredient is in a micronised form, at least 90% of the amoxycillin trihydrate having a major dimension of less than 25 microns.
20. A preparation substantially as hereinbefore described with reference to the examples.
21. A process for preparing a veterinary preparation for intramuscular and subcutaneous administration as claimed in any preceding claim comprising the step of suspending amoxycillin trihydrate in a micronised form in a low viscosity oily vehicle.
22. A process as claimed in claim 21 wherein the vehicle is previously sterilised and an agent for sustained release is added to the vehicle and the mixture is allowed to cool to form a gel base.
23. A process as claimed in claim 22 wherein the amoxycillin trihydrate is suspended in the gel base.
24. A process as claimed in claim 22 or 23 wherein an agent for quick release which also forms a dual wetting and dispersing agent is added to the gel base prior to the addition of amoxycillin trihydrate.
25. A process substantially as hereinbef ore described with reference to the examples.
26. A preparation whenever prepared by a process as claimed in any of claims 21 to 25.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE169589A IE64620B1 (en) | 1989-06-01 | 1989-06-01 | A veterinary preparation |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9012096D0 GB9012096D0 (en) | 1990-07-18 |
GB2232082A true GB2232082A (en) | 1990-12-05 |
GB2232082B GB2232082B (en) | 1993-02-24 |
Family
ID=11030322
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9012096A Expired - Lifetime GB2232082B (en) | 1989-06-01 | 1990-05-31 | Sustained-release composition comprising amoxycillin trihydrate |
Country Status (2)
Country | Link |
---|---|
GB (1) | GB2232082B (en) |
IE (1) | IE64620B1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002015937A2 (en) * | 2000-08-24 | 2002-02-28 | Schwarz Pharma Ag | Pharmaceutical composition for the systematic administration of pharmacologically active ingredients containing polyol fatty acid esters |
US8604076B2 (en) | 2000-08-24 | 2013-12-10 | Ucb Pharma Gmbh | Method for producing a pharmaceutical composition comprising rotigotine |
-
1989
- 1989-06-01 IE IE169589A patent/IE64620B1/en not_active IP Right Cessation
-
1990
- 1990-05-31 GB GB9012096A patent/GB2232082B/en not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002015937A2 (en) * | 2000-08-24 | 2002-02-28 | Schwarz Pharma Ag | Pharmaceutical composition for the systematic administration of pharmacologically active ingredients containing polyol fatty acid esters |
WO2002015937A3 (en) * | 2000-08-24 | 2002-07-18 | Sanol Arznei Schwarz Gmbh | Pharmaceutical composition for the systematic administration of pharmacologically active ingredients containing polyol fatty acid esters |
US8604076B2 (en) | 2000-08-24 | 2013-12-10 | Ucb Pharma Gmbh | Method for producing a pharmaceutical composition comprising rotigotine |
Also Published As
Publication number | Publication date |
---|---|
IE64620B1 (en) | 1995-08-23 |
GB9012096D0 (en) | 1990-07-18 |
GB2232082B (en) | 1993-02-24 |
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