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(11) Patent Number KE 393

(21) Application Number: KE/Pt2003/ 000274

(71) Inventor:BLAKELY WlLLJAM; CROMJE LJLLJAN aod DUFFY SEAN

(73) 0wner:NORBROOK LABORATORIES LIMITED of STATION WORKS, CAMLOUGH ROAD NEWRY BT35 6JP, United Kingdom

(22) Filing Date: 31103!2003   

(54)  Title: INJECTABLE VETERINARY COMPOSITION FOR SMALL ANIMALS

(57) Abstract: An injectable aqueous composition for veterinary use containing a non-steroidal anti-inflammatory compound in an amount of from about 0.25 to 30% (w/v) together with a physiologically acceptable oxygenated polymeric surfactant in an amount of from about 0.5 to 20% (w/v).
 

Injectable Veterinarv Composition for Small Animals

This invention relates to the use of non-steroidal anti-inflammatory drugs (NSAIDs), particularly the formulation of such drugs in solutions suitable for injection, especially for use in veterinary medicine for the purposes of treating small animals, such as companion animals.

Background of the Invention

Non-steroidal anti-inflammatory drugs find wide application in the treatn1ent of inflammatory conditions and the alleviation of pain in veterinary and human medicine. Such drugs are often characterised by the presence of a carboxylic acid fimction or

10    derivative thereof Examples of such non-steroidal anti-inflanunatories include carprofen, ibuprofen, ketoprofen, benoxaprofen, naproxen, sulindac, zomepirac, fenclofenac alcofenac, ibufenac, flunixin and indomethacin. The administration of such compounds parenterally can present the difficulty of local irritation and induce haemolytic side effects.

15 In EP-A-0 280 887, Ferro and Steffen teach the fonnulation of NSAIDs, by utilising salts of cholanic acid and certain lipids to form mixed micelles in aqueous systems. These compositions have reduced side effects, in comparison with conventional fonnulations, when administered by injection to dogs.

Obiects of the Invention

20 lt is an object of the pr~sent im•~mi~lll l\• pn.IYiJ..: novel pharmaceutical preparations of non-stt=roidal anti-intl~mlm:Jh)r~ dru~~ :>uit;tbk ~~)r ini~..:tion. It is a further object of the invention to provide such preparations adapted for the provision of analgesia in small animals, especially companion animals.

SummarY of the lm l'ntinn

~5 It has been surprisingly found that NS.-\lDs, preferably carprofen (6-chloro-a-mcthyl-c3fbazole-2-acdic acid) or a salt thereof. \l11JSt prckrab!y carprofen in the form of its arginine or lysine salt, can be readily formul.ttl'J in aqueous systems by the use of certain phannaccutical!y acceptable synthetic polymer agents to the effect that the problems of local irrituncy and haemolysis associated \-Vith conventional formulations of
30    these drugs art= avoided or at least greatly reduc..:d.

Accordingly, the aforesaid objects are achievable by this invention which provides an injectable aqueous composition for veterinary use containing an effective amount of a non-steroidal anti-inflammatory compound together with a physiologically acceptable oxygenated polymeric smfactant.

An additional teclmical benefit in comparison with formulations utilising the prior art cholanic acid/lipid solubilising method is also achieved by the present invention which offers enhanced stability at room temperature.

Polyoxypropylene/polyoxyethylene block co-polymers (poloxamers) or derivatives thereof are the preferred polymeric agents used for the purposes of the

10    invention as illustrated in the following examples for a composition containing carprofen or physiologically acceptable salts thereof as the active ingredient. Such a solution is

especially useful in veterinary medicine for a variety of analgesic, anti-pyretic, and anti-inflammatory purposes such as the treatment of, musco-skeletal and visceral pain in horses, pre-and post-operative pain in cats and dogs and of acute inflammation associated

15    with respirt~tory disease.

The amount ofNSAID that can be acconunodated in the injection solutions of the present invention can vary over wide limits, for example from 0.5 to 30% (w/v), depending on the required dose for effective treatment of the subject. The quantity of poloxamer can also vary over wide limits, for example 0.5 to 20% (w/v), the upper limit

20    for a given formulation being determined by viscosity considerations. In norrnal use the solution may be readily administered by conventional hypodermic syringe.

The prese11t invention provides another means of formulating NSAID's in aqueous solution, in a form that is suitable for parenteral administration to animals or humans especially companion animals such as cats and dogs.   The compositions of the present

25    invention provide simpler fom1lllations than those of EP 0 280 887, without the requirement for lipids and cbolanic acids. It is a further feature of these simpler fonnulatiLill:ii that they r~main stable, without the anticip3tCJ precipit,uion or turbidity and c3n be sturcd at ruom temperature:, contrasting with the chubnic acid/lipid tOrmulation. which typically requirc:s refrigerated storage (2-8 C).

30    The non-steroidal anti-intla.nunatory compound may be present in an amount of from about 2.5 to 7.5°/;, (w/,) or mor~. preferably 2.5 to Y\) {\\-/\").  llowc,•cr. it will be understood by those skilled in the art that a useful lower range of from about 0.25% (w/v) may be employed where small volume changes in delivery volwne are not significant, e.g. in treating felines with a non-steroidal anti-inflammatory compound such as carprofen.

Arginine may be present in an amount from about 1% to 20% (w/v).

The poloxamers are generally present in an amount of :from about 2 to 12% (w/v). Moreover an organic solvent can be also present with the poloxamer, generally in the range of about 0.5 to 20% (w/v), in which case the poloxamers can be present in an amount from 1% to 12% (w/v).

10 A poloxamer generally confirms to the formula HO(CH2CH20)x(CCH3HCH20)y(CH2CH2)zH, wherein x, y and z are variables which are independently and selectively controllable. The values of x, y and z are respectively whole numbers in the range 2 to 128 and represent target values which will vary slightly according to commercial sources. An example of a preferred poloxamer is
!5    HO(CH2CH20)75(CCH,HCH,0)3o(CH,CH,)75H.

The present invention provides an aqueous injectable composition comprising carprofen or a physiologically acceptable salt thereof in an amount of :from at least 0.25%, preferably 0.5% to 30% (w/v), a polymeric species selected from the group of polyoxypropylene/polyoxyethylene block co-polymers in the amount of from 0.5% to
20    20% (\\•/v), a presen•ativc a.nJ '>Vater su1llcient for injection.

According to the im•ention there is also provided a method of producing a room-temperature stable injectable aqueous composition for veterinary use comprising bringing together carprofcn or a physiologically acceptable salt and a poloxamer, and adding sufficient water for injection. Additionally prcser\'atives may also be included.
25    Preferably the poloxamer is HO(CH2CI•l20hs(CCH3I-l.CH20)3o(CH2CH2) 75 H.

Fmih..:nnor(' the invention also rc!Jtes to the use of polyoxypropylene/polyoxyethylene block co-polymers for the manufactme of locally tolerable aqueous injection solutions of non-steroidal compounds.
 
Mode fo1• J>erform:u)ce of the Invention

The invention \viii now be described further by way of illustrative example with reference to the accompanying Figure, which represents data showing the mean levels of carprofen found in the blood plasma of dogs following administration of a formulation of the invention.

A suitable formulation of carprofen, in this embodiment provided as its arginine salt, can be made by bringing together, following standard industry procedures, the

10    following ingredients to form a mixture which is brought up to injection volume by addition of an appropriate amow1t of water for injection:

Carprofen 5.0% w/v

L-Arginine EP 3.1% w/v

Lutro! fM\ (!xlloxamer 1SS, NF, EP) 5.0% w/v

15    Nipagin M (_BP, EP, USP/NF) 0.15% w/v (preservative) Water for injection ad 100% w/v

Other examples of suitable fonnulations include:


20    Carproll!n 5.011,-o w/v L-Argmin..: lP 311/o w/v
Lutrol F6S (jJolo:\amer I 88, NF EP) 10% w/v Propyll!nc Glycol 20% 'vV/v

25

Carpn.1fcn ~.0°<• '"/\•

L-Argininc.: EP 3% w/v

Lutrol f6~ (polo:-;:amer ISS. Nf EP) 2.4% w/v

30    Propylene Glycol20% 'vV/v Wato:r flH• in}.::ction ad I OO'X1 w/v
 
Examnle4

Carprofen 5.0% w/v L-Arginine EP 3% w/v

Lutrol F68 (poloxamer 188, NF EP) 12% w/v Propylene Glycol 20% w/v

Water for injection ad 100% w/v

Example 5

Carprofen 5.0% w/v

10    L-Arginine EP 3% w/v

Lutrol F68 (poloxamer 188, NF EP) 3.5%w/v Propylene Glycol20% w/v

Water for injection ad 100% w/v

15    Example 6

Carpmfen 5.0% w/v

L-Arginine EP 3.1% w/v

Lutrol F68 (poloxamer 188, NF EP) 5% w/v

Propylene Glycol 20% w/v

~0    Water for injection ad I 00% w/v

r.\:ttnnk 7

larpm!l:n :'.0°"riw 1Y

L-ArginineEP 3.1% w/v

25    Lutrol F68 (poloxamer 188, NF EP) 5% w/v Water for injection ad I 00% w/v

Example 8

CarproJ~n 5.0% w/v

:-o    L-Arginin<! EP 3.1% \v/v

Lutrol f6S (potoxam<!r ISS. Nf EP) 7% w/v Propyl en<! Glycol 20% w/v

Water for injection ad 100% .,v/v
 
Example 9

Carprofen 5.0% w/v L-Arginine EP3.1% w/v

Lutrol F68 (poloxamer 188, NF EP) 5% w/v

Benzyl Alcohol!% w/v

Water for injection ad 100% w/v

Example !0

Carprofen 5.0% w/v

10    L-ArginineEP3J%w/v

Lutrol F68 (poloxamer 188, NF EP) 6% w/v Water for injection ad I 00% w/v

Example ll

15    Carprofen 5.0% w/v L-Arginine EP 3% w/v
Lutrol F6S (poloxamer 188, NF EP) 5% w/v Benzyl Alcohol!% w/v

Water for injection ad I 00% w/v

20

Examole 12

Carprofen 5.0% w/v L-Arginine EP 3.1% w/v

Lutrol F68 (poloxamer 188, NF EP) 5% w/v

1.5    Benzyl Alcohol 0.3% w/v

Water for injection ad 100% w/v

Example l3

Carprofen 5.0% w/v
:.o    L-Arginine EP 1.7% w/v

Lutrol F6S (poloxamer 188. NF EP) 5% w/v

Benzyl Alcohol 1% w/v

Water for injection ad 100% w/v
 
Example 14

Carprofen 5.0% w/v L-Arginine EP 3.3% w/v

Lutrol F68 (poloxamer 188, NF EP) 5% w/v Benzyl Alcohol I% w/v

Water for injection ad 100% w/v

Example 15

Carprofen 5.0% w/v

10    L-ArginineEP3.1%w/v

Lutrol F68 (poloxamer 188, NF EP) 5% w/v Benzyl Alcohol 1% w/v

SFS 0.25% w/v

Water for injection ad I 00% w/v

15

Example 16

Carprofen 5.0% w/v

L-Arginine EP 3.1% w/v

Lutrol F6S (poloxamer 188, NF EP) 5% w/v

20    Benzyl Alcohol 1% w/v SFS O.l%w/v

Water for injection ad 100% \\"\

Example 17

25    Carprofen 5.0% w/v L-Arginine EP 3.1% w/v

Lulrol F6S (poloxamcr ISS, Nf EP) )~,o \\-•\ Benzyl Alcohol l% w/v

SfS 0.4%w/v

30    Water for injection ad I 00% W/Y
 
Example 18

Carprofen 5.0% w/v

L-A.rginine EP 2.5% w/v

Lutrol F68 (po!oxamer 188, NF EP) 5% w/v

Benzyl Alcoholl% w/v

SFS 0.25%wlv

Water for injection ad 100% w/v

Example 19

10    Carprofen 5.0% w/v

L-Arginine EP 3.1% w/v

Lutrol F68 (poloxamer 188, NF EP) 3% w/v Benzyl Alcohol 1% w/v

SFS 0.25% w/v

15    Water for injection ad 100% w/v

Examples of fonnulations which failed to achieve satisfactory conunerciai objectives are

shown below:

Comparative Example l

20    Carprofen 5.0% w/\•

L-Arginine EP 3% w/v

Lutrol F68 (polox:.ulh:r ISS, i\F I:P) ~tl~ o \\•,, Propylene Glycol ~u':1, \\"/\"

Water for injection ad 100% w/v

Comparative Ex::unp!c.,

Carprofen 5.0% w/v

L-A.rginine EP 3.1% w/v

Lutrol F68 (polox.amcr ISS. 1\F FP) ~u••n wr\•

30    Benzyl Alcohol l% \v/v

SFS 0.25% w/v

\Vater for injection ad 100% \V/v
 
A comparison was made with the prior art formulation (derived from EP 0 280 887) that uses about 26% (w/v), of cholanic acid and lecithin, in a similar strength carprofen fonnulation. This formulation demonstrates bioequivalence to the aforesaid cholanic acid/lipid formulations but utilises only 5% (w/v) of the inventive polymeric surfactant additive. Thus compositions of the present invention can substantially reduce the burden of auxiliary ingredients injected into the subject on treatment These formulations have also been found to have low side effects, with no injection site reactions such as swelling, hardness, softness, heat, redness or pain being observed during studies involving dogs.

10 A further benefit of compositions according to the invention is that of room temperature stability. A trial lot of the formul.ation given in t.h~ example has been studied over a period of eleven months at ambient temperatures without loss of potency being observed. The trial lot was assayed as containing 5.16% carprofen on manufacture,

5.10%  after seven months, and 5.26% after eleven months, these apparent differences

1:; hcing accounted for .bY slight moisture loss. Currently available fommlations typically require controlled chilled storage at 2-8 C, i.e. refrigeration, cool room, or chiller cabinet storag<!.

A study was undertaken with a view to evaluating the mean levels of carprofen found in dogs following the administration of a dose of approximately 4 mg/kg of a

~0    composition according to the Example in comparison with results obtained by ;!,!ministration of a conunercial!y available product of comparable strength.

    The  results  of  the  phannacokinetic  study  are  tabulated  below  and  shown
    graphically  in  Figure  1.   The  Table  compares  the  mean  plasma  concentrations  of
    carprofL:n  found  in  dogs  after  subcutaneous  injection  of  carprofen  at  a  dose  of
.-::;    appm:-.:imatdy    4mg/kg  using  a    commercially  available  fOrmulation,  and  using    the
    formulation  given  in  the  Exan1ple.   Statistical  ;malysis  of  these  results  confinned
    hi\ll'qui\•alcnce    in   accordance    with   European    Guidelines    (Volume    of

\-"\IF:\ 'CV:'dP/016-00/final).
 

        10
Time after injection    Carprofen!Lutrol formulation    Commercially available
(hours)    (~tglm!)    Carprofcn formulation ()lg/ml)
0.5    5.73    3.27
    8.24    5.S6
1.5    9.24    7.16
    9.85    8.76
2.5    ll.l8    8.53
    11.36    9.63
3.5    9.94    10.29
    9.23    7.99
    9.12    7.6
    6.57    6.75
10    5.98    6.18
24    2.39    2.41
30    1.37    lAS
48    0.39    0.6
72    0.13    0.18
 
II

CLAIMS

1.    An injectable aqueous composition for veterinary use containing a non-steroidal

anti-inflammatory compound in an amount of from about 0.5 to 30% (w/v) together with

a physiologically acceptable oxygenated pol}'meric surfactailt in an amount of from about

0.5    to 20% (w/v).

2.    An  injectable  aqueous  composition  accorcling  to  Claim  1  wherein  the  non-

steroidal anti-inflammatory compound is selected from the group consisting of carprofen,

Io   ibuprofen,  ketoprofen,  benoxaprofen,  naproxen,  sulindac,  zomepirac,  fenclofenac,

alcofenac, ibufenac, fbmixin and indomethacin.

..J. An injectable aqueous composition according to Claim 2 wherein the non-steroidal anti-inflammatory compmmd is carprofen (6-chloro-a-methyl-carbazole-2-acetic
15    acid) or a physiologically acceptable salt thereof

4. An injectable aqueous composition according to Claim 3 whereiu the carprofen salt is in the form of an arginine salt.

20    5. An injectable aqueous composition according to Claim 3 \.Vherein the carprofcn salt is in the form of a lysine salt.

6.    An injectable aqueous composition according to any one of Claims I 10 3 who.:rcin

lhe non-steroidal anti-inflanunatory is present in an amount of from about 2.5  to 7.5%

25    (vdv).

7. An injectable aqueous composition a..:cording to :my one of Claims 1 to 3 \\•herl!in the non-steroidal anti-inflammatory is present in an amount of from about 2.5 to 5% (w/v).

30

8.    An  injectable  aqueous  composition  according  to  any  one  of  Claims  1-7

comprising arginine in an amount of from about l to 20% (w/v).
 
9. An inj<'!ctable aqueous composition for veterinary use containing a non-steroidal anti-inflammatory compound, preferably carprofen, in an amount of from at least about

0.25% (w/v) together with a physiologically acceptable oxygenated polymeric surfactant in an amount from about 0.5 to 20% (w/v).

10. An injectable aqueous composition according to any one of Claims I to 9 wherein the polymeric surfactants ru.-e selected from polyoxypropylene/polyoxyethylene block co~ polymers (Poloxamers) or derivatives thereof.

10    11. An injectable aqueous composition according to Claim 10 wherein the poloxamers are present in an amount of from about 2 to l2% (w/v).

12.    An injectable aqueous  composition according  to  Claim  10  wherein  an  organic

solvent is present with the poloxamer.

13.    An injcctabl~ aqueous composition ;1ccording tu Claim 12 wher~in the organic solvent is present in the range of0.5 to 20% (w/v).

14.    An injectable aqueous  composition according  to  Claims  12  or  13  wherein  the

20    poloxamerS are present in an amount offroml% to 12%  (w/v).

15. An  iqi~ctablc aqueous  compositi(l/1  according  10 Cbims  TO  to  14  wherdn  the

polo:-::amer is  HO(CH~CI-bOMCCH.:;HCH~O),(CH~Cf•h) .. TJ wherein  x  is ah0ut  75.  y  is

about30 and z is about 75.

25

16.    An injectable  aqueous  composition  for  veterinary  use  containing  from  about

0 ..25~ 0 to 30'~" t w/\") of carpr~_,f\:n arginine s,llt together \Vith a poloxamcr in an amount

from a.bm1t 0.5 to 20% (w/v).

30    17

comprising arginine in an amount of from  I to 20% ( \\•/v).

18. An aqueous injectable C(lmposition comprising carprofen or a physiological!y acceptable salt thereof in an amount 0f (rom 0.25%) to 30% (wN). a polymeric speci~s !3 selected from the group of polyoxypropylendpulyoxyethylene block CG-polym.ers in the amount of from 0.5% to 20% (w/v), a preservative and '-Vatersufficient for injection.

19. A method of producing a room-temperature stable injectable aqueous composition !Or veterina..')' use comprising bringing together an effective amount of ca.rprofeu or a physiologically acceptable salt thereof and a poloxamer, and adding sufficient water for
injection.

20.    A    method    according to Claim 19    wherein    the    poloxamer    is

10    HO(CHzCH20)x(CCH3HCH20)y(CH2CH2)zH wherein x is about 75, y is about 30 and z is about 75.

21.    A method of producing an injectable aqueous composition according to Claims 19

or 20 wherein said method further comprises the inclusion of a preservative.

15

22. An injectable aqueous composition for veterinary use according to any one of the Examples 1 to 19 hereinbefore.

:23.    A  method  of  producing  an  injectable  aqueous  composition  substantially  as

20    Jescrib<!d in th<! Example I.

:24. The US<..' or polyoxypropy(<:'.nc/p0lyo:.:yethylene block co-polymyrs for the m~nufactun.' of locally t0ler~bk aquL'nus in.iL'ction solutions of non-steroidal compounds.

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