AU662580B2 - Subcutaneous or intramuscular injectable compositions containing benzimidazole as active agent for the treatment of gastrointestinal helminthiasis and method for their preparation - Google Patents

Description

I. .9 P100/Oi11 Regulation 3.2

AUSTRALIA

Pajgtents ct 1 990 J% r 5" 0% 10% Efh

%)U

J SUBSITUTE CO0 MPLETE SPECIFICATION STANDAR4D PATENT Invention ritia: *06 00#00 so0 SUBCUTANEOUS OR INTRAMUSCULAR INJECTAOILE COMPOSITIONS CONTAINING BENZIMIDJAZOLE AS ACTIVE AGENT FOR THE TREATMENT OF GASTROINTESTINAL HELMINTHIASIS AND METHOD FOR THEIR

PREPARATION

The following 0tatement is a full description of this invention, including the best method of performing it known to us:.

GH&CO REF., P22579-A:AMP:RK I I SUBCUTANEOUS O INTRAMUSCULAR I1JECTABLE OMPOSITIONS coNAI'ING BENZIMIDAZOLE AS ACTIVE AGENT FOR THE TREATMENT OF GASTROINTESTINAL HELMINTHIASIS AND METHOD FOR THE%R PREPARATION BACXGR)UND OF THE INVENTION The family of compounds generically call.ed "benzimidazoles" has an important role in the treatment of animals affected with helminthiasis. They are bicyolic compounds having the formula

N

NH-CO

4 6 4 0 4

S

to .4.

4 9 4 0# 64 4 4 where R is a-

(C

1

-C

4 and

R

1 -S (O)m

R

2 lower alkyl group, preferably an alkyl group is a group having the formult where m is zero, one or tito; R 2 is an inferior alkyl group, cyclo alkyl, phenyl, inferior phenylalkyl, naphthyl, alenyl or alkynyl; where R, has the above mentioned values. -OR 2 (CH2) n Y2 R3 where Y is oxygen, sulfur or sulfinyl;

R

3 is phenyl, naphthyl or lower alkyl and

Y

2 independently assumes the values indicated for Y, being n an integral number from 1 to 4.

In the group of "benzimidazoles" represented by the formula of special significance are those compounds where R is a miethyl group and R 1 isl a group (albendazole), 5-phenylthio (phernbendazole) and others commercially known as Oxfendazole, Oxibendazole, including the more recently developed "albendatzole sulfoxide"', which comprises the methyl esters having the formula where R 1 is f, a group C 3

H

7 -50- in position 5 R 2 is a propyl group (the preparation of Albendazole has been described in Argentine ee patent No. 207,248 -Smith Kline Corp., which has already too* S: expired).

e*e* These are compounds not very soluble in water (from 2 to 10% Therefore, in veterinary medicine they are presented for oral administration for human beings and for oral and/or intraruminal administration in veterinary (incluided in bolus for ruminants), in a form where the benzimidazole is mixed with high density substances (iron, sand, etc.) or they are administered in a form for long term or delayed release, as disclosed in Argentine patent No. 238,411 irtended to control and delay the release ofI the active agent, while retained in the rumen).

Benzimidazoles having the formula are extensively and 1 iitensively use I in the treatment of both human and animal ii including pets- I digestive system helminthiasis Examplas of parasite Helminthes of the digestive tract are 4emat )da, such 'is intesti ,nal 'Worms, Oxyura, Cestoda (intest~inal taenia), l4/ Prematoda, etc'. (for example, Aggaris suun pig loarasite, Oestertacria sst~ Chabertis ssp, Nematodirus sopm, eto. bovine and ovine animotls).

In actual practice, benzimidazole is f ,rmulated to be administered, 12.%Y os (vide supra) usually with a tolerable 110 veterinary pha/imaceutical carrier or us3ing fodder as a carrier.

This prac!tice was based on the belief that as parasites were located in the gastrointestinal tract, 't.he treatment should be car ried out by making the active agent reach the environment 'of the infecting parasite, disregarding any incidence orparticipation of the circulatory 1 ystem. of course, the :poor solubility of benzimidazoles hars been an important anja permanent 'ncorvenience in this practice, since approximate ly 95-96% of the benzimidazole administered is lost in faeces. Further, as they are intraruminant doses, it requires the previous immobilization of each animal and the administration of the doses through a cannula or tiube inserted in to' inien, which steps should be repeated in long-term treatmbents-. These requirements are not only cost~ly but also dang~lrous for the personnel and traumatizing for the animal~s titeated.

IRecerlt investigations have conclusively shown that the plasmatic level of th~e benzimidazole is decisively important in the antdel6mintic therapy as the therapeutical bioavailability depends exclusively or at least to a l~arge extent on the concentratioh and permanence of the benzimidazoles in the bloodI. This" unexpected connection between the plasmal;ic level of the bepizimidazoles and their "in situ"l anthc.±mintio, activity i a therapeutical activity) has led to conceive injecptable compositionis containing benziiiazole as anthelmintic agent.

THE XIVT rON Thet pain object of the pv. sent invention are injectable to compostions, especially subcutaneous or intramuscular injtjctvibDe compositions for treating gastrointestinal tract helzinthip~sis, characterized in that they comprise 06* **0 41 of benzifl~id oie as anthelmintic agent solubilized in a thO~ape~i -,)ally iacceptable means.

toI Anolther dbjedt of this invention is the method to prepare said in~ectahle compositions, where the benzimidazoles are ;00O previousily dAls7olved in polyethylene glycol and then the i~ solution formed is dissolved with a solvent in an amount 5 sufficiont to keep the benzimidazole in permanent solution.

Tile- present invention permits formulations having benzim$.dazole concentrations much higher than usual ones, ranging from values of 15 to 20% w/v. With these values it is possible to formulawts compositions of high benzimidazole levels in more reduced volumes. Further, the handling or applioation thereof in animals is simplified, since it is no longer necessary for the total and traumatic immobilization of each animal, as required for the intraruminal dose or for oral administration, in whichcases, besides, usually losses of the medicine occur as a result of inevitable spilling.

In a first aspect, the present invention provides a suboutaneous or intramuscular injectable composition for the treatment of gastrointestinal helminthiasis, the composition comprising a benzimidazole as an anthelmintic agentt in solution in a therapeutically acceptable carrier wherein the carrier comprises a low molecular weight C 1

-C

4 polyalkylene glycol and a cosolvent.

This invention does not depend on a particular benazimidazole; aiy of the known benzimidazoles having anthelmintic capabilities is useful for the present invention, prefetably the albendazole (5-propylthio IH benzimidazole 2 yl) methyl carbamate, fenbenzadole 20 phenylthio I- H benzimidazole 2 yl) methyl carbamate, oxibendazole (5 propyloxy IH benzimidazole 2 yl) methyl carbamate, albendazole sulfoxide and oXfendazole, etc.

The highest limit value of the benzimidazole 23 concentration is the benzimidazole solubility in the carrier and obviously, the toleranlce of the patient or 0 00 •00 a treated animals.

It is even possible to prepare concentrated solutions, which may be later diluted. Preferably the benzimidazole concentration in the injectable 0. compositions of the present invention is of 2 to 20% w/w; *e even more preferably from 5 to It is piossible to formulate compositions having such high benzimidazole concentrations by resorting to biologically tolerable solvents formulated with polyalkyleno (CI -C4) low molecular weight glycols polyalkyleno glycols (CI-C4) and proper cosolvents, preferably polyethylene glycol or polypropylene glycol, especially polyethylene glycol 50-1500. As cosolvents, water and alkanoles (C 2

-C

8 are preferred.

In a second aspect, the present invention provides a method for preparing a composition according to the first aspect of the present invention, the method comprising dissolving the bensimidazole in the glycol, preferably polyethylene glycol 400, if necessary by heating, and subsequently increasing the volume by addition of the cosolvent As cosolvent, water and 2 to 8 carbon atom alkanols, such as n-butanol are preferably used.

Glycerol, glycols such as the moaoethylene or monopopylene glycol and their esters are also applicable.

Other operative variants for the preparation of the injectable compositions fo the present invention are also possible. For example, dIssolving with heating and while agitating the finely divided benzimidazole, slowly .0 incorporated while the cosolvent is added in fractions or drops until the benzimidazole is completely dissolved.

After the operation is completed, it is increased up to 20 the required volume.

9 Final steps for dissolving the benzimidazole, independently of the technique used, comprise the elimination of the insolubles by filtering; for example, by agitating the solution obtained with Celite and later S 25 filtering it. Finally it is sterilized and bottled.

The sterilization may be carried out thermically for the fractionated and bottled product or chemically, by Sadding a suitable amount of formalin to the prepared solution and after

C**

ff,^ S:,225' t 9A/70 leaving it stationary for 24 hours at room temperature, by neutralizing it addll -s'iu bisulphate.

The following examples are given for illustrative purposes only and are solely intended to show how the invention is put into practice.

Said examples corres~pondc to the preparation of injectable subcutaneous solutions having a zootechnical intere~st.

Examn1 solutions having water as cosolvent.

:4064" QUANTITATIVE FORMLA: Every 100 ml of the solution contain Albendazole sulfoxide ~~Polyethylene glycol 0m Water ml.

enough quantity to reach 100 ml.

V.

A Dissolve the benzimidazole in the polyethylene glycol,* then heat it up until it is totally dissolved (approximately from 600C to 160'C) Let -it get cool and increase up to 100 mnl with cistilled Water. Add 1 g of Celite; agitate for 30 minutes and then filter.

)example 2 St solutions having n-ButariDl as cosolvent.

QUAW 4tTATIVB FO RMLA: Every 100 Mnl of the so:lution contain Polyethylene glycol 400 0m r-Butanol e.g.r. 3.Dml Add the polyethylene glycol, to the benzimidazole and hea,, unti~l total dissolution. Let it get cool and increase Up to ml with n-butanol.

:4,106"Add 1 g of Celite and agitate during 30 minutes; thon filter.

2 eziiaol...bnazl Poytyeegyo .tf1t ,7.m ft...

and hetutlifstoaltisle.Lo ogtc m 44 .4 00 4 4 0 0**B 0 .4 0 0 *044 4404 0 0 0404 44 *0 4 4 44 40 04 4 4 00 .4 4.

00 40 0 .4 4 *0*0 4**4 00 4* 4 0* 0 .4.4 0 404400 4 increase up to '100 ml With distille,!, wvater. Add 1 g of Celite and agitate du,,Iing 30 wpnutes. Theqn filter.

7. solut iomi having n-buta'ol. as dissolvent.

QUNIAIE RUA Every 100 i~l iof the solution contain Pheilbendazole 7. 5 g Polyethylene gly'col 490O 60. xl n-Oi'tanol e, q. inl Add all the Polyethylene gl~tcol to the Benzimaidazole and heat until it is totally d smblved. Let it get cold and increase up to 100 ml Vith r,,,-Btanol. Add 1I of Celite and agitate durIng 30 minuteis. Tlien filter.

10% solutions havir~q W atele as cosolvent.

OUAI'AXbT CVE F-OPLA:&- Eil~y l(00 ml of the solution contain oxpherndazole 0 Polyethyleino g~lyco, 400 .m Wator o0gqz 0 I09 0044 100 ml Method Add all the Polyethylene glycol to the Benzimidazole and heat until it is totally dissolved. Let it get cold and increase up to 100 ml with distilled water. Add 1 g of Celite and agitate during 30 minutes. Then filter.

Example 6 solutions having n-butanol as cosolvent.

QUANTITATIVE FORMU1tLA: Every 100 ml of the solution contain Benzimidazole.... 10 g Polyethylene glycol 400 60. ml :4,300 n-Butanol e.q.r. 100 ml Method Add all the Polyethylene glycol to the Benzimnidazole and heat until total dissolution. Let it get cold and increase up to 100 ml with n-Butanol. Add 1 g of Celite and agitate during 30 minutes. Then filter.

o e Distilled water e.q.r. 1004 ml Mgtbr~d Add all the Polyethyl1,ne glycol to the Benzimidazole and heat until total dissolution.,Let it get cold and increase up to 100 ml with distilled water, Add I g of Celite and agitate during 30 minutes. The~n filter.

Example 8 1.2.5% solutions having n-Butanol as cosolvent.

!OUANTITATIVE FORMULA: Every 100 ml of the solution contain Albendazole sulfoxidd #12.5g :64'0*6 Polyethylene glycol 400 4.S...M n-Butanol e.q.r. 100 m I Method Add all the Polyethylene glycol, to the Benzimidazole and heat until total dissolution. Let it get cold and increase up to 100 ml with n-Butanol. Add 1 g of Celite and a'gitato during 30 minutes. Then filter.

.9 9m~e,.

souin aigCBuao scsle 00CCT---OMM.t~y10 lo h olto oti Oxphendazole 15. g.

Polyethylene glycol 400 n-Butano e.q.r. 100 ml kethod Add all the Polyethylene glycol to the Benzimidazole and heat until total dissolution. Let it get cold and increase up to 100 mi with n-Butanol. Add 1 g uf Celite and agitate during minutes. Then filter.

Ajmple 17.5% solutions having n-Butanol as cosolvent.

t 4 S1 4" QUANTITATIVE FORMLA: Every 100 ml of the solution contain Phenbendazole 17. g 5Polyethylene glycol 400 n-Butanol e.q.r. 100 ml

S

5

SI

M-ethod Add all the Polyethylene glycol to the Benzimidazole and h: ~heat until total dissolution. Let it get cold and increase up to 100 ml with n-Butanol. 4d 1 g of Colite and agitate during minutes. Then filter.

B 2ample Il solutions having n-Butanol as cosolvent.

'I

QUANTITATIVE FORMULA: Every 100 ml of the solution contain 20. g.

Polyethylene glycol 400 n-Butanol 100 ml Method Add all the Polyethylene glycol to the Ben~'imidazo1e and heat until total dissolution. Let it get cold and increase, up to 100 ml with n-Butanol. Add 1 g of Celite and agitate during .0 30 minutes. Then filter.

44 4.

4. 4

C

4 4 4 4 4 44 44 se 4 4 4 04 40 .4 4

S

4 .4 4.

4.

4* 04 04 4 4 0 *004 4 0 4.

0* 0 44 4 4404 0 .4.4.4 4

Claims (10)

1. A subcutaneous or intramuscular injectable composition for the treatment of gastrointestinal helminthiasis, the composition comprising a benzimidazole as an anthelmintic agent in solution in a therapeutically acceptable carrier wherein the carrier comprises a low molecular weight Ci-C 4 polyalkylene glycol and a cosolvent.

2. A composition as claimed in claim 1 wherein the glycol is polyethylene glycol 50-15000.

3. A composition as claimed in claim 2 wherein the glycol is polyethylene glycol 400.

4. A composition as claimed in any one of the preceding claims wherein the cosolvent is any one of the group consisting of water, a C 2 -Cg alkanol, a C2-CS monoalkylene glycol, a fatty acid ester of a C2-C, monoalkylene glycol and glycerol.

5. A composition as claimed in claim 4 wherein the cosolvent is n-butanol. 00*r 20 6. A composition as claimed in any one of the O preceding claims wherein the benzimidazole is Salbendazole, phenbendazole, albendazole sulfoxide or oxphendazole.

7. A composition as claimed in any one of the preceding claims having a benzimidazole concentration of 2-20% w/v.

8. A method for preparing a composition as claimed in any one of the preceding claims comprising dissolving the benzimidazole in the glycol and subsequently increasing the volume by addition of the cosolvent.

9. A method as claimed in claim 8 wherein the benzimidazole is dissolved in the glycol with heating. A method as claimed in claim 9 wherein the benzimidazole is dissolved in the glycol at a temperature in the range of 60-100°C. S.979A703 15

11- A subcutaneous or intramuscular injectable composition for the tr~eatment of gastrointestinal helminthiasis, the composition being substantially as herein described with ref e,'ence to any Example. 1.2. A method for preparing a subcutaneous or intramuscular injectable oomposition for the treatment of gastrointestinal helmir thiasis, the method being substantially as herein ;described with reference to any Example. DATED this 6th day of JTuly 1995 DdIgROSULES ARGENTINA S.A. DE 3ERVICIOS C.I.I.A. By its Patent Attorney11 GRIFFITH HACK &CO. Soo* se:

444.. A S,:22570AI703 ABSTRACT Subcutaneous or intaiuscu.a' injectable compositions for thea treatment of gastrointestinal halminthiasis, i oharaoterized in that it contains benzimidazoles as anthalmintio agent in ~O3ution in a therapeuticaliy aacieptable carrier which ompisiea po1yalkyleno (CI-C 4) glYcOls havibg a low molecular weight and a cosolvent. 69 00 a. 0 0 000 00