WO2000004906A1

WO2000004906A1 - Non-aqueous anthelmintic composition

Info

Publication number: WO2000004906A1
Application number: PCT/GB1999/002364
Authority: WO
Inventors: Sean Duffy; Lillian Cromie
Original assignee: Norbrook Laboratories Limited
Priority date: 1998-07-24
Filing date: 1999-07-21
Publication date: 2000-02-03
Also published as: AU5054099A; UY25622A1; JO2129B1; GB9816132D0; DZ2853A1; CO5070578A1; GB2339691A; AR020613A1; PE20001064A1; GB9915531D0

Abstract

A veterinary composition, for combating endoparasites and ectoparasites, and offering an improved pharmacokinetic profile, contains as parasiticide an Avermectin, especially Ivermectin or a Milb emycin, in an amount of from about 0.1 %w/v to 20 %w/v, dissolved in a solvent system containing up to about 75 %v/v of polyethylene glycol and not less than about 25 %v/v glycerol formal.

Description

Non-aqueous anthelmintic composition

Technical Field

The present invention relates to the preparation of veterinary compositions for combating infestations of endoparasites and ectoparasites, and in particular to improved parenteral compositions containing an anthelmintic such as an Avermectin, particularly Ivermectin, or a Milbemycin.

Background Art

The Avermectin family, of which Ivermectin is a member, is a series of very potent antiparasitic agents which are useful against a broad spectrum of endoparasites and ectoparasites in mammals as well as having agricultural uses against various parasites found in and on crops and soil. The basic Avermectin compounds are isolated from the fermentation broth of the soil micro-organism Streptomyces avermitilis and these compounds are described in US patent US4310519. Furthermore, derivatives of these basic Avermectin compounds have been prepared by a variety of chemical means.

Some of the Avermectin group of compounds contain a 22, 23-double bond and others contain a disaccharide at the 13-position which consists of α-L-oleandrosyl-α-L-oleandrosyl group. One or both saccharide units can be removed forming a monosaccharide or an aglycone (where both saccharides are removed) as described in US patent US 4206205. The aglycone derivatives possess a hydroxy group at the 13 position which may be removed to form the 13-deoxy compound as described in US patents US 4171314 and US 4173571. Acylation of hydroxy groups on the Avermectin compounds and derivatives can be carried out as described in US patent US 4201861.

On the other hand the Milbemycin series of compounds, disclosed in US patent US 3950360, are structurally similar to the Avermectin family in that they contain the sixteen membered macrocyclic ring. However, they do not contain the disaccharide subunit and there are differences in the substituent groups.

Ivermectin, disclosed in the US patent US 4199569, is prepared by the selective reduction of the 22, 23 double bond of the Avermectin compounds. Ivermectin is a mixture of

22, 23-dihydro Avermectin Bla and Bib in a ratio of at least 80:20. Since it is known to have activity against both endoparasites and ectoparasites, it is desirable to couple the convenience of a parenteral formulation and the broad spectrum activity of Ivermectin.

An aqueous micelle formulation, such as that disclosed in

US patent US4389397, is useful for parenteral administration however higher activity has been noted against endoparasites than ectoparasites.

An object of the present invention is to provide a parenteral composition that demonstrates improved levels of the active parasiticidal agent e.g. Ivermectin in the blood so that activity against both endo- and ectoparasites is established more quickly and maintained for as long a period as possible. Thus an optimum pharmacokinetic profile is desired to maximise the anti-parasitic activity of the Ivermectin molecule.

Disclosure of Invention

According to the present invention there is provided a veterinary composition comprising an amount of anthelmintic agent in the range about 0.1%w/v to about 20%w/v, dissolved in a volume of up to a maximum of about 75% v/v of polyethylene glycol and a minimum of about 25% v/v glycerol formal.

Such a composition is suitable for use as a parenteral composition, showing the desired properties with regard to solubility, injectability, and improved pharmacokinetic profile with respect to the anthelmintic.

Preferably the amount of anthelmintic agent is l%w/v. Advantageously the anthelmintic agent is an Avermectin or a Milbemycin but more preferably Ivermectin.

Preferably the ratio of polyethylene glycol to glycerol formal in the mixture is about 60:40v/v.

Preferably also the polyethylene glycol (PEG) has an average molecular weight in the range of 100 - 1000, with PEG 200 being considered surprisingly useful.

The present invention provides an improved parenteral composition in which, unexpectedly, the pharmacokinetic profile of the anthelmintic, particularly avermectin type of compound, is enhanced by the use of the compositions described herein, enabling remedial therapy for livestock affected by endoparasites and ectoparasites to be accomplished.

Typical compositions provided by the invention consist of polyethylene glycol and glycerol formal with an avermectin or milbemycin compound. They are generally prepared by dissolving the avermectin or milbemycin compound in either polyethylene glycol or glycerol formal and, upon complete dissolution, the remaining solvent is added to volume so that the target final active molecule and excipient concentration are achieved.

The amount of avermectin or milbemycin can vary from about 0.1%w/v to 20%w/v but is generally l%w/v and is dissolved in a solvent system consisting of polyethylene glycol (PEG) and glycerol formal (GF) which can be in the ratio such that there is up to about 75%v/v PEG, and not less than about 25%v/v GF, but generally a ratio of about 60:40 v/v PEG to GF is preferred. Sterilisation of the composition is preferably carried out by the use of membrane filtration as the active drug may be susceptible to degradation at normal sterilisation temperatures, as will be recognised by persons skilled in this art and familiar with such compounds. The present invention will now be described below in more detail by way of the following example, which is provided in order that the invention may be more fully understood but it is not intended that the scope of the invention should be limited to the detail of the specific example described: rather, reference should be made to the patent claims hereinafter appearing.

Mode for Carrying Out the Invention

Example In the preparation of a 1.0%w/v Ivermectin parenteral solution the composition was as follows:

Ivermectin 1.0%w/v

Glycerol Formal 40%v/v

Polyethylene Glycol (PEG 200) q.s. 100%v/v

The Ivermectin was dissolved in the glycerol formal, upon completion of dissolution half of the required volume of polyethylene glycol was added with further stirring. Finally the remainder of the polyethylene glycol was added to the final desired volume, the solution was sterilised by membrane filtration and packaged aseptically.

A trial was conducted to compare the pharmacokinetic profile of the invention against a commercial anthelmintic preparation with established safety and efficacy. The trial consisted of twenty healthy beef cattle and was of a cross- over design to compare plasma levels of Ivermectin following the subcutaneous administration of the preparations.

The results (Table l^a) demonstrate that the invention had a more rapid initial rate of absorption as evidenced by the higher mean value for C_maX (ng/ml) and a greater extent of absorption as evidenced by the higher values for AUC

(ng/ml/hr) , where C_π___x is maximum plasma concentration, and AUC is a value understood in this art and refers to the mean area under the curve where the data is represented graphically. Thus greater bio-availability was demonstrated for the composition of this invention with respect to the control article showing that the invention provides for greater levels of Ivermectin in the blood for a greater length of time maximising the activity against both endo- and ecto-parasites.

Table l^a

The mean C_maχ and AUC parameters presented for the invention and the commercial formulation were calculated in a manner recognised in this art wherein the empirical data was first modelled using a computer pharmacokinetic modelling package "PC NONLIN". The pharmacokinetic parameters when calculated directly from the empirical data are as shown in the following Table l^b.

Table

The mean C_ma for the invention has been shown to be significantly different (greater) from the commercial formulation but the difference in AUC for each formulation is not significant. Therefore it is evident that the invention described herein provides for optimum levels of Ivermectin in the plasma.

In addition to the pharmacokinetic studies referred to above, clinical studies have now been completed which demonstrate the efficacy of the invention with respect to the commercial formulation. The efficacy of the invention and the commercial formulation was determined against Ostertagia ostertagi and Cooperia oncophora infections in cattle as measured by the reduction in fecal nematode egg counts post treatment. Ostertagia ostertagi and Cooperia oncophora were selected as they are considered as the dose-limiting parasites for the activity of the drug molecule. The study was designed so that calves were infected with Ostertagia ostertagi and Cooperia oncophora on Day -22 and on Day 0 fecal nematode egg counts were taken and the calves were divided into treatment groups . Group 1 acted as a non-treated control group and Groups 2 and 3 were treated with the invention and commercial formulation (Comm F) respectively. Fecal egg counts were subsequently carried out at Day +1, +7, +14 and +21 with the mean fecal egg count results and the associated % efficacy (% Eff) presented in the following Table 2.

Table 2: Mean fecal egg counts and % efficacy for the invention and commercial formulation against Ostertagia ostertagi and Cooperia oncophora infections in cattle. It is evident from the results of this clinical study that both invention and commercial formulation were efficacious against the infection from both parasites at Day 1 and 7. However at Day +21 the invention provides greater protection against the parasitic infection as it was demonstrated that fecal egg counts for the invention were significantly different from the non-treated control (p<0.001) but the fecal egg counts for the commercial formulation were not significantly different from the control (p>0.05). Therefore it is evident that the composition of the invention unexpectedly provides for increased levels of Ivermectin in the plasma with respect to the commercial formulation which is manifested as greater efficacy in the efficacy studies. Thereby, it may be concluded that the composition of the invention provides for greater protection against parasitic infections in the target species .

Clearly an advantage offered by the present invention is that the pharmacokinetic profile of the anthelmintic compounds is enhanced by the use of the compositions described above, such that an optimum pharmacokinetic profile is obtainable: thus maximising the anti-parasitic activity of the anthelmintic molecule. Furthermore, the parenteral composition of the present invention provides optimum levels of Ivermectin in the blood so that activity against both endo- and ectoparasites is established more quickly and maintained for as long a period as possible.

Industrial Applicability

In view of the aforesaid advantages and properties of the compositions described herein, the invention will be usefully applied in the field of veterinary medicine in particular for combating endoparasites and ectoparasites typically afflicting livestock such as bovines, equines and ovines.

Claims

1. A veterinary composition comprising an amount of an anthelmintic agent in the range of from 0.1%w/v to 20%w/v, dissolved in a volume of solvent containing up to about 75% v/v of polyethylene glycol and not less than about 25%v/v glycerol formal.

2. A veterinary composition according to claim 1, wherein the amount of anthelmintic agent is l%w/v.

3. A veterinary composition according to claim 1 or claim 2, wherein the anthelmintic agent is an Avermectin.

4. A veterinary composition according to claim 1 or claim 2, wherein the anthelmintic agent is a Milbemycin.

5. A veterinary composition according to claim 3, wherein the anthelmintic agent is Ivermectin.

6. A veterinary composition according to claim 1 or claim 2, wherein the ratio of polyethylene glycol to glycerol formal in the mixture is 60:40v/v.

7. A veterinary composition according to claim 5, wherein the Ivermectin is dissolved in a co-solvent system consisting of about 60%v/v polyethylene glycol and about 40%v/v glycerol formal.

8. A veterinary composition according to claim 1 or claim 2, wherein the polyethylene glycol has an average molecular weight in the range of 100 to 1000.

9. A veterinary composition according to claim 1 or claim 7 wherein the polyethylene glycol is PEG 200.

10. A parenteral composition for combating endoparasites and ectoparasites in livestock consisting of an anthelmintic agent in an amount of from 0.1%w/v to 20%w/v in a co- solvent mixture of about 60%v/v polyethylene glycol 200 and about 40%v/v glycerol formal.

11. A method of combating endoparasites and ectoparasites in livestock consisting of the parenteral administration of an anthelmintic agent in an amount of from 0.1%w/v to 20%w/v in a co-solvent mixture of about 60%v/v polyethylene glycol 200 and about 40%v/v glycerol formal to livestock affected by such parasites.

12. A method according to claim 11, wherein the anthelmintic administered is Ivermectin, and the amount thereof is l%w/v.