COMPOSITIONS COMPRISING TIGOLANER FOR CONTROLLING PARASITES

Abstract

The present invention relates to a composition comprising tigolaner and, optionally endoparasiticidal agents, a method for its manufacture and its use as a medicament for controlling parasites. Compositions can include tigolaner and 1,2-isopropylideneglycerol, or the composition can include praziquantel, emodepside a solvent component, and tigolaner. The composition can be used in the treatment and/or prevention of parasite infections in animals.

Claims

1. A composition comprising tigolaner and 1,2-isopropylideneglycerol.

2. The composition according to claim 1 comprising ≥1 weight-% to ≤15 weight-% tigolaner

3. The composition according to claim 1, further comprising praziquantel.

4. The composition according to claim 3, comprising ≥1 weight-% to ≤15 weight-% praziquantel.

5. A composition comprising praziquantel, emodepside and a solvent component, characterized in that the composition further comprises tigolaner.

6. The composition according to claim 5, wherein the solvent component comprises 1,2-isopropylideneglycerol.

7. (canceled)

8. The composition according to claim 6, comprising: ≥1 weight-% to ≤15 weight-% praziquantel; ≥1 weight-% to ≤10 weight-% emodepside; ≥1 weight-% to ≤15 weight-% tigolaner; wherein the weight-percentages are based on the total weight of the composition and add up to 100 weight-%.

9. The composition according to claim 6, further comprising an anti-oxidant.

10. The composition according to claim 9, wherein the anti-oxidant is butyl hydroxyanisole (BHA) and/or butyl hydroxytoluene (BHT).

11. The composition according to claim 6, further comprising an acid.

12. The composition according to claim 11, wherein the acid is lactic acid.

13. The composition according to claim 6, comprising: ≥1 weight-% to ≤15 weight-% praziquantel; ≥1 weight-% to ≤10 weight-% emodepside; ≥1 weight-% to ≤15 weight-% tigolaner; ≥0.01 weight-% to ≤1 weight-% butyl hydroxyanisole (BHA) and/or butyl hydroxytoluene (BHT); ≥1 weight-% to ≤5 weight-% lactic acid; wherein the weight-percentages are based on the total weight of the composition and add up to ≤100 weight-%.

14. A method for producing a composition according to claim 5, comprising the step of dissolving praziquantel, emodepside and tigolaner in a solvent component.

15-19. (canceled)

20. The composition according to claim 6, wherein the water content of the composition is at most 5% by weight.

21. The composition according to claim 20, wherein the solvent component comprises only 1,2-isopropylideneglycerol.

22. A drug for treating and/or preventing parasite infections in animals, comprising tigolaner and 1,2-isopropylideneglycerol.

23. A drug for treating and/or preventing parasite infections in animals, comprising praziquantel, emodepside and a solvent component, characterized in that the drug further comprises tigolaner.

24. The drug according to claim 22, wherein the animals are cats.

25. The drug according to claim 23, wherein the animals are cats.

Description

EXAMPLES

[0105] The present invention will be further described in the following examples without wishing to be limited by them. Solketal is 1,2-isopropylideneglycerol. All examples shown include Solketal that already contains 0.3% BHA for general stability of the solvent.

[0106] Examples were prepared by mixing the ingredients using a stirrer. In compositions containing praziquantel and tigolaner, praziquantel was added first to facilitate the dissolution of tigolaner. In compositions containing emodepside and tigolaner, a preferred option is that emodepside is added first to facilitate the dissolution of Tigolaner. In compositions containing praziquantel, emodepside and tigolaner, the preferred option is that praziquantel and emodepside are added first to facilitate the dissolution of Tigolaner. All examples are homogeneous solutions.

Example 1

[0107]

TABLE-US-00001 Ingredient % w/w Tigolaner 9.7 Solketal to 100.0

Example 2

[0108]

TABLE-US-00002 Ingredient % w/w Tigolaner 10.7 Praziquantel 7.4 Solketal to 100.0

Example 3

[0109]

TABLE-US-00003 Ingredient % w/w Tigolaner 11.0 Praziquantel 7.4 Emodepside 1.7 Solketal to 100.0

Example 4

[0110]

TABLE-US-00004 Ingredient % w/w Tigolaner 8.9 Praziquantel 7.4 Emodepside 1.85 Milchsäure 2.0 BHT 0.1 Solketal to 100.0

Example 5

[0111]

TABLE-US-00005 Ingredient % w/w Tigolaner 8.9 Praziquantel 7.4 Emodepside 1.85 Milchsäure 2.0 BHT 0.2 Solketal to 100.0

Example 6

[0112]

TABLE-US-00006 Ingredient % w/w Tigolaner 8.9 Praziquantel 7.4 Emodepside 1.85 Milchsäure 2.0 BHT 0.4 Solketal to 100.0

Example 7

[0113]

TABLE-US-00007 Ingredient % w/w Tigolaner 9 Solketal to 100.0

Example 8

[0114]

TABLE-US-00008 Ingredient % w/w Tigolaner 9.5 Solketal to 100.0

Example 9

[0115]

TABLE-US-00009 Ingredient % w/w Tigolaner 9 BHT 0.1 Solketal to 100.0

Example 10

[0116]

TABLE-US-00010 Ingredient % w/w Tigolaner 9.5 BHT 0.1 Solketal to 100.0

Example 11

[0117]

TABLE-US-00011 Ingredient % w/w Tigolaner 9 BHT 0.2 Solketal to 100.0

Example 12

[0118]

TABLE-US-00012 Ingredient % w/w Tigolaner 9.5 BHT 0.2 Solketal to 100.0

Example 13

[0119]

TABLE-US-00013 Ingredient % w/w Tigolaner 9 BHT 0.4 Solketal to 100.0

Example 14

[0120]

TABLE-US-00014 Ingredient % w/w Tigolaner 9.5 BHT 0.4 Solketal to 100.0

Example 15

[0121]

TABLE-US-00015 Ingredient % w/w Tigolaner 9 Praziquantel 7.94 Emodepside 1.984 BHT 0.4 Solketal to 100.0

Example 16

[0122]

TABLE-US-00016 Ingredient % w/w Tigolaner 9 Praziquantel 7.94 Emodepside 1.984 BHT 0.2 Lactic acid 2.0 Solketal to 100.0

Example 17

[0123]

TABLE-US-00017 Ingredient % w/w Tigolaner 9 Praziquantel 7.54 Emodepside 1.885 BHT 0.2 Lactic acid 2.0 Solketal to 100.0

Example 118

[0124]

TABLE-US-00018 Ingredient % w/w Tigolaner 9 Praziquantel 7.54 Emodepside 1.885 BHT 0.4 Lactic acid 2.0 Solketal to 100.0

Example 19

[0125]

TABLE-US-00019 Ingredient % w/w Tigolaner 9 Praziquantel 7.54 Emodepside 1.885 BHT 0.1 Lactic acid 2.0 Solketal to 100.0

Example 20

[0126]

TABLE-US-00020 Ingredient % w/w Tigolaner 8.909 Praziquantel 7.409 Emodepside 1.864 BHT 0.4 Lactic acid 2.0 Solketal to 100.0

Example 21

[0127]

TABLE-US-00021 Ingredient % w/w Tigolaner 9.1 Praziquantel 7.94 Emodepside 1.98 BHT 0.4 Lactic acid 2.0 Solketal to 100.0

Example 22

[0128]

TABLE-US-00022 Ingredient % w/w Tigolaner 9.1 Praziquantel 7.94 Emodepside 1.98 BHT 0.2 Lactic acid 2.0 Solketal to 100.0

Example 23

[0129]

TABLE-US-00023 Ingredient % w/w Tigolaner 9.1 Praziquantel 7.94 Emodepside 1.98 BHT 0.1 Lactic acid 2.0 Solketal to 100.0

Example 24

[0130]

TABLE-US-00024 Ingredient % w/w Tigolaner 8.909 Praziquantel 7.409 Emodepside 1.864 BHT 0.2 Lactic acid 2.0 Solketal to 100.0

Example 25

[0131]

TABLE-US-00025 Ingredient % w/w Tigolaner 8.909 Praziquantel 7.409 Emodepside 1.864 BHT 0.1 Lactic acid 2.0 Solketal to 100.0

Biological Examples

[0132] A. Summary of in-vitro test results for Tigolaner as disclosed in WO2014/122083:

[0133] Test methods and results have already been described in WO2014/122083. Results disclosed therein for Tigolaner (Ex. Ic-2 in WO2014/122083) for parasites relevant in the veterinary field are summarized below:

[0134] Amblyomma hebraeum: 100% efficacy at 100 ppm

[0135] Boophilus microplus—Dip test: 100% efficacy at 100 ppm

[0136] Boophilus microplus—injection test: 100% efficacy at 20 μg/tick

[0137] Ctenocephalides felis—oral test: 100% efficacy at 100 ppm

[0138] Ctenocephalides felis—contact test: 100% efficacy at 1 μg/cm.sup.2

[0139] Lucilia cuprina: 100% efficacy at 100 ppm

[0140] Musca domestica: 100% efficacy at 100 ppm

[0141] Rhipicephalus sanguineus—contact test: 100% efficacy at 1 μg/cm.sup.2

[0142] Ixodes ricinus—contact test 100% efficacy at 1 μg/cm.sup.2

[0143] Amblyomma hebraeum—contact test: 100% efficacy at 1 μg/cm.sup.2

[0144] B. Summary of In-Vivo Test Results for Tigolaner in Rats as Disclosed in WO2014/122083:

[0145] Test methods and results have already been described in WO2014/122083. Results for Tigolaner (Ex Ic-2 in WO2014/122083) for parasites relevant in the veterinary field are summarized below:

[0146] Dermacentor variabilis—systemic in vivo activity against American dog tick nymphs on rats: Efficacy of >90% against tick nymphs on day 2 at an application rate of 10 mg/kg.

[0147] Ctenocephalides felis—systemic in vivo activity against fleas on rats: efficacy of >95% on day 2 and of >90% on day 9 at an application rate of 10 mg/kg.

[0148] C. In-Vivo Study Endoparasites: Efficacy of a Spot-On Formulation against Patent Toxocara cati and Dipylidium caninum Infections in Experimentally Infected Cats.

[0149] Before treatment 16 cats were experimentally infected each with T. cati (larvated eggs) and a feline strain of D. caninum (using infected C. felis fleas—oral and topical infestations).

[0150] On Day -1, 14 cats with patent infections of both T. cati and D. caninum were included in the study. Cats were allocated to 2 groups consisting of 7 cats each.

[0151] The spot-on Investigational Veterinary Product (IVP) was a composition according to the present invention containing 10% tigolaner, 7.94% praziquantel and 1.98% emodepside (w/v) in a solution on solketal basis. The IVP was administered to the cats in the IVP group (group 2) on Day 0 at a dose rate of 3.2 mg emodepside plus 12.7 mg praziquantel and 16 mg tigolaner/kg BW (BW=body weight), corresponding to 0.16 mL of the spot-on formulation/kg BW. Cats in group 1 served as the negative control group. On Day 10 the cats were subjected to euthanasia and gastrointestinal helminths were recovered during necropsy. Worms were identified and counted. Efficacy calculations were based on the number of worms recovered at necropsy in the IVP group, compared to the negative control group. The following formula was used:

Efficacy (%)=100×(Mc−Mt)/Mc,

[0152] where

[0153] Mc=Geometric mean number of worms/scoleces in the negative control group (group 1)

[0154] Mt=Geometric mean number of worms/scoleces in the IVP group (group 2)

[0155] All cats in the control group contained T. cati worms, whilst 5 cats contained D. caninum scoleces. An efficacy of 100% was obtained in IVP group against both T. cati and D. caninum.

[0156] No Adverse Events (AEs) occurred.

[0157] D. In-Vivo Study Ectoparasites: Efficacy of a Spot-On Formulation Against Experimental Ticks and Flea Infestations in Cats.

[0158] On SD—4 twelve cats were included in the study. On SD-1, cats were experimentally infested with Ixodes ricinus ticks, which were counted without removal on SD 0 (for group allocation) and were removed and counted on SD 2 (treatment efficacy). On SD 0, six cats were treated with the IW applied once as a spot-on at a dosage of 14 mg tigolaner+3 mg emodepside+12 mg praziquantel per kg bodyweight. Six cats served as untreated controls.

[0159] The IVP contained 10% (m/V) Tigolaner, 8.58% (m/V) Praziquantel and 2.14% (m/V) emodepside in a solution on solketal basis.

[0160] Cats were experimentally infested with ticks and fleas fortnightly. Efficacy of the IW was determined by comparison of tick and flea counts of the treatment group versus the control group. General health was observed daily.

TABLE-US-00026 TABLE 1 Study design Day Days of infestations No. Treatment of and counts of and treat- I. ricinus C. felis Group cats dosage ment ticks* fleas** 1 6 IVP 0 Infestations: Infestations: [14 mg SDs −1, 16, SDs 1, 15, Tigolaner + 29, 43, 42, 56, 3 mg emo- 57, 72, 85 71, 78 depside + Counts (48 h): Counts: 12 mg SDs 0, 2, SDs 2, 16, pra- 18, 31, 45, 29, 43, ziquantel] 59, 74, 87 57, 72, 85 2 6 n/a n/a *Each cat was infested with 20 female and 20 male Ixodes ricinus ticks. **Each cat was infested with 100 C. felis

TABLE-US-00027 TABLE 2 Efficacy against fleas and ticks based on arithmetic means Efficacy against fleas SD 2 SD 16 SD 29 SD 43 SD 57 SD 72 SD 85 100.00 99.09 100.00 100.00 100.00 100.00 99.59 Efficacy against ticks SD 2 SD 18 SD 31 SD 45 SD 59 SD 74 SD 87 100.00 100.00 100.00 97.60 100.00 100.00 100.00

[0161] Efficacy (≥99%) against fleas could be claimed on all study days up to SD 85.

[0162] Therapeutic efficacy (≥90%) against ticks could be claimed on SD 2 and preventive efficacy against ticks could be claimed up to SD 87.

[0163] The IVP was very well tolerated in cats upon single topical treatment. There were no adverse events related to IVP-treatment during this study