WO2008075984A2 - Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents - Google Patents
Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents Download PDFInfo
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- WO2008075984A2 WO2008075984A2 PCT/NZ2007/000383 NZ2007000383W WO2008075984A2 WO 2008075984 A2 WO2008075984 A2 WO 2008075984A2 NZ 2007000383 W NZ2007000383 W NZ 2007000383W WO 2008075984 A2 WO2008075984 A2 WO 2008075984A2
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- 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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Definitions
- the invention relates to a tablet formulation. More specifically, the invention relates to a tablet formulation containing at least one macrocyclic lactone compound with anthelmintic activity dissolved in at least one organic solvent along with levamisole and optionally at least one further anthelmintic compound for use in treatment of animal parasites.
- Anthelmintic chemical compounds are widely known agents that are destructive to worms and used for treating internal and external parasitic infestations in animals including humans.
- a difficulty in formulating such compounds is that many are extremely insoluble in aqueous environments such as extracellular ' fluids thus they need to be formulated to ensure they are bioavailable.
- different conditions may be required resulting in situations where one compound may be solubilized by for example, by reducing pH. This change can cause other compounds in the formulation to become insoluble, or the change may cause physical or chemical degradation of another compound in the formulation. In addition, the change may cause adverse side effects in the animal.
- an aim is to provide a tablet formulation containing at least two different anthelmintic compounds ideally from different families of anthelmintic activity.
- One preferred method of administration is by injection however, as the solubility of the anthelmintic is often poor, drugs delivered by injection are not always readily absorbed and often may cause pain to the animal or human absorption or precipitate formation.
- the macrocyclic lactone family of anthelmintic compounds which family includes abamectin and ivermectin, present a different challenge again with such compounds being lipophilic and largely insoluble in aqueous environments.
- a tablet formulated to include one or more anthelmintic agents is a challenge particularly where the agents are lipophilic, require specific conditions in which to dissolve or may lose viability when stored over time.
- Another problem specific to tablets is ensuring that the tablet dissolves on administration and releases the active agents in a form that is bioavailable and does not simply pass through the animal without achieving the desired therapeutic effect.
- an albendazole capsule for the treatment of gastrointestinal parasites in adult sheep and lambs (marketed in New Zealand as EXTENDER® 100).
- This product is formulated to provide a slow release of albendazole to 'control' parasites over a time period of 100 days.
- a disadvantage of this product is the continuous release of albendazole at levels below that required to kill adult parasites.
- the drug levels are designed to the kill incoming larvae, which require a lower dose rate for control than adult parasites - in effect the product's main use may be as a prevention method and not to address infestation once it occurs.
- Another product is a slow release capsule containing ivermectin (marketed in New Zealand as IVOMEC® MaximiserTM CR). It gives a slow release of ivermectin over 100 days with ivermectin levels dropping below that required to kill adult parasites for a substantial amount of that time. It consequently suffers from the disadvantages previously described.
- tablette refers to the formulation being administered orally and in a consistency able to be administered as a granular material, discrete tablet or capsule, or alternatively expelled by device such as a 'pill popper', stomach tube or other delivery device.
- a tablet formulated for administration to an animal characterised in that the tablet includes: (a) at least one macrocyclic lactone compound having anthelmintic activity and; (b) at least one levamisole compound with anthelmintic activity; and, wherein the macrocyclic lactone compound or compounds are dissolved in at least one organic solvent.
- macrocyclic lactone compounds used in the tablet are generally characterised by being lipophilic and having poor solubility and/or poor dispersion characteristics in an aqueous environment. It is understood by the inventors that this poor solubility and/or poor dispersion results in corresponding poor oral absorption, which may lead to poor pharmacokinetics. These factors may contribute to the macrocyclic lactone compound(s) having poor oral bioavailability. If such a compound is administered absent of a suitably formulated delivery system, the compound may either not be absorbed or be only poorly absorbed within an aqueous environment such as the blood stream.
- a compound may display 'poor oral bioavailability' if, when orally delivered to an animal on its own (i.e. absent of a suitably formulated delivery system), it achieves less than approximately 20% absorption of the compound into the blood stream when compared with the results obtained using an equivalent single active oral drench.
- an 'aqueous environment' may be extracellular fluid.
- the macrocyclic lactone compound or compounds may be selected from: abamectin, ivermectin, moxidectin, eprinomectin, doramectin and combinations thereof. More preferably, the macrocyciic lactone compound is abamectin or ivermectin.
- the macrocyclic lactone compound or compounds and levamisole compound or compounds included in the tablet are at a dose sufficient to: prevent growth of parasites; reduce parasite numbers; kill parasites; kill incoming parasite larvae; lower the number of surviving incoming parasite larvae; kill or reduce the number of hypobiotic state parasites; and combinations thereof.
- the tablet includes sufficient macrocyclic lactone and levamisole compound or compounds to provide the animal with a dose of the compound or compounds equivalent to that which would be obtained from an oral drench containing the same compound or compounds
- the abamectin is included at a rate of at least approximately 0.2mg to 0.6 mg of abamectin or ivermectin per kg of animal body weight. More preferably, the rate is approximately 0.2 mg/kg. Most preferably the rate is approximately 0.4mg/kg. It should be appreciated that this dose is sufficient to kill or at least reduce parasite infestation including both larvae and adult parasites.
- the amount of active ingredient per tablet for a cattle formulation is 64mg abamectin per tablet dosed to an animal weighing approximately 160kg. It is the inventor's experience that this level of abamectin provides a blood level of abamectin to the animal equivalent to that which would be obtained from an oral drench containing abamectin such as the product GenesisTM. It should be appreciated that the dosage of abamectin may be varied depending on the amount of abamectin desired to be administered and that levels of abamectin above or below 64mg may be used without departing from the scope of the invention. Similarly, the dose may be varied for different animals.
- the levamisole compound is levamisole hydrochloride (HCI).
- HCI levamisole hydrochloride
- the levamisole is levamisole HCI included at a rate of approximately 5 to 9 mg levamisole per kg of animal body weight, more preferably, approximately 7.5 mg levamisole per kg of animal body weight. It should be appreciated that it is unexpected to be able to produce a single dose tablet that includes both a macrocyclic lactone compound or compounds co-administered with a levamisole compound or compounds and maintain efficacy and stability. This is because each agent has very different solubilities and simply mixing the two compounds would not obviously result in a stable and efficacious formulation. In addition, tablets have different pharma-kinetics to solutions such as drenches so combinations in the art which use drenches and pour-on formulations are not suitable guidance when developing a tablet.
- the tablet rapidly releases the macrocyclic lactone and levamisole compounds on oral administration.
- the macrocyclic lactone and levamisole compound or compounds remain present in the bloodstream of the animal for at least 24 hours.
- the macrocyclic lactone and levamisole compound or compounds are formulated so that the compound or compounds dissipate from the bloodstream of the animal in a similar manner as an oral drench containing each compounds individually. It is understood by the applicant that the compound has left the blood stream after a time period of no more than two weeks.
- the tablet includes at least one additional compound with anthelmintic activity.
- the additional anthelmintic compound or compounds have a different spectrum of anthelmintic activity than the macrocyclic lactone or levamisole compounds used.
- the additional anthelmintic targets parasites which have resistance to macrocyclic lactone compounds.
- the additional compound with anthelmintic activity is a substituted or unsubstituted benzimidazole compound with anthelmintic activity.
- the substituted or unsubstituted benzimidazole compound has the structure:
- the substituted or unsubstituted benzimidazole compound may be selected from: albendazole, ricobendazole, fenbendazole, oxfenbendazole, parbendazole, triclabendazole and combinations, analogues and derivatives thereof.
- the benzimidazole compound is albendazole.
- the substituted or unsubstituted benzimidazole compound or compounds included in the tablet are at a dose sufficient to: prevent growth of parasites; reduce parasite numbers; kill parasites; kill incoming parasite larvae; lower the amount of incoming parasite larvae; and combinations thereof.
- the tablet includes sufficient benzimidazole compound or compounds to provide the animal with a dose of the compound or compounds equivalent to . that which would be obtained from an oral drench containing the same benzimidazole compound or compounds
- the albendazole is included at a rate of at least 1 mg albendazole per kg of animal body weight.
- albendazole is included at a rate of approximately 3.7 mg albendazole per kg of animal body weight where the animal is a sheep.
- albendazole is included at a rate of approximately 7.5 mg albendazole per kg of animal body weight where the animal is a bovine. It should be appreciated that this dose is sufficient to kill or at least reduce parasite infestation including both larvae and adult parasites.
- the amount of active ingredient per tablet for a cattle formulation is 1200mg albendazole per tablet dosed to an animal weighing approximately 160kg. It is the inventor's experience that this level of albendazole provides an oral bioavailability equivalent to that which would be obtained from an oral drench containing albendazole such as the product ValbazenTM. It should be appreciated that the dosage of albendazole may be varied depending on the amount of albendazole desired to be administered and that levels of albendazole above or below 1200mg may be used without departing from the scope of the invention. Similarly, the dose may be varied for different animals.
- the tablet is formulated to also rapidly release the benzimidazole compound or compounds on oral administration.
- the benzimidazole compound or compounds or their active metabolites remain present in the bloodstream of the animal for at least 12 hours.
- the benzimidazole compound or compounds are formulated so that the compound or compounds or its active metabolites dissipate from the bloodstream of the animal in a similar manner as an oral drench. It is understood by the applicant that the compound has left the blood stream after a time period of no more than two weeks.
- the benzimidazole raw material is formulated into the tablet as a dry micronised particulate powder.
- the inventors have found that this is a further key characteristic. Without a micronised particle structure, the desired degree of bioavailability of the benzimidazole compound or compounds in the tablet is difficult to achieve.
- a tablet formulated for administration to an animal including:
- the macrocyclic lactone compound or compounds are also subsequently mixed with at least one second organic solvent (termed a 'co-solvent' for the purposes of this specification).
- a 'co-solvent' for the purposes of this specification.
- the solvent or solvents and co-solvent or co-solvents are different compounds.
- the first organic solvent or solvents may be selected from: an alcohol, a glycol, an ether, a pyrrolidone compound with two or more carbon atoms, and combinations thereof. More preferably, the solvent or solvents may include: ethyl alcohol, benzyl alcohol, phenethyl alcohol, ethyl benzyl alcohol and other aromatic monohydric alcohols; glycols, glycol ethers, glycol ether acetates, C 1 to C 8 alkyl pyrrolidones, and combinations thereof.
- the solvent is benzyl alcohol which is preferred as it not only dissolves the macrocyclic lactone compound, but also, acting with the co-solvent, stabilises the compound increasing the overall stability of the product.
- the co-solvent or co-solvents are alcohol or ether compounds with three or more carbon atoms. More preferably, the co-solvent or co-solvents include: diol alcohols or ethers including glycols, aromatic monohydric alcohols, glycol ethers, glycol ether acetates, and combinations thereof.
- the co-solvent is a propylene glycol compound such as monopropylene glycol which is preferred as it not only mixes with the macrocyclic lactone compound and solvent but also stabilises the compound increasing stability and provides emulsifying properties. It is understood that the emulsifying properties assist in preventing crystallisation / precipitation of the macrocyclic lactone compound on 5 release in the gut although other factors may also account for the increased bioavailability effect and this description should not be seen as limiting.
- a further advantage of the organic solvents and co-solvents chosen are that they provide improved bioavailability by the solvents giving a transmucosal effect whereby the solvents o and co-solvents assist in transfer, of the agent or agents from the gut and into the animal bloodstream.
- the macrocyclic lactone compound or compounds would pass through the animal on administration with no or only sparing5 absorption.
- the macrocyclic lactone anthelmintic compound(s) are made absorbable and can be mixed with levamisole and other anthelmintic agents without risk of reducing efficacy or tablet stability.
- the tablet as described above includes the above components in a ratio within the range of approximately 1 part macrocyclic lactone to 0.8-1.2 parts organic solvent to 3.2- 3.6 parts organic co-solvent.
- the amount of active ingredient per tablet for a cattle formulation is 64mg abamectin, 1200mg levamisole HCI and 1200mg albendazole per tablet dosed to an animal weight of approximately 160kg. It is the inventor's experience that these levels of agent provide sufficient bioavailability to the animal on administration equivalent to that which would be obtained from single agent oral drenches. It should be appreciated that the dosage of each agent may be varied depending on the amount of agent desired to be administered and that levels of agent above or below the example provided may be used without departing from the scope of the invention. Similarly, the dose may be varied for different animals.
- the term 'stable' refers to at least 6 months (preferably 18 months) chemical stability (e.g. within +10% w/w active agent of the stated composition) of active agent when stored at 40 0 C or below and at a high humidity (relative humidity of less than 75%) and of a reasonable physical stability such that no physical alteration is observed in the tablet during storage or at the time of administration.
- Other agents are also envisaged as being added to the formulation including other anthelmintic agents as well as other non-anthelmintic agents.
- other nutrients such as trace minerals may be added to the formulation to allow the animal to be dosed for parasites but also to enhance the animal's nutrition.
- mineral supplementation may be included in the formulation to provide a source of cobalt, copper, iodine, selenium and zinc.
- additional inert compositions are added to the tablet including: binders, fillers, bulking agents, carriers, disintegration agents, glidants, lubricants, and combinations thereof.
- the tablet disintegrates within approximately 15 minutes when placed in water at 37°C.
- the tablet is administered orally to an animal.
- the animal is non-human animal. More preferably, the animal is a ruminant animal. In specific embodiments envisaged by the inventors, the animals are ovine or bovine species although it is anticipated that any animal susceptible to parasite infestation treatable using an anthelmintic composition may be treated.
- the parasites treated include endoparasites.
- kits containing a pill administration device and a package of tablets substantially as described above.
- the tablet may be sold commercially in bulk or in smaller kits. Smaller kits containing a package of tablets have the advantage over existing drenches and pour on formulations in that large amounts of formulation need not be purchased. It should be noted that, due to the stability of the tablets of the present invention, the packaging need not provide specific stabilising properties but rather is likely to be best used to assist in administration such as by use of labelling to identify sequence or dose information. Commercially sold drenches and pour on formulations are typically sold in containers including 500 or more doses which is excessive for the small lifestyle farmer or other purchasers. The convenience of a package also lends itself well to smaller dosing runs with little mess and fuss required.
- the package may be sold with a disposable tablet applicator in order to further simplify the process for the user.
- Applicator devices such as a pill popper or gas actuated applicator may also be included.
- there may be, in the place of an applicator, a dough in which the tablet is encased and which masks the tablet from the animal.
- Tablets may be supplied with or without an applicator.
- a further advantage of the formulation is that, as multiple agents are included, product effectiveness is increased (several classes of parasite may be targeted in one dose) and has labour savings in terms of not having to dose two or more times with different products.
- a yet further advantage of the present invention is that tablets may be advantageous in small farm applications. At present drenches and topical pour-on solutions are packaged in large containers for use in dosing large numbers of animals (typically 500 doses). The cost of these containers is considerable. In contrast, the present invention may be sold as a package containing any number of doses which, for a small farm of lifestyle block would be preferable than purchasing a large container at significant cost. Purchase of a small number of tablets would also remove the need to dump unused drenches or pour-on solutions that have passed their expiry date.
- Figure 1 shows a graph of levamisole bloo.d levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2;
- Figure 2 shows a graph of abamectin blood levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2;
- Figure 3 shows a graph of albendazole sulfoxide blood levels measured post administration based on two formulations labelled Reformulation 1 and Reformulation 2;
- Figure 4 shows a graph of levamisoie blood levels measured post administration based on a third formulation labelled Reformulation 3 and a Reference levamisoie oral drench product;
- Figure 5 shows a graph of abamectin blood levels measured post administration based on a third formulation labelled Reformulation 3 and a Reference abamectin oral drench product;
- Figure 6 shows a graph of albendazole sulfoxide blood levels measured post administration based on a third formulation labelled Reformulation 3 and a
- Figure 7 shows a graph of levamisoie blood levels measured post administration based on Reformulation 2 and a Reference levamisoie oral drench product
- Figure 8 shows a graph of abamectin blood levels measured post administration based on Reformulation 2 and a Reference abamectin oral drench product
- Figure 9 shows a graph of albendazole sulfoxide blood levels measured post administration based on Reformulation 2 and a Reference albendazole oral drench product
- Figure 10 shows a graph of levamisoie blood levels measured post administration based on an active only capsule with no carriers or surrounding formulation
- Figure 11 shows a graph of albendazole sulfoxide blood levels measured post administration based on an active only capsule with no carriers or surrounding formulation
- Figure 12 shows a graph of abamectin blood levels measured post administration of a- fourth formulation (Reformulation 4) compared to a Reference abamectin oral drench;
- Figure 13 shows a graph of albendazole sulfoxide blood levels measured post administration of a fourth formulation (Reformulation 4) compared to a
- Figure 14 shows a graph of levamisoie blood levels measured post administration of a fourth formulation (Reformulation 4) compared to a Reference levamisoie oral drench.
- Reformulation 1 includes abamectin, levamisole HCI, and albendazole.
- Abamectin is dissolved in one solvent (monopropylene glycol) and includes:
- Reformulation 2 includes abamectin, levamisole HCI, and albendazole. Abamectin is dissolved in two solvents (benzyl alcohol and monopropylene glycol) and includes: Table 2: Reformulation 2 Composition
- Reformulation 3 includes abamectin, levamisole HCI, and albendazole.
- Abamectin is dissolved in one solvent (monopropylene glycol) and a surfactant (sodium lauryl sulphate) and includes:
- Reformulation 1 and Reformulation 2 were investigated during the first treatment session. In the second treatment session, Reformulation 3 and the Reference products (see below) were compared. The animals were then re-randomised for the third sampling session, in which Reformulation 2 was compared with the Reference products.
- Blood was collected from the jugular vein via venipuncture, directly into heparinised vacutainer tubes and refrigerated at 4°C until processing. It was then centrifuged at 2500 rpm for 10 minutes before the plasma was collected, and divided into test (2ml/analyte) and • reserve (2ml), samples and frozen. Test and reserve samples were maintained at -.18 0 C in separate freezers before laboratory analysis.
- the plasma profile for levamisole is shown in Figure 1. There appears to be a delayed absorption of the levamisole in this formulation, as the T max shown here is much later than expected. It is likely that the true C max occurred between the 0.5h and 6h sampling time, and the 6h sampling actually reflected the plasma concentration decreasing. The results found were otherwise as expected.
- the plasma profile obtained for albendazole sulfoxide (the active metabolite) is shown ( Figure 3).
- the plasma concentrations peaked at 4.6 ⁇ g/ml and 5.1 ⁇ g/ml for Reformulation 1 and Reformulation 2.
- the T ma ⁇ for both formulations occurred 15h post administration.
- the levamisole plasma profiles obtained for Reformulation 3 and the Reference treatment groups are shown ( Figure 4).
- the C max for levamisole was 0.78 ⁇ g/ml and 0.52 ⁇ g/ml for Reformulation 3 and the Reference groups respectively. This showed that the degree of absorption of levamisole from Reformulation 3 was comparable to the Reference NilvermTM oral drench.
- Albendazole ⁇ The albendazole plasma profiles observed for Reformulation 3 and the Reference products are shown ( Figure 6).
- the C max observed for the Reformulation 3 and Reference treatment groups were 0.54 ⁇ g/ml and 2.2 ⁇ g/ml respectively.
- T max was 15h after administration.
- Reformulation 3 showed some release and absorption of albendazole but not to the extent desired to be comparable to Reference oral drench product ValbazenTM.
- Treatment Session 3 After comparing the Reformulation 2 results from Treatment Session 1 with the Reference results from Treatment Session 2, it was decided to compare Reformulation 2 with the Reference products in a third Treatment Session (Treatment Session 3). This was done as a side by side trial to re-confirm the results observed in Treatment Sessions 1 and 2.
- the albendazole plasma profiles observed for Reformulation 2 and the Reference product is shown ( Figure 9).
- the C max observed for the Reformulation 2 and Reference treatment groups were 0.64 ⁇ g/ml and 0.92 ⁇ g/ml respectively.
- the T max for both formulations occurred 15h post administration, and the error bars calculated (showing standard deviations) demonstrate the variation between individuals to be considerable and may largely explain the difference observed in the plasma profile of two formulations. Therefore it may be concluded that Reformulation 2 compared well against the Reference product ValbazenTM.
- Example 1 Given the results in Example 1 , a further trial was completed to determine the influence of the formulation on the degree of absorption of each anthelmintic compound. This was completed by ascertaining baseline levels of drug bioavailability when animals are dosed with raw actives (no excipients).
- the blood was collected from the jugular vein via venipuncture, directly into heparinised vacutainer tubes and refrigerated at 4 0 C until processing. It was then centrifuged at 2500 rpm for 10 minutes before the plasma was collected, and divided into test (2ml/analyte) and reserve (2ml), samples and frozen. Test and reserve samples were maintained at -18°C in separate freezers before laboratory analysis.
- Levamisole The plasma profile for levamisole is shown in Figure 10.
- the T max shown here is later than predicted by publications, but consistent with previous studies by the inventor's. It is envisaged that this is because the drugs were all administered in a gelatine capsule, and this would have taken several minutes to break down, which may have delayed the release of the levamisole to the rumen.
- the C max was approximately 50% of that generally considered necessary for full therapeutic efficacy.
- the plasma profile for levamisole was similar to that observed in previous studies, suggesting that formulations do not cause delayed absorption of the drug as previously thought. Rather, this delay may be due to the active passing through the mucosal layer between the gut and bloodstream.
- T max for albendazole sulfoxide occurred between the 6h and 15h sampling times ( Figure 11).
- C max was approximately 50% of that generally considered necessary for full therapeutic efficacy.
- the low bioavailability of albendazole was surprising, ' as this drug is usually formulated as a suspension, with the majority of excipients being included as aids keeping the drug in suspension and not necessarily to assist in bioavailability.
- the formulation in tablet usage appears to have an effect on albendazole bioavailability.
- Plasma concentrations of abamectin were lower than those obtained previously for example that shown in Example 1.
- the formulation included abamectin, albendazole and levamisole.
- the abamectin was dissolved and mixed with two organic solvents during manufacturing (benzyl alcohol and monopropylene glycol). More specifically, the formulation was as follows (formulated for cattle weighing 160kg):
- the animals used were catt e with ot er characteristics of the study remaining the same as in Example 1 except that the formulation was altered as noted above.
- Abamectin is lipophilic and requires formulation in order for the abamectin to be absorbed.
- the formulation was altered to increase this absorption by dissolving and mixing the abamectin with solvents.
- the dosage of abamectin was approximately doubled in order to achieve a comparable result to the Reference product.
- Increasing the dose for abamectin is standard practice when designing cattle formulations as sheep have a greater absorption, distribution, metabolism and excretion (ADME) profile than cattle.
- ADME absorption, distribution, metabolism and excretion
- albendazole the amount of albendazole used was approximately doubled in order to ensure that the amount of albendazole provided was comparable to that used normally for cattle.
- a second trial was also commenced with 12 tablets placed into an environment held at a constant temperature if 4O 0 C and 75% relative humidity.
- the above temperatures and humidity's were chosen as being 'trying' conditions in which the tablets might be stored and represent worst case scenarios where deterioration might occur.
- the first trial was conducted over 18 months and the second trial over 6 months.
- the tablets were tested using the same tests as that completed during the initial test and the results compared. Where there were no variations to initial results, the stored tablet was said to 'comply'.
- Table 5 Storage Stability for a Temperature of 30°C and Relative Humidity of 60%
- the tablet product was remarkably stable and did not breakdown under trying conditions in terms of temperature and humidity over significant time periods.
- the tablet is water resistant and not hydroscopic or too hydroscopic to prevent disintegration when administered.
- tabjet formulations described above were manufactured as described and packaged in 5 a blister pack sealing the tablets into a package. Markings may be included on the packaging indicating the user when the tablets should be administered and any dosing instructions such as how to use an applicator device such as a pill popper device.
- the blister pack is attached to a pill applicator device or composition and placed into a o package for sale jointly as a kit.
- the applicator may be replaced by an administration/swallowing-enhancing coating such as a dough composition which encases the pill and which masks the pill from5 the animal.
- an administration/swallowing-enhancing coating such as a dough composition which encases the pill and which masks the pill from5 the animal.
- a disposable applicator is preferred.
- kit may contain as little as one dose or many thousands of doses as may be required.
- Tablets may also be sold in containers absent of a blister pack and again may be sold with or without an applicator.
- ivermectin has similar lipophilic properties as abamectin, similar results may be achieved if ivermectin were used. In addition, similar results may also be expected for other benzimidazole compounds based on results found for albendazole.
- tablets provide a fixed and known dose of agent and there is no need to dilute, measure out and use specialised equipment such as drench guns.
- tablets may.easily be sold in large or small numbers whereas oral drenches for example are only sold in large volumes (and at greater expense).
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AU2007334747A AU2007334747A1 (en) | 2006-12-21 | 2007-12-20 | Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents |
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NZ552293 | 2006-12-21 | ||
NZ552293A NZ552293A (en) | 2006-12-21 | 2006-12-21 | Tablet formulation comprising a macrocyclic lactone and a levamisole compound having anthelmintic activity |
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WO2008075984A2 true WO2008075984A2 (en) | 2008-06-26 |
WO2008075984A3 WO2008075984A3 (en) | 2008-07-31 |
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PCT/NZ2007/000383 WO2008075984A2 (en) | 2006-12-21 | 2007-12-20 | Tablet formulation including macrocyclic lactone and levamisole anthelmintic agents |
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AU (1) | AU2007334747A1 (en) |
NZ (1) | NZ552293A (en) |
WO (1) | WO2008075984A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010014015A1 (en) * | 2008-07-29 | 2010-02-04 | Bomac Research Limited | Tablet manufacturing method |
JP2012525384A (en) * | 2009-04-30 | 2012-10-22 | ダウ アグロサイエンシィズ エルエルシー | Insecticide composition comprising macrolactone, polymer and proteinaceous material |
WO2013030702A3 (en) * | 2011-08-16 | 2013-05-30 | Virbac Sa | Anthelmintic formulations and treatments |
US9198430B2 (en) | 2011-06-23 | 2015-12-01 | Bayer New Zealand Limited | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation |
CN110151910A (en) * | 2019-05-28 | 2019-08-23 | 石家庄九鼎动物药业有限公司 | A kind of antiparasite drugs for animals albendazole ivermectin piece and preparation method thereof |
CN111067875A (en) * | 2020-01-16 | 2020-04-28 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010014015A1 (en) * | 2008-07-29 | 2010-02-04 | Bomac Research Limited | Tablet manufacturing method |
JP2012525384A (en) * | 2009-04-30 | 2012-10-22 | ダウ アグロサイエンシィズ エルエルシー | Insecticide composition comprising macrolactone, polymer and proteinaceous material |
US9480256B2 (en) | 2009-04-30 | 2016-11-01 | Dow Agrosciences Llc | Pesticide compositions exhibiting enhanced activity |
US9198430B2 (en) | 2011-06-23 | 2015-12-01 | Bayer New Zealand Limited | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation |
WO2013030702A3 (en) * | 2011-08-16 | 2013-05-30 | Virbac Sa | Anthelmintic formulations and treatments |
EP2744495B1 (en) | 2011-08-16 | 2017-01-18 | Virbac | Anthelmintic formulations and treatments |
AU2012303747B2 (en) * | 2011-08-16 | 2017-07-06 | Virbac | Anthelmintic formulations and treatments |
CN110151910A (en) * | 2019-05-28 | 2019-08-23 | 石家庄九鼎动物药业有限公司 | A kind of antiparasite drugs for animals albendazole ivermectin piece and preparation method thereof |
CN111067875A (en) * | 2020-01-16 | 2020-04-28 | 兰州大学 | Albendazole liquid-solid compressed tablet and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
AU2007334747A1 (en) | 2008-06-26 |
WO2008075984A3 (en) | 2008-07-31 |
NZ552293A (en) | 2009-03-31 |
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