WO2010014015A1 - Tablet manufacturing method - Google Patents
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- WO2010014015A1 WO2010014015A1 PCT/NZ2008/000190 NZ2008000190W WO2010014015A1 WO 2010014015 A1 WO2010014015 A1 WO 2010014015A1 NZ 2008000190 W NZ2008000190 W NZ 2008000190W WO 2010014015 A1 WO2010014015 A1 WO 2010014015A1
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- 0 CC1(*)C=C2NC(*)=NC2=CC=C1 Chemical compound CC1(*)C=C2NC(*)=NC2=CC=C1 0.000 description 1
Classifications
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- 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
- 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
- A61K31/415—1,2-Diazoles
-
- 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
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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 manufacturing method. More specifically, the invention relates to a method of manufacturing a tablet formulation containing at least one lipophilic compound with anthelmintic activity and at least one further anthelmintic compound for use in treatment of an animal
- 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 make them 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 method of manufacturing a tablet formulation containing at least two different anthelmintic compounds from different families of anthelmintic activity where these compounds would not normally be able to be mixed together.
- a further aim is to increase the bioavailability of a lipophilic compound with anthelmintic activity.
- a problem found in the prior art with existing anthelmintic compounds including benzimidazole anthelmintics is the need to deliver the compound as an oral suspension due to the poor solubility of this type of compound in aqueous environments.
- 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.
- providing 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.
- 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.
- a method of manufacturing a tablet formulated for administration to an animal containing at least one solubilisable lipophilic compound with anthelmintic activity and at least one additional anthelmintic compound formed by the steps of:
- step (b) mixing the mixture of step (a) with at least one co-solvent;
- step (c) mixing the mixture of step (b) with:
- the term 'tablet' 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 1 , stomach tube or other delivery device.
- at least one of the anthelmintic compounds used in the tablet may be 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 may result in corresponding poor oral absorption, which may lead to poor pharmacokinetics. These factors may contribute to the compound 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 orat drench.
- an 'aqueous environment 1 may be extracellular fluid.
- the method includes a further step (e) after step (d) of:
- step (e) mixing the dried mixture of step (d) with at least one further compound with properties selected from: a disintegrant, a glidant/free flowing agent; a lubricant; and combinations thereof.
- the final mixture after step (d) or step (e) if present may be compressed into a tablet.
- the solubilisable lipophilic active compound is a macrocyclic lactone.
- the solubilisable lipophilic anthelmintic compound is abamectin or ivermectin. More preferably, the solubilisable lipophilic anthelmintic compound is abamectin, although it should be appreciated that as ivermectin also has similar lipophilic properties to abamectin, ivermectin is also encompassed within the present invention.
- the solubilisable lipophilic 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 solubilisable lipophilic 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 lipophilic 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.
- 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 solubilisable lipophilic compound is formulated to be rapidly released on oral administration.
- the solubilisable lipophilic compound is formulated so that the compound or compounds remain present in the bloodstream of the animal for at least 24 hours.
- the solubilisable lipophilic compound is formulated so that the compound or compounds 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 additional anthelmintic compound or compounds added in step (c) are compounds with different spectrum anthelmintic activity than the solubilisable lipophilic compound used in step (a).
- the anthelmintic compound added at step (c) is a substituted or unsubstituted benzimidazole compound.
- the substituted or unsubstituted benzimidazole compound includes the structure:
- n 1 or 2;
- 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.
- 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 for example the varied doses described above between sheep and cattle.
- the benzimidazole compound or compounds are formulated to be rapidly released on oral administration.
- the benzimidazole compound or compounds are formulated so that the compound or compounds or its 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 one week.
- the benzimidazole raw material is a dry micronised particulate powder.
- micronised powder is a further key property. Without a micronised particle structure, the desired degree of oral bioavailability may be difficult to achieve.
- the additional anthelmintic compound added to the mixture in step (c) is levamisole.
- the levamisole is levamisole hydrochloride (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.
- both a substituted or unsubstituted benzimidazole compound and levamisole HCI compound are added in step (c).
- the solubilisable lipophilic compound is dissolved in at least one organic solvent.
- the solubilisable lipophilic compound is subsequently mixed with at least one second organic solvent (termed 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 pyrrolido ⁇ e 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 solubilisable lipophilic 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 solubilisable lipophilic 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 lipophilic compound on 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 improve oral bioavailability by conferring a transmucosal effect on the tablet formulation whereby the solvents and co-solvents assist in transfer of the agent - or agents from the gut and into the animal bloodstream.
- solubilisable lipophilic compound or compounds would pass straight through the animal on administration with no or only sparing absorption.
- the solubilisable lipophilic anthelmintic compound is increased in oral bioavailability.
- the tablet as described above includes a ratio of solubilisable lipophilic compound to solvents and co-solvents within the range of approximately 1 part lipophilic compound to 0.8-1.2 parts organic solvent to 3.2- 3.6 parts organic co-solvent.
- the binder in step (c) is a pyrrolidone compound. More preferably, the binder is a polyvinyl pyrrolidone compound.
- the filler, disintegrant, glidant/free flowing agent and lubricant used in , steps (c) and step (e) if present include: corn starch, sodium starch glycolate, silica or silica based compositions, magnesium stearate or other anionic salts.
- step (d) is completed by air drying at 40 0 C. It should be appreciated that the formulation may be dried using other methods including spray drying, freeze drying and the like without departing from the scope of the invention.
- the tablet produced by the method disintegrates within approximately 15 minutes when placed in water at 37°C.
- 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 oral bioavailability to the animal on administration that blood levels obtained are 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.
- step (b) mixing the dissolved agent or agents of step (a) with at least one co- solvent.
- 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.
- a tablet manufactured in accordance with the method substantially as described above.
- the non-human animal is a ruminant animal.
- 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.
- lipophilic or sparingly soluble agents may be mixed with hydrophilic agents to form combination formulations. Without the method described above, the lipophilic agent may not mix with the hydrophilic agent or on mixing, the compounds may produce unwanted reactions or degradation in agent activity.
- 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 treatments is considerable. In contrast, the present invention may be sold as a package such as a bottle or box 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 blood 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 levamisole blood levels measured post administration based on a third formulation labelled Reformulation 3 and a Reference levamisole 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 Reference albendazole oral drench product
- Figure 7 shows a graph of levamisole blood levels measured post administration based on Reformulation 2 and a Reference levamisole 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 levamisole 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
- 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 Reference albendazole oral drench; and, Figure 14 shows a graph of levamisole blood levels measured post administration of a fourth formulation (Reformulation 4) compared to a Reference levamisole 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:
- 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°C in separate freezers before laboratory analysis.
- 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 m3x 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 m3x for levamisole was 0.78 ⁇ g/ml and 0.52 ⁇ g/ml for Reformulation 3 and the Reference groups respectively.
- 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).
- the levamisole plasma profiles observed for Reformulation 2 and the Reference products are shown ( Figure 7).
- the C max observed for Reformulation 2 and Reference treatment groups were 0.74 ⁇ g/ml and 0.66 ⁇ g/ml respectively.
- the Tm a x for both formulations occurred 2h post administration, and the error bars calculated (showing standard deviations) demonstrate the variation between individuals to be greater than that resulting from the different formulations.
- 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).
- Gelatine capsules containing a single anthelmintic drug one capsule per sheep per drug for levamisole and abamectin, two capsules per sheep for albendazole were used.
- the capsules were dark green in colour, to prevent the light sensitive abamectin from being prematurely exposed to light.
- the 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°C in separate freezers before laboratory analysis.
- the plasma profile for levamisole is shown in Figure 10.
- the Tm 3x 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 n ⁇ x 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.
- albendazole bioavailability 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:
- the finished product is a tablet of an approximately 21mm diameter that breaks down within approximately 15 minutes in 37°C water. During storage, the tablet remains stable and active agent levels remain stable.
- the animals used were cattle with other characteristics of the study remaining the same as in Example 1 except that the formulation was altered by doubling the amount of albendazole to provide an equivalent dose rate as reference treatments.
- 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.
- albendazole the amount of albendazole used was approximately doubled in order to ensure the preferred cattle dose level was achieved.
- a second trial was also commenced with 12 tablets placed into an environment held at a constant temperature if 40 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.
- Table 5 Storage Stability for a Temperature of 30 0 C and Relative Humidit of 60%
- the tablet formulations described above were manufactured as described and packaged in 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 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 from the animal.
- an administration/swallowing-enhancing coating such as a dough composition which encases the pill and which masks the pill from 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 be supplied 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
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BRPI0822980-5A BRPI0822980A2 (pt) | 2008-07-29 | 2008-07-29 | Método de fabricação de tabuleta |
PCT/NZ2008/000190 WO2010014015A1 (en) | 2008-07-29 | 2008-07-29 | Tablet manufacturing method |
AU2008360070A AU2008360070B2 (en) | 2008-07-29 | 2008-07-29 | Tablet manufacturing method |
ZA2011/01565A ZA201101565B (en) | 2008-07-29 | 2011-02-28 | Tablet manufacturing method |
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PCT/NZ2008/000190 WO2010014015A1 (en) | 2008-07-29 | 2008-07-29 | Tablet manufacturing method |
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PCT/NZ2008/000190 WO2010014015A1 (en) | 2008-07-29 | 2008-07-29 | Tablet manufacturing method |
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AU (1) | AU2008360070B2 (pt) |
BR (1) | BRPI0822980A2 (pt) |
WO (1) | WO2010014015A1 (pt) |
ZA (1) | ZA201101565B (pt) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103919745A (zh) * | 2014-05-08 | 2014-07-16 | 成都乾坤动物药业有限公司 | 兽用苯并咪唑类着色驱虫药物配方及其工艺 |
WO2018038623A1 (en) * | 2016-08-23 | 2018-03-01 | Donaghys Limited | Improvements in parasite treatments |
CN111067875A (zh) * | 2020-01-16 | 2020-04-28 | 兰州大学 | 一种阿苯达唑液固压缩片及其制备方法 |
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WO2000074489A1 (en) * | 1999-06-04 | 2000-12-14 | Nufarm Limited | Stable biocidal compositions |
US20040151759A1 (en) * | 2002-08-16 | 2004-08-05 | Douglas Cleverly | Non-animal product containing veterinary formulations |
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-
2008
- 2008-07-29 BR BRPI0822980-5A patent/BRPI0822980A2/pt not_active Application Discontinuation
- 2008-07-29 AU AU2008360070A patent/AU2008360070B2/en not_active Withdrawn - After Issue
- 2008-07-29 WO PCT/NZ2008/000190 patent/WO2010014015A1/en active Application Filing
-
2011
- 2011-02-28 ZA ZA2011/01565A patent/ZA201101565B/en unknown
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US20040151759A1 (en) * | 2002-08-16 | 2004-08-05 | Douglas Cleverly | Non-animal product containing veterinary formulations |
US20050032719A1 (en) * | 2003-08-08 | 2005-02-10 | Ian Cottrell | Anthelmintic formulations |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103919745A (zh) * | 2014-05-08 | 2014-07-16 | 成都乾坤动物药业有限公司 | 兽用苯并咪唑类着色驱虫药物配方及其工艺 |
WO2018038623A1 (en) * | 2016-08-23 | 2018-03-01 | Donaghys Limited | Improvements in parasite treatments |
CN111067875A (zh) * | 2020-01-16 | 2020-04-28 | 兰州大学 | 一种阿苯达唑液固压缩片及其制备方法 |
CN111067875B (zh) * | 2020-01-16 | 2021-11-30 | 兰州大学 | 一种阿苯达唑液固压缩片及其制备方法 |
Also Published As
Publication number | Publication date |
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ZA201101565B (en) | 2015-10-28 |
AU2008360070A1 (en) | 2010-02-04 |
BRPI0822980A2 (pt) | 2015-06-23 |
AU2008360070B2 (en) | 2015-04-30 |
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