AU2015261543B2 - Controlled release compositions and their methods of use - Google Patents

Controlled release compositions and their methods of use Download PDF

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AU2015261543B2
AU2015261543B2 AU2015261543A AU2015261543A AU2015261543B2 AU 2015261543 B2 AU2015261543 B2 AU 2015261543B2 AU 2015261543 A AU2015261543 A AU 2015261543A AU 2015261543 A AU2015261543 A AU 2015261543A AU 2015261543 B2 AU2015261543 B2 AU 2015261543B2
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composition
surfactant
active agent
colloidal silica
oil
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AU2015261543A1 (en
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Fadil Al Alawi
Olaf Bork
Ian George Tucker
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Elanco New Zeeland
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Elanco New Zeeland
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Abstract

James & Wells 133072AU/76 The present invention relates to a composition, the composition including a therapeutically effective amount of at least one active agent, and a base including, an amount of colloidal silica; at least one oil; and at least one surfactant, wherein the viscosity of the composition is below 1000 mPas at a shear rate of 100 1/s and at a temperature of 200C. James & Wells 133072AU/76 dynamic viscosity r /m Pas =r Inn .1/ 16 . M ~rn C oo WJ Q&J PJ I

Description

CONTROLLED RELEASE COMPOSITIONS AND THEIR METHODS#F (JSE TECHNICAL FIELD
This invention relates to controlled release GompesitiOis and their method of use, and preferably, but not specifically, to low viscosity contralled release compositions for the treatment of mastitis in lactaing animals.
In order to treat laetatmg animals with mastitis or another microbial infection, antibiotic (impositions are most often utilised. There are a number of commercially iyeilibie antibiotic compositions used for intramammary mastitis treatment during the lactation period.
However, one of the major problems encountered with antibiotic treatments is a poor controlled release Of the active agent over the treatment period. This can lead to problems with maintaining the active agent concentrations above the minimum inhibitory concentration wherein 90% of the microbes are killed (termed the MIC9Q). For instance, if the antibiotic is released too quickly, the antibiotic can come out with the first milking after administration; Then, the concentration of the antibiotic can be too low for the remaining period before receiving the subsequent administration, often 12 hours later. This can lead to failures in effectively treating the infection, longer treatment periods, and/or ultimately increased resistance against antibiotics.
To counter these problems, compositions such as NitroClox™ (Long Acting) LA and DfbeninTW LA are often designed to have a higher Viscosity; a known technique to slow the release profile of an active agent from a composition.
Indeed; this is^ the approach taken for lactation and dry cow mastitis therapy known as long acting formulations, where the active is slowly released from a generally thick paste over an extendea oeriod of time. For instance, if the antibiotic gets administered 48 hourly during the lactation period, the antibiotic is released slowiy with concentrations above M!C90 for about 36 hours after treatment. Then, the concentrations of the antibiotic are too low for the remaining period before receiving the subsequent administration, often 12 hours later,i^gain, this can lead to failures in effectively treating the infection.
Further reasons why chemists develop high viscosity compositions are because 1 can enhance the physical stability of the composition.
However, in the treatment Of many conditions such as mastitis during the lactation period, a higher viscosity can lead to other problems. For example, high viscosity can lead to prolonged low levels of antibiotics in the milk and such milk must be withheld from the market, A long with-holding period (WHF| leads to lost revenue.
Also, a higher yisobSity com position requires more force for infusion of injection of a formulation. This can ibad to problems associated with increased difficulty with infusion |herein referred to as injectability) through a syringe to the udder.
For mastitis treatment, a higher viscosity of the composition can also lead to poorer distribution in the udder.
The need for thickeners or other excipients to increase viscosity of the compositions ©an also make the manufacturing process more time consuming and costly. Also, it is generally understood in the industry that the higher the viscosity of the composition, the more difficult it ©an be to handle during the manufacturing process, A further problem that can be encountered with many suspensions use| for mastitis treatment compositions is sedimentation of the suspension during storage, pf Course, a higher viscosity of a ©brnposition can help to stabilise physically the suspension but a higher viscosity can not usually prevent sedimentation, it only siovvs the sedimentation. Consequently, even viscous Suspensions wilf eventually sediment and the sediment may then cafee; often proving difficult to re-disperse prior to administration. A high viscosity composition can hinder the re-dispersability of the sediments.
Therefore, there is a iongjelt need In the industry to develop improved compositions for the treatment of conditions such as mastitis during the lactating period of an animal. In the ease of mastitis treatment, desired traits of such a composition may include: * controllable release profile of the active agent; - a short with-holding period (WHP) - for example, for treatment of conditions such as mastitis difing the lactation period of the animal; - good re-dispersability after storage; or before administration; ;ir ease of injectability or other mode of administration; - good distribution of the composition into the region to be treated; * the composition’s base being adaptable to use with different active agents for treating or preventing any disease or condition, yet controlled and/or sustained release of the active; - the composition’s base being adaptable to account for different treatment regimes (i.e. different controiied release profiles); and / or - easy to manufacture, and using pharmaceutically acceptable excipients.
It Is an object of the present invention to addpSS the foregoing problems or at least to provide tie public with a useful choice.
All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. IMo admission is made that any reference constitutes prior art. fbi discussion ©ftp references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents, it wii! be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part pf the common genera! knowledge in the art, in New Zealand or in any other country.
Throughout this specification, the word “comprise”, or variations thereof such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
Further aspects and advantages of the present invention will become apparent from the ensuing description which is given oy way of exampie only.
PISSIOSUKE OF INVENTION
According to one aspect of the present invention there is provided a composition, the composition including a therapeutically effective amount of an active agent or active agents, and a base including, an amount of colloidal silica at least one oii; and at least one surfactant, wherein the viscosity of the composition is below 1000 mPas at a shear rate of 100 1/s and at a temperature of 20°C.
The inventors surprisingly found that the composition was particularly effective in the case of mastitis treatment as it may help to provide: - a controllable release profile of the active agent, for instance which may be used to maintain active agent concentrations above MIC90 during the treatment period: ~ a low viscosity to help with injectability, re-dispersabilily and/or good distribution in the udder, and/or ~ a shorter WHP compared to other currently available mastitis compositions,
As will be discussed further, the inventors have recognised the particular importance of this invention to antibiotic treatment of mastitis. However, it would be reasonably expected by someone skilled in the art that the same inventive concept of the disclosed composition would apply to a controllable release profile of substantially any active agent or compound in need thereof for treatment of other conditions.
Without wishing to being limited to a mode of action, it is believed that this controllable release may be due to the surfactant interacting with the colloidal silica, with the result being a change in the release profile of the active agent from the composition.
Importantly this control of the release profile of the active agent may be achieved without overly altering the viscosity of the composition a"d in particular without a substantial increase in me composition’s viscosity.
By example in Figure 2, in vitro studies showed the inventors were able to decrease drug recovery ^equating to $ decreased release profile in vivo) in dissolution media from approximately |0% to 5% w/w over a 180 minute time period. This beneficial effect was obtainable while the viscosity of the composition only increased marginally from 90 mPas to 118 mPas (at a shear rate of 1:0© 1/s at a temperature of 20°C). As shown in Figure 2, this recovery rate of 5% w/w was similar to that obtained by a competing product, Orbenin™ LA. However,
Grhenin™ LA has a viscosity of 1080 mPas approximately 10 fold of that seen in this example in the present invention.
Obviously, if the need arises for a higher viscosity composition, this can be achieved by using thickeners as well knoWn in the art:
For example, when treating mastitis during the lactation period, a lower viscosity composition may be achieved which helps to provide numerous advantageous features such as easy re-dispersabiiity, injectabiiity, manufacturing and/or a shorter WHP; Such features may be provided whiist altering the release profile Of the composition’s active agent to suit the requirements desired, In the treatment of mastitis for example, this controlled release may be used to ensure the active agent is kept above the MIC90 during the entire treatment period.
The inventors have conducted preliminary trials as exemplified herein which illustrates the significant advantages.
Preferred embodiments of the composition
Active agent
Preferabiy, the active agent is an antibiotic, a combination of antibiotics or an antibiotic combined with a non-antibiotic active agent. The inventors acknowledge a preferred antibiotic is cloxaciiiin due to its effectiveness in treating mastitis.
Preferably, the cloxacillin is given as cloxacillin sodium. Of course, other forms of cioxaciiiin, such as cioxaciilin benzathine, may also be used.
Other pisfornsd active agents include beta-lactams, penicillins, cephalosporins, aminoglycosides, quinolones, fosfomycin, sulphonamides, tetracyclines and macrolide antibiotics.
Preferred combinations of active agents include amoxicillin and iieyuianic acid; penicillin active agent and aminoglycoside; cloxacillin and tyiosin; and an antibiotic and a non-steroidal anti-inflammatory drug.
However, sobiforitiilly any antibiotic, non-antibiotic active agent, or functional derivatives thereof may be utilised in the present invention.
For example, the inventors have exemplified that the invention also works in a similar fashion when the acpve agent is a tyiosin base, cephapirin sodium or cephapirin benzathine antibiotic.
It was also surprising to find that the release rate can be affected depending on the type of active agent used When the type/amount of silica and surfactant is kept constant, altering the active agent from cephapirin and cloxacillip (both kept at a concentration of approkimateiy 4.5% w/w) respited in a very different release rate. Cephapirin was released much slower than cloxacillin. This illustrates that by adjusting the type arid possibly the concentration of active agent (and if appropriate the silica and surfactant), a desired release of substantially any active agent may be achieved.
Preferably, the active agent is micronised. The term mieronised should be taken as meaning a particle with a mass mean diameter d50 between to 1 —20 pm Micronisation helps to reduce sedimentation velocity. Furthermore, larger particles may form bridges in front of the syringe nozzle which may affect syringeibility.
Throughout this specification, the term injectability or syringeabiiity should he taken as meaning the ease of administering the medicament to the animal through a syringe. This is typically affected by viscosity, as well as the particle size pf the drugs or formulation excipients; which can sometimes partially or fully block the tip Of the syringe path during administration of the medicament
IgllQidaisihca
Throughout this specification the term colloidal silica should be taken as meaning particles of fumed amorphous silica with a greatest diameter of a single silica particle between approximately 1 nm and 1000 nm (1 pm). A further discussion on the known traits and uses of eoflOidal silica is provided later in this specifications This helps to illustrate that the present use of colloidal silica is very different to the previously known Uses as a thickening and/or anti-caking agent.
Preferably, the colloidal silica is fumed colloidal silicon dioxide,
Many different types of fumed colloidal Silica are currently available. A person skilled in the art would appreciate that all currently available and futpre types of fumed colloidal silica would provide the same advantages as discussed herein. As exemplified in this specification, fumed colloidal silicon dioxide was fpund to be partipu la rly effective.
Preferably; the fumed colloidal silica has hydrophobic properties.
The inventors identified hydrophobic colloidal silica may be significantly more effective than hydrophilic colloidal silica at altering the release profile of the active agent, whilst keeping the viscosity relatively low and/or substantially unchanged.
This was a surprising result as formulations using hydrophobic colloidal silica have a lower viscosity than those using its hydrophilic counter-part. Hydrophilic colloidal silica is known to be used as a thickening agent, which imparts a slower release profile as result of the thickened composition. instead, When the inventors Used hydrophilic silica, inclusion of a surfactant tended to increase: the viscosity of the composition more than when compared to using hydrophobic silica. This was a particularly surprising result, as the use of hydrophobic silica instead of hydrophilic silica in the present invention tended to provide a greater control of the active agent’s release. A preferred commercially available hydrophobic colloidal silicon dioxide is AerosiP RS72 (Supplied by Aerosil).
Preferably, the concentration of colloidal silica is between 0.1-5% w/w. This amount was found to be particularly effective when used in a treatment of mastitis during the lactation period, as per the preferred dosage regimes discussed herein. lyiCre preferably, the concentration of colloidal silica is between 1 -3% w/w. A particularly preferred amount of colloidal Silica was in the order of 1.75¾ w/w. For example, this was found to allow suitable release of the active over the treatment period (typically 24 hours) to maintain the eloxacillin above the MIC9|, yet simultaneously provided a beneficially shorter WHP than competing reference products. This is just one example of how the controlled release mechanism of the present invention may be effectively utilised.
As discussed above, the amount of colloidal Silica used may be governed partially by the type of active used, and the desired release rate. For example, cephacirin is shown to release considerably slower from the base of the Composition than eloxacillin.
For this reason, one may decide to lower the amount of colloidal silica to achieve a similar release rate to that provided when using cloxacillin if so desired;
In-vivo protocols are well known in the industry and provide a straightforward test to determine the resulting active agent concentration in milk from a given composition. From such studies, a person skilled in the art would be able to easily adjust the amount of colloidal silica (or for that matter the active, or amount|type of surfactant) to achieve the desired release rate of substantially any composition.
Overall, if was found by the inventors that the higher the concentration of colloidal silica in the base of the composition, the slower the release rate ff the active agent. Importantly, this slowed release rate may be achieved without overly affecting the viscosity of the compositions. In competing compositions, such as NitroOIOkTW LA or Orbehin™ LA, a similar release rate can only be achieved through a much higher viscosity, which has numerous disadvantages as discussed.
Throughout this specification the term surfactant should be taken as meaning any compound that lowers the surface tension of a liquid, any compound that lowers the interfacial tension between two liquids, or any compound that lowers the interfacial tension between a liquid and a soiid. Surfactants may also act as emulsifiers, detergents* wetting agents and so forth.
Preferably, the surfactant is a non-ionic surfactant.
However, the inventors consider amphoteric, anionic or cationic surfactants should work as well.
Preferably, the non-ionic surfactant has a hydrophiiic-lipophilic balance (HLB| rahgeletween 0.5 and 30.
More preferably, the norf-iOnic surfactant has a HLB range between 4 and 16,
More preferably, the surfactant Is chosen from the group selected from sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor Oil derivatives, polyoxyethylene stearates, and polyethylene oxide monooleate, and combinations thereof.
Surprisingly, some surfactants appeared to work better than others at controlling a chosen active agent’s release rate.
For example, 0.1% w/w PEG12-oieate hod a greater effect at slowing the release rate of doxacillin than 0.1% w/w Span ii, while all other variables were kept constant.
Preferably, the surfactant is at a eonoentration between 0.01 to 10% w/w.
The inyehtbrs found that the more surfactant in the base of the composition, the slower the release rate of the active agent.
For this reason, the amount/type of the surfactant and/or the ratio of surfactant to collOidai silica may provide a means to control the release rate of the active agent.
Preferably, the ratio Of colloidal silica to surfactant is between 1:100 and 500.1
Most preferably the ratio of colloidal silica to surfactant is between 1:5 and 6:1;
Optionally, the base may include m°re than one type of surfactant. It would be reasonable to expect that the resulting composition's release profile (and Other characteristics such as WMP) may be more finely controlled by using a combination Of sirfaetants in a single composition, and/or in different compositions administered during the course of treatment. lit
In many compositions, oils are needed as 9 vehicle. For exemple, antibiotic compositions including actives such as cldxaciiiin or cephapirin are typically based oh ari oily vehicle. For example, this helps the composition to be administered as an infusion through the teat canai or an injection and/or achieving sufficient chemical stability during its shelf life.
Preferably, the oil has a low viscosity.
The USO of a low viscosity oil helps to ensure the resulting composition retains a low viscosity. This may help ensure the composition has good distribution within the udder, is easy to re-disperse after storage, and is easy to administer through a Syringe.
Preferably, the viscpSly of the oil is#ehyefn 1 and 100 mPas at 2Q°C,
More preferably, the viscosity of the oil is less than 40mPas at 20°C.
More preferably, the oil is Selected from the group consisting of medium chain triglycerides {eg Migiyol 812 or Miglyoi 840), ethyl oleate, light liquid paraffin, sesame oil and peanut oil. However, it should be appreciated that other similar low viscosity oils may be utilised for the present invention.
Preferably, the oil has a low density between 0.80 and 0.99 g/cm3.
As exemplified in Figure 6, the inventors found that different oils used altered the recovery late of the active agent. The effect was not as pronounced when compared to alterations in the type/amount of surfactant, coiloidal silica or active agent used. Therefore, it is possible such changes may be due simply to the viscosity of the oil, and that of the psuiting composition, Therefor#, ih a preferred embodiment, a lower viscosity oil is used to maintain a lower viscosity of the Composition.
Yet, the inventors also consider that the oil may be interacting with one or more of the components in the base of the composition to affect the recovery rate of the active agent in a separate manner to just viscosity-reiated controlled release.
Viscosity of the final composition
Obviously, the viscosity of the composition may be tailored to the specific requirements needed. Por Some compositions, a relatively high viscosity may be used. In others, a iow viscosity may be maintained by not adding excipients such as thickeners or high viscosity oils. Such viscosity modifiers may also contribute, if necessary, to the release profile of the active.
The preferred viscosity ranges and values discussed below are those which the inventors have found to be particularly beneficial for the intramammary treatment of mastitis during the lactation period.
Unless specified otherwise, viscosities of the composition referred to within this specification are based on measurements using a concentric cylinder method at a shear rate of 100 1/s and at a temperature of 20°C. The Viscosity of the compositions according to the present invention are below 1000 m Pas when measured at these conditions.
More preferably; the final composition has a viscosity below 300 mPas.
Most preferably, the composition has a viscosity below 150 mPas.
NitroClox™ LA and Orbenin™ LA have a viscosity above 1000 mPas at a shear rate Of 100 1/s and a temperature of 20°C. Similarly, dry cow mastitis treatments
Or other OOffipositions vvtiich include colloidal silica typically have a viscosity well above this upper lire it.
The inventors identified that a composition for the treatment of mastitis during the lactation period preferably has a viscosity below 1000 mPas (and more preferably below 300 mPas) may provide better characteristics in terms of good syringeability, re-dispersabiiity, udder distribution and/or short WHP when compared to competing compositions such as NitroCiox™ LA and Orbenin™ LA. These beneficial features may be retained whilst ensuring the release profile of the active is suitably controlled to allow the active to maintain substantially above the MIC90 during the entire treatment period.
Preferred method of treatment
Preferably, the composition described herein is used to treat mastitis as an infra mammary infusion during the lactation period,
In the ease of mastitis arising during the lactation period, the composition may be used in bovine^ ovine or other animals typically used for commercial milk production.
This helps to differentiate the preferred use of the present invention from dry period mastitis treatment (i.e. treatment outside the lactation perio||.
Yet, it is clear that the present invention may be used to treat substantially any eohditidn or disease depending on the active agent selected. The underlying inventive concept of the composition should not be limited to compositions for ihtraraammary treatment of mastitis.
According to a further aspect of the present invention there is provided a method of treating a microbial infection in an ammai in need thereof with a composition as substantially described herein wherein the method includes the step of administering the composition by intramammary infusion.
The method of administering the composition may typically be through infusion through thileat carpi,
Preferably, the method includes a dosage regime of between 1-12 doses of 1-10 g composition with a treatment regime of administration every 12, l4sOf:48 hours. (Viore preferably, the method includes a dosage regime of 3 or 6 doses of 5 g composition with a treatment regime of 24 hours over a treatment period of 48 hours (3 doses) to 120 hours (6 doses).
This dosage regime may be sufficient to successfully treat an animal with pre-clinicai or clinical mastitis during the lactation period.
After the calculated WHP, norma! milking production can resume again. Again, the inventors found the WHP of the present invention may be substantially lower than other currently available formulations, such as NitroClox™ LA when the same treatment periods were compared.
Pigufe 14 exemplifies one composition of the present invention having a WHP of 72 hours compared to NitroClox™ LA with a WHP of 108 hours (treatment regime three doses at 24h intervals). Based on the assumptions in the paragraph below, this would equate to an increased profit of |24 per cow due to a 36 hour shorter WHP. When this is multiplied over a large dairy farm, or indeed an entire nation, one can easily see the importance of this invention.
The increased profit of $24 per cow assumes what is generally understood in the New Zealand dairy industry, as outlined below. Each milking typically provides approximately 10 L of milk (equalling 1kg of milk soiids), and a farmer sells 11g of milk soiids for $8 to a company such as Fonterra. Furthermore, each cow wiil typically be milked every 12 hours. A particularly advantageous use of the present invention may be the combination treatments of different compositions having different release pro'iles during the treatment period. lo illustrate this, a mastitis treatment may encompass the initial use of a relatively slow active-releasing composition over the first part of the treatment period, yet the latter treatment(s) may use a faster active-releasing composition.
This may help in the sense that fewer treatments may be required towards the beginning of the treatment period. St may also help to ensure the active is kept above th© MIC9C·. Towards the end of the treatment period, a faster releasing composition may be used essentially to top up the active agent levels. Yef, because the active Is released faster, the WHP period may still be kept shorter.
Preferred method of manufacture
According to a further aspect of the present invention there is provided a method of manufacturing the composition as substantially described above including the steps of: a) mixing the oil and surfactant in a container to form a homogenous oii mixture:; b) dispersing the active agent in the oii mixture; and d§ subsequently adding the colloidal siiica to the oil mixture.
Optionally, at least one preservative Is mixed in with the oil and surfactant in step a). For example, methyl paraben and propyl paraben may be used as preservatives.
Preferably the Oil mixture formed from step a) is heat sterilised. For example, the inventors utilise a three hour incubation at 140°C, and then subsequently allow the mixture to cool.
Preferably. Step b) and step c) utilise high shear dispersion equipment.
Preferably, 'he col o'dal Silica in step c) is also heat sterilised; before being added tp the oil mixture.
Preferably, the oil mixture firmed after step c) is homogenously mixed.
The inventors identified that the composition’s preferred low viscosity also helps with the manufacturing process, Ljhfike other compositions, there is no extra heating Step required to mix in a thickener (βφ hydroxystearin).
Also, the lower viscosity may help when syringes need ig he filled after manufacturing the composition and prior to administration.
The preferred use of micronised active agents aiso helps to prevent quick settling of the com position. Additionally, the inventors consider it possible that the release of a micronised active is easier to control than non-micronised equivalents, potentially because the particle size distribution is likely more consistent. Also, it is possible that any interaction with other components from within the composition is likely to be enhanced with the larger surface area of the smaller micronised particles.
Additionaf background of colloidal silica
Fumed coltoidal silica, such as colloidal silicon dioxide, is typically used as viscosity modifiers, and more particularly, thipliening agents in liquid formulations. Some examples of how colloidal silica has been used follows. In line with what was commoniy understood in the art, colloidal silica was known to aid in altering the release of actives from a composition, but only in the sense of it acting as a thickener. As discussed before, generally the thicker a composition becomes, the slower the release profile of the active is, and vice versa. This is an entirely different concept from the present invention. NZ523128 discloses a veterinary drench product indudihg in active dissolved in a solvent then adsorbed on a sorbing medium such as Aerosii |t972 fumed alee, then dispersing the solvent into another liquid that contains another active dissolved or suspended therein. WO ©3070155 discloses a formulation for oral administration including an active agent suspended in an oily matrix, with surfactant and colloidal silicon dioxide. The composition is made into a viscous solution with the addition of hydrogenated vegetable oil, including yeilow beeswax as a suspending agent, lecithin. Silicon dioxide is used as a dispersion aid and pseudoephedrine HCI, for use in a gelatin capsule. WO0160409 discloses a paste formulation including an active agent, fumed silica, a viscosity modifier, an absorbent, a colourant, and a carrier. The viscosity modifier includes PEG 200-600, monoethylamine, glycerol, and propylene glycol. W09824436 discloses a gel formulation including colloidal silicon dioxide and triicetin. |P 3153623 (based on English translation of Abstract) discloses a aemisOlid plarmaceuticai composition for oral administration. The composition includes a drug, a physiologically permissible liquid, an edible oil, a colloidal silicon dioxide, aluminum stearate or a high-molecular weight polyethylene glycol, US 4980175 discloses a liquid compositions for oral administration, including antacid ingredient (aluminium hydroxide etc.) and colloidal silicon dioxide suspended in medium chain triglycerides. An emulsifier (hexaglycerol monoleate) is included to reduce the taste of the oil. US 4781920 discloses an anthelmintic paste including mineral oil, polysorbate 20 surfactant, fumed silica and tetramisole resinate.
These documents do not disclose that the combination of the components (and in particular the surfactant and the colloidal silica) would interact to provide a controlled release mechanism of the active agent. Furthermore, those that do include both surfactant and a colloidal silica are described as viscous liquid compositions or pastes which would not fall within the scope of the present invention (a composition with a viscosity below 1000 mPas). The colloidal silica used in such compositions are typically used as viscosity modifiers (thickeners) to directly impart a controlled release.
In other instances, fumed colloidal silica is used for tablet or powder formulations as a free-flow agent. AEROSIL discusses other typical applications of colloidal silica on their website, such as anti-caking and a stabiliser (wvyw.a&fosiLcoffi).
Fumed colloidal silica exists in particles (termed primary, secondary or tertiary particles depending on their level of aggregation and/or agglomeration).
Under mechanical stress, the silica tertiary structure is broken down to primary or secondary aggregates, the system becomes more fluid, and the viscosity drops. Once returning to rest, the tertiary structure of agglomerated silica particles builds up again, and the viscosity returns to its original value.
As stated in the Technical Information 1279, Aerosil, Degussa, hydrophobic AEROSIL® (“R“) grades have been treated during manufacture to obtain a hydrophobic surface. During this process, silanol groups are reacted. Interestingly, hydrophobic AEROSIL® types often exhibit lower thickening efficiency compared to hydrophilic types.
Therefore for liquid dosage forms, hydrophilic fumed silica is recommended for viscosity control and therefore slower active agent release and hydrophobic fumed Silica is recommended for stabilisation to prevent hard sediments (i.e. caking) from forming, particularly during storage fwww.aerosil.com).
The general principle as employed in formulation chemistry is: an increase of thickening agent concehtfatioh in a formulation, the greater the viscosity, and the slower the active agent release from the resulting formulation.
Therefore it was surprising to find that altering the components of the present composition substantially influences ttve release profile of the active agent without overly affectirig the viscosity. This js cleirly exemplified the examples provided in this specification.
As exemplified in FigurelQ, cioxacillin release from a preferred «imposition can be finely controlled and extended with concentrations in milk above M!C90=G.5mg/L (for Cioxacillin in New Zealand, number taken from Salomon etal, 1998 J Dairy Sci 81:570-578) for more than # hours after treatment (example 17). This can not be achieved with current products in the market with a treatment regime of 48 hours, such as NitroClox™ LA (Figure 13) and Orbenin™ LA (Figure 15) even though the viscosity is much higher in comparison.
OoSSoidal silica has been employed in the Orbenin™ LA formulation manufactured by Pfizer, yet only for conventional uses, such as a thickener and/or anti-caking agent A further thickener, hydroxystearin, is added With the colloidal silica to increase the Jormuifistion’s viscosity which is used to achieve a slow release of the active agent: There is no inclusion of a surfactant in the Orbenin™ LA formulation, unlike the present invention.
As a result of the thickener used in (he Orbenin™ LA composition, it has a much higher viscosity thin that achieved by the present invention {as outlined in the examples) As previously discussed, this can lead to problems with injeetability. therefore, the inventors consider the present invention, which is alle to achieve a lower viscosity whilst being able to control active agent release effectively, has significant advantages over Orbenin™ LA. WO 87/03876 also discloses a treatment/prevention formulation for mastitis during the dry period. WD 87103876 discusses the use of colloidal silica together with the addition Of further thickeners in order to provide a viscous formulation. Again, the result of this highly viscous formulation iS to provide a controlled release of the active oyer a longer treatment period (during the dry period °PPosed to iactatihg period). This is different to the use of colloidal silica in the present invention; WO 03/063877 also discloses the use of Colloidal silica for mastitis treatment during the dry period. Again, the dim is tg provide a high viscosity formulation using colloidal silica as a thickener for stow release of the antibiotic, US 4;401,674 discloses an intramammary formulation containing penicillin and a molecular sieve. Colloidal silica is different to molecular sieves. Molecular sieves are typically a few microns (pm) In diameter making pern considerably larger than colloidal silica particles. Unlike colloidal silica, molecular sieves do not have thickening properties and, as such, are not typically used as thickening agents.
Column 1, line 54 to 58 of US 4,401,674 discusses that if the formulation is to be used for Iactatihg cows, an emulsifying agent (or alternatively a Coconut oil) may be added into the composition to “hasten the mixing of the composition wit,tithe Bqueom secretions in the udder" This is quite different to the concept of the present ihvehtion, where the surfactant appears to be chemically interacting with the silica structure tp impart a change ip the release rate. For example, the release rate of the active agent is slowed down with increasing surfactant concentration. Depending gn the type/amount of surfactant, silica and/or active agent, the release rate of the active agent from the composition may be altered, and importantly without overly affecting viscosity.
Also, US 4,401,674 does not disclose or teach that an emulsifying agent would alter the release rate of the active agent. It merely is provided to hasten the mixing of the composition.
BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention will become apparent from the ensuing description which is given by way of example only and with reference to the accompanying drawings in which:
Figure 1 Comparison of dynamic viscosities between mastitis treatment compositions (lactation period treatment)
Figure 2 Influence of surfactant on active agent recovery rate (in vitro)
Figure 3 influence of surfactant on active agent recovery rate (in vitro}
Figure 4 Influence of colloidal silica concentration on active agent recover rat m(in vitro)
Figure 5 Influence df Colloidal silica type (hydrophobic vs hydrophilic) on active agent recovery rate # v/fro)
Figure 6 Influence of oil on active agent recovery rate (in vitro)
Figure 7 Exemplification of cioxacillin bioavailability in tissues 2 hours after treatment (in vivo)
Figure 8 infiuence of active agent type on active agent concentration in mi!k (in vivo)
Figure 1 Influence of active agent type on active agent Goneeitraflon in milk (in vivo)
Figure 10 Influence on composition characteristics on WHP (in vivo)
Figure 11 Influence on the number of treatments of example composition 1 on WHP (in vivo)
Figure 12 WHP determination of Example 1 composition based on AC1M guideiines (in vivo)
Figure 13 Comparison of treatment between Example 1 composition and NitfsClox™ LA (in vivo)
Figure 14 Comparison of WHP between Example 1 composition and NitroClox™ LA (in vivo)
Figure 15 Comparison of treatment between Example 1 composition and Orbenth11'* LA (in vivo)
Figure 16 Comparison of WHP between Example 1 composition and Orbenm™ LA (in vivo)
BEST MODES FOR CARRYING OUT THE INVENTION PART 1: Example Compositions
Note that the cloxacillin sodium used in Examples 1-17 (and also Example 18 shown below) are in a micronised form.
Figure 1 illustrates the comparatively low viscosity of the preferred composition of the present invention compared to reference products currently on the market.
Recovery rates in dissolution media (shown in Figures 2-6) are considered by the inventors to be indicative of in vivo release rates.
Figure # clearly illustrates one of the major advantages of the present invention. Compared to Orbenin™ LA, the two test compositions in Figure 2 have very low viscosity (90-150 mPas vs 1080 mPas). Orbenin™ LA is abie to maintain a relatively slow cloxacilljn release (approximately 5%) by using a thickener (hydroxystearin). This viscosity of Orbenin™ LA compared to the current compositions can be visualised in Figure 1.
The lyre test compositions depicted in Figure 2 do not include a thickener to impart a slow recovery profile. Instead, careful selection of the surfactant (SpanSO vs. PEG12-e!eate) can be used to significantly alter the recovery profile of the cloxacillin without a significant rise in the viscosity. The test composition containing PEG12-oleate has a recovery profile substantial identica! (if not slower) than prbenin™ LA, yet the viscosity beneficially remains relatively low (180 mPas).
Figure 3 illustrates that the recovery rate of the active agent can be affected not only by the choice Of the surfactant type, but also the concentration thereof. This is exemplified by the increase of the concentration of Span80 (HLB=4.3) from 0.05% to 1% (Examples 8 to 11). Only a small rise in the viscosity is seen, yet a disproportionate decrease in the active recovery is provided.
Similarly, alteration Of the concentration of PEG12-Qleate (HLB=13.7) (Examples 6 and 7) is shown, with corresponding changes in the recovery profile. Therefore, this illustrates that different types and concentrations of surfactants may be used to control the release profile of compositions in vivo.
Figure 4 illustrates that the concentration Of colloidal silica also affected recovery rates of the active agent. St was found that as the concentration of colloidal Silica (In this case Aerosil R972) increased from 1.75% to 3% w/w, the recovery rate was lowered,
Again, although the recover profile slowed dramatically as the silica concentration increased from 1.75 to 3%, the viscosity only increased slightly from 90 mPas to 127 mPas.
Figdre 5 illustrates that the type of colloidal silica day also affect the recovery rate of the active agent. Here, hydrophobic colloidal silica (Aerosi! R972) is shown to significantly iower the recovery rate compared to hydrophilic colloidal silica (Aerosil 200). This is despite the hydrophobic silica imparting a lower viscosity on the composition compared to the same composition using hydrophilic silica. This is contrary to the common understanding in the art.
Figure 6 illustrates that the type of oil used may also affect the recovery rate of the active agent.
Figure 7 illustrates the disthbution Of cloxacillin in different tissues two hours after treatment, In this ease tissue is defined as remaining udder directly after milking, which includes extracellular liquid, blood vessels, and potentially some remaining milk which is not milked put-
Figures 8 and 9 illustrates how different active agents can also have an affect on Ihe release profile of the active agent itself, ail else being substantially equal. In figure 8, When cloxacillin in the example composition 1 is replaced with cephapirin (as shown in example composition |), the release profile is substantially slowed, in ifigure 9, differences were also seen between cloxacillin and tylosin. This was indeed a surprising result and suggests that the active's release may be influenced b| ail interaction with a possible structural network formed with some or all of the excipients in the composition’s base.
Figures 10 -14 illustrate how? the WMF of the composition may be affected by the characteristics of the compdSipn.
Figure 10 illustrates how an increase in the amount of colloidal slca from 1.75% to 3.00% w/w can alter the WHR significantlp
Figure 11 illustrates that the number of treatments does not affect WHP. The WHR is approximately equal regardless of whether the animal is treated with a 6 X 24 hour or 3 X 24 hour regime.
Figure 12 illustrates the calculated WHP of example 1 composition according to ACVM (Agricultural Compounds & Veterinary Medicines) guidelines.
Figure 13 illustrates the effectiveness of example 1 composition versus NitroClox™ LA. Of particular interest is that aftereach treatment, the amount of active agent is higher when administered with the example 1 composition than NitroClox™ LA, suggesting a higher bigavailability of example 1,24h after treatment. Similar tg NitroClox™ LA, the example 1 composition does not decrease below the MIC90 (solid line) 24h after treatment, yet is more rapidly removed from the milk after the final treatment at 0 hrs.
Figure 14 reflects the results shown in Figure 13. The example 1 composition is calculated to have a WHP of only 72 hours compared to 108 hours for NitroClox™ LA.
Figure 15 compares the example 1 composition to Orbenin™ LA, albeit W?ith a different treatment regime (6 X 24 hours vs. 3 X 48 hours, respectively). If can be seen that although the treatment regime using example 1 composition provides a much longer and consistent level of active agent in the milk than the treatment regime using Orbenin™ LA, the active agent is released from the milk much quicker after the final treatment. As can be s|en, the final treatment of Orbenin™ LA is at 96 hours, whereas the final treatment with example 1 composition is at 120 hours; providing a iori|er treatment period. Figure 16 illustrates that the calculated WHP is 12 hours and 24 hours shorter in the example 1 composition’s 6 x 24 hour treatment regime compared to QrbenirTs 3 x 48 hour and 5 x 24 hour treatment regimes, respectively. PART 3: Manufacturing method a) Mix Migiyol 812, methyl paraben, propyl paraben and Span 80 well to form homogeneous oil mixture, b) Sterilise the mixture a! 140°C for 3 hours arid then cool to room temprature. c) In a separate container, load the required amount of Aerosil Rill Pharma. d) Sterilise at 140°C for 3 hours and then cool to room temperature. e) Disperse and homogenise the cloxaclin sodium into the sterilised oil mixture. f) Disperse the sterilised Aerosil R972 Pharma into the sterilised Oil suspension. g) Homogenise the mixture. PART 3 Animal Study
As part of a study commenced in November 2011, the Example 18 formulation.....as detailed plow, was investigated for efficacy in the treatment of bovine mastitis.
*5% overages added
The animals used in the study were dairy cows diagnosed with elinfcai mastitis. On day 0, milk samples were obtained for bacteriological analysis and the animals were treated with iritfamammary infusions of Example 18 three times, With each treatment 24 hours apart. Tie dose for each treatment was 200 mg of cioxaciilin as the sodium salt.
On days 28 and |5; further milk samples were obtained for bacteriological analysis to determine the cure rate. A successful bacteriological eyre required the animal to be clinically cured of mastitis, and for the pathogen identified in the day 0 sample to be absent in the day 28 and day 35 samples.
Interim psults available as of 1 November 2p|2, provided a bacteriological cure proportion of 69.6% when treated with Example 18, from ~1p0 cows enrolled With clinical mastitis, and with gram positive bacteria identified at tie time of enrolment. A comparable study is that reported by MD Wraight, New Zealand Veterinary Journal 51(1), 26-32, 2003 “ A comparative efficacy trial between eeforoxime and cioxaciilin as intramammary treatments for clinical mastitis in lactating cows on commercial dairy forms”. In this study, 200 mg of cioxaciilin in a long-acting formulation was administered as an intra mammary every 48 hours fpf three treatments, which resulted in a bacteriological cure proportion of 64.3%.
The interim study results on Example 18 demonstrate high efficacy of compositions of the invention, even when compared to more intensive long-acting treatments using the same active. This indicates that obtaihihg an advantageous, shorter withhold period by using compositions of the invention, does not reduce or compromise the efficacy of the treatment RART 4: Formulation Stability A stability study was conducted on three batches of Example 18. These batches were packed into 5mL polyethylene syringes and stored at designated storage temperatures and humidity conditions of 25°C/60%RH, 30°C/65%RH and 40°C/75%RH> The physical and chemical eharacferistics of the batches were recorded at regular intervals as recommended by ACVM. Based on the stability data, at a storage temperature of 25°C a shelf life of at least 18 months is expected.
Aspects Of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.

Claims (28)

  1. WHAT I/WE CLAIM IS:
    1. A composition, the composition including a therapeutically effective amount of at least one active agent, and a base configured to provide a controlled release of the at least one active ingredient, the base including, an amount of colloidal silica wherein the colloidal silica is a hydrophobic type; at least one oil; and at least one surfactant, wherein the active agent is an antibiotic; wherein the viscosity of the composition is below 1000 mPas at a shear rate of 100 1/s and at a temperature of 20°C; and wherein the colloidal silica is dispersed in the oil.
  2. 2. The composition as claimed in claim 1 wherein the antibiotic is selected from the group consisting of a beta-lactam, penicillin, cephalosporin, aminoglycoside, quinolones, sulphonamides, tetracyclines and macrolide antibiotic.
  3. 3. The composition as claimed in claim 1 wherein the antibiotic is selected from the group consisting of cloxacillin or a functional derivative thereof, tylosin or a functional derivative thereof, cephapirin or a functional derivative thereof, and combinations thereof.
  4. 4. The composition as claimed in claim 1 wherein the composition includes at least two active agents, wherein the active agents are antibiotics or at least one antibiotic and at least one non-antibiotic active agent.
  5. 5. The composition in claim 4 wherein the active agent combination is: - amoxicillin and clavulanic acid; - penicillin active agent and aminoglycoside; - cloxacillin and tylosin; - an antibiotic and a non-steroidal anti-inflammatory drug.
  6. 6. The composition as claimed in any one of claims 1 to 5 wherein the active agent is micronised.
  7. 7. The composition as claimed in any one of claims 1 to 6 wherein the colloidal silica is fumed colloidal silicon dioxide.
  8. 8. The composition as claimed in any one of claims 1 to 7 wherein the concentration of colloidal silica is between 0.1-5% w/w.
  9. 9. The composition as claimed in any one of claims 1 to 8 wherein the concentration of colloidal silica is between 1-3% w/w.
  10. 10. The composition as claimed in any one of claims 1 to 9 wherein the surfactant has an HLB between 0.5 and 30.
  11. 11. The composition as claimed in any one of claims 1 to 10 wherein the surfactant has an HLB between 4 and 16.
  12. 12. The composition as claimed in any one of claims 1 to 13 wherein the surfactant is an anionic, cationic, amphoteric or non-ionic surfactant.
  13. 13. The composition as claimed in any one of claims 1 to 12 wherein the surfactant is a non-ionic surfactant and is selected from the group consisting of sorbitan esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyethylene oxide monooleate and combinations thereof.
  14. 14. The composition as claimed in any one of claims 1 to 13 wherein the concentration of surfactant is between 0.01 to 10 % w/w.
  15. 15. The composition as claimed in any one of claims 1 to 14 wherein the ratio of colloidal silica to surfactant in the base is between 1:100 and 500:1.
  16. 16. The composition as claimed in any one of claims 1 to 15 wherein the ratio of colloidal silica to surfactant in the base is between 1:5 and 6:1.
  17. 17. The composition as claimed in any one of claims 1 to 16 wherein the base includes more than one surfactant.
  18. 18. The composition as claimed in any one of claims 1 to 17 wherein the viscosity of the oil is between 1 to 100 mPas at 20°C.
  19. 19. The composition as claimed in any one of claims 1 to 18 wherein the viscosity of the oil is less than 40 mPas at 20°C.
  20. 20. The composition as claimed in any one of claims 1 to 19 wherein the oil is selected from the group consisting of medium chain triglycerides, light liquid paraffin, ethyl oleate and sesame oil.
  21. 21. The composition as claimed in any one of claims 1 to 20 wherein the density of the oil is between 0.80 and 0.99 g/cm3.
  22. 22. The composition as claimed in any one of claims 1 to 21 wherein the composition has a viscosity below 300 mPas at a shear rate of 100 1/s and temperature of 20°C.
  23. 23. The composition as claimed in any one of claims 1 to 22 wherein the composition has a viscosity below 150 mPas at a shear rate of 100 1/s and temperature of 20°C.
  24. 24. A method of manufacturing a composition as claimed in any one of claims 1 to 23 including the steps of: a) mixing the oil and surfactant in a container to form a homogenous oil mixture; b) dispersing the active agent in the oil mixture; and c) subsequently adding the colloidal silica to the oil mixture.
  25. 25. A method of treating a non-human animal in need thereof with a composition as claimed in any one of claims 1 to 23 wherein the method includes the step of administering the composition to the animal by intramammary infusion.
  26. 26. The method as claimed in claim 25 including a dosage regime of between 1 - 6 doses of 5 g formulation composition over a period of 0 to 120 hours administered 3 x 24 hours or 6 x 24 hours.
  27. 27. The method as claimed in either of claims 25 or 26 for the treatment or prevention of mastitis during the lactation period of a non-human animal.
  28. 28. A use in the manufacture of a composition as claimed in any of claims 1 to 23 for the treatment or prevention of a pre-clinical or clinical mastitis in an animal in need thereof.
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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO1987003876A1 (en) * 1985-12-23 1987-07-02 Beecham Group P.L.C. Benzathine cephalothin, a process for its preparation and compositions containing it
WO2000001372A2 (en) * 1998-07-02 2000-01-13 Reckitt & Colman Products Limited Chewable oral unit dosage
WO2001060409A1 (en) * 2000-02-16 2001-08-23 Merial Limited Improved paste formulations
WO2003063877A1 (en) * 2002-02-01 2003-08-07 Akzo Nobel N.V. Cefquinome composition for intra-mammary administration in cattle
WO2006008640A1 (en) * 2004-07-15 2006-01-26 Pharmacia & Upjohn Company Llc Non-aqueous suspension containing a drug having an unpleasant taste

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Publication number Priority date Publication date Assignee Title
WO1987003876A1 (en) * 1985-12-23 1987-07-02 Beecham Group P.L.C. Benzathine cephalothin, a process for its preparation and compositions containing it
WO2000001372A2 (en) * 1998-07-02 2000-01-13 Reckitt & Colman Products Limited Chewable oral unit dosage
WO2001060409A1 (en) * 2000-02-16 2001-08-23 Merial Limited Improved paste formulations
WO2003063877A1 (en) * 2002-02-01 2003-08-07 Akzo Nobel N.V. Cefquinome composition for intra-mammary administration in cattle
WO2006008640A1 (en) * 2004-07-15 2006-01-26 Pharmacia & Upjohn Company Llc Non-aqueous suspension containing a drug having an unpleasant taste

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Title
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