NZ607636B2 - Controlled Release Compositions and Their Methods of Use - Google Patents
Controlled Release Compositions and Their Methods of UseInfo
- Publication number
- NZ607636B2 NZ607636B2 NZ607636A NZ60763613A NZ607636B2 NZ 607636 B2 NZ607636 B2 NZ 607636B2 NZ 607636 A NZ607636 A NZ 607636A NZ 60763613 A NZ60763613 A NZ 60763613A NZ 607636 B2 NZ607636 B2 NZ 607636B2
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- active agent
- viscosity
- treatment
- colloidal silica
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Abstract
607636 Disclosed is 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 agent, the 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 20°C. Also disclosed is the method for preparing the composition, the method of treating a non-human animal for mastitis and the use of the composition for the manufacture of a medicament for treating mastitis. 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. Also disclosed is the method for preparing the composition, the method of treating a non-human animal for mastitis and the use of the composition for the manufacture of a medicament for treating mastitis.
Description
Disclosed is 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 agent, the base including, an amount of colloidal silica; at least one oil; and at least one
surfactant, wherein the viscosity of the ition is below 1000 mPas at a shear rate of 100
1/s and at a temperature of 20°C. Also disclosed is the method for ing the composition,
the method of treating a non-human animal for mastitis and the use of the composition for the
manufacture of a medicament for treating mastitis.
NZ 607636
CONTROLLED RELEASE COMPOSITIONS AND THEIR METHODS OF USE
TECHNICAL FIELD
This invention relates to controlled release compositions and their method of use,
and preferably, but not specifically, to low viscosity lled release compositions
for the treatment of mastitis in lactating animals.
BACKGROUND ART
In order to treat lactating animals with is or another microbial infection,
otic compositions are most often utilised. There are a number of
commercially available antibiotic compositions used for intramammary mastitis
treatment during the lactation .
However, one of the major problems encountered with antibiotic treatments is a
poor controlled release of the active agent over the ent . This can
lead to problems with maintaining the active agent concentrations above the
minimum tory concentration n 90% of the microbes are killed (termed
the MIC90). 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 Orbenin™ LA are often designed to have a higher viscosity, a known
technique to slow the release profile of an active agent from a composition.
, this is the approach taken for lactation and dry cow mastitis therapy known
as long acting ations, where the active is slowly released from a generally
thick paste over an extended period of time. For instance, if the antibiotic gets
administered 48 hourly during the ion period, the antibiotic is released slowly
with concentrations above MIC90 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. Again, this can lead
to failures in effectively treating the ion.
Further reasons why chemists develop high viscosity compositions are e it
can enhance the physical stability of the ition.
However, in the treatment of many conditions such as mastitis during the lactation
period, a higher ity 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 (WHP) leads to lost revenue.
Also, a higher viscosity composition requires more force for infusion or injection of
a formulation. This can lead to problems associated with increased difficulty with
infusion (herein referred to as ability) 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 ners or other excipients to se viscosity of the
compositions can 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 can be to handle during the manufacturing
process.
A further problem that can be encountered with many suspensions used for
mastitis treatment compositions is sedimentation of the suspension during storage.
Of course, a higher viscosity of a composition can help to ise physically the
suspension but a higher viscosity can not usually prevent ntation, it only
slows the sedimentation. Consequently, even viscous suspensions will eventually
sediment and the sediment may then cake, often proving difficult to re-disperse
prior to administration. A high viscosity composition can hinder the re-dispersability
of the nts.
ore, there is a long felt need in the industry to develop improved
compositions for the treatment of conditions such as mastitis during the ing
period of an animal. In the case of mastitis treatment, desired traits of such a
composition may include:
- llable release profile of the active agent;
- a short with-holding period (WHP) – for example, for treatment of conditions
such as mastitis during the lactation period of the animal;
- good re-dispersability after storage, or before administration;
- ease of injectability or other mode of administration;
- good distribution of the composition into the region to be d;
- the composition’s base being adaptable to use with different active agents
for treating or ting 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 controlled release profiles); and / or
- easy to manufacture, and using pharmaceutically acceptable excipients.
It is an object of the present invention to address the foregoing problems or at least
to provide the public with a useful choice.
All references, including any patents or patent applications cited in this
specification are hereby incorporated by reference. No admission is made that any
reference tutes prior art. The discussion of the references states what their
authors assert, and the applicants reserve the right to challenge the accuracy and
pertinency of the cited documents. It will be clearly understood that, although a
number of prior art publications are referred to , this nce does not
constitute an admission that any of these documents form part of the common
general 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 rs or steps, but not the
exclusion of any other element, integer or step, or group of elements, integers or
steps.
Further s and advantages of the present invention will become nt
from the ensuing description which is given by way of example only.
DISCLOSURE 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 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 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-dispersability and/or good
distribution in the udder, and/or
- a shorter WHP compared to other currently ble mastitis compositions.
As will be discussed further, the inventors have recognised the ular
importance of this invention to antibiotic treatment of mastitis. However, it would
be ably expected by someone skilled in the art that the same inventive
concept of the sed composition would apply to a controllable e profile
of substantially any active agent or nd in need thereof for treatment of
other conditions.
t 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, and in particular without a
ntial se in the composition’s viscosity.
By example in Figure 2, in vitro studies showed the inventors were able to
decrease drug recovery (equating to a decreased release profile in vivo) in
dissolution media from approximately 50% to 5% w/w over a 180 minute time
period. This beneficial effect was obtainable while the viscosity of the composition
only increased ally from 90 mPas to 118 mPas (at a shear rate of 100 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 t, Orbenin™ LA. However,
Orbenin™ 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
ed 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 ageous
features such as easy re-dispersability, injectability, manufacturing and/or a shorter
WHP. Such es may be provided whilst 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 inary trials as exemplified herein which
illustrates the significant advantages.
red embodiments of the composition
Active agent
Preferably, the active agent is an antibiotic, a combination of otics or an
antibiotic ed with a non-antibiotic active agent. The inventors ledge
a preferred antibiotic is cloxacillin due to its effectiveness in treating mastitis.
Preferably, the cloxacillin is given as cloxacillin sodium. Of course, other forms of
cloxacillin, such as cloxacillin benzathine, may also be used.
Other preferred active agents e beta-lactams, penicillins, cephalosporins,
aminoglycosides, quinolones, fosfomycin, sulphonamides, tetracyclines and
macrolide antibiotics.
Preferred combinations of active agents include amoxicillin and clavulanic acid;
llin active agent and aminoglycoside; cloxacillin and tylosin; and an antibiotic
and a non-steroidal anti-inflammatory drug.
However, substantially any antibiotic, non-antibiotic active agent, or functional
derivatives thereof may be ed in the present invention.
For example, the inventors have ified that the invention also works in a
similar fashion when the active agent is a tylosin 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 cloxacillin (both kept at a
concentration of approximately 4.5% w/w) resulted in a very different release rate.
Cephapirin was released much slower than cloxacillin. This illustrates that by
ing the type and possibly the concentration of active agent (and if appropriate
the silica and surfactant), a desired release of ntially any active agent may
be achieved.
ably, the active agent is micronised. The term micronised should be taken
as meaning a particle with a mass mean diameter d50 between to 1 – 20 µm
Micronisation helps to reduce sedimentation ty. Furthermore, larger particles
may form bridges in front of the syringe nozzle which may affect syringeability.
Throughout this specification, the term injectability or syringeability should be taken
as meaning the ease of stering the medicament to the animal through a
syringe. This is typically affected by viscosity, as well as the particle size of the
drugs or formulation excipients, which can mes partially or fully block the tip
of the syringe path during administration of the medicament.
Colloidal silica
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 µm).
A further discussion on the known traits and uses of colloidal silica is provided later
in this specification. This helps to illustrate that the present use of colloidal silica is
very different to the usly 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 iate that all currently available and future types of
fumed colloidal silica would provide the same advantages as discussed herein. As
exemplified in this specification, fumed colloidal n dioxide was found to be
particularly effective.
Preferably, the fumed colloidal silica has hobic properties.
The inventors identified hydrophobic colloidal silica may be significantly more
effective than hydrophilic colloidal silica at altering the e profile of the active
agent, whilst keeping the viscosity relatively low and/or substantially unchanged.
This was a surprising result as formulations using hobic colloidal silica have
a lower viscosity than those using its hydrophilic r-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
hobic 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 l of the active agent’s release.
A preferred commercially available hobic colloidal silicon dioxide is l®
R972 (supplied by l).
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 sed herein.
More preferably, the concentration of colloidal silica is between 1-3% w/w. A
particularly preferred amount of colloidal silica was in the order of 1.75% w/w. For
example, this was found to allow le release of the active over the treatment
period (typically 24 hours) to maintain the cloxacillin above the MIC90, 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, cephapirin
is shown to release considerably slower from the base of the composition than
cloxacillin.
For this reason, one may decide to lower the amount of colloidal silica to achieve a
similar e rate to that provided when using illin if so desired.
In-vivo protocols are well known in the industry and provide a straightforward test
to determine the resulting active agent tration 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 e rate of substantially any composition.
Overall, it was found by the inventors that the higher the concentration of colloidal
silica in the base of the composition, the slower the release rate of the active
agent. Importantly, this slowed release rate may be achieved without overly
affecting the viscosity of the compositions. In competing compositions, such as
NitroClox™ LA or Orbenin™ LA, a similar release rate can only be achieved
through a much higher ity, which has numerous disadvantages as discussed.
Throughout this specification the term tant 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 solid. Surfactants may also act as
emulsifiers, detergents, g agents and so forth.
Preferably, the surfactant is a nic surfactant.
However, the inventors consider amphoteric, anionic or ic tants should
work as well.
Preferably, the non-ionic surfactant has a hydrophilic-lipophilic e (HLB)
range between 0.5 and 30.
More preferably, the non-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, yethylene stearates, and hylene oxide monooleate, and
ations 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-oleate had a greater effect at slowing the release
rate of cloxacillin than 0.1% w/w Span 80, while all other variables were kept
constant.
Preferably, the surfactant is at a concentration between 0.01 to 10% w/w.
The inventors found that the more surfactant in the base of the composition, the
slower the release rate of the active agent.
For this reason, the /type of the surfactant and/or the ratio of surfactant to
colloidal 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 more than one type of surfactant. It would be
reasonable to expect that the resulting composition’s release profile (and other
characteristics such as WHP) may be more finely controlled by using a
combination of surfactants in a single composition, and/or in different compositions
administered during the course of treatment.
In many itions, oils are needed as a vehicle. For example, antibiotic
compositions including s such as cloxacillin or cephapirin are typically based
on an oily vehicle. For example, this helps the composition to be administered as
an infusion through the teat canal or an injection and/or achieving sufficient
chemical stability during its shelf life.
Preferably, the oil has a low ity.
The use of a low viscosity oil helps to ensure the resulting composition retains a
low ity. 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 viscosity of the oil is between 1 and 100 mPas at 20ºC.
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 Miglyol 812 or l 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 ified in Figure 6, the inventors found that different oils used altered the
recovery rate of the active agent. The effect was not as pronounced when
ed to alterations in the type/amount of surfactant, colloidal 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 ing composition. Therefore, in a preferred
embodiment, a lower viscosity oil is used to maintain a lower viscosity of the
composition.
Yet, the ors also consider that the oil may be cting 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-related lled release.
Viscosity of the final composition
Obviously, the viscosity of the composition may be tailored to the specific
requirements needed. For some compositions, a relatively high viscosity may be
used. In others, a low ity may be maintained by not adding excipients such
as thickeners or high viscosity oils. Such viscosity modifiers may also contribute, if
ary, 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 ammary 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 ion are below 1000 mPas 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 ents
or other compositions which e colloidal silica typically have a ity well
above this upper limit.
The ors 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-dispersability, udder distribution and/or short WHP when compared to
competing compositions such as NitroClox™ 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.
red method of treatment
Preferably, the ition described herein is used to treat mastitis as an
intramammary on during the lactation period.
In the case of is 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 period).
Yet, it is clear that the present ion may be used to treat substantially any
condition or disease depending on the active agent selected. The underlying
inventive concept of the composition should not be limited to compositions for
intramammary ent of mastitis.
ing to a further aspect of the present invention there is provided a method of
treating a microbial infection in an animal in need thereof with a composition as
substantially bed 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 the teat canal.
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, 24 or 48 hours.
More 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 preclinical
or clinical mastitis during the lactation period.
After the calculated WHP, normal milking production can resume again. Again, the
ors found the WHP of the present invention may be substantially lower than
other currently available ations, such as NitroClox™ LA when the same
treatment periods were compared.
Figure 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 tions 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 ion.
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
imately 10 L of milk (equalling 1kg of milk solids), and a farmer sells 1 kg of
milk solids for $8 to a company such as ra. rmore, each cow will
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 profiles during the
treatment .
To 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. It may also help to ensure the active is kept
above the MIC90. Towards the end of the treatment period, a faster releasing
composition may be used ially to top up the active agent levels. Yet,
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 ner to form a homogenous oil
mixture;
b) dispersing the active agent in the oil mixture; and
c) uently adding the colloidal silica 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, the colloidal silica in step c) is also heat sterilised before being added to
the oil mixture.
ably, the oil mixture formed after step c) is homogenously mixed.
The ors identified that the composition’s preferred low viscosity also helps
with the manufacturing process. Unlike other itions, there is no extra
heating step required to mix in a thickener (e.g. hydroxystearin).
Also, the lower viscosity may help when es need to be filled after
cturing the ition and prior to administration.
The preferred use of micronised active agents also helps to prevent quick settling
of the composition.
Additional background of colloidal silica
Fumed colloidal silica, such as colloidal silicon dioxide, is lly used as viscosity
modifiers, and more particularly, thickening agents in liquid formulations. Some
examples of how colloidal silica has been used follows. In line with what was
commonly understood in the art, colloidal silica was known to aid in ng 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 including an active dissolved in a
solvent then adsorbed on a sorbing medium such as Aerosil R972 fumed silica,
then dispersing the solvent into another liquid that contains another active
dissolved or suspended therein.
WO 03070155 discloses a formulation for oral administration including an active
agent suspended in an oily matrix, with tant and dal silicon dioxide. The
composition is made into a viscous on with the addition of hydrogenated
vegetable oil, including yellow beeswax as a suspending agent, lecithin. Silicon
dioxide is used as a dispersion aid and pseudoephedrine HCl, 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, hylamine, glycerol, and propylene glycol.
WO9824436 discloses a gel formulation including colloidal n dioxide and
triacetin.
JP 3153623 (based on English translation of Abstract) discloses a semisolid
pharmaceutical composition for oral administration. The composition includes a
drug, a physiologically permissible liquid, an edible oil, a colloidal silicon dioxide,
um stearate or a high-molecular weight polyethylene glycol.
US 4980175 discloses a liquid compositions for oral administration, including
d ingredient nium 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 0 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 e 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
ion (a composition with a viscosity below 1000 mPas). The colloidal silica
used in such compositions are typically used as ity modifiers (thickeners) to
directly impart a controlled release.
In other instances, fumed colloidal silica is used for tablet or powder formulations
as a low agent. AEROSIL discusses other typical applications of colloidal
silica on their website, such as anti-caking and a stabiliser (www.aerosil.com).
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 ity drops.
Once returning to rest, the ry ure 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 cture to obtain a
hydrophobic e. During this process, l 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 t hard sediments (i.e. caking) from
forming, particularly during storage (www.aerosil.com).
The general principle as employed in formulation chemistry is: an increase of
thickening agent concentration in a formulation, the r the viscosity, and the
slower the active agent release from the resulting formulation.
Therefore it was surprising to find that ng the components of the present
composition substantially influences the release profile of the active agent without
overly affecting the viscosity. This is clearly exemplified the es provided in
this specification.
As ified in Figure10, cloxacillin release from a preferred composition can be
finely controlled and extended with concentrations in milk above MIC90=0.5mg/L
(for illin in New Zealand, number taken from Salomon et al, 1998 J Dairy Sci
–578) for more than 48 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.
dal 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 dal silica to
increase the formulation’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 the Orbenin™ LA composition, it has a much
higher viscosity than that achieved by the present invention (as outlined in the
examples). As usly discussed, this can lead to problems with injectability.
Therefore, the inventors consider the present invention, which is able to achieve a
lower ity whilst being able to control active agent release ively, has
significant advantages over Orbenin™ LA.
WO 87/03876 also discloses a treatment/prevention formulation for mastitis during
the dry period. WO 87/03876 discusses the use of dal 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 over a longer ent period (during the dry period opposed to lactating
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 aim is to provide a high viscosity formulation
using colloidal silica as a thickener for slow release of the otic.
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 (µm) in diameter making them considerably larger than
colloidal silica particles. Unlike colloidal silica, molecular sieves do not have
thickening ties and, as such, are not typically used as thickening .
Column 1, line 54 to 58 of US 4,401,674 discusses that if the ation is to be
used for lactating cows, an emulsifying agent (or alternatively a t oil) may be
added into the composition to “hasten the mixing of the composition with the
aqueous secretions in the udder.” This is quite different to the concept of the
present invention, where the surfactant appears to be ally interacting with
the silica structure to impart a change in the release rate. For example, the release
rate of the active agent is slowed down with increasing surfactant concentration.
Depending on the type/amount of surfactant, silica and/or active agent, the release
rate of the active agent from the composition may be altered, and antly
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 ed to hasten the mixing
of the composition.
BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention will become nt 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
itions (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
rate (in vitro)
Figure 5 Influence of colloidal silica type (hydrophobic vs hydrophilic) on
active agent ry rate (in vitro)
Figure 6 nce of oil on active agent recovery rate (in vitro)
Figure 7 Exemplification of illin bioavailability in tissues 2 hours after
treatment (in vivo)
Figure 8 Influence of active agent type on active agent concentration in milk
(in vivo)
Figure 9 Influence of active agent type on active agent concentration 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 ACVM
guidelines (in vivo)
Figure 13 Comparison of treatment between e 1 composition and
NitroClox™ 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 ition and
Orbenin™ LA (in vivo)
Figure 16 Comparison of WHP between Example 1 composition and
Orbenin™ LA (in vivo)
BEST MODES FOR CARRYING OUT THE INVENTION
PART 1: Example Compositions
Example 1
mg w/w-%
illin sodium 231 4.62%
Methyl paraben 3.75 0.075%
Propyl n 1.25 0.025%
Aerosil R972 Pharma 87.5 1.75%
Span 80 25 0.50%
Miglyol 812 4651.5 93.03%
Total 5000 100.00%
Example 2
mg w/w-%
Cephapirin sodium 220.9 4.42%
Methyl paraben 3.75 0.075%
Propyl paraben 1.25 0.025%
Aerosil R972 Pharma 87.5 1.75%
Span 80 25 0.50%
Miglyol 812 4651.5 93.03%
Total 5000 100.00%
Example 3
mg w/w-%
Cloxacillin sodium 231 4.62%
Aerosil R972 Pharma 100 2.00%
Span 80 25 0.50%
Miglyol 812 4644 92.88%
Total 5000 100.00%
Example 4
mg w/w-%
Cloxacillin sodium 231 4.62%
Aerosil R972 Pharma 150 3.00%
Span 80 100 2.00%
Miglyol 812 4519 90.38%
Total 5000 100.00%
Example 5
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 87.5 1.75%
Span 80 100 2.00%
l 812 4354 87.07%
Total 5000 100.00%
Example 6
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
PEG12Oleate 5 0.10%
Miglyol 812 4423.5 88.47%
Total 5000 100.00%
Example 7
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
PEG12Oleate 2.5 0.05%
Miglyol 812 4426 88.52%
Total 5000 100.00%
Example 8
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
Span 80 2.5 0.05%
Miglyol 812 4426 88.52%
Total 5000 100.00%
Example 9
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
Span 80 5 0.10%
l 812 4423.5 88.47%
Total 5000 100.00%
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
Span 80 25 0.50%
Miglyol 812 4403.5 88.07%
Total 5000 100.00%
Example 11
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
Span 80 50 1.00%
Miglyol 812 4378.5 87.57%
Total 5000 100.00%
Example 12
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 112.5 2.25%
Span 80 100 2.00%
Miglyol 812 4328.5 86.57%
Total 5000 100.00%
Example 13
mg w/w-%
Cloxacillin sodium 459 9.18%
l R972 Pharma 150 3.00%
Span 80 100 2.00%
Miglyol 812 4291 85.82%
Total 5000 100.00%
Example 14
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil 200 Pharma 150 3.00%
Span 80 100 2.00%
Miglyol 812 4291 85.82%
Total 5000 100.00%
Example 15
mg w/w-%
Cloxacillin sodium 459 9.18%
Aerosil R972 Pharma 150 3.00%
Span 80 100 2.00%
Peanut Oil 4291 85.82%
Total 5000 100.00%
mg w/w-%
Cloxacillin sodium 200 2.00%
Tylosin base 250 2.50%
Aerosil R972 Pharma 400 4.00%
Span 80 200 2.00%
Methyl paraben 0.4 0.004%
Propyl paraben 0.2 0.002%
Miglyol 812 8949.4 89.49%
Total 10000 100.00%
Example 17
mg w/w-%
Cloxacillin sodium 437 8.74%
Aerosil R972 Pharma 150 3.00%
Span 80 100 2.00%
Methyl paraben 0.4 0.008%
Propyl paraben 0.2 0.004%
Miglyol 812 4312.4 86.25%
Total 5000 100.00%
PART 2: Exemplification of controlled release rate of active agent
Figure 1 illustrates the comparatively low viscosity of the preferred composition of
the present invention compared to reference products tly on the market.
Recovery rates in dissolution media (shown in Figures 2-6) are ered by the
inventors to be indicative of in vivo release rates.
Figure 2 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 0 mPas vs 1080 mPas). n™ LA is able to in a
relatively slow cloxacillin 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 two test compositions depicted in Figure 2 do not include a thickener to impart
a slow recovery profile. Instead, careful selection of the surfactant (Span80 vs.
PEG12-oleate) can be used to significantly alter the recovery profile of the
cloxacillin without a significant rise in the ity. The test composition containing
PEG12-oleate has a recovery profile substantially identical (if not slower) than
Orbenin™ 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
ified by the increase of the tration 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-Oleate (HLB=13.7) (Examples 6
and 7) is shown, with corresponding changes in the recovery e. 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. It was found that as the concentration of colloidal silica
(in this case Aerosil R972) increased from 1.75% to 3% w/w, the ry rate was
Again, although the ry profile slowed dramatically as the silica concentration
increased from 1.75 to 3%, the viscosity only increased slightly from 90 mPas to
127 mPas.
Figure 5 illustrates that the type of colloidal silica may also affect the recovery rate
of the active agent. Here, hydrophobic dal silica (Aerosil R972) is shown to
significantly lower the ry 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 distribution of cloxacillin in different s two hours after
treatment. In this case tissue is defined as remaining udder directly after milking,
which includes extracellular liquid, blood vessels, and potentially some remaining
milk which is not milked out.
Figures 8 and 9 illustrates how different active agents can also have an affect on
the release profile of the active agent itself, all else being substantially equal. In
Figure 8, when illin in the example composition 1 is replaced with cephapirin
(as shown in example composition 2), the release profile is substantially slowed. In
Figure 9, differences were also seen between illin and tylosin. This was
indeed a surprising result and suggests that the active’s release may be influenced
by an 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 WHP of the composition may be affected by the
characteristics of the composition.
Figure 10 illustrates how an increase in the amount of colloidal silica from 1.75% to
3.00% w/w can alter the WHP significantly.
Figure 11 illustrates that the number of treatments does not affect WHP. The
WHP is approximately equal regardless of whether the animal is treated with a 6 X
24 hour or 3 X 24 hour regime.
Figure 12 rates the ated 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 after each treatment, the amount of active agent is
higher when administered with the example 1 composition than NitroClox™ LA,
suggesting a higher bioavailability of example 1, 24h after treatment. Similar to
NitroClox™ LA, the example 1 composition does not decrease below the MIC90
(solid line) 24h after treatment, yet is more rapidly d from the milk after the
final treatment at 0 hrs.
Figure 14 ts the results shown in Figure 13. The example 1 composition is
calculated to have a WHP of only 72 hours ed to 108 hours for NitroClox™
Figure 15 compares the example 1 composition to n™ LA, albeit with a
ent treatment regime (6 X 24 hours vs. 3 X 48 hours, respectively). It can be
seen that although the treatment regime using example 1 ition provides a
much longer and tent level of active agent in the milk than the treatment
regime using Orbenin™ LA, the active agent is ed from the milk much
quicker after the final treatment. As can be seen, the final treatment of Orbenin™
LA is at 96 hours, whereas the final treatment with example 1 composition is at 120
hours; providing a longer 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 Orbenin’s 3 x 48 hour and 5 x 24 hour treatment
regimes, respectively.
PART 3: Manufacturing method
a) Mix Miglyol 812, methyl n, propyl paraben and Span 80 well to form
homogeneous oil mixture.
b) Sterilise the mixture at 140°C for 3 hours and then cool to room
temperature.
c) In a separate container, load the required amount of Aerosil R972 Pharma.
d) Sterilise at 140°C for 3 hours and then cool to room temperature.
e) Disperse and homogenise the illin sodium into the sterilised oil
mixture.
f) Disperse the sterilised Aerosil R972 Pharma into the sterilised oil
suspension.
g) Homogenise the mixture.
PART 4: Animal Study
As part of a study commenced in November 2011, the Example 18 formulation, as
detailed below, was investigated for efficacy in the treatment of bovine mastitis.
Example 18
mg w/w-%
ised cloxacillin sodium 229.2 4.584*
Methyl paraben 3.75 0.075
Propyl paraben 1.25 0.025
Sorbitan mono-oleate (Span 80) 25 0.5
Hydrophobic silica (Aerosil R972
87.5 1.75
Pharma)
Fractionated coconut oil ol
4653.3 93.066
812N)
Total 5000 100
*5% overages added
The animals used in the study were dairy cows diagnosed with clinical mastitis. On
day 0, milk samples were obtained for bacteriological is and the animals
were treated with intramammary infusions of Example 18 three times, with each
ent 24 hours apart. The dose for each ent was 200 mg of cloxacillin as
the sodium salt.
On days 28 and 35, further milk samples were obtained for bacteriological analysis
to determine the cure rate. A successful bacteriological cure 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 results available as of 1 November 2012, ed a bacteriological cure
proportion of 69.6% when treated with Example 18, from ~100 cows ed with
clinical mastitis, and with gram positive bacteria identified at the time of enrolment.
A comparable study is that reported by MD Wraight, New Zealand Veterinary
Journal 51(1), 26-32, 2003 “ A comparative cy trial between xime and
cloxacillin as intramammary treatments for clinical mastitis in lactating cows on
commercial dairy farms”. In this study, 200 mg of illin in a long-acting
formulation was administered as an intramammary every 48 hours for 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 obtaining an advantageous, shorter
ld period by using compositions of the invention, does not reduce or
compromise the efficacy of the treatment.
PART 5: Formulation ity
A stability study was ted 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 teristics 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 ed claims.
James & Wells 133072/76
WHAT I/WE
Claims (4)
1. A composition, the composition including a eutically effective amount of at least one active agent, and a base configured to provide a controlled release of the at least one active agent, the base ing, 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 20°C.
2. The composition as claimed in claim 1 wherein the active agent is an antibiotic.
3. The composition as claimed in claim 2 wherein the antibiotic is selected from the group consisting of a beta-lactam, penicillin, cephalosporin, aminoglycoside, quinolones, sulphonamides, tetracyclines and macrolide antibiotic.
4. The composition as claimed in claim 2 wherein the antibiotic is selected from the group consisting of cloxacillin or a functional derivative thereof, tylosin or a onal derivative thereof, cephapirin or a functional derivative thereof, and combinations thereof. James & Wells
Publications (1)
Publication Number | Publication Date |
---|---|
NZ607636B2 true NZ607636B2 (en) | 2022-12-16 |
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