Formulations for sustained release dressings and their use

The invention concerns a sustained release formulation comprising an agent (A) which is to be released and a vehicle (B) therefor. The vehicle comprises a hydrophilic component such as a polyhydroxylated organic substance such as a polyethylene glycol, glycerol, sorbitol, mannitol or lactose and curable silicone composition which is capable of curing at ambient temperature and contains a polysiloxane having alkylhydrogen units, a polysiloxane having unsaturated groups and a platinum or rhodium catalyst. The formulation may be applied to the human or animal body or a cavity in the latter to cure in situ to give a dressing capable of sustained release of the therapeutic or diagnostic agent (A) to the body. The invention is applicable in the field of pharmacy.

This invention is concerned with formulations for sustained release 
dressings and their use. 
Numerous proposals have been made for sustained release products, 
especially for example, in the field of delivery of therapeutic and/or 
diagnostic materials to the human or animal body. Prior proposals include, 
for example, external application of a transdermal patch to the body, 
insertion of a preformed implant into the body, attachment of a dressing 
to the tissue of a cavity and oral administration of a preformed element 
containing an active substance intended for administration orally. 
In the field of controlled release of therapeutic and diagnostic agents 
into the human or animal body from implants, it is known to employ 
silicone based materials as a matrix or membrane through which a 
lipophilic agent is able to diffuse at a controlled rate into the body. 
Silicone based materials proposed for the purpose are generally inert to 
body fluids and therefore highly acceptable for use in the body. However, 
the rates at which therapeutic and other compounds are released from or 
through silicone materials are generally very low due to the diffusion 
characteristics from the silicone matrix and are generally considered to 
be "first order" i.e. the quantity of substance liberated is a linear 
function of the square root of time. This is beneficial for controlled 
release of those therapeutic and other agents which are required to be 
introduced to the body at a comparatively low rate over a long period of 
time. However, it would be beneficial if a wide range of therapeutic and 
other agents could be delivered into the body at a comparatively high rate 
of more than several mg to one g per day for one or more days or even 
weeks, at an at least substantially constant rate independent of time, 
which is to say at zero order release rate. For these requirements the 
silicone based materials employed heretofore have been regarded as 
unsuitable due to the need to employ lipophilic agents whose rate of 
diffusion through the silicone material is slow. In the field of dressings 
which may be applied for example to the exterior of the body or to a 
natural cavity thereof it is desirable to employ a material which is 
capable of remaining in the chosen location for a period of time during 
which a therapeutic or diagnostic agent may be delivered at a desired 
rate. One of the requirements is thus a prolonged residence time coupled, 
in some cases, with an ability to release the agent at a constant rate 
over a period of several hours or days. 
We have now found that one may provide an element formed in situ on or in 
the human or animal body, hereinafter referred to as a dressing, capable 
of releasing a therapeutic or diagnostic agent at a desired rate during 
several hours to several days or more by use of a formulation comprising a 
room temperature curable silicone composition, a hydrophilic component and 
a therapeutic or diagnostic agent (A). 
The present invention provides in one of its aspects a sustained release 
formulation suitable for use as a dressing in or on the human or animal 
body comprising an agent (A), and a vehicle (B) therefor which comprises a 
hydrophilic component (a) and a curable silicone composition (b) which is 
formulated to cure at room temperature within 10 minutes of mixing and 
application to a human or animal body comprising a polysiloxane having 
alkylhydrogen siloxane units, a polysiloxane having unsaturated groups for 
reaction therewith and a platinum or rhodium catalyst for the 
hydrosilylation reaction. 
The invention is concerned with formulations for forming dressings for the 
human or animal body which are capable of delivering a therapeutic or 
diagnostic agent to the body. It is a characteristic of the invention that 
the dressings are formed in situ by use of a formulation which comprises a 
silicone composition which is curable in a short time after mixing and 
application to the body. The dressing may be formed by coating a 
formulation according to the invention onto intact or damaged skin or by 
casting the formulation into a natural or artificial cavity of the body. 
The cavity may be for example the occular, buccal, nasal, aural, vaginal 
or rectal cavity or a cavity developed for example in a tooth or an open 
wound. The formulation is allowed to cure in situ. Characteristics of the 
dressings may be controlled within wide limits by appropriate selection of 
the components. 
The agent (A) of a formulation according to the invention is a material 
capable of release from a dressing formed by use of the formulation when 
the dressing is exposed to biological fluids of the human or animal body, 
i.e. when the dressing is in an aqueous environment. Suitable materials 
include those agents (A) which are not soluble in or do not diffuse 
through silicone materials i.e. those materials which are hydrophilic and 
include therapeutic or diagnostic agents. The agent (A) may be a solid or 
liquid material and is incorporated into the formulation before curing of 
the formulation. It is important to ensure that the agent (A) chosen does 
not interfere with the curing of the silicone composition to an 
unacceptable extent. The invention is especially applicable to those 
therapeutic and diagnostic agents which it is desired to deliver to the 
body over a period of time at a controlled rate. As is known the rate of 
delivery required of a given drug falls within a therapeutic window. By 
tailoring a formulation according to the invention it is possible to 
provide dressings from which many drugs can be delivered at rates within 
their therapeutic window. Therapeutic or diagnostic agents suitable for 
use as the agent (A) of the present invention include those which are 
intended to be released into the body via the blood stream and may be 
hydrophilic or lipophilic substances. The agent (A) may be chosen in 
accordance with normal pharmaceutical practice and will normally have a pH 
appropriate to the conditions at the region in the body where it is to be 
released. Normally, the pH anticipated is greater than 4.5. If the pH is 
more acidic, then a suitable buffer substance may be used to modify the 
properties of the dressing to permit a more suitable swelling and/or 
release profile. Therapeutic agents which may be employed include for 
example antibiotic, antiseptic, antiinflammatory, cardiovascular, 
antihydrogen, bronchodilator, analgesic, antiarrythmic, antihistamine, 
.alpha. -1 blocker, beta blocker, ACE inhibitor, diuretic, antiaggregant, 
sedative, tranquiliser, anticonvulsant and anticoagulant agents, vitamins, 
agents for treating gastric and duodenal ulcers, proteolytic enzymes, 
healing factors, cell growth nutrients and peptides. Specific examples of 
suitable therapeutic agents include penicillins, cephalosporins, 
tetracyclines, macrolides, epinephrine, amphetamines, aspirin, 
barbiturates, catecholamines, benzodiazepine, thiopental, codeine, 
morphine, procaine, lidocaine, sulphonamides, tioconazole, perbuterol, 
furosamide, prazosin, prostaglandins, salbutamol, indomethicane, 
diclofenac, glafenine, dipyridamole and theophylline. Some of the 
operative therapeutic and diagnostic agents may contribute to the 
activities of the hydrophilic component and may modulate the rate of 
delivery of the agent (A). This factor influences the proportion of agent 
(A) present in the formulation, as does the extent to which the agent (A) 
may inhibit or accelerate the cure of the formulation. The proportion of 
the agent (A) employed in a formulation according to the invention is 
chosen in accordance with the concentration of the agent (A) required in 
the dressing to deliver the dosage required at the proposed delivery rate 
and may be varied within a very wide range. The agent (A) may provide a 
major or a minor amount of the formulation. The efficient delivery 
achieved with dressings made from formulations according to the invention 
permits use of comparatively low dosage levels. However, it is generally 
desirable to include as large a proportion of therapeutic or diagnostic 
agent as possible consistent with the desired delivery of the agent. 
The silicone polymer formed by curing the silicone composition of the 
formulation serves as a binder matrix for the other components and 
ingredients, and may be employed to generate a greater or lesser 
proportion of the matrix depending on the intended site of application and 
the use for which the dressing is intended. For example, those 
formulations which are intended for the formation of dressings by casting 
into a body cavity preferably employ from 40 to 80% more preferably up to 
60% of the silicone composition by weight of the vehicle, to ensure 
sufficient shape retention during use or to restrict the rate of release 
of the agent (A). If desired the formulation may comprise additional 
ingredients, for example fillers (which may be, for example opaque to X 
rays or other diagnostic radiation), extenders, for example silicone 
fluids, and excipients employed in pharmacy and compounds intended to 
perform as pH buffers in controlling the environment immediately in and 
around the dressing when it is in an aqueous environment. 
Release of the agent (A) from a dressing prepared from a formulation 
according to the invention is dependent upon presence of water in the 
environment in which the dressing is present. No swelling occurs, and at 
least substantially no release of the agent (A) takes place until the 
dressing is in contact with an aqueous medium. When the dressing is 
exposed in an aqueous environment the dressing swells, at least to a small 
extent, as a result of intake of water and then the agent (A) is 
progressively released. The rate at which the agent (A) is released 
appears to be dependent upon the surface area of the dressing and the 
extent to which the dressing swells, and this extent is dependent upon the 
quantity and pH of the aqueous environment of the dressing and upon the 
dissolution rate and/or the contribution to hydrophilic or modulating 
activity of the agent (A), upon the nature of the hydrophilic component 
(a) and upon the nature of other components of the formulation. The 
mechanism by which this phenomenon occurs is not fully understood. 
However, without wishing to be bound by any particular theory, we believe 
that in one aspect the silicone polymer (which has a measure of 
elasticity) and the hydrophilic component in combination are essential for 
satisfactory sustained release through a combination of elastomeric and 
osmotic properties, the hydrophilic component serving to draw water into 
the dressing, for example to provide a hypertonic environment and to cause 
the silicone polymer to become distended, and also to co-operate with 
attempted contraction of the distended silicone polymer to deliver the 
agent (A) to the surrounding medium from the dressing. 
In a formulation according to the invention, the hydrophilic component (a) 
is preferably a liquid at relevant temperatures, but solid materials (for 
example sorbitol, manitol, sodium chloride and certain drugs) dissolved in 
suitable solvent may be used. This component is suitably an organic 
hydrophilic material having two, more preferably three or more, hydroxyl 
groups per molecule and may be chosen, for example, from the liquid 
polyethylene glycols having a molecular weight in the range of 100 to 600, 
propylene glycol, glycerol, sorbitol and mannitol. The hydrophilic 
component is preferably a hygroscopic material. Whilst some swelling and 
release of the agent (A) takes place from dressings having each of these 
as the hydrophilic component, we prefer to use a material which is a 
liquid at the temperature at which the agent is to be released, and 
preferably also liquid at the temperature at which the dressing is made. 
The hydrophilic component selected preferably does not interfere unduly 
with curing of the formulation. This component is most preferably selected 
from the water soluble, polyhydric alcohols having a melting point of less 
than 25.degree. C. The most preferred material is glycerol. In order to 
ensure release of the agent (A) at a desired rate from the dressing, we 
prefer to employ the hydrophilic component in the formulation in a 
proportion within the range of 5 to 40% by weight of the vehicle. If less 
than 5% by weight of the hydrophilic component is present the beneficial 
effects are not realised, whereas if more than 40% is employed not only 
are the beneficial effects not realised, but also the cure characteristics 
of the curable silicone may be very adversely influenced and/or some or 
all of the hydrophilic material may be lost from the dressing. Proportions 
within the range specified may be selected with regard to the intended 
life cycle time of the dressings. In general, when glycerol is used, we 
prefer to employ from 10% to 25% glycerol by weight of the vehicle. 
A formulation according to the invention preferably also comprises a 
modulating component which controls delivery of the agent (A) from the 
dressing formed upon curing of the formulation. If no modulating component 
is present in the dressing, a burst of the agent (A) is delivered from the 
dressing initially at a somewhat high rate followed by a somewhat reduced 
rate until the dressing is no longer capable of delivering the agent (A). 
The modulating component serves to modulate the release of the agent (A) 
and may be selected in accordance with the modulation desired. For 
example, those materials which do not swell substantially in water may be 
expected to modulate the delivery of the agent (A), to improve the 
constancy of the delivery of the agent (A) and the proportion released and 
possibly also lengthen the overall useful life of the dressing. When a 
faster constant delivery is desired, a modulating component may be 
employed which swells substantially in water in order to modulate the 
delivery of the agent (A) to enhance the period during which the agent is 
delivered at a somewhat higher rate, with a consequently short overall 
useful life of the dressing. 
The modulating component may be selected from a wide range of organic 
materials. Modulating components which do not swell substantially in 
biological fluids encountered by dressings include organic hydrophilic 
substances (I) having two or more hydroxyl groups per molecule. Modulating 
components which serve to promote release of the agent (A) at a high rate 
include hydrophilic polymers (II) which swell in an aqueous medium. The 
particular substance (I) or polymer (II) used, and the proportion employed 
in the formulation, are selected in accordance with the rate of delivery 
and the period during which delivery is required and the nature of the 
dressing required. The substances (I) serve to regulate or eliminate the 
initial burst of the agent from the dressing and may extend the life of 
the dressing during which the drug is delivered at a constant and 
optionally comparatively high rate. In contrast, polymers (II) serve to 
increase the ability of the dressing to swell and consequently serve to 
increase the ability of the dressings to discharge the agent at a very 
high rate even though the aqueous media which are available on the body or 
in cavities thereof is present in comparatively small volume. 
The organic hydrophilic substance (I) may have two, more preferably three 
or more hydroxyl groups per molecule and may be chosen, for example, from 
the polyethylene glycols having a molecular weight in excess of 600, 
sorbitol, mannitol, lactose and mixtures thereof. The material used is 
selected in accordance with the characteristics required of the dressing 
and especially the release profile desired in the selected location for 
the dressing. We prefer to use a material which is a solid at the 
temperature at which the formulation is prepared and a solid at the 
temperature at which the agent (A) is to be released. We prefer to employ 
a material which is hygroscopic. The substance is most preferably selected 
from the water soluble, polyhydric alcohols having a melting point of 
greater than about 40.degree. C. The organic substance may also preferably 
be selected from the group consisting of the solid polyethylene glycols of 
molecular weight greater than 600, sorbitol, mannitol and lactose and is 
present to an extent from 5% to 25% by weight of the vehicle. The most 
preferred substance (I) is sorbitol. In order to ensure release of the 
agent (A) at a desired rate when dressings formed from the formulation are 
subjected to biological fluids, we prefer to employ the sorbitol in the 
formulation in a proportion of up to 40%, more preferably the hydrophilic 
agent comprises from 5 to 25% by weight of the vehicle. 
The hydrophilic polymer (II) may be any one, or a mixture of any two or 
more, of those organic polymers known to be capable of swelling in aqueous 
media of pH as found in biological fluids at the intended site of the 
dressing, i.e. greater than about 4.5 for natural body cavities, provided 
that it does not interfere unduly with curing of the formulation. 
Generally, in order to achieve prolonged fast delivery of the agent (A) it 
is preferred that the polymer exhibit significant swelling as determined 
by its water inhibition during a short time. The polymer may be chosen, 
for example from the group consisting of cellulosic materials, e.g. 
cellulose and cellulose derivatives for example carboxymethylcellulose, 
sodium carboxymethyl cellulose whether crosslinked or not, 
hydroxypropylcellulose and acetylated chitin. The potential of these 
polymers to swell should be borne in mind especially in those cases where 
the dressing is likely to be subjected to copious wetting. In the absence 
of copious amounts of water however, the swelling of these polymers is 
limited. 
Some of these polymers (II) swell in aqueous medium of pH &gt;4 and may be 
caused to swell at more acidic pH, if desired, by incorporation of a salt 
capable of performing as a buffer to modify the physiological pH at which 
the dressing swells. We have found that swelling of dressings comprising 
sodium carboxymethylcellulose may be induced to a desired extent to 
release agent (A) in aqueous medium of pH 4 or less by inclusion of sodium 
acetate in the formulation. However, the time required for curing 
formulations including such salts is extended and their use is generally 
not preferred in those subject formulations which are intended to cure 
very rapidly. The hydrophilic polymer (II) which is selected from the 
group consisting of hydroxypropyl cellulose, carboxymethyl cellulose and 
sodium carboxy methyl cellulose, whether crosslinked or not, is preferably 
present to an extent of 10% to 45% by weight of the vehicle. 
Certain of the swellable polymers (II) suitable for use in the invention, 
for example sodium carboxy methylcellulose, contribute not only to 
swelling and to the ability of the dressing to release the agent (A) but 
also to bioadhesive characteristics of the dressing, i.e. the ability of 
the dressing to adhere to the skin or mucosa of the body. Bioadhesive 
characteristics of the dressing may also be promoted by presence in the 
vehicle of certain polymers and copolymers of acrylic acid (e.g. 
polyacrylic acid cross linked with polyalkyl sucrose or 
3,4-dihydroxy-1,5-hexadiene), acrylates e.g. poly(hydroxyethyl 
methacrylate), vinylpyrrolidones, vinyl acetate, polycarboxylic acids, 
poly(ethylene oxide), alginates, gelatin, pectin, pectin derivatives, 
natural gums, proteins, pharmaceutically active salts of these and 
mixtures thereof. The property of greater or lesser adhesion of the 
swollen dressing to the body is pertinent to the intended mode of use of 
the dressing. For example, in some cases it may be advantageous to have 
good adhesive properties to ensure that the dressing adheres well to body 
tissues, whereas in other cases it may be advantageous if the adhesive 
properties are poor. The adhesive properties conferred also appear to be 
dependent on the degree of swelling and therefore pH dependent. For 
example, dressings which contain sodium carboxymethylcellulose as a 
modulating component are substantially non-adhesive to body tissues in 
aqueous medium of pH 1 to 3.5, but adhere well in aqueous media at pH 4 to 
8 such as are normally found in biological fluids in the body cavities. In 
addition to the possibility to design formulations to make dressings 
having bioadhesion, it will be apparent that dressings which contain a 
hydrophilic substance (I) as modulating agent and which are not intended 
to swell substantially, may also contain a swellable polymer (II) to 
induce bioadhesion. This may be especially beneficial, for example, in 
dressings intended for application to the buccal, nasal or occular 
cavities and possibly the rectal or vaginal cavities where the extent of 
swelling is restricted by the smaller proportions of aqueous medium 
present. 
The curable silicone composition of a formulation according to the 
invention is curable to a cellular or noncellular gel or elastomeric form 
in which it serves to bind, i.e. contain or entrap, the other components 
of the formulation and may provide a major or minor proportion of the 
formulation. The composition is curable at room temperatures i.e. 
20.degree..+-.5.degree. C. and thus permits the formulation to be used to 
provide in situ cured dressings. The polysiloxanes employed have 
silicon-bonded unsaturated organic groups, e.g. vinyl groups, available 
for reaction with silicon-bonded hydrogen atoms in presence of a 
hydrosilylation catalyst for example a platinum or rhodium compound. The 
addition reaction which occurs is appropriate to yield chain extended or 
crosslinked unfoamed resinous or elastomeric silicone products. 
Suitable polysiloxanes having unsaturated groups for reaction with 
polysiloxanes having silicon-bonded hydrogen atoms include 
polydiorganosiloxanes which have sufficient unsaturated groups for 
formation of the polymer network, for example polysiloxanes having 
siloxane units according to the general formula 
##STR1## 
in which each R represents a monovalent hydrocarbon group having up to 20 
carbon atoms, for example a lower alkyl or phenyl group e.g. a methyl 
radical, m is 1 or 2 and R' represents an aliphatically unsaturated group, 
for example cyclohexenyl or a group R"CH.dbd.CHR'", where R" represents a 
divalent aliphatic chain linked to the silicon atom and R'" represents a 
hydrogen atom or an alkyl group; examples of groups R' are thus vinyl, 
allyl and hexenyl. These polysiloxanes also comprise units 
##STR2## 
in which R is as referred to above, and n is 1, 2 or 3. Preferably, these 
polysiloxanes have from 0.01% to 1% by weight of aliphatically unsaturated 
groups and a viscosity of the order of about 10 mm.sup.2 /s to about 25000 
mm.sup.2 /s. More preferably their viscosity lies in the range 100 
mm.sup.2 /s to 2000 mm.sup.2 /s. 
Suitable polysiloxanes having alkylhydrogensiloxane units include polymers 
having units according to the general formula 
##STR3## 
in which each R represents a monovalent hydrocarbon group containing 1 to 
20 carbon atoms, for example a lower alkyl or phenyl group e.g. a methyl 
group and p is 1 or 2. The alkylhydrogen polysiloxanes may also comprise 
units 
##STR4## 
as referred to above. Preferably this polysiloxane has from 0.5% to 2.5% 
by weight of silicon-bonded hydrogen atoms. We prefer that each R 
represents a methyl group. Preferably, terminal groups of the 
alkylhydrogen polysiloxane have the formula R.sub.3 SiO.sub.1/2 where each 
R represents a methyl group. Suitable alkylhydrogen polysiloxanes include 
those comprising MeHSiO units with or without the presence of Me.sub.2 SiO 
units and having viscosities of the order of from about 1 to about 1000 
mm.sup.2 /s more preferably from about 5 to about 50 mm.sup.2 /s. 
The formulations cure within 10 minutes or more preferably within five 
minutes or less of mixing, so that the patient is required to remain 
immobile for only a short time whilst curing takes place. In order to 
achieve satisfactory cure it is important that the ratio of silicon-bonded 
hydrogen atoms of the polysiloxanes to all groups reactive therewith in 
the formulation is appropriate, so that enough of the alkylhydrogen 
polysiloxane is present to effect the desired cure. We have found it 
possible to provide formulations according to the invention which cure 
within three minutes or less of mixing of the formulation at room 
temperature and humidity (i.e. about 60% to 80% relative humidity). The 
curing time is dependent on various factors, including the type and 
proportion of other components present in the formulation and especially 
the salt materials, which tend to retard the cure significantly. The rate 
at which the agent (A) is released from the dressing is also dependent to 
some extent upon the resilience of the silicone polymer. 
Platinum catalysts may take any of the known forms, ranging from platinum 
as deposited on carriers such as silica gel or powdered charcoal, to 
platinic chloride, salts of platinum and chloroplatinic acids. A preferred 
form of platinum is chloroplatinic acid either as the commonly obtainable 
hexahydrate or the anhydrous form, on account of its easy dispersibility 
in organosilicon systems and its non-effect on colour of the mixture. 
Platinum complexes may also be used e.g. those prepared from 
chloroplatinic acid hexahydrate and divinyl tetramethyldisiloxane. It is 
desired to prolong the cure time one may include in the composition one of 
the known platinum catalyst inhibitors such as cyclic 
polymethylvinylsiloxane compound or an acetylenic alcohol e.g. methyl 
butynol but these are not generally preferred in a formulation according 
to the invention. The rate of cure of the formulation from which the 
vehicle (B) is formed is dependent not only upon the silicone polymer 
forming ingredients but also upon the nature of the other ingredients of 
the mixture, including the agent (A) and any salts present during the 
curing. Presence of ionic salts, e.g. sodium acetate, in the formulation 
tends to extend the cure time and in such cases it is desirable to reduce 
or eliminate the proportion of inhibitor present and/or to increase the 
proportion of platinum catalyst employed. 
If desired foaming of the silicone composition as it cures may be induced, 
for example by inclusion among the silicone forming materials of a 
polysiloxane having silicon-bonded hydroxyl groups with a view to reaction 
with the polysiloxane having silicon-bonded hydrogen atoms as more fully 
described for example in U.S. Pat. No. 4,026,845, and/or by inclusion of 
water or an aliphatic alcohol (for example a primary aliphatic or 
araliphatic alcohol for example a lower aliphatic monofunctional alcohol 
having up to 12 carbon atoms, e.g. ethanol, n-propanol, or benzyl alcohol) 
or by inclusion in the composition of a volatile blowing agent as more 
fully described for example in U.S. Pat. No. 4,550,125. Preferred foamable 
formulations include compounds having silicon-bonded or carbon-bonded 
hydroxyl groups which foam and cure in presence of a platinum catalyst 
according to the scheme .tbd.SiH+HOQ.fwdarw..tbd.SiOQ+H.sub.2. The group Q 
may be for example an aliphatic group or a polysiloxane having one or more 
reactive hydroxyl groups so that by virtue of the plurality of 
silicon-bonded or carbon-bonded hydroxyl groups the hydrogen evolved as a 
gas serves to form cells within the developing network of interconnected 
polysiloxane chains. Curable silicone compositions employed for 
preparation of cellular dressings may also comprise foam stabilisers or 
surfactants. Suitable materials include fluorinated silicones. 
If desired, other adjuvants may be incorporated in the silicone composition 
for example fillers, colorants, coloured indicators, extenders, diluents 
and processing aids for example cyclic or linear polydiorganosiloxanes. 
The presence of some silica filler is desirable when dressings having 
strongly elastomeric properties are required. 
Formulations according to the invention are curable at room temperature 
when mixed, and therefore are normally used to produce sustained release 
dressings immediately upon mixing the various components. In those cases 
in which it is desired to store the formulation prior to admixture and 
formation of a drug delivery dressing, this may be achieved by storing the 
formulation in separate parts one of which contains the catalyst for the 
curable silicone composition and one of which contains the alkylhydrogen 
polysiloxane. When the agent (A) is present in the formulation during 
storage, it may be preferable to include it in one only of the parts of 
the formulation in order to preserve its effectiveness. 
A formulation according to the invention preferably comprises from 10 to 
70% by weight of the agent (A) and from 90 to 30% by weight of the other 
components of the formulation in a proportion of 10 to 40 parts by weight 
of the hydrophilic component, 40 to 80 parts by weight of the 
polysiloxanes and 10 to 40 parts by weight of a hydrophilic substance (I) 
selected from the group consisting of polyethylene glycols of molecular 
weight greater than 600, sorbitol, mannitol and lactose. 
The present invention offers numerous advantages. The silicone and other 
materials chosen enable sustained release dressings to be formed by simple 
and easily controlled methods in situ which cure into a desired shape and 
have selected combinations of properties (e.g. bioadhesion, release rate 
and release profile). One may produce the formulations and process them 
without imposing severe processing conditions upon incorporation of the 
substance to be released, e.g. high temperatures or pressures, which might 
be damaging to medicaments used. The silicone materials and other 
ingredients used are acceptable in the human or animal body. The dressings 
may be formulated to give a moderate to rapid release of agent (A), which 
is in many cases highly advantageous in that high zero order release rates 
of from 1 to 100 mg per day over several days may be achieved. The drug 
delivery profile of dressings according to the invention may be 
predetermined by appropriate selection of the types and proportions of 
components and ingredients used. A particular advantage of dressings 
according to the invention is their ability to release agent (A) at a 
controlled rate in substantially larger proportion than heretofore 
achieved with silicone materials. We have found for example that both 
lipophilic and hydrophilic agents may be released from the dressings. It 
is a further advantage of the present invention that the dressings can be 
elastomeric materials able to withstand many of the pressures exerted 
during normal activities of the patient. 
In order that the invention may become more clear there now follows a 
description of various formulations, Example 5 being illustrative of the 
invention. In the Examples, all parts and percentages are expressed by 
weight. 
The Examples show the dependence of cure rate upon the components of the 
formulation and show the dependence of swelling of dressings upon the 
components of the formulation and the dependence of bioadhesion and drug 
delivery upon swelling. 
The silicone materials employed in the Examples were as follows: 
Silicone Part 1A comprised 69 parts of dimethyl vinyl endblocked 
polydimethylsiloxane fluid having a viscosity at 25.degree. C. of about 
2,100 mm.sup.2 /s, 6 parts hexamethyl disilazane, 1 part water, 0.1 part 
of a platinum catalyst, being a complex of chloroplatinic acid hexahydrate 
and vinyl siloxanes, and 24 parts of fume silica; 
Silicone Part 1B comprised 88 parts of the dimethylvinyl endblocked 
polysiloxane, 12 parts of a copolymer of polydimethyl and 
polymethylhydrogen siloxanes having a viscosity at 25.degree. C. of about 
5 mm.sup.2 /s and 0.75% hydrogensiloxane units (as % H) and 0.4 part 
methylvinyl cyclic polysiloxanes; 
Silicone Part 2A comprised silicone Part 1A with an additional 1% of the 
platinum catalyst; 
Silicone Part 2 B comprised silicone Part 1B without the cyclic siloxanes; 
Silicone Part 3A comprised silicone Part 1A with an additional 2% of the 
platinum catalyst; 
Silicone Part 4A comprised silicone Part 1A with an additional 0.5% of the 
platinum catalyst; 
Silicone Part 5A comprised silicone Part 1A with an additional 0.3% of the 
platinum catalyst; 
Silicone Part 6A comprised silicone Part 1A with an additional 0.2% of the 
platinum catalyst; 
Silicone Part 7A comprised silicone Part 1A with an additional 0.1% of the 
platinum catalyst; 
Cellulosic materials used in the Examples were as follows: 
Cellulosic material 1 was a sodium carboxymethylcellulose supplied under 
the trade name Tylopur 1000 by Hoechst; 
Cellulosic material 2 was a hydroxypropyl methylcellulose phthalate 
supplied under the trade name HP50 by Seppic having an average molecular 
weight of 20,000 and a carboxybenzoyl groups content of 20 to 24%; 
Cellulosic material 3 was a hydroxypropyl methylcellulose phthalate 
supplied under the trade name HP55 by Seppic having an average molecular 
weight of 20,000 and a carboxybenzoyl group content of 27 to 35%; 
Cellulosic material 4 was a blend of microcrystalline cellulose and sodium 
carboxymethylcellulose supplied under the trade name Avicel RC591 by 
Seppic having an average particle size of 28 micrometers; 
Cellulosic material 5 was a crosslinked sodium carboxy methyl cellulose 
supplied under the trade name ACDI SOL by Seppic having a degree of 
substitution of 0.6 to 0.85; 
Cellulosic material 6 was a hydroxypropyl methylcellulose supplied under 
the trade name METOLOSE 60S H50 by Seppic having an average molecular 
weight of about 8,600, and 
Cellulosic material 7 was a methyl cellulose supplied under the trade name 
METOLOSE SM15 by Seppic having approximately 30% of methoxy groups. 
Solutions referred to as having specified pH were prepared as follows: 
pH=1.2 and pH=2 were made from a KCl, HCl buffer (Carlo Erba); 
pH=3, 4, 5 and 6 were made from a potassium biphthalate buffer (Carlo 
Erba); 
pH=7 and 8 were made from KH.sub.2 PO.sub.4 buffer (Carlo Erba); 
pH=4.5 was made according to USP XX1 from an acetate buffer.

EXAMPLE 1 
In this Example, the effect of varying the proportions of catalyst and 
inhibitor upon the cure rate of the silicone composition is demonstrated. 
Formulations were prepared using 8 parts of a mixture of a silicone Part A 
and silicone Part B using different ratios of Part A to Part B, 2 parts of 
tetracycline and optionally with a hydrophilic material. The drug was 
mixed with the Part A, the Part B added and the formulation mixed for 1 
minute. The time taken for the formulation to become cured at room 
temperature, as demonstrated by its transition from a stiff liquid to a 
solid mass, was noted. The results are shown in Table 1 and Table 1(a). 
TABLE 1 
______________________________________ 
Ratio 
Silicone Silicone Part A: 
Formulation 
Part A Part B Part B 
______________________________________ 
1 1A 2B 8:3 
2 1A 2B 6:5 
3 2A 2B 10:1 
4 2A 2B 8:3 
5 2A 2B 6:5 
6 3A 2B 10:1 
7 3A 2B 8:3 
8 3A 2B 6:5 
9 4A 1B 8:3 
10 4A 2B 10:1 
11 4A 2B 9.5:1.5 
12 4A 2B 9:2 
13 4A 2B 8.5:2.5 
15 4A 2B 8:3 
16 4A 2B 6:5 
17 5A 2B 7:4 
18 5A 2B 8:3 
19 5A 2B 8:3 
20 5A 2B 8:3 
21 5A 2B 8:3 
22 5A 2B 8:3 
23 5A 2B 8:3 
24 5A 2B 8:3 
25 5A 2B 8:3 
26 5A 2B 8:3 
27 5A 2B 8:3 
28 6A 2B 8:3 
29 7A 2B 8:3 
30 7A 2B 6:5 
______________________________________ 
TABLE 1 (a) 
______________________________________ 
Cure 
Formu- Hydrophylic 
Time 
lation Substance (mins) Remarks 
______________________________________ 
1 -- 40 V. tacky - poor consistency 
2 -- -- No cure after 2 hours 
3 -- 12 Tacky 
4 -- 2.5 No tack - good surface 
5 -- 1 
6 -- 10 Tacky 
7 -- 2.5 No tack - good surface 
8 -- &lt;1 
9 -- 35 Good surface 
10 -- 13 Very tacky 
11 -- 8 Very tacky 
12 -- 5 Tacky 
13 -- 3.5 Slight tack 
15 -- 2.5 No Tack 
16 -- 2 
17 -- 3 Tacky 
18 10 parts A 4 No tack 
19 30 parts A 4 No tack - release of A 
20 10 parts B 2.5 No tack 
21 30 parts B 2.5 Slight tack - good surface 
22 10 parts C 3 
23 30 parts C 2.5 Slight tack - poor cohesion 
24 10 parts D 2.5 No tack after 10 minutes 
25 10 parts E -- No tack after 10 minutes 
26 10 parts F 8 No tack 
27 10 parts G 4 No tack 
28 -- 4 Tacky 
29 -- 5.5 Very tacky 
30 -- 11 V. tacky - low consistency 
______________________________________ 
A = propylene glycol 
B = glycerol 
C = Dsorbitol 
D = polyethylene glycol 200 
E = polyethylene glycol 600 
F = polyethylene glycol 1000, melted 
G = polyethylene glycol 1000, 1 g/ml in water 
From these results, it is apparent that the rate of cure of the silicone 
composition can be adjusted by variation of the catalyst and inhibitor 
proportions employed and by variation of the ratio of Parts A and B, which 
varies also the ratio of the polysiloxanes. The cure rate is also 
influenced by the nature and proportion of the hydrophilic material used. 
Nevertheless it will be apparent that one may provide a formulation 
capable of curing within 10 minutes or less, which is appropriate to 
permit mixing of the formulation and application to the body where it 
cures within a few minutes. For many dressing applications, the 
formulations which cure to a non-tacky condition are preferred, but those 
which cure to a tacky condition are also acceptable for some applications. 
EXAMPLE 2 
Formulations were prepared by mixing ingredients in the proportions shown 
in Table 2. Discs were prepared by mixing the components of each 
formulation using a Heidolph RGL 500 bench homogenizer. The mixed 
formulations were pressed into a mould between two 50 micron polyester 
films then cured at 22.degree. C. to give a matrix with a thickness 2 to 
2.2 mm and 2 cm discs were punched therefrom. To determine swelling, each 
disc was weighed then placed into 200 ml of deionized water (pH=6) at 
22.degree. C. Each disc was removed and all water removed from its surface 
using a filter paper, then weighed again. The Weight Swelling Ratio Ws/Wd 
is recorded as the ratio between weight in the swollen (Ws) and dry (Wd) 
state. 
TABLE 2 
______________________________________ 
Formulation 
Component 1 2 3 4 5 
______________________________________ 
Silicone Part 1A 
50 50 50 30 50 
Silicone Part 1B 
-- -- -- 10 -- 
Silicone Part 2B 
10 10 10 -- 10 
Propylene glycol 
15 -- -- -- -- 
Polyethylene glycol 200 
-- -- 15 -- -- 
Glycerol -- -- -- 15 15 
Sorbitol -- 15 -- -- -- 
Cellulosic material 1 
25 25 25 25 25 
Sodium acetate -- -- -- 20 -- 
Cure time at 22.degree. C. 
20' 3' &gt;2 H &gt;1 H 8' 
______________________________________ 
The time required for cure of these compositions is dependent upon the 
polyol used and presence or absence of sodium acetate as well as on the 
nature of the Silicone Part B. 
Formulation 3, which included polyethylene glycol, and Formulation 4, which 
included sodium acetate and an inhibited catalyst, failed to cure within 
10 minutes of mixing. The Formulations containing the Silicone Part 2B 
became cured in 20 minutes or less, with those containing sorbitol or 
glycerol curing more quickly than the others. It was found that the discs 
swelled in water and the discs of formulation 4 swelled most quickly to 
double their size within 1 to 3 hours and continued to swell at a 
substantially constant rate throughout a 24 hour period. Formulations 2 
and 5 swelled in a substantially constant fashion over 24 hours to a 
Weight Swelling Ratio in the range 1.6 to 5, with Formulation 5 showing 
the most constant swelling and the degree of swelling of Formulation 5 
being greater than that of Formulation 2. Formulations 1 and 3 swelled at 
the same rate as each other for 8 hours and then showed a slower swelling. 
EXAMPLE 3 
The swelling and bioadhesive properties were examined of discs made from 
formulations comprising 60 parts of a mixture of silicone Parts 1A and 1B 
in a ratio of 8:3, 25 parts of cellulosic materials 1 to 7 and 15 parts of 
glycerol. The discs were made as described in Example 2 except that the 
curing was conducted at 100.degree. C. The discs were allowed to swell in 
deionized water (pH=6) at 22.degree. C. for 48 hours and tested as 
described in Example 2. Results are shown in Table 3. 
TABLE 3 
______________________________________ 
Cellulosic 
Material Ws/Wd W % Remarks 
______________________________________ 
1 6.3 530 Slight tack, 
gel like surface 
2 6.4 540 Dry surface 
3 3.5 250 Dry surface 
4 4.6 360 Dry surface 
5 6.6 560 Very dry surface 
6 2.3 130 Very dry surface 
7 1.9 90 Very dry surface 
______________________________________ 
As can be seen from Table 3 the Formulation comprising cellulosic material 
1 demonstrated surface tackiness whereas the others did not. Maximum 
swelling was demonstrated by the discs of Formulations comprising 
cellulosic materials 1, 2 or 5. Discs formed from the Formulation 
including cellulosic material 1 also demonstrated adherence to a mucous 
membrane as in the buccal cavity. W % is the weight increase due to 
swelling. 
EXAMPLE 4 
The swelling behaviour of discs made, as described in Example 3, from 
formulations comprising materials in the proportions shown in Table 4 was 
studied. 
TABLE 4 
______________________________________ 
Formulation 
Component 1 2 3 4 5 6 
______________________________________ 
Silicone Part 1A 
62.5 50 45.85 41.7 37.5 33.3 
Silicone Part 1B 
12.5 10 9.15 8.3 7.5 6.7 
Glycerol 0 15 20 25 30 35 
Cellulosic 25 25 25 25 25 25 
material 1 
______________________________________ 
A formulation containing 40% glycerol needed 15 minutes at 100.degree. C. 
to be fully cured. The sample discs were allowed to swell for 48 hours in 
deionized water (pH=6) at 20.degree. C. The results are given in Table 5. 
TABLE 5 
______________________________________ 
Formulation 
Ws/Wd Remarks 
______________________________________ 
1 1.7 Very dry surface 
2 6.3 Slight tack, gel like surface 
3 7.2 Tacky, gluey surface 
4 8.3 Tacky, gluey surface 
5 2.3 Very gluey surface 
6 1.1 Decrease in volume 
______________________________________ 
As can be seen, presence of glycerol together with the cellulosic material 
in the Formulation provides a dramatic increase in swelling and 
bioadhesion. These results also show that the proportion of glycerol 
employed can be optimized in order to get desired swelling and good 
bioadhesion. Maximum swelling was obtained using 25% glycerol. At glycerol 
levels of 35 and 40% a decrease in volume of the disc is observed due to 
loss of integrity of the matrix after maximum swelling. The swelling and 
bioadhesion behaviour was examined of samples made from formulations using 
proportions of material as shown in Table 6. Discs were prepared and 
swelled for 48 hours in deionized water (pH=6) at 20.degree. C. The 
results are reported in Table 7. 
TABLE 6 
______________________________________ 
Formulation 
Component 7 8 9 10 
______________________________________ 
Silicone Part 1A 
70.8 62.5 50.0 29.4 
Silicone Part 1B 
14.2 12.5 10 5.8 
Glycerol 15 15 15 15 
Cellulosic material 1 
0 10 25 50 
______________________________________ 
TABLE 7 
______________________________________ 
Formulation Ws/Wd W % Remarks 
______________________________________ 
7 1.8 80 Very dry surface 
8 2.1 110 Very slight tack 
9 6.3 530 Slight tack 
10 5.3 430 Gel like surface 
______________________________________ 
The results show that for a constant glycerol content a minimum proportion 
of cellulosic material is necessary in order to get significant swelling 
and tack. At 50% cellulosic polymer (which represents only 35% silicone in 
the composition) cohesion of the swelled material is poor, which results 
in an erosion of the surface of the disc and loss of the cellulosic 
material into the solution. 
The swelling behaviour of sample discs made as described in Example 3 using 
50 parts of Silicone Part 1A, 10 parts of Silicone Part 1B, 15 parts 
glycerol and 25 parts cellulosic material 1 was examined. Sample discs 
were allowed to swell over 48 hours at 20.degree. C. at eight different 
pH: pH=1.2, 2, 3, 4, 5, 6, 7 and 8. The Weight Swelling Ratio, Ws/Wd, was 
recorded every hour (H) during the first eight hours and then after 24 
hours, 48 hours and every day up to 6 days. The results are reported in 
Table 8. 
TABLE 8 
______________________________________ 
(H) pH 1.2 pH 2 pH 3 pH 4 pH 5 pH 6 pH 7 pH 8 
______________________________________ 
0 1.000 1.000 1.000 
1.000 1.000 
1.000 
1.000 1.000 
1 1.101 1.134 1.208 
1.277 1.290 
1.310 
1.297 1.286 
2 1.135 1.184 1.293 
1.438 1.462 
1.466 
1.466 1.434 
3 1.173 1.229 1.389 
1.619 1.643 
1.652 
1.648 1.601 
4 1.204 1.274 1.468 
1.787 1.827 
1.816 
1.817 1.738 
5 1.235 1.310 1.540 
1.959 2.011 
2.002 
1.988 1.899 
6 1.264 1.349 1.605 
2.127 2.176 
2.178 
2.149 2.049 
7 1.291 1.385 1.677 
2.293 2.346 
2.344 
2.311 2.205 
8 1.314 1.416 1.742 
2.437 2.489 
2.500 
2.444 2.346 
24 1.607 1.852 2.548 
3.656 3.682 
3.813 
2.644 3.610 
32 1.704 2.019 2.772 
4.123 4.114 
4.218 
4.033 4.020 
48 1.821 2.243 3.101 
4.663 4.668 
4.920 
4.570 4.579 
72 1.995 2.536 3.448 
5.07 5.04` 
5.266 
4.918 4.921 
144 2.19 3.198 3.933 
5.228 5.076 
5.262 
4.976 4.961 
______________________________________ 
For all pH values swelling is linear until the 8th hour. At any time, 
maximum swelling was obtained for pH between 4 and 7 (Ws/Wd=2.4 to 2.5 
after 8 hours) much superior than at very acidic pH (Ws/Wd=1.3 at pH=1.2 
after 8 hours). 
EXAMPLE 5 
An illustrative Formulation was prepared comprising 37.5 parts of silicone 
Part 2A and 25 parts of silicone Part 2B, 9 parts of sorbitol, 19.5 parts 
of glycerol and 9 parts of the drug tetracycline hydrochloride. Matrices 
were formed from this composition by casting the Formulation into a cavity 
mould and allowing the Formulation to cure at room temperature. The 
matrices weighed 961.3 mg, had an average diameter of 1.275 cm, an average 
thickness of 0.66 cm and a surface area of about 5.2 cm.sup.2. Release of 
the drug from the cured Formulation was examined by a dissolution study at 
pH 4.5 according to the USP XXXI Standard test and the basket method using 
a fully automatic SOTAX AT6, including the dissolution apparatus itself, 
linked to a microprocessor-controlled pneumatic pump and fraction 
collector. Six dissolution vessels were filled with 900 ml of dissolution 
medium. One matrix was placed in each basket. Stirring was effected at 150 
rpm with the outer thermostatic bath at 37.degree..+-.0.1.degree. C. 5 ml 
samples of dissolution medium were collected at preprogrammed time 
intervals with automatic replenishment with fresh medium. UV spectra of 
these samples were recorded with a UVIKON 860 spectrophotometer and 
tetracycline hydrochloride released was calculated from the calibration 
curve. The mean value of the cumulative amount, as a percentage, of 
tetracycline hydrochloride released from the six cells is shown in Table 
9. 
TABLE 9 
______________________________________ 
Time (Hrs) Mean Value (%) 
______________________________________ 
0 0 
0.5 1.30 
1 1.70 
2 2.36 
3 2.85 
4 3.24 
5 3.56 
6 3.97 
12 5.80 
18 7.68 
24 9.62 
36 14.84 
48 18.57 
60 22.98 
72 27.01 
84 30.52 
96 34.46 
108 38.57 
120 41.95 
132 46.02 
144 48.88 
156 52.38 
168 55.33 
180 58.51 
192 60.44 
204 67.59 
216 68.64 
228 69.56 
240 70.20 
______________________________________ 
As can be seen 70% of the tetracycline hydrochloride was released 
progressively over the 10 day period. These results show that about 0.317% 
tetracycline hydrochloride was released per hour and 7.6% was released per 
day during dissolution. The release occurred at substantially constant 
rate over the whole test period. The proportion liberated attained a 
plateau after 8.5 days and 70.2% of the drug had been released at the 
ninth day. At the end of the dissolution test the mean surface area of the 
matrices was 8.7 cm i.e. 1.7 times the original surface area. 
The experiment was repeated using second, third and fourth illustrative 
Formulations; these Formulations comprised respectively 41.7 parts of 
silicone Part 2A and 27.8 parts of silicone Part 2B, 21.5 parts of 
glycerol and 9 parts of tetracycline hydrochloride; 35.7 parts of silicone 
Part 2A, 23.8 parts of silicone Part 2B, 21.5 parts of glycerol, 10 parts 
of sorbitol and 9 parts of tetracycline hydrochloride; and 29.7 parts of 
silicone Part 2A, 19.8 parts of silicone Part 2B, 21.5 parts of glycerol, 
20 parts of sorbitol and 9 parts of tetracycline hydrochloride. When the 
second illustrative Formulation was subjected to the dissolution test it 
was found that 25% of the drug was released in the first 100 hours and a 
further 25% of the drug was released in the next 92 hours; the release 
during each period was at substantially constant rate. When the third 
illustrative Formulation was subjected to the dissolution test it was 
found that 60% of the drug was released during the first 120 hours and a 
further 10% was released during the subsequent 72 hours, the release 
during each period being at a substantially constant rate. When the fourth 
illustrative Formulation was subjected to the dissolution test it was 
found that 50% of the drug was released during the first 40 hours, a 
further 25% was released in the next 70 hours and a further 8% was 
released during the subsequent 40 hours but no further release of the drug 
occurred after 150 hours, the release during each period being at a 
substantially constant rate. Thus, high release rates are dependent on 
presence of sorbitol as well as glycerol, the fastest release being 
obtained by use of the largest proportion of sorbitol.