GEL FORME IN SITU POUR USAGE THERAPEUTIQUE

IN SITU GEL FOR THERAPEUTIC USE

Abrégé français

L'invention concerne une composition d'apport d'un médicament pharmaceutique, et destinée notamment à un usage ophtalmologique, comprenant une solution hypotonique liquide d'au moins un polymère hydrophile du type subissant une gélification par transition de phase liquide-gel in situ au contact d'une solution physiologique, et un composé pharmaceutiquement actif, ainsi que son utilisation pour l'administration locale de médicaments.

Abrégé anglais

Pharmaceutical drug delivery composition especially for opthalmological use, comprising: a liquid hypotonic solution of at least
one hydrophilic polymer of the type which undergoes liquid-gel phase transition gelling in situ in contact with a physiological solution, and
a pharmaceutically active compound, as well as the use thereof for local administration of drugs.

Revendications

Claims
1. Pharmaceutical drug delivery composition comprising
- a liquid hypotonic solution of at least one hydrophilic
polymer of the type which undergoes liquid-gel phase transition
gelling in situ in contact with a physiological solution, and
- at least one pharmaceutically active compound.
2. Composition according to claim 1, wherein the
concentration of polymer is 0.1-10 wt-%.
3. Composition according to claim 1 or 2, wherein the
hydrophilic polymer is a polysaccharide, for instance gellan
gum.
4. Composition according to any one of claims 1 to 3,
wherein the osmolality is 25-200 mOs/kg.
5. Composition according to claim 4, wherein the
osmolality is 25-150 mOs/kg.
6. Composition according to claim 5, wherein the
osmolality is 50-150 mOs/kg.
7. Composition according to any one of claims 1-6, wherein
the active drug is present as a solution or in the form of
particles.
8. Composition according to claim 7, wherein the drug is
incorporated in or associated with a polymeric matrix, complex-
forming matrix, lipid matrix or ion-exchange resin.
9. Composition according to any one of claims 1-8 wherein
the composition additionally contains one or more component
selected from preservatives, solubilizing agents, non-ionic
tonicity adjusting agents, pH-adjusting agents or complexing
agents.
10. Composition according to any one of claims 1-9 which
is intended for ophthalmological use and the physiological
solution is lacrimal fluid or aqueous humour.
11. Method for local administration of a pharmacologically
active drug characterized by the use of a composition according
to any one of claims 1-10.

Description

W094/27~78 PCT/SE94/00522
2~ ~4~3
In situ gel for therapeutic use.
The present invention is related to the field of slow
release drug delivery systems for therapeutic use, especially
in the ophthalmic field, and provides an aqueous liquid
composition which in contact with a physiological solution
forms a gel matrix which has been found to stay for a
considerable time in the administration area, for instance the
eye, without causing any problems to the patient. This gel can
be utilized for controlled continuous administration of drug
over a prolonged period of time.
A composition according to the invention can be used in a
number of situations, e.g. oral, buccal, nasal and vaginal
administration, when a slow release system is advantageous but
will in the following be discussed mainly in connection with
it s ophthalmological use since the requirements here are
especially high.
There are a number of situations when topical
administration of a drug to the eye would be the most efficient
form of therapy and various drop solutions have been developed
for this purpose. However, natural mechanisms such as tear
rates and blinking, which are important for the protection of
the eye by removing dust and contaminants from the surface of
the eye, make drug delivery difficult.
A fairly large group of patients have considerable
problems to instill a solution onto the eye by themself and
the need for slow release systems has therefore been recognized
for a long time. There are also a number of therapeutic
situations where the efficacy of the drug would benefit from a
prolonged occular contact time. According to one concept a
solid implant containing the active drug is manufactured and
delivered to the doctor or nurse for application onto the
patient's conjunctiva, preferably under one of the eye lids.
These type of implants often have an outer membrane layer
through which the drug is allowed to diffuse. The release rate
depends on the membrane structure as well as the internal
matrix in which the drug is incorporated. According to another

W094/27578 ~1 6 ~1 1 3 2 PCT/SE94/00522
concept a composition which at room temperature and below this
value is liquid (non-solid) is instilled into the eye and due
to the rise in temperature forms a polymer matrix, for instance
a gel. A somewhat similar approach utilizes the fact that
certain polymer solutions in contact with salt ions form a gel.
Some systems have been disclosed which are physiologically
acceptable and which form a gel in contact with a physiological
salt solution, for instance a tear solution. It is readily
appreciated that according to this concept potentially very
useful systems for drug delivery are provided. Laboratoires
Merck, Sharp & Dohme-Chibret have in a series of patent
applications described the use of components which undergo
liquid-gel phase transition under the effect of an increase in
the ionic strength, see for instance AU8663189, EP227494,
EP424042 and EP437368. In EP227494 it is mentioned that the
test substance fluorescein is still persisting 5 hours after
instillation when administered in such a composition.
In these publications an extracellular anionic
heteropolysaccharide produced by the bacterium Pseudomonas
elodea, known by the name of gellan gum and marketed under the
brand name GelriteTM, is presented as the most preferred gel
formation component. An aqueous solution of the gel-forming
components is prepared containing no or only a very small
amount of ionic substances together with the drug in a suitable
form and optionally a preservative. It is also pointed out that
the non-solid composition should preferably be isotonic and a
tonicity adjusting substance, for instance mannitol, is added.
We have now surprisingly found that considerably improved
drug delivery systems are obtained if compositions of the type
mentioned above in contrast to the teaching of the prior art
are made hypotonic. Gels formed under these conditions have
been found to stay considerably longer in the eye compared to
gels formed at higher tonicity values, e.g. under isotonic
conditions, hence providing a more efficient delivery system.
The invention is accordingly related to a liquid hypotonic
ophthalmic solution comprising a pharmaceutically active drug
and at least one hydrophilic polymer of the type which
undergoes liquid-gel phase transition gelling in situ in

W094l27578 PCT/SE94/00522
~16~1].3
contact with the physiological solution, for instance tear
solution or humour solution when used for intraocular
administration.
In another aspect of the invention a method for
administration of a drug is provided using a composition as
defined in this specification.
The hydrophilic polymer is functionally defined by the
ability of an aqueous solution of the polymer to form a solid
polymer structure, for instance a gel, when the ionic strength
is raised to physiological values. Examples of components
belonging to this group include polysaccharides and natural as
well as synthetic polysaccharide derivatives. The preferred
component at present is an extracellular anionic
heteropolysaccharide produced by the bacterium Pseudomonas
elodea, known as gellan gum and marketed as GelriteTM. The gel
forming component may in more general terms be any component
which before administration is a liquid but forms a gel upon
contact with a physiological fluid due to exchange of
components between said liquid and the physiological fluid.
Such exchange of components include but is not limited to
proteins, such as lysozymes, and ionic components as discussed
above. The concentration of the gel forming component in cases
when Gelrite is used is preferably in the range of from 0.1 to
10 % by weight, especially 0.1-2 ~ by weight.
The inventive concept is as mentioned above that the non-
solid composition containing the hydrophilic polymer solution
is hypotonic. It has been found, however, that the tonicity
should not be too low since this causes undesirable side-
effects, such as more or less severe initial irritation when
the composition is applied.
The osmolality of the non-solid composition should
accordingly be lower than that of an isotonic solution (about
290 mOs/kg) and a selected range according to this invention is
from about 25 - 200 mOs/kg, preferably 25-150 mOs/kg and
especially 50-150 mOs/kg. The at present most prefered
composition has a value around 100 mOs/kg.
The drug component contained in the composition should
preferably be present as a dispersive system, either as a

W094/27578 4 PCT/SE94/00522
6~16411~ ,
suspension of particles or as an emulsion. The drug could be
incorporated in or associated with carrier substances in the
form of particles e.g. polymers (biodegradable, non-
biodegradable or polymers which dissolve or degrade upon
contact with a physiological fluid), lipids or ion-exchange
reslns.
In EP424042 is disclosed a system based on compositions of
the Gelrite type in which the drug is present in particles
which dissolve due to change in pH when the composition is
instilled into the eye. The pH and the buffering capacity of
the composition being such that the neutralizing action of
lachrymal fluid is sufficient for dissolving the solid
microparticles.
Examples of methods for producing lipid particles
containing an ophthalmologically active substance are given in
EP 437368.
The drug component contained in the composition could also
be present as a solution. It may be solubilized by surfactants,
lipids or by complex-forming agents.
The active drug to be administered according to the
present invention can be chosen among a great number of
components, for instance for ophthalmological use. Examples of
such components include
- antihistaminics and decongestants, for instance pyrilamine,
tetrahydrazoline, antazoline and analogues thereof,
- anti-inflammatories such as flubiprofen, diclofenac,
acetylsalicylic acid, cortisone, hydrocortisone, dexamethasone,
prednisone, indomethacin and analogues thereof
- antiparasitc and/or antiprotozoal compounds
- antibacterial substances such as tetracyclines, penicillin,
bacitracin, sulphonamides and analogues thereof,
- mydriatics, for instance cyclopentanol and tropicamide
- cytotoxics, for instance 5-fluorouracil
- antiglaucoma drugs, for instance prostaglandins like the
omega chain modified derivatives disclosed in EP0364417 (esp.
13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2a-isopropylester)
and timolol, pilocarpine, epinephrine, dipivalylepinephrine,
and their analogues.

W094/27578 PCT/SE94/00522
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- antivirals
- antioxidants
- anticataracts
- antiallergics
- anaesthetics
The composition may contain other additives such as
polymers, preservatives, nonionic tonicity agents,
solubilizers, buffer agents, complexing agents and chelating
agents.
Examples.
The relevance of the concept was verified in a series of
experiments in which compositions comprising
Gelrite (various concentrations)
Benzalkonium chloride 0.01 g
and Glycerol (0 - 3%), for adjusting the tonicity,
in 100 ml of ultrapure water
were instilled into one of the eyes of a healthy volounteer.
For measuring the duration time, or contact time, the
composition also contained a small amount of fluorescent
particles. The time these particles were detectable in the
instillation area was measured and taken as an indication of
the effectiveness of the drug delivery system.
A glycerol concentration of 3~ is close to an isotonic
solution and represents a comparison with a prior art system.

W094t27578 PCT/SE94/00~22
~lfi 1113 6
Gelrite glycerol duration
0.4% 1.5% 4-5 hours
0.6% 0 >16 hours
0.6% 0.5% >24 hours
0.6% 1.5% > 4.5 hours
0.6% 3% 2 hours
0.8% 0 >20 hours
0.8% 1.5% > 7 hours
1.0% 0 >20 hours
1.0% 1.5% >10 hours
1.0% 3% 3-5 hours
It should be noticed that with no addition of the tonicity
adjusting component, glycerol, initial pain for half a minute
or even more was reported by the test persons. A composition
for use in the eye should for this reason have an osmolatity
value of at least 25 mOs/kg.
From the results presented above it can be concluded that
considerably longer contact times have now been achieved
compared to the results indicated in the prior art literature.