`Intematlonal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) Intemamnal Patent Classiflcafio" 6 1
`
`W0 98/47535 A61K 47/36, 9/00
`
`(11) International Publication Number:
`_
`_
`(43) International Publication Date:
`
`A1
`
`29 October 1998 (29.l0.98)
`
`(21) International Application Number:
`_
`(22) International Filing Date:
`
`PCT/GB98/01147
`
`20 April 1998 (20.04.98)
`
`(81) Designated States: AU, CA, GB, JP, NO, NZ, US, European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(30) Priority Data:
`9707934.7
`
`18 April 1997 ( 18.04.97)
`
`GB
`
`(71) Applicant (for all designated States except US): DANBIOSYST
`UK LIMITED [GB/GB]; Albert Einstein Centre, Highfields
`Science Park, Nottingham NG7 2TN (GB).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): WATTS, Peter, James
`[GB/GB]; Flat 2, 47 Highfield Road, West Bridgford,
`Nottingham NG2 6DR (GB). ILLUM, Lisbeth [DK/GB];
`The Park, 19 Cavendish Crescent North, Nottingham NG7
`1BA (GB).
`
`(74) Agent: BASSETI‘, Richard; Eric Potter Clarkson, Park View
`House, 58 The Ropewalk, Nottingham NG1 5DD (GB).
`
`(54) Title:
`
`IMPROVED DELIVERY OF DRUGS TO MUCOSAL SURFACES
`
`125
`
`—U"'—'
`
`Fexofenadine HCIIHP-B-CD
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`Fexofenadine HCIIHP-B-CDIpeclin 100
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`III¢9
`
`~l(II
`
`U!G
`
`(%) 3
`ThereleaseoffexofenadineHCI
`
`
`0
`
`250
`
`500
`
`750
`
`1000
`
`1250
`
`1500
`
`1750
`
`2000
`
`(57) Abstract
`
`Time (Seconds)
`
`Liquid pharmaceutical compositions for administration to a mucosal surface, comprising a therapeutic agent and a pectin with a low
`degree of esterification are described. Such compositions gel, or can be adapted to gel, at the site of application in the absence of an
`extraneous source of divalent metal ions.
`
`
`
`
`Lannett Holdings, Inc. LAN 1010
`
`
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`LS
`SI
`Slovenia
`Lesotho
`Slovakia
`SK
`LT
`Lithuania
`SN
`Luxembourg
`Senegal
`Swaziland
`SZ
`Latvia
`TD
`Monaco
`Chad
`TG
`Togo
`Republic of Moldova
`TJ
`Madagascar
`Tajikistan
`TM
`Turkmenistan
`The former Yugoslav
`TR
`Turkey
`Republic of Macedonia
`TT
`Mali
`Trinidad and Tobago
`UA
`Ukraine
`Mongolia
`UG
`Mauritania
`Uganda
`US
`United States of America
`Malawi
`Mexico
`UZ
`Uzbekistan
`VN
`Viet Nam
`Niger
`Netherlands
`YU
`Yugoslavia
`ZW
`Zimbabwe
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lauka
`Liberia
`
`
`
`
`
`WO 98/47535
`
`PCT/GB98/01147
`
`IMPROVED DELIVERY OF DRUGS TO MUCOSAL SURFACES
`
`This invention relates to an improved system for the delivery of drugs to
`
`mucosal surfaces such as the nose, the eye, the vagina, the rectum and the
`
`back of the throat.
`
`10
`
`15
`
`20
`
`25
`
`Administration of therapeutic agents to mucosa is well known in the art.
`
`A variety of drugs may be administered to the nose,
`
`including those
`
`intended for the local
`
`treatment of nasal diseases, nasal vaccines, and
`
`those intended for systemic circulation. Because the nose has a reasonable
`
`surface area and a good blood supply, certain lipophilic drugs, such as
`
`nicotine and propranolol, can be absorbed rapidly into the blood, resulting
`
`in a bioavailability which is similar to that seen with intravenous injection.
`
`More polar drugs are less well absorbed,
`
`though absorption may be
`
`improved by the use of enhancing agents such as surfactants, powders
`
`such as microcrystalline cellulose, gelling microspheres (eg. starch). and
`
`the bioadhesive polymer, chitosan. Examples of these systems are well
`
`known in the art and have been reviewed by Illum and Fisher
`
`in
`
`“Inhalation Delivery of Therapeutic Peptides and Proteins”, Adjei and
`
`Gupta (eds.) Marcel Dekker Inc., New York (1997) 135-184.
`
`In a similar fashion,
`
`it
`
`is useful
`
`to deliver therapeutic agents, such as
`
`drugs and vaccines, to the vaginal cavity for a systemic effect or for the
`
`local
`
`treatment of diseases
`
`(particularly infectious diseases
`
`such as
`
`candidiasis and bacterial vaginitis) as well as for prophylaxis of diseases
`
`(e.g. HIV).
`
`Locally acting formulations may also be used to deliver
`
`contraceptive and spermicidal agents.
`
`
`
`
`
`
`
`‘W0 98/47535
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`PCT/GB98/01 147
`
`Drugs may also be administered to mucosa in the eye and the rectum in
`
`order to achieve local effects or for systemic activity.
`
`Considerable advantages in terms of improved efficacy are expected to be
`
`gained if a nasally administered formulation were capable of retaining a
`
`drug, a vaccine, or DNA intended for local effect,
`
`in the nose for
`
`relatively long time periods. Previous workers have used a variety of
`
`strategies for this purpose.
`
`For example, Illum and others found that biodegradable microspheres
`
`based on materials such as starch could delay clearance to a period of
`
`hours as compared to a normal half life of clearance of about 10 to 15
`
`minutes (Illum et al, Int. J. Pharm., 39 (1986) 189-199). Surprisingly,
`
`such systems were also found to give an improved absorption by affecting
`
`the integrity of the tight junctions of the epithelial cells in the nasal cavity
`
`and are expected therefore to be best suited to drugs acting systemically.
`
`Similarly,
`
`Illum and others have shown that
`
`the bioadhesive material
`
`chitosan can modify mucociliary clearance with an increase in drug
`
`absorption (Illum ez al, Pharm Res. , 11 (1994) 1186-1189).
`
`It would be most beneficial, due to ease of use and of administration, to
`
`have available a simple solution spray system that was suitable for the
`
`administration of drugs to the nose and, better still,
`
`for
`
`the drugs
`
`administered via such a system to have a long retention in the nasal cavity.
`
`The skilled person may envisage various strategies to this end, including
`
`the use of pharmacological agents that decrease mucociliary clearance by a
`
`10
`
`15
`
`20
`
`25
`
`
`
`
`
`
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`'WO 98/47535
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`PCT/GB98/01 147
`
`3
`
`direct effect on the action of cilia, such as cocaine, as well as formulation
`
`methods such as environmentally-responsive gels.
`
`Liquids that gel
`
`in response to a change in environment are known to
`
`those skilled in the art. The environmental change can be temperature,
`
`pH or ionic strength or a combination of these factors. Examples of all of
`
`these systems can be found in the prior art literature (see, for example, the
`
`smart hydrogel from Gelmed as described by Potts er al in Proceed.
`
`Intern. Symp. Control Rel., 24, 335 (1997)). However,
`
`the majority of
`
`these have been found to be unsuitable for nasal use in man because of
`
`factors such as irritation, discomfort (eg. administration of cold solutions),
`
`mucosal damage, an unwanted enhancement of drug absorption into the
`
`systemic circulation, and many are unavailable due to lack of regulatory
`
`approval .
`
`In summary, it would present considerable advantages to provide a single
`
`component nasal delivery system, which was in the form of a liquid for
`
`ease of administration, and in particular one that gelled in the nose upon
`
`contact with the nasal tissues, which could be used to administer, and to
`
`modify absorption characteristics, of drugs (therapeutic agents) intended to
`
`act locally or systemically.
`
`It would also be desirable to provide a system
`
`which is well accepted by patients, does not enhance the absorption of
`
`drug intended for a local effect into the systemic circulation (as this could
`
`lead to side effects), and comprises materials that are approved by
`
`10
`
`15
`
`20
`
`25
`
`regulatory authorities.
`
`Those skilled in the art will appreciate that there are similar problems to
`
`be solved in respect of drug delivery for the improved treatment of
`
`conditions that affect the vaginal cavity, the rectum, the eye, and the back
`
`
`
`
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`WO 98/47535
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`PCT/GB98/01147
`
`4
`
`of the throat, as well as for the improved delivery of vaccines to the local
`
`lymphoid tissue, or for the improved delivery of DNA for the transfection
`
`of epithelial cells.
`
`For example, drugs intended for the treatment of vaginal infections, or
`
`drug free formulations intended to act as vaginal moisturising agents
`
`(especially useful in post—menopausal conditions), should spread well
`
`in
`
`the vaginal cavity and be retained for long periods of time. However, it
`
`has been reported that so—called bioadhesive formulations that are intended
`
`10
`
`to be retained in the vaginal cavity for days can be expelled rapidly, with
`
`more that 80% of the dose leaving the vagina in less than 2 hours (Brown
`
`et al, 14, 1073 (1997)). Thus,
`
`it would be advantageous to provide a
`
`single component liquid composition that could be inserted into the vagina
`
`as a simple liquid and that gelled under the local environmental conditions
`
`15
`
`to give good retention.
`
`For rectal enemas, it would be most beneficial if the liquid enema formed
`
`a gel once applied, ensuring close contact with the local environment and
`
`preventing early discharge.
`
`20
`
`25
`
`Similar problems may be identified in respect of administration to the eye,
`
`by virtue of the fact that liquid formulations are rapidly cleared from the
`
`eye through drainage down the naso-lacrymal duct. A single component
`
`liquid composition that gelled upon application to the eye would be
`
`advantageous for the treatment of conditions such as eye infections and
`
`inflammation.
`
`Pectins are materials which are found in the primary cell wall of all green
`
`land plants. They are heterogeneous materials, with a polysaccharide
`
`
`
`
`
`
`
`' WO 98/47535
`
`PCT/GB98/01147
`
`5
`
`backbone that is uniform as ot-1,4-linked polygalacturonic acid. Various
`
`neutral sugars have been identified in pectins such as xylose, galactose,
`
`rhamnose, arabinose.
`
`A critical property of pectins, which is known to affect their gelation
`
`properties, is the extent to which the galacturonic acid units are esterified.
`
`The degree of esterification (DE) of pectins found naturally can vary
`
`considerably (from 60_ to 90%). The term DE is well understood by those
`
`skilled in the art and may be represented as the percentage of the total
`
`10
`
`number of carboxyl groups which are esterified, or as the methoxyl
`
`content of the pectin. The respective theoretical maximum for each is
`
`100% and 16% respectively. DE as used herein refers to the total number
`
`of carboxyl groups which are esterified.
`
`Low DE pectins (ie.
`
`those
`
`having less than 50% esterification) are usually prepared by the de-
`
`esterification of extracted pectins, normally on a bench scale, by way of
`
`an enzymatic process, or, on an industrial scale, by the treatment with
`
`acid or ammonia in an alcoholic heterogeneous medium. For pectins with
`
`a low degree of methoxylation (DM;
`
`less
`
`than 45%)
`
`the gelation
`
`properties are known to depend on the DM and the molecular weight of
`
`the pectin. The chemistry of low methoxyl pectin gelation is described by
`
`Axelos and Thibault
`
`in “The Chemistry and Technology of Pectin”,
`
`Academic Press, New York, pp. 109-118, (1991).
`
`Various prior art documents discuss the potential use of pectin as a
`
`bioadhesive and gelling material.
`
`Studies by Smart er al, J. Pharm.
`
`Pharmacol. 36, 295 (1984)
`
`in relation to the adhesiveness of various
`
`materials to mucus have shown that pectin is poorly adhesive in in vitro
`
`tests. A tablet capable of adhering to the mucus membrane containing
`
`pectin has been described in EP 306 454. Oechslein et al (Int. J. Phar1n.,
`
`20
`
`25
`
`
`
`
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`
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`"W0 98/47535
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`.
`
`6
`
`PCT/GB98/01147
`
`139,
`
`(1994), 25-32), have described the potential of various powder
`
`formulations to enhance the nasal absorption of the somatostatin analogue
`
`peptide octreotide. Pectin (type FPA) powder was used, and gave rise to
`
`an increase in the absolute bioavailability of the drug as compared to the
`
`drug administered in a saline solution.
`
`In none of these documents was
`
`the use of a solution formulation containing a pectin with a low DE, or a
`
`pectin that gels in contact with nasal secretions, described.
`
`Pectin has also been studied as a mucoadhesive ophthalmic material by
`
`10
`
`Chetoni et al (Bull. Chem. Farm., 135, 147 (1996)). Salt complexes of
`
`drugs with pectin for administration to the oral mucosa as patches have
`
`been described by Burgalassi et al, World Meet. Pharm. Biopharrn.
`
`Pharrn. Technol., (1995), p. 839, APGI, Paris. Popovici and Szasz (in
`
`“Buccal
`
`and Nasal Administration
`
`as Alternatives
`
`to Parenteral
`
`Administration”, Minutes of a European Symposium (1992), Duchene,
`
`D., Ed., Sante, Paris, France. p. 292-6) have described mucoadhesive
`
`hydrogels containing cellulose and pectin and a bivalent cation in the form
`
`of magnesium. The use of a low DE pectin as a solution that would gel in
`
`contact with mucosal
`
`surfaces was not described in any of
`
`these
`
`20
`
`documents .
`
`US 4,826,683 describes a nasal decongestant containing vegetable oil, aloe
`
`Vera, zinc, vitamin C, vitamin A, vitamin E, Vitamin B6, biotin and fruit
`
`pectin. The content of fruit pectin was to a maximum of 2 g per litre.
`
`25
`
`The solubilised fruit pectin supplied by General Foods under the trade
`
`name “Certo” was preferred.
`
`JP 62236862 describes an artificial mucus
`
`composed of a mixture of a spinnable water soluble polymer and a
`
`polysaccharide, protein or vinyl polymer.
`
`Pectin is listed as a suitable
`
`polysaccharide, though the type of pectin is not specified.
`
`
`
`
`
`
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`"W0 98/47535
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`PCT/GB98/01147
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`US 5,147,648 (EP 289 512) describes a pharmaceutical formulation made
`
`from at least two components which, when added separately, can form a
`
`gel for treating a mucosa. The two components are applied separately to
`
`the same area of a mucous membrane. The components may be added
`
`simultaneously or
`
`sequentially.
`
`One of
`
`the gel
`
`forming solution
`
`components includes a calcium salt (eg. calcium gluconate) and the other
`
`may include a pectin. There is no suggestion in this prior art document
`
`that a solution comprising pectin may be administered as a single
`
`10
`
`component,
`
`in the absence of a separately applied solution of calcium
`
`ions, which will gel once in contact with the mucosa.
`
`US 5,318,780 describes aqueous pharmaceutical vehicles containing two
`
`components,
`
`a
`
`film forming polymer
`
`(eg.
`
`pectin)
`
`and
`
`an ionic
`
`polysaccharide, which are then gelled in situ by contacting the mixture
`
`with a counter-ion. Polygalacturomc acids such as pectin are mentioned in
`
`an extensive listing of representative useful polymers for application in the
`
`eye as corneal mastis protective corneal shields. No examples of the use
`
`of a pectin solution alone, nor of pectins with a low DE, or pectins that
`
`would gel in contact with the mucosa, are disclosed.
`
`The preparation of pectin beads by ionotropic gelation has been described
`
`by Aydin and Akburfa (1996) Int. J. Pharrn., 137, 133-136.
`
`In summary, although it is known in the art that all pectins will form gels
`
`in the presence of calcium ions, for the pectins employed previously in
`
`pharmaceutical systems to be applied to mucosal surfaces,
`
`it has been
`
`hitherto understood that high levels of calcium are needed, which levels
`
`are well above physiological concentrations.
`
`This has necessitated the
`
`20
`
`25
`
`
`
`
`
`
`
`WO 98/47535
`
`,
`
`8
`
`PCT/GB98/0l147
`
`utilisation of pectin systems which are applied either in the form of
`
`preformed gels, or before or after the addition of exogenous calcium in
`
`order to produce a gel
`
`in situ.
`
`That
`
`liquids (especially solutions)
`
`comprising low DE pectins may be applied as such, and may gel upon, or
`
`just after, application to mucosa is neither described nor suggested in any
`
`of the aforementioned prior art documents. Further, the importance of the
`
`DB of pectin upon such gelation properties is not mentioned in any of
`
`these prior art documents.
`
`We have now found, surprisingly,
`
`that certain pectin materials, namely
`
`those with a low DE, may be administered in the form of single
`
`component, simple liquid formulations (ie. in an aqueous carrier) which
`
`will gel, or can be readily adapted to gel, upon application to mucosa in
`
`the nasal, rectal and vaginal cavities,
`
`in the eye, or at the back of the
`
`throat. We have also found, surprisingly,
`
`that gelation may occur at
`
`physiologically acceptable pH values in the presence of very much
`
`reduced
`
`calcium concentrations,
`
`ie.
`
`those which
`
`can
`
`be
`
`found
`
`physiologically in the nasal secretions, as well as in the vaginal lumen, the
`
`rectal cavity and the tear fluid of the eye.
`
`5
`
`10
`
`20
`
`According to a first aspect of the invention there is provided a single
`
`component
`
`liquid pharmaceutical composition for administration to a
`
`mucosal surface comprising a therapeutic agent, a pectin with a low DE
`
`and an aqueous carrier, that gels or can be adapted to gel at the site of
`
`25
`
`application.
`
`We have found,
`
`in particular,
`
`that such compositions gel, or can be
`
`adapted to gel, at the site of, and upon, or just after, application to a
`
`mucosal surface in the absence of an extraneously (ie. separately and/or
`
`
`
`
`
`
`
`WO 98/47535
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`PCT/GB98/01147
`
`9
`
`independently) applied (simultaneously or sequentially) solution of calcium
`
`(or other divalent metal) ions. There is thus provided a single component
`
`liquid pharmaceutical composition for application directly to a mucosal
`
`surface comprising a therapeutic agent, a pectin with a low DE and an
`
`aqueous carrier, which composition is adapted to gel at
`
`the site of
`
`application in the absence of an extraneous source (eg.
`
`solution) of
`
`divalent metal ions applied to the same site.
`
`According to a further aspect of the invention, there is provided a kit of
`
`parts comprising a liquid pharmaceutical composition for administration to
`
`a mucosal surface, comprising a therapeutic agent, a pectin with a low DE
`
`and an aqueous carrier, provided that the kit does not comprise a solution
`
`of divalent metal ions to be added extraneously to said surface.
`
`In particular,
`
`there is provided a kit of parts comprising a liquid
`
`pharmaceutical composition for administration to a mucosal surface,
`
`which composition comprises a therapeutic agent, a pectin with a low DE
`
`and an aqueous carrier, and which kit of parts is packaged and presented
`
`with instructions to administer said composition to said surface in the
`
`10
`
`15
`
`20
`
`absence of an extraneous source of divalent metal ions.
`
`The liquid pharmaceutical compositions for administration to mucosal
`
`surfaces comprising therapeutic agent, low DE pectin and aqueous carrier,
`
`which are, or are to be,‘ administered as a single component, and which
`
`25
`
`gel, or are adapted to gel,
`
`in the absence of an extraneous source of
`
`divalent metal ions are referred to hereinafter as “the compositions of the
`
`invention” .
`
`
`
`
`
`
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`‘WO 98/47535
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`PCTlGB98/01 147
`
`10
`
`By “liquid” composition, we mean a composition which is in the form of a
`
`mobile fluid upon application to the mucosa. The compositions of the
`
`invention are in the form of an aqueous formulation comprising a solution,
`
`a suspension, or an emulsion,
`
`including pectin and therapeutic agent,
`
`in
`
`water. The compositions of the invention will gel, or may be adapted to
`
`gel, upon, or shortly (eg. up to 5 minutes) after, application, to a form a
`
`solid or semi-solid gel material, which gel
`
`is suitable to provide a
`
`retaining effect at the site of administration.
`
`10
`
`15
`
`20
`
`25
`
`By
`
`“degree of esterification (DE)”, we mean the percentage of
`
`galacturonic acid units which are esterified, for example as described in
`
`the article by Walter in “The Chemistry and Technology of Pectin”,
`
`Academic Press, New York (1991), p. 192. By “low DE”, we mean a
`
`pectin in which less than 50%, and more preferably less than 35%, of the
`
`galacturonic acid units are esterified.
`
`By “extraneous source” of divalent metal
`
`ions, we include a separate
`
`and/or independent (ie. exogenous) source of such ions.
`
`Ions which are
`
`present in a gel resulting from administration of a composition of the
`
`invention to a mucosa are not derived from either the composition, or
`
`from the bodily secretions of the patient to which the composition is to be
`
`applied (eg. endogenous ions derived from nasal secretions,
`
`tear fluid,
`
`etc.). Divalent metal ions which may be mentioned include calcium ions.
`
`According to a further aspect of the invention,
`
`there is provided a
`
`pharmaceutical
`
`gel
`
`composition
`
`obtainable
`
`by
`
`applying
`
`a
`
`liquid
`
`composition, comprising a therapeutic agent, a pectin with a low DE and
`
`an aqueous carrier,
`
`to a mucosal surface of a mammalian patient in the
`
`
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`absence of extraneous application of a solution of divalent metal ions to
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`said surface.
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`The gels so formed upon contact with mucosal surfaces will contain only
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`endogenous divalent metal ions (i.e.
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`those derived directly from bodily
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`secretions) and will not include exogenous divalent metal ions (i.e those
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`derived from an extraneous source). According to a further aspect of the
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`invention there is provided a pharmaceutical gel composition, which gel
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`comprises a therapeutic agent and a pectin with a low DE, which gel is
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`obtainable by applying a liquid composition, comprising said therapeutic
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`agent and pectin in an aqueous carrier, to a mucosal surface, and which
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`gel is substantially free of divalent metal ions derived from an extraneous
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`source applied to said mucosal surface before, or at the same time as, or
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`after, said liquid composition is applied.
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`Because the compositions of the invention are not added in conjunction
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`with an extraneous source of such ions, by “substantially free” of divalent
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`metal ions, we mean greater than 97%, preferably greater than 99%, more
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`preferably greater than 99.9%, and especially greater than 99.99% free.
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`Pectins with a low DE can be obtained from known sources, or can be
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`obtained via de-esterification of high DE pectins (which may be obtained
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`from, for example, Sigma Fine Chemicals),
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`in accordance with known
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`techniques, such as those described in the article by Rollin in “Industrial
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`Gums”, Academic Press, New York (1993) p. 257, or as described
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`hereinbefore.
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`Low DE pectin may,
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`for example, be obtained from
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`Copenhagen Pectin A/S as the commercial material known as Slendid
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`Type 100 and Slendid Type 110. These pectins have been extracted from
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`citrus peel
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`and
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`standardised by
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`the
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`addition of
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`sucrose.
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`The
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`standardisation process is as described by Rollin in the abovementioned
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`article. The DE is less than 50% for both pectins and of the order of 10%
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`for type 100 and 35% for type 110. Further materials which may be
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`employed include GENU pectin types LM 1912 CS and Pomosin pectin
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`types LM 12 CG and LM 18 CG.
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`The compositions of the invention may be prepared by dissolving or
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`dispersing the pectin of low DE and therapeutic agent
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`in an aqueous
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`system,
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`to form a solution, a suspension or an emulsion in accordance
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`with known techniques.
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`For example,
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`the therapeutic agent may be
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`dissolved in a prior prepared aqueous solution of the pectin, or may be
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`added as, or to form, a suspension in an aqueous system, where the drug
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`particles are less than 100 microns in size, preferably between 1 and 20
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`microns. Alternatively, drug may be dissolved or suspended in a suitable
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`oily vehicle such as a vegetable oil, and then dispersed into the aqueous
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`pectin solution to form an emulsion.
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`It will be appreciated by those
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`skilled in the art that the type of aqueous formulation so developed will
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`depend upon to mucosa to be treated, as well as the dose, and the physical
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`characteristics and properties, of the drug (e.g.
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`its solubility, basicity
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`etc.).
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`The concentration of low DE pectin in compositions of the invention
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`depends upon the nature of the pectin, the presence of other components,
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`and other factors which influence gelation properties of the composition
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`(see below), but may be from 1 g/L to 100 g/L, and is preferably from 1
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`g/L to 50 g/L, more preferably from 2 g/L to 10 g/L and especially from
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`5 g/L to 10 g/L.
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`Compositions of the invention may be used with a View to the prevention
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`of a major problem in the delivery of drugs to the nose for local treatment,
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`namely the rapid mucociliary clearance mechanism. This natural process,
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`which removes deposited material from the front of the nose to the throat,
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`can clear material from the nose with a half—time of about 10 to 20
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`minutes. Such clearance rates can be measured readily in man using the
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`saccharin clearance test or by gamma scintigraphy (Aspden et al, J.
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`Pharm. Sci., 86, 509 (1997); Illum et al, Int.
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`J. Pharm., 39 (1987) 189-
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`199).
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`Compositions of the invention may be employed to retain a therapeutic
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`agent which is intended to act locally at a mucosal surface for a relatively
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`long period when compared to mucosal delivery systems known in the art.
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`If the therapeutic agent is easily absorbed, absorption may be retarded,
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`thus keeping more of the drug at
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`the site of application, where it
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`is
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`needed.
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`Therapeutic agents which may be employed in the compositions of the
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`invention include,
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`for nasal administration, drugs that are employed
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`locally to treat conditions such as rhinitis, viral infections, as well as those
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`which act as decongestants. The compositions of the invention may also
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`be used as a way of improving the delivery of vaccines to the nose
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`associated lymphoid tissue and for the better presentation of DNA for the
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`transfection of nasal epithelial cells.
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`The following list of therapeutic agents are suitable for use in the
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`compositions of the invention, for local treatment of a mucosal surface, is
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`provided by way of illustration and is not meant to be exclusive: antiviral
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`agents such as [CAM-l, pirovadir, acyclovir, bromovinyldeoxyuridine, ot,
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`B and 7-interferon, zidovudine; decongestants such as oxymetazaline; anti-
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`allergic agents, such as sodium cromoglycate and budesonide; steroids,
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`such as fluticazone; vaccines, such as DNA, influenza, pertussis, measles
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`and diphtheria vaccines; antibacterial agents; antifungal agents, such as
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`amphotericin, nystatin; contraceptive and/or spermicidal agents; antibodies
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`especially for the treatment of RSV infection in children; prophylactic
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`agents
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`against HIV;
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`antihistamines,
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`such
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`as
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`diphenhydramine
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`hydrochloride; genes.
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`Combinations of the abovementioned therapeutic agents may also be
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`employed.
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`Compositions of the invention may also be employed to control the plasma
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`level versus time profile for readily absorbable drugs which are intended
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`to act systemically (ie. to give a flatter profile), either by altering the rate
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`of transport into the general circulation, or by retarding absorption of
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`readily absorbable drugs. This can, for example, be of importance when
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`side effects from high peak plasma levels are to be avoided.
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`The compositions of the invention may thus be used for the modification
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`of the systemic absorption of mucosally administered drugs, including, but
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`not limited to, apomorphine, nicotine, hyoscine hydrobromide, lignocaine,
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`fentanyl, naratriptan, pheromones and propranolol.
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`Combinations of the abovementioned therapeutic agents may also be
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`employed.
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`For the avoidance of doubt,
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`the term “therapeutic agents” is intended
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`herein to include agents which are suitable for use in the treatment, and in
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`the prevention, of disease.
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`The compositions of
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`the
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`invention may be used to treat/prevent
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`diseases/conditions in mammalian patients depending upon the therapeutic
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`agent(s) which is/are employed. For the above, non—exhaustive lists of
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`locally acting and systemic drugs, diseases/conditions which may be
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`mentioned include those against which the therapeutic agent(s) in question
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`10
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`are known to be effective, and include those specifically listed for the
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`drugs in question i11 Martindale,
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`“The Extra Pharmacopoeia”, 31st
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`Edition, Royal Pharmaceutical Society (1996).
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`Preferred drugs include nicotine and apomorphine.
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`The amount of
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`therapeutic agent which may be employed in the
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`compositions of the invention will depend upon the agent which is used, and
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`the disease to be treated, but may be in the range 0.01 to 40% w/w.
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`However,
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`it will be clear to the skilled person that suitable doses of
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`therapeutic agents can be readily determined non-inventively. For example,
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`estimates of dosage can be made from known injectable products assuming
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`that from 0.1 to 90% of the dose is absorbed. Suitable single unit doses are
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`in the range 10 ug to 500 mg depending upon the therapeutic agent(s) which
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`is/are employed and the route of administration. Suitable daily doses are in
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`the range 10 ug to l g/day depending upon the therapeutic agent(s) which
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`is/are employed and the route of administration.
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`Most compositions comprising drug and a low DE pectin will gel upon
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`application at the site of application,
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`i.e. upon, or shortly (e.g. up to 5
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`minutes) after, contact with the relevant mucosal surface. However,
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`in
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`some formulations, the nature of the drug and/or the pectin which is/are
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`employed may require that the composition is adapted such that it gels
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`upon, or shortly (e.g. up to 1 minute) after, contact. This may be achieved
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`readily via techniques which are well known to those skilled in the art:
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`For example,
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`the concentration of pectin may be selected such that the
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`aqueous formulation will gel once in contact with the mucosal surface.
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`Furthermore,
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`the addition of monovalent ions to aid the gelling process
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`may be required (for example, simple monovalent electrolytes, eg. NaC1,
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`may be added to adapt the liquid formulation to gel, as well as to provide
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`isotonicity) .
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`The quantity and nature of the drug in the aqueous formulation may also
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`have an influence on the gelation properties. For example, the addition of
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`a high level of a certain drugs, including those which are weak bases (such
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`as nicotine), which are known to form reversible complexes with anionic
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`materials such as pectin, may require a change in the ratio between drug
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`and pectin, so that preferably 30%, more preferably 50%, and most
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`preferably 60%, of the negative charges on the pectin molecule are
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`uncomplexed.
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`Alternatively, sugars in the form of, for example, sucrose can be added to
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`the formulation to aid gelation. Non-ionic polysaccharides (such as
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`hydroxypropyl methyl cellulose) may also be used.
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`The pH of the composition has also been found to affect gelation
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`properties. The pH of the compositions of the invention may be from 2 to
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`9, more preferably from 3 to 8 and most preferably from 4 to 7, taking
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`into account the gelation properties of the composition and the properties
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`of the therapeutic agent. For example, in general, we have found that the
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`lower the DB of the pectin,
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`the lower the pH at which the composition
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`will gel. pH may be adjusted in accordance with techniques which will be
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`well known to those skilled in the art,
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`such as
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`the addition of
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`pharmaceutically acceptable buffering agents, especially those of low ionic
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`strength. Axelos and Thibault
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`in_ “The Chemistry and Technology of
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`Pectin”, Academic Press, New York, pp. 109-118, (1991) describe how
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`the gelation properties of low DE pectin solutions are somewhat sensitive
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`to pH and ionic strength.
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`The abovementioned techniques, which may be used to adapt
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`the
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`compositions of the invention to gel, may be investigated and determined
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`in the normal course of routine experimentation by those skilled in the art.
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`Combinations of these techniques may also be employed in order to affect
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`gelation properties.
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`The compositions may also contain other additives
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`in the form of
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`pharmaceutical excipients, such as preservatives (e.g.
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`low concentrations
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`of materials such as sodium metabisulphate), stabili