U.S. patent application number 11/562173 was filed with the patent office on 2007-04-26 for delivery of drugs to mucosal surfaces.
This patent application is currently assigned to ARCHIMEDES DEVELOPMENT LIMITED. Invention is credited to Lisbeth Illum, Peter James Watts.
Application Number | 20070092535 11/562173 |
Document ID | / |
Family ID | 10811025 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070092535 |
Kind Code |
A1 |
Watts; Peter James ; et
al. |
April 26, 2007 |
DELIVERY OF DRUGS TO MUCOSAL SURFACES
Abstract
Liquid pharmaceutical compositions for administration to a
mucosal surface, including 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.
Inventors: |
Watts; Peter James;
(Nottingham, GB) ; Illum; Lisbeth; (Nottingham,
GB) |
Correspondence
Address: |
AKIN GUMP STRAUSS HAUER & FELD L.L.P.
ONE COMMERCE SQUARE
2005 MARKET STREET, SUITE 2200
PHILADELPHIA
PA
19103
US
|
Assignee: |
ARCHIMEDES DEVELOPMENT
LIMITED
Albert Einstein Centre Nottingham Science ?amp; Technology Park,
Univ. Blvd.
Nottingham
GB
NG7 2TN
|
Family ID: |
10811025 |
Appl. No.: |
11/562173 |
Filed: |
November 21, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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|
10196590 |
Jul 15, 2002 |
|
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11562173 |
Nov 21, 2006 |
|
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|
09402976 |
Jan 20, 2000 |
6432440 |
|
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PCT/GB98/01147 |
Apr 20, 1998 |
|
|
|
10196590 |
Jul 15, 2002 |
|
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Current U.S.
Class: |
424/204.1 ;
424/130.1 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 37/08 20180101; A61P 9/12 20180101; A61P 29/00 20180101; A61P
25/18 20180101; A61P 11/02 20180101; A61K 9/06 20130101; A61P 31/04
20180101; A61P 15/02 20180101; A61P 25/04 20180101; A61P 11/00
20180101; A61P 9/08 20180101; A61P 11/06 20180101; A61P 15/18
20180101; A61P 31/16 20180101; A61P 25/00 20180101; A61P 43/00
20180101; A61P 23/02 20180101; A61K 47/36 20130101; A61P 9/06
20180101; A61K 9/0043 20130101; A61P 31/14 20180101; A61K 9/12
20130101 |
Class at
Publication: |
424/204.1 ;
424/130.1 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 39/12 20060101 A61K039/12 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 18, 1997 |
GB |
97097934.7 |
Claims
1. A liquid pharmaceutical composition for administration to the
mucosa of the nasal cavity comprising: a therapeutic agent, a
pectin that has a degree of esterification that is less than 50%,
and an aqueous carrier, wherein the composition gels or is adapted
to gel at a site of application on the mucosal surface in the
absence of an extraneous source of divalent metal ions.
2. The composition of claim 1, wherein the therapeutic agent acts
locally at the mucosa of the nasal cavity.
3. The composition of claim 2, wherein the therapeutic agent is
selected from the group consisting of a steroid, an antiviral
agent, a decongestant, an anti-allergic agent, and an
antihistamine.
4. The composition of claim 2, wherein the therapeutic agent is
selected from the group consisting of an antifungal agent and an
anti-bacterial agent.
5. The composition of claim 2, wherein the therapeutic agent is a
gene.
6. The composition of claim 2, wherein the therapeutic agent is
selected from the group consisting of a vaccine, an antibody, and a
prophylactic agent against HIV.
7. The composition of claim 2, wherein the therapeutic agent is
selected from fluticasone, pirovadir ICAM- 1, acyclovir,
bromovinyldeoxyuridine, .alpha.-interferon, .beta.-interferon,
.gamma.-interferon, zidovudine, oxymetazoline, sodium cromoglycate,
budesonide and diphenhydramine hydrochloride.
8. The composition of claim 2, wherein the therapeutic agent is
selected from the group consisting of amphotericin, nystatin, a
vaccine against influenza, a vaccine against pertussis, a vaccine
against measles, and a vaccine against diphtheria.
9. The composition of claim 2, wherein the therapeutic agent is
selected from the group consisting of a deoxyribonucleic acid
vaccine and an antibody against respiratory syncytial virus.
10. The composition of claim 2, wherein the therapeutic agent is
fexofenadine.
11. The composition of claim 1, wherein the therapeutic agent acts
systemically.
12. The composition of claim 11, wherein the therapeutic agent is
selected from the group consisting of nicotine, hyoscine
hydrobromide, lignocaine, naratriptan, a pheromone, and
propranolol.
13. The composition of claim 11, wherein the therapeutic agent is
apomorphine.
14. The composition of claim 11, wherein the therapeutic agent is
fentanyl.
15. The composition of claim 1, wherein the pectin has a degree of
esterification that is less than 35%.
16. The composition of claim 1, wherein the composition is in a
form selected from the group consisting of a free flowing system
and a spray.
17. The composition of claim 1, wherein the composition has a pH of
2 to 9.
18. The composition of claim 1, wherein the pectin is present in a
concentration of 1 g/L to 100 g/L.
19. The composition of claim 1, wherein the pectin is present in a
concentration of 1 g/L to 50 g/L.
20. A pharmaceutical gel composition prepared by applying a liquid
composition according to claim 1 to the mucosa of the nasal cavity
of a mammal in the absence of extraneous divalent metal ions.
21. The pharmaceutical gel composition of claim 20, wherein the
pectin has a degree of esterification of less than 35%.
22. A kit comprising a composition adapted for administration to
the mucosa of the nasal cavity, the composition comprising a
therapeutic agent, a pectin that has a degree of esterification of
less than 50%, and an aqueous carrier which gels or is adapted to
gel at the mucosa of the nasal cavity, but the kit does not include
a solution of divalent metal ions.
23. The kit of claim 22, wherein the therapeutic agent that acts
locally at the mucosa of the nasal cavity is selected from the
group consisting of a steroid, an anti-viral agent, a decongestant,
an anti-allergic agent, an antihistamine, an anti-fungal agent, an
antibacterial agent and a gene.
24. The kit of claim 22, wherein the therapeutic agent that acts
locally at the mucosa of the nasal cavity is selected from the
group consisting of a vaccine, an antibody, a prophylactic agent
against HIV, fluticasone, ICAM-1, pirovadir, acyclovir,
bromovinyldeoxyuridine, .alpha.-interferon, .beta.-interferon,
.gamma.-interferon, zidovudine, oxymetazoline, sodium cromoglycate,
budesonide, and diphenhydramine hydrochloride.
25. The kit of claim 22, wherein the therapeutic agent that acts
locally at the mucosa of the nasal cavity is selected from the
group consisting of amphotericin, nystatic, a vaccine against
influenza, a vaccine against pertussis, a vaccine against measles,
and a vaccine against diphtheria, a deoxyribonucleic acid vaccine,
and an antibody against respiratory synctial virus.
26. The kit of claim 22, wherein the therapeutic agent that acts
locally at the mucosa of the nasal cavity is fexofenadine.
27. The kit of claim 22, wherein the pectin has a degree of
esterification that is less than 35%.
28. The kit of claim 22, wherein the composition is in a form
selected from the group consisting of a free flowing system and a
spray.
29. The kit of claim 22, wherein the composition has a pH of 2 to
9.
30. The kit of claim 22, wherein the pectin is present in the
composition in a concentration of 1 g/L to 100 g/L.
31. The kit of claim 22, wherein the pectin is present in the
composition in a concentration of 1 g/L to 50 g/L.
32. The kit of claim 22, wherein the therapeutic agent that acts
systemically is selected from the group consisting of nicotine,
hyoscine hydrobromide, lignocaine, naratriptan, a pheromone, and
propranolol.
33. The kit of claim 22, wherein the therapeutic agent that acts
systemically is apomorphine.
34. The kit of claim 22, wherein the therapeutic agent that acts
systemically is fentanyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/196,590, filed Jul. 15, 2002, which was a
continuation of U.S. patent application Ser. No. 09/402,976, filed
Jan. 20, 2000, now U.S. Pat. No. 6,432,440, issued Aug. 13, 2002,
which was a .sctn. 371 filing of International Application No.
PCT/GB98/01147, filed Apr. 20, 1998, published in the English
language on Oct. 29, 1998, under International Publication No.
WO98/47535, the contents of each of which are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] Administration of therapeutic agents to mucosa is well known
in the art.
[0004] 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 (e.g., 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.
[0005] 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.
[0006] Drugs may also be administered to mucosa in the eye and the
rectum in order to achieve local effects or for systemic
activity.
[0007] 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.
[0008] 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.
[0009] Similarly, Illum and others have shown that the bioadhesive
material chitosan can modify mucociliary clearance with an increase
in drug absorption (Illum, et al., Pharm Res., 11 (1994)
1186-1189).
[0010] 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
direct effect on the action of cilia, such as cocaine, as well as
formulation methods such as environmentally-responsive gels.
[0011] 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 et 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 (e.g., 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.
[0012] 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 regulatory authorities.
[0013] 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 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.
[0014] For example, drugs intended for the treatment of vaginal
infections, or drug free formulations intended to act as vaginal
moisturizing 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 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 to give good
retention.
[0015] 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.
[0016] 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.
[0017] Pectins are materials which are found in the primary cell
wall of all green land plants. They are heterogeneous materials,
with a polysaccharide backbone that is uniform as
.alpha.-1,4-linked polygalacturonic acid. Various neutral sugars
have been identified in pectins such as xylose, galactose,
rhamnose, and arabinose.
[0018] 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 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 (i.e., 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).
[0019] Various prior art documents discuss the potential use of
pectin as a bioadhesive and gelling material. Studies by Smart et
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. Pharm., 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.
[0020] Pectin has also been studied as a mucoadhesive ophthalmic
material by 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. Biopharm. Pharm. 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 documents.
[0021] U.S. Pat. No. 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 liter. The solubilized
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.
[0022] U.S. Pat. No. 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 (e.g., 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
component, in the absence of a separately applied solution of
calcium ions, which will gel once in contact with the mucosa.
[0023] U.S. Pat. No. 5,318,780 describes aqueous pharmaceutical
vehicles containing two components, a film forming polymer (e.g.,
pectin) and an ionic polysaccharide, which are then gelled in situ
by contacting the mixture with a counter-ion. Polygalacturonic
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.
[0024] The preparation of pectin beads by ionotropic gelation has
been described by Aydin and Akburfa (1996) Int. J. Pharm., 137,
133-136.
[0025] 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 utilization 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 DE of pectin upon such gelation
properties is not mentioned in any of these prior art
documents.
BRIEF SUMMARY OF THE INVENTION
[0026] The invention provides a single component liquid
pharmaceutical composition for administration to a mucosal surface
that includes (i) a therapeutic agent, (ii) a pectin with a low
degree of esterification, (iii) and a aqueous carrier. The aqueous
carrier gels or can be adapted to gel at the site of
application.
[0027] The invention also provides a kit of parts that includes a
liquid pharmaceutical composition for administration to a mucosal
surface. The composition of the kit of parts includes a therapeutic
agent, a pectin with a low degree of esterification, and an aqueous
carrier. The composition gels or is adapted to gel at the site of
application. Additionally, the kit does not include a solution of
divalent metal ions to be added extraneously to the surface. The
kit of parts of the invention may be packaged and presented with
instructions to administer the composition to the mucosal surface
in the absence of an extraneous source of divalent metal ions.
[0028] The invention is also directed to a pharmaceutical gel
composition obtainable by applying a liquid composition, comprising
a therapeutic agent, a pectin with a low degree of esterification,
and an aqueous carrier for application to a mucosal surface of a
mammalian patient in the absence of extraneous application of a
solution of divalent metal ions to the surface.
[0029] The invention also describes a method of treatment of a
patient. The method comprises the administration of a liquid
pharmaceutical composition. The composition includes a therapeutic
agent, a pectin with a low degree of esterification, and an aqueous
carrier. The composition gels or is adapted to gel at the site of
application to a mucosal surface of the patient in the absence of
extraneous application of a solution of divalent metal ions to the
surface.
[0030] Further described herein is a method of treatment of
prophylaxis of a disease that comprises administration of a liquid
pharmaceutical composition. The composition includes a therapeutic
agent that is effective against the disease, a pectin with a low
degree of esterification, and an aqueous carrier. The composition
gels or is adapted to gel at the site of the application. The
composition is applied to a mucosal surface of a patient in need of
such treatment in the absence of extraneous application of a
solution of divalent metal ions to the surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] The foregoing summary, as well as the following detailed
description of preferred embodiments of the invention, will be
better understood when read in conjunction with the appended
drawings. For the purpose of illustrating the invention, there is
shown in the drawings embodiments which are presently preferred. It
should be understood, however, that the invention is illustrated,
but in no way limited, by the following examples with reference to
the figures in which:
[0032] FIG. 1 shows the effect of systemic uptake of salmon
calcitonin when administered intranasally to sheep in formulations
comprising low DE pectin.
[0033] FIG. 2 shows the cumulative release/diffusion of
fexofenadine HC1 from HP-.beta.-CD and HP-.beta.-CD/pectin 100
solutions to simulated nasal electrolyte solution.
DETAILED DESCRIPTION OF THE INVENTION
[0034] 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 (i.e., 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, i,e., 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.
[0035] 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 application.
[0036] 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
(i.e., separately and/or 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 (e.g., solution)
of divalent metal ions applied to the same site.
[0037] 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 the surface.
[0038] 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 the
composition to the surface in the absence of an extraneous source
of divalent metal ions.
[0039] 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 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".
[0040] 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 (e.g., 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.
[0041] By "degree of esterification (DE)", it is meant 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", it is meant a pectin in which less than 50%, and more
preferably less than 35%, of the galacturonic acid units are
esterified.
[0042] The term "extraneous source" of divalent metal ions includes
a separate and/or independent (i.e. 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 (e.g., endogenous
ions derived from nasal secretions, tear fluid, etc.). Divalent
metal ions which may be mentioned include calcium ions.
[0043] 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 absence of extraneous application of a solution of
divalent metal ions to the surface.
[0044] The gels so formed upon contact with mucosal surfaces will
contain only endogenous divalent metal ions (i.e., those derived
directly from bodily secretions) and will not include exogenous
divalent metal ions (i.e., those derived from an extraneous
source). According to a further aspect of the invention there is
provided a pharmaceutical gel composition, which gel comprises a
therapeutic agent and a pectin with a low DE, which gel is
obtainable by applying a liquid composition, comprising the
therapeutic agent and pectin in an aqueous carrier, to a mucosal
surface, and which gel is substantially free of divalent metal ions
derived from an extraneous source applied to the mucosal surface
before, or at the same time as, or after, the liquid composition is
applied.
[0045] Because the compositions of the invention are not added in
conjunction with an extraneous source of such ions, by
"substantially free" of divalent metal ions, it is meant greater
than 97%, preferably greater than 99%, more preferably greater than
99.9%, and especially greater than 99.99% free.
[0046] Pectins with a low DE can be obtained from known sources, or
can be obtained via de-esterification of high DE pectins (which may
be obtained from, for example, Sigma Fine Chemicals), in accordance
with known techniques, such as those described in the article by
Rollin in "Industrial Gums", Academic Press, New York (1993) p.
257, or as described hereinbefore. Low DE pectin may, for example,
be obtained from Copenhagen Pectin A/S as the commercial material
known as Slendid Type 100 and Slendid Type 110. These pectins have
been extracted from citrus peel and standardized by the addition of
sucrose. The standardization process is as described by Rollin in
the above-mentioned article. The DE is less than 50% for both
pectins and of the order of 10% for type 100 and 35% for type 110.
Further materials which may be employed include GENU pectin types
LM 1912 CS and Pomosin pectin types LM 12 CG and LM 18 CG.
[0047] The compositions of the invention may be prepared by
dissolving or dispersing the pectin of low DE and therapeutic agent
in an aqueous system, to form a solution, a suspension or an
emulsion in accordance with known techniques. For example, the
therapeutic agent may be dissolved in a prior prepared aqueous
solution of the pectin, or may be added as, or to form, a
suspension in an aqueous system, where the drug particles are less
than 100 microns in size, preferably between 1 and 20 microns.
Alternatively, drug may be dissolved or suspended in a suitable
oily vehicle such as a vegetable oil, and then dispersed into the
aqueous pectin solution to form an emulsion. It will be appreciated
by those skilled in the art that the type of aqueous formulation so
developed will depend upon mucosa to be treated, as well as the
dose, and the physical characteristics and properties, of the drug
(e.g., its solubility, basicity etc.).
[0048] The concentration of low DE pectin in compositions of the
invention depends upon the nature of the pectin, the presence of
other components, and other factors which influence gelation
properties of the composition (see below), but may be from 1 g/L to
100 g/L, and is preferably from 1 g/L to 50 g/L, more preferably
from 2 g/L to 10 g/L and especially from 5 g/L to 10 g/L.
[0049] Compositions of the invention may be used with a view to the
prevention of a major problem in the delivery of drugs to the nose
for local treatment, namely the rapid mucociliary clearance
mechanism. This natural process, which removes deposited material
from the front of the nose to the throat, can clear material from
the nose with a half-time of about 10 to 20 minutes. Such clearance
rates can be measured readily in man using the saccharin clearance
test or by gamma scintigraphy (Aspden et al, J. Pharm. Sci., 86,
509 (1997); Illum et al, Int. J. Pharm., 39 (1987) 189-199).
[0050] Compositions of the invention may be employed to retain a
therapeutic agent which is intended to act locally at a mucosal
surface for a relatively long period when compared to mucosal
delivery systems known in the art. If the therapeutic agent is
easily absorbed, absorption may be retarded, thus keeping more of
the drug at the site of application, where it is needed.
[0051] Therapeutic agents which may be employed in the compositions
of the invention include, for nasal administration, drugs that are
employed locally to treat conditions such as rhinitis, viral
infections, as well as those which act as decongestants. The
compositions of the invention may also be used as a way of
improving the delivery of vaccines to the nose associated lymphoid
tissue and for the better presentation of DNA for the transfection
of nasal epithelial cells.
[0052] The following list of therapeutic agents are suitable for
use in the compositions of the invention, for local treatment of a
mucosal surface, is provided by way of illustration and is not
meant to be exclusive: antiviral agents such as ICAM-1, pirovadir,
acyclovir, bromovinyldeoxyuridine, .alpha., .beta. and
.gamma.-interferon, zidovudine; decongestants such as
oxymetazaline; anti-allergic agents, such as sodium cromoglycate
and budesonide; steroids, such as fluticazone; vaccines, such as
DNA, influenza, pertussis, measles and diphtheria vaccines;
antibacterial agents; antifungal agents, such as amphotericin,
nystatin; contraceptive and/or spermicidal agents; antibodies
especially for the treatment of RSV infection in children;
prophylactic agents against HIV; antihistamines, such as
diphenhydramine hydrochloride; and genes.
[0053] Combinations of the above-mentioned therapeutic agents may
also be employed.
[0054] Compositions of the invention may also be employed to
control the plasma level versus time profile for readily absorbable
drugs which are intended to act systemically (i.e., to give a
flatter profile), either by altering the rate of transport into the
general circulation, or by retarding absorption of readily
absorbable drugs. This can, for example, be of importance when side
effects from high peak plasma levels are to be avoided.
[0055] The compositions of the invention may thus be used for the
modification of the systemic absorption of mucosally administered
drugs, including, but not limited to, apomorphine, nicotine,
hyoscine hydrobromide, lignocaine, fentanyl, naratriptan,
pheromones and propranolol.
[0056] Combinations of the above-mentioned therapeutic agents may
also be employed.
[0057] The term "therapeutic agents" is intended herein to include
agents which are suitable for use in the treatment, and in the
prevention, of disease.
[0058] The compositions of the invention may be used to
treat/prevent diseases/conditions in mammalian patients depending
upon the therapeutic agent(s) which is/are employed. For the above,
non-exhaustive lists of locally acting and systemic drugs,
diseases/conditions which may be mentioned include those against
which the therapeutic agent(s) in question are known to be
effective, and include those specifically listed for the drugs in
question in Martindale, "The Extra Pharmacopoeia", 31st Edition,
Royal Pharmaceutical Society (1996).
[0059] Preferred drugs include nicotine and apomorphine.
[0060] The amount of therapeutic agent which may be employed in the
compositions of the invention will depend upon the agent which is
used, and the disease to be treated, but may be in the range 0.01
to 40% w/w. However, it will be clear to the skilled person that
suitable doses of therapeutic agents can be readily determined
non-inventively. For example, estimates of dosage can be made from
known injectable products assuming that from 0.1 to 90% of the dose
is absorbed. Suitable single unit doses are in the range 10 .mu.g
to 500 mg depending upon the therapeutic agent(s) which is/are
employed and the route of administration. Suitable daily doses are
in the range 10 .mu.g to 1 g/day depending upon the therapeutic
agent(s) which is/are employed and the route of administration.
[0061] Most compositions comprising drug and a low DE pectin will
gel upon application at the site of application, i.e., upon, or
shortly (e.g., up to 5 minutes) after, contact with the relevant
mucosal surface. However, in some formulations, the nature of the
drug and/or the pectin which is/are employed may require that the
composition is adapted such that it gels upon, or shortly (e.g., up
to 1 minute) after, contact. This may be achieved readily via
techniques which are well known to those skilled in the art:
[0062] For example, the concentration of pectin may be selected
such that the aqueous formulation will gel once in contact with the
mucosal surface.
[0063] Furthermore, the addition of monovalent ions to aid the
gelling process may be required (for example, simple monovalent
electrolytes, e.g., NaC1, may be added to adapt the liquid
formulation to gel, as well as to provide isotonicity).
[0064] The quantity and nature of the drug in the aqueous
formulation may also have an influence on the gelation properties.
For example, the addition of a high level of a certain drugs,
including those which are weak bases (such as nicotine), which are
known to form reversible complexes with anionic materials such as
pectin, may require a change in the ratio between drug and pectin,
so that preferably 30%, more preferably 50%, and most preferably
60%, of the negative charges on the pectin molecule are
uncomplexed.
[0065] Alternatively, sugars in the form of, for example, sucrose
can be added to the formulation to aid gelation. Non-ionic
polysaccharides (such as hydroxypropyl methyl cellulose) may also
be used.
[0066] The pH of the composition has also been found to affect
gelation properties. The pH of the compositions of the invention
may be from 2 to 9, more preferably from 3 to 8 and most preferably
from 4 to 7, taking into account the gelation properties of the
composition and the properties of the therapeutic agent. For
example, in general, we have found that the lower the DE of the
pectin, the lower the pH at which the composition will gel. pH may
be adjusted in accordance with techniques which will be well known
to those skilled in the art, such as the addition of
pharmaceutically acceptable buffering agents, especially those of
low ionic strength. Axelos and Thibault in "The Chemistry and
Technology of Pectin", Academic Press, New York, pp. 109-118,
(1991) describe how the gelation properties of low DE pectin
solutions are somewhat sensitive to pH and ionic strength.
[0067] The above-mentioned techniques, which may be used to adapt
the compositions of the invention to gel, may be investigated and
determined in the normal course of routine experimentation by those
skilled in the art. Combinations of these techniques may also be
employed in order to affect gelation properties.
[0068] The compositions may also contain other additives in the
form of pharmaceutical excipients, such as preservatives (e.g., low
concentrations of materials such as sodium metabisulphate),
stabilizers, flavoring agents, absorption enhancers such as bile
salts, phospholipids, as well as agents which are known to interact
with the drug, for example to form inclusion or salt-bridge
complexes, and promote a controlled release in the nasal cavity
from the formed gel, such as cyclodextrins and ion exchange
resins.
[0069] Additional pharmaceutically acceptable excipients which may
be added to the compositions of the invention include agents such
as glycerol.
[0070] According to a further aspect of the invention there is
provided a process for the preparation of a composition of the
invention which comprises mixing together the therapeutic agent and
the pectin in the aqueous carrier.
[0071] The compositions of the invention may be administered in
suitable dosage forms, in accordance with techniques, and via
delivery devices, all of which are known to those skilled in the
art. For example, for nasal delivery, the compositions of the
invention are preferably administered by way of a spray device, for
example the Pfeiffer metered dose pump or the Valois metered dose
pump, or via a liquid free flow system (such as nasal drops). For
vaginal and rectal administration (infusion) a syringe-type
applicator may be used, or plastics ampoules fitted with a suitable
nozzle, where the contents of the ampoule can be delivered to the
vaginal or rectal surface via the application of a slight pressure.
Suitable systems for delivery of the compositions of the invention
to the back of the throat include spray devices which are well
known to those skilled in the art. Suitable systems for delivery of
the compositions of the invention to eye include liquid free flow
system which are well known to those skilled in the art (such as
eye drops).
[0072] The compositions of the invention have the advantage that
they may be readily administered to mucosal surfaces in the form of
single component, simple liquid formulations, in the absence of an
additional component comprising an extraneous source of divalent
metal ions, using devices which are well known to those skilled in
the art. The compositions of the invention also have the advantage
that they gel upon, or shortly after, contact with mucosa, at
physiologically acceptable pHs, in the presence of endogenous
calcium (only) found physiologically in the nasal secretions, as
well as in the vaginal lumen, the rectal cavity and the tear fluid
of the eye.
[0073] Compositions of the invention also have the advantage that
they may be used to retain a locally-acting drug at a mucosal
surface, or to control drug absorption into the systemic
circulation.
[0074] Compositions of the invention may also have the advantage
that they may be well accepted by patients, and may comprise
materials that are approved by regulatory authorities.
[0075] According to a further aspect of the invention there is
provided a method of treatment of a patient which comprises the
administration of a liquid pharmaceutical composition, comprising a
therapeutic agent, a pectin with a low DE and an aqueous carrier,
which composition gels or is adapted to gel at the site of
application, to a mucosal surface of the patient in the absence of
extraneous application of a solution of divalent metal ions to the
surface.
[0076] There is provided further a method of treatment or
prophylaxis of a disease which comprises administration of a
composition of the invention including a therapeutic agent which is
effective against the disease to a mucosal surface of a patient in
need of such treatment in the absence of extraneous application of
a solution of divalent metal ions to the surface.
EXAMPLE 1
[0077] To Demonstrate that Pectins with Low DEs Gel Under Simulated
Conditions of the Nasal Cavity while Pectins with Higher DEs Do
Not
[0078] Materials: [0079] Pectin, esterified, potassium salt (DE:
31%; lot 22H0548; Sigma) [0080] Pectin, esterified, potassium salt
(DE: 67%; lot 74H1093; Sigma) [0081] Pectin, esterified (DE: 93%;
lot 125H0123; Sigma). [0082] Pectin, Slendid type 100 (lot 620970;
Hercules; Denmark). [0083] Pectin, Slendid type 110 (lot 626790;
Hercules, Denmark). [0084] Pectin, GENU type LM 12 CG (lot G 63481;
Pomosin GmbH; Hercules; Germany). [0085] Pectin, GENU type LM 18 CG
(lot G 63484; Pomosin GmbH; Hercules; Germany). [0086] Sodium
chloride (BDH). [0087] Potassium chloride (BDH). [0088] Calcium
chloride dehydrate (Sigma).
[0089] A simulated nasal electrolyte (SNES) solution was prepared,
composed of the following ingredients: TABLE-US-00001 Sodium
chloride 8.77 g/L Potassium chloride 2.98 g/L Calcium chloride
dehydrate 0.59 g/L
[0090] The SNES was prepared in double strength: [0091] 3.508 g of
sodium chloride, 1.192 g of potassium chloride and 0.236 g of
calcium chloride dehydrate were weighed into three weighing boats
respectively, and [0092] dissolved and transferred into a 200 mL
volumetric flask. [0093] The solution was stirred on a magnetic
stirrer until the drug had dissolved. [0094] Water was added to
volume.
[0095] Preparation of 20 g/L pectin solutions [0096] 1 g of each
type of pectin was weighed into a 100 mL bottle. [0097] 50 mL of
ultrapure water was added to each bottle. [0098] The content was
stirred on a magnetic stirrer until pectin had dissolved, and
[0099] the pH of the solution was measured and adjusted to pH 4 or
pH 6.5 with 0.1 M sodium hydroxide solution.
[0100] Preparation of various formulations containing SNES and
pectin with different concentrations (2 to 10 g/L) [0101]
Appropriate volumes of 20 g/L pectin solution, to obtain the final
concentrations of 2, 3, 4, 5, 6, 7, 8, 9 and 10 g/L, were measured
in a series of 10 mL screw capped glass tubes. [0102] Appropriate
volumes of water were added to obtain a total volume of 2.5 mL
firstly, then 2.5 mL of the two fold concentration SNES was added.
[0103] The tubes were cooled in an ice water bath for 15 minutes.
[0104] The test tubes were tilted to check the phase state and flow
property. [0105] The tubes were vigorously shaken to check the
phase state and flow property again.
[0106] Results
[0107] The results are shown in Table 1: [0108] 1. Pectin type 100
and 110 gelled with simulated nasal electrolyte solution when the
final concentration of pectin was >2 g/L and formed a strong gel
when the final concentration was >4 g/L at pH values of 4 and
6.5. The gel was transparent and homogeneous. The strength of gel
increased with the increasing pectin concentration in system.
[0109] 2. Pectin type LM 12 CG and LM 18 CG gelled at final pectin
concentrations of 4 g/L and 6 g/L (pH 4) and 4 g/L (pH 6.5)
respectively. These two pectin types only formed solid gels at pH
6.5 and at concentrations higher than 6 g/L and 8 g/L respectively.
[0110] 3 . Pectin with a DE of 31% (Sigma) gelled at a
concentration of >2 g/L and formed a solid gel at concentrations
>4 g/L. Pectin 67% and 93% did not form solid gels at
concentrations up to 10 g/L at neither pH 4 nor at pH 6.5.
EXAMPLE 2
[0111] Nasal Drug Formulation Prepared from Pectins with Low
DEs
[0112] Formulations were prepared containing drugs in the form of
nicotine (a weak base) and cromolyn sodium (sodium cromoglycate; a
weak acid). Pectin formulations were prepared at a pectin
concentration of 10 mg/mL using Slendid 100 and Slendid 110. The
formulations were mixed with the simulated nasal electrolyte
solution (the method of preparation of which was as in Example 1).
The formulations were filled into a nasal delivery device (Pfeiffer
metered dose pump) and the spray properties evaluated by visual
examination.
[0113] The gelation of the formulation in the nasal electrolyte
solution was evaluated as solution, gel or solid by visual
observation and the flow properties before and after shaking. The
results, which are set out in Table 2, show that when the
formulation contained a weak acid (cromolyn sodium), gelation
occurred in the nasal electrolyte solution. When the formulation
contained a high level of a weak base (nicotine) then gelation did
not occur.
[0114] It is believed that the reason for this difference is that
the ionized nicotine may interact with the charged carboxyl groups
on the pectin molecules and thereby influence the gelation
characteristics of the low esterified pectin. Thus, with weakly
basic drugs, a person skilled in the art is able to adjust the
pectin concentration to take this interaction into account (see
above).
EXAMPLE 3
[0115] To Demonstrate that Nasal Formulations Containing Low DE
Pectin Do Not Enhance the Systemic Uptake of a Poorly Absorbed
Drug
[0116] For the local delivery of drugs it is important to retain
the drug at its site of action, namely the nasal, rectal and
vaginal cavities. In such cases, the formulation should not enhance
the absorption of the drug. It is known that some bioadhesive
gelling formulations may increase systemic uptake. Therefore,
experiments have been conducted in an animal model to demonstrate
that pectins with low DE do not enhance the nasal uptake
(systemically) of a model polar drug, salmon calcitonin (S-CT).
[0117] Sheep
[0118] Eight female, cross-bred sheep of known weight were used in
this study. The average weight of the sheep was in the region of 60
kg. The sheep were weighed and labeled 1 to 8. An in-dwelling
Secalon cannula fitted with a flowswitch was placed approximately
15 cm into one of the external jugular veins of each animal on the
first day of the study. Whenever necessary, the cannula was kept
patent by flushing it with heparinised (25 IU/mL) 0.9% saline
solution. This cannula remained in-dwelling in the jugular vein of
each animal for the duration of the study and was removed upon
completion of the study.
[0119] Preparation of Salmon Calcitonin (S-CT) Formulations
[0120] Two S-CT formulations were prepared. Each formulation
contained 2000 IU/mL S-CT, which was sufficient material to
administer a dose of 20 IU/kg in a volume of 0.01 mL/kg. The sheep
were randomly divided into two groups of four animals and each
group was dosed with a different S-CT formulation.
[0121] Summary of the Dose Groups TABLE-US-00002 S-CT Chitosan G210
Pectin Slendid 100 Formulation (IU/kg) (mg/kg) (mg/kg) I 20 -- --
II 20 -- 0.1
[0122] Prior to dose administration the sheep were sedated with an
intravenous dose of Ketamine Vetalar.RTM. (100 mg/mL injection) at
2.25 mg/kg. Intranasal doses were administered at 0.01 mL/kg. The
dose was divided equally between each nostril. For dose
administration, a blueline umbilical cannula was inserted into the
nostril of the sheep to a depth of 10 cm, before the delivery of
the appropriate volume of solution from a 1 mL syringe.
[0123] Blood Sampling
[0124] Blood samples of 4 mL were collected from the cannulated
jugular vein of the sheep at 15 and 5 minutes prior to S-CT
administration and at 5, 15, 30, 45, 60, 90, 120, 150, 180, 240,
300, 360, 420 and 480 minutes post-administration. They were then
mixed gently in 4 mL heparinised tubes and kept on crushed ice
before plasma separation. Plasma was separated by centrifugation
for 10 minutes at 4.degree. C. approximately 3000 rpm. Each plasma
sample was divided into two equal aliquots of approximately 1 mL
and stored at -20.degree. C. One set of plasma samples was used for
calcium analysis.
[0125] Calcium Analysis
[0126] Plasma calcium analysis was performed by the Clinical
Chemistry Department, Queens Medical Centre, University of
Nottingham. The results showed that for the formulation I and II
the plasma calcium levels were very similar and that the presence
of pectin in the formulation did not lead to an increase in the
systemic bioavailability of the model drug.
EXAMPLE 4
[0127] Simulated Nasal Electrolyte Solution-Pectin Gelling System
for Controlled Release of Fexofenadine Hydrochloride
[0128] Preparation of Formulations
[0129] Formulation 1-10 mg/mL fexofenadine HC1/100 mg/mL
HP-.beta.-CD: 2 g of HP-.beta.-CD was dissolved in 18-19 mL of
water in a 20 mL volumetric flask. 200 mg of fexofenadine was added
to the solution and stirred until the drug has dissolved. The pH of
the solution was adjusted to 4.0, then the solution was made up to
volume with water.
[0130] Formulation 2-10 mg/mL fexofenadine HC1/100 mg/mL
HP-.beta.-CD/10 mg/mL pectin 100:
[0131] 50 mg of pectin 100 (SLENDID type 100, Hercules, Denmark)
was dissolved in 5 mL of Formulation 1 in a 5 mL volumetric
flask.
[0132] Release/Diffusion Testing
[0133] A Franz diffusion cell apparatus was set up in a closed loop
arrangement and parameters were listed as follows: [0134] Medium:
Simulated nasal electrolyte solution [0135] Temperature: 37.degree.
C. [0136] Membrane: Cellulose nitrate, 0.45 Tm pore size [0137]
Volume of the closed loop arrangement: 8.8 mL [0138] Stirring speed
of a magnetic stirrer: 4 [0139] Peristaltic pump flow rate: 1 (The
Cole-Parmer Masterflex peristaltic pump, Model 7518-60, fitted with
Masterflex L/Sth 14 silicone tubing) [0140] Sample volume: 0.4 mL
(contained 4 mg of fexofenadine HCl, the maximum concentration of
the drug in medium will be around 450 Tg/mL) [0141] Wavelength: 260
nm
[0142] Results
[0143] The results are shown in FIG. 2. (Every point on the graphs
represents a mean value of two points.)
[0144] The maximum UV absorbance of Formulation 1 (control) reached
during the diffusion experiment was used as 100% release to
calculate the percentage of release at each selected time
point.
[0145] The results show a clear difference in release
characteristics of the two formulations.
[0146] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *