U.S. patent application number 10/421111 was filed with the patent office on 2004-02-19 for anti-obesity compositions.
Invention is credited to Bailly, Jacques, Martin, Rainer Eugen, Raab, Susanne.
Application Number | 20040033983 10/421111 |
Document ID | / |
Family ID | 29265897 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040033983 |
Kind Code |
A1 |
Bailly, Jacques ; et
al. |
February 19, 2004 |
Anti-obesity compositions
Abstract
The present invention relates to compositions and methods for
treating obesity. More particularly, the invention relates to a
composition comprising a lipase inhibitor such as orlistat, and
glucomannan such as konjac as well as methods for utilizing such
compositions and kits for carrying out this method.
Inventors: |
Bailly, Jacques; (Rixheim,
FR) ; Martin, Rainer Eugen; (Grenzach-Wyhlen, DE)
; Raab, Susanne; (Leinfelden-Echterdingen, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
29265897 |
Appl. No.: |
10/421111 |
Filed: |
April 23, 2003 |
Current U.S.
Class: |
514/54 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61P 3/04 20180101; A61K 9/48 20130101; A61K 36/888 20130101; A61K
9/0056 20130101; A61P 1/00 20180101; A61K 31/365 20130101; A61K
31/736 20130101; A61K 31/365 20130101; A61K 2300/00 20130101; A61K
31/736 20130101; A61K 2300/00 20130101; A61K 36/888 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/54 |
International
Class: |
A61K 031/715 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 26, 2002 |
EP |
02009254.0 |
Claims
What is claimed:
1. A pharmaceutical composition comprising from about 0.1% by
weight to about 20% by weight, based upon the weight of the
composition, of a lipase inhibitor and from about 10% by weight to
about 75% by weight, based upon the weight of the composition, of
glucomannan and from about 0.1% to about 90% by weight, based upon
the weight of the composition, of one or more pharmaceutically
acceptable excipients.
2. The composition of claim 1 wherein the glucomannan is present as
konjac.
3. The composition of claim 2 wherein the konjac is present as
konjac flour.
4. The composition of claim 2 where in the konjac contains at least
80% by weight of glucomannan.
5. The pharmaceutical composition of claim 4 wherein the konjac
contains at least 90% by weight glucomannan.
6. The composition of claim 1 wherein the lipase inhibitor is
present in an amount of from about 0.1% by weight to about 10%,
based upon the weight of said composition, and glucomannan is
present in an amount of from 20% to 75% by weight, based upon the
weight of the composition.
7. The composition of claim 1, wherein the pharmaceutically
acceptable excipient is selected from the group consisting of
fillers, surfactants, disintegrants, binders, lubricants,
flowability enhancers, sweeteners, and colorants.
8. The composition of claim 7 wherein the composition comprises a)
from about 0.1% to about 20% (w/w) lipase inhibitor; b) from about
10 to about 75% (w/w) glucomannan; and pharmaceutically acceptable
excipients selected from the group consisting of, from about 0.1 to
about 20% (w/w) fillers, from about 0.1 to about 10% (w/w)
surfactants, about 0.1 to about 10% (w/w) disintegrants, from about
0.1 to about 10% (w/w) binder, about 0.1 to about 10% (w/w)
lubricants, from about 0.1 to about 10% (w/w) flowability
enhancers, about 0.1 to about 10% (w/w) sweeteners, from about 0.1
to about 5% (w/w) colorants and mixtures thereof, with all said
weight percents being based upon the weight of the composition.
9. The composition of claim 1 wherein the composition contains from
about 5 mg to about 1,000 mg of said lipase inhibitor and from
about 0.5 g to about 10 g of glucomannan.
10. The composition of claim 9 wherein said composition is in unit
oral dosage form.
11. The composition of claim 10 wherein the composition contains
from about 0.5 to 6 grams of glucomannan.
12. The composition of claim 11 wherein said composition contains
from about 10 mg to 500 mg of the lipase inhibitor.
13. The composition of claim 12 wherein said composition contains
from about 10 mg to about 360 mg of the lipase inhibitor.
14. The composition of claim 9, wherein the pharmaceutically
acceptable excipient is selected from the group consisting of
fillers, surfactants, disintegrants, binders, lubricants,
flowability enhancers, sweeteners, and colorants.
15. The composition of claim 14, comprising a) from about 5 to
about 1000 mg of said lipase inhibitor; b) from about 0.5 to about
10 g glucomannan; and pharmaceutically acceptable excipients
selected from the group consisting of from about 0.1 to about 10 g
fillers, from about 0.05 to about 5.0 g surfactants, from about
0.05 to about 2.0 g disintegrants, from about 0.02 to about 5.0 g
binder, from about 0.001 to about 1.0 g lubricants, from about 0.1
to about 5.0 g flowability enhancers, from about 0.01 to about 4.0
g sweeteners, from about 0.001 to about 0.5 g colorants and
mixtures thereof.
16. The composition of claim 1 wherein said lipase inhibitor is
orlistat.
17. The composition of claim 16 wherein the glucomannan present as
konjac.
18. The composition of claim 17 wherein the konjac is present as
konjac flour.
19. The composition of claim 18 where in the konjac contains at
least 80% by weight of glucomannan.
20. The pharmaceutical composition of claim 19 wherein the konjac
contains at least 90% by weight glucomannan.
21. The composition of claim 16 wherein the glucomannan is present
in said composition in an amount of from about 20% to 75% by
weight, based upon the weight of the composition and the orlistat
is present in an amount of from 1% to about 10% based upon the
weight of the composition.
22. The composition of claim 16, wherein the pharmaceutically
acceptable excipient is selected from the group consisting of
fillers, surfactants, disintegrants, binders, lubricants,
flowability enhancers, sweeteners, and colorants.
23. The composition of claim 22 wherein the composition comprising
from a) about 0.1% to about 20% (w/w) of orlistat; b) about 10 to
about 75% (w/w) glucomannan; and pharmaceutically acceptable
excipients selected from the group consisting of from about 0.1 to
about 20% (w/w) fillers, from about 0.1 to about 10% (w/w)
surfactants, from about 0.1 to about 10% (w/w) disintegrants, from
about 0.1 to about 10% (w/w) binder, from about 0.1 to about 10%
(w/w) lubricants, from about 0.1 to about 10% (w/w) flowability
enhancers, from about 0.1 to about 10% (w/w) sweeteners, from about
0.1 to about 5% (w/w) colorants and mixtures thereof wherein the
percents are based upon the weight of the composition.
24. The composition of claim 16 wherein the composition contains
from about 5 mg to about 1,000 mg of said lipase inhibitor and from
about 0.5 g to about 10 g of glucomannan.
25. The composition of claim 16 wherein said composition contains
from about 10 mg to 500 mg of orlistat.
26. The composition of claim 24 wherein said composition contains
from about 10 mg to about 360 mg of orlistat.
27. The composition of claim 16, comprising from: a) about 5 to
about 1000 mg orlistat; b) about 0.5 to about 10 g glucomannan; and
pharmaceutically acceptable excipients selected from the group
consisting of from about 0.1 to about 10 g fillers, from about 0.05
to about 5.0 g surfactants, from about 0.05 to about 2.0 g
disintegrants, from about 0.02 to about 5.0 g binder, from about
0.001 to about 1.0 g lubricants, from about 0.1 to about 5.0 g
flowability enhancers, from about 0.01 to about 4.0 g sweeteners,
from about 0.001 to about 0.5 g colorants and mixtures thereof.
28. A method of combating obesity in human patients comprising
administering to said human patients a lipase inhibitor in an
amount effective to combat said obesity, said lipase inhibitor
being administered in conjunction with glucomannan, said
glucomannan being administered in an amount sufficient to reduce
the gastro-intestinal adverse events caused after administration of
a lipase inhibitor.
29. The method of claim 28 wherein the lipase inhibitor is
administered for treatment or prevention of obesity.
30. The method of claim 29 wherein said lipase inhibitor and
glucomannan are administered simultaneously or sequentially or
separately.
31. The method of claim 30 wherein said lipase inhibitor is
administered in an amount of from about 5 mg to 1000 mg per day and
the glucomannan is administered in an amount of from 0.5 to 10 g
per day.
32. The method of claim 31 wherein said lipase inhibitor is
administered in an amount of from about 60 mg to 720 mg per
day.
33. The method of claim 31 wherein said administration is oral.
34. The method of claim 33 wherein the glucomannan and the lipase
inhibitor are administered within two hours of each other.
35. The method of claim 31 wherein the glucomannan is administered
for combating gastrointestinal side effects caused by the lipase
inhibitor, which side effects are selected from the group
consisting of oily spotting, fatty/oily stools, fecal urgency,
increased defecation and fecal incontinence.
36. The method of claim 33 wherein the combination of lipase
inhibitor and the glucomannan are administered from two to three
times per day.
37. The method of claim 35 wherein the combination is orally
administered.
38. The method of claim 31 wherein said lipase inhibitor is
orlistat.
39. The method of claim 38 wherein orlistat is orally administered
in an amount of from about 10 mg to about 500 mg per day.
40. The method of claim 39 wherein the orlistat is administered in
an amount from about 10 mg to 360 mg per day.
41. The method of claim 40 wherein the orlistat is administered in
an amount from about 30 mg to 120 mg per day.
42. The method of claim 41 wherein the orlistat is administered in
an amount from about 40 mg to 80 mg per day.
43. The kit for the treatment of obesity containing as a first
component a lipase inhibitor and as a second component
glucomannan.
44. The kit of claim 43 wherein both of the components within the
kit contain unit oral dosage forms to be administered to a human
patient.
45. The kit of claim 44 wherein said lipase inhibitor is
orlistat.
46. The kit of claim 45 wherein the oral unit dosage forms which
comprise the first component orlistat each contain from about 5 to
about 120 mg of the orlistat and the unit oral dosage forms which
comprise the second component glucomannan each contain from about
0.5 to about 10 g of glucomannan.
47. The kit of claim 45 wherein the oral unit dosage forms which
comprise the first component orlistat each contain from about 16 mg
to about 720 mg of orlistat and the unit oral dosage forms which
comprise the second component glucomannan each contain from about
0.5 to about 10 g of glucomannan.
48. The kit of claim 46 wherein each component contains from 1 to
100 oral unit dosage forms of glucomannan and from 1 to 100 oral
unit dosage forms of orlistat.
49. The kit of claim 47 wherein each component contains from 1 to
100 oral unit dosage forms of glucomannan and from 1 to 100 oral
unit dosage forms of orlistat.
Description
FIELD OF THE INVENTION
[0001] The field of this invention is the field of combating
obesity utilizing compositions containing lipase inhibitors.
BACKGROUND OF THE INVENTION
[0002] Adverse effects which occasionally are observed in patients
treated with lipase inhibitors are anal leakage of oil (oily
spotting) and fecal incontinence. Oily spotting results from
physical separation of some of the ingested but unabsorbed dietary
fat from the bulk of the fecal mass in the colon.
[0003] In U.S. Pat. No. 5,447,953 it has been shown that by
combining a lipase inhibitor with substantial amounts of water
insoluble crude fibers, the inhibiting effect on fat absorption can
be increased. International Patent Application WO 00/09123
demonstrates that by combining a lipase inhibitor such as orlistat
with low amounts of chitosan or a derivative or a salt thereof, the
phenomenon of anal leakage of oil can be strongly reduced. Various
approaches to control oily leakage have been discussed. Among such
strategies are i) use of a surfactant to stabilize the oil/water
interface in order to prevent coalescence of the oil emulsion in
the colon, ii) enhancing water viscosity in the colon to reduce
both intensity and frequency of droplet-droplet interactions and by
that reducing the probability of coalescence, iii) physical
absorption of oil by a lipophilic compound, or iv) increasing the
natural stool mass by facilitating bacterial growth in the
colon.
SUMMARY OF THE INVENTION
[0004] The present invention relates to pharmaceutical compositions
and methods for preventing and treating obesity. More particularly,
the invention relates to a composition comprising a lipase
inhibitor, preferably a compound of formula I (orlistat), 1
[0005] and glucomannan, optionally containing one or more
pharmaceutically acceptable excipients.
[0006] The invention also relates to the compositions as described
above for use in the treatment and prevention of obesity and to a
process for preparing a composition as described above, comprising
mixing a lipase inhibitor with glucomannan and optionally one or
more pharmaceutically acceptable excipients.
[0007] The invention also refers to a kit for treatment of obesity,
said kit comprising a) a first component which is a lipase
inhibitor and b) a second component which is glucomannan as defined
above, e.g. in an oral unit dosage form, preferably comprising a)
from 1 to 100 doses units of orlistat and b) from 1 to 100 doses
units of a glucomannan.
[0008] Another embodiment of the present invention refers to a kit
for treatment of obesity, said kit comprising a) a first component
which is a lipase inhibitor and b) a second component which is
glucomannan in oral unit dosage forms.
[0009] The present invention also relates to the use of a
composition as defined above in the manufacture of medicaments
useful for the treatment and prevention of obesity and to the use
of a lipase inhibitor as defined above in the manufacture of a
medicament for the treatment and prevention of obesity in a patient
who is also receiving treatment with glucomannan as defined above.
This use of glucomannan and lipase inhibitor refers to the
simultaneous, separate or sequential use for the treatment and
prevention of obesity.
[0010] Further the invention is directed to a method of treatment
of obesity in a human in need of such treatment which comprises
administration to the human of a therapeutically effective amount
of a lipase inhibitor and a therapeutically effective amount of
glucomannan as defined above. The method refers to the
simultaneous, separate or sequential administration of the
compounds. A further embodiment of the present invention is a
lipase inhibitor and glucomannan or konjac as defined above as a
combined preparation for simultaneous, separate or sequential use
for the treatment and prevention of obesity. The invention also
refers to the use of glucomannan or konjac as defined above in the
manufacture of medicaments useful for the treatment and prevention
of gastrointestinal side effects selected from the group of oily
spotting, fatty/oily stools, fecal urgency, increased defecation
and fecal incontinence and to a method of treatment or prevention
of gastrointestinal side effects selected from the group of oily
spotting, fatty/oily stools, fecal urgency, increased defecation
and fecal incontinence in a human in need of such treatment which
comprises administration to the human of a therapeutically
effective amount of konjac or glucomannan as defined above. Further
the invention is directed to a lipase inhibitor and glucomannan or
konjac as defined above for simultaneous, separate or sequential
use for the treatment and prevention of obesity.
FIGURES
[0011] FIG. 1 displays test emulsions of konjac after
centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. After a centrifugation time of t=300 min, only for
emulsions containing konjac in concentrations higher than 1.5%
(w/w) a weak emulsification stabilization is observed.
[0012] FIG. 2 shows test emulsions of konjac after centrifugation
at 3100 g for t=1 min (a) and t=300 min (b), respectively. The
emulsions contained 1.0% (w/w) konjac at different pH values. After
a centrifugation time of t=300 min minor emulsion stabilization was
observed at pH 6 and 7, respectively. For all other emulsions
extensive coalescence was observed.
[0013] FIG. 3: The free oil reducing effect of different types of
glucomannan in % relative to controls (data as means .+-.SE).
DETAILED DESCRIPTION OF THE INVENTION
[0014] In accordance with this invention the administration of
glucomannan in conjunction with lipase inhibitors for combating
obesity reduces the gastro-intestinal side effects produced by the
lipase inhibitor such as oily spotting, fatty/oily stools, fecal
urgency, increased defecation and fecal incontinence in humans.
[0015] In accordance with an embodiment of this invention,
pharmaceutical compositions are provided which contain the lipase
inhibitors, preferably orlistat, and glucomannan. These
compositions may contain pharmaceutically acceptable excipients. In
accordance with one embodiment, the pharmaceutical composition
contains from about 0.1% by weight to about 10% by weight, based
upon the weight of the composition, of the lipase inhibitor and
from about 10% by weight to about 75% by weight, based upon the
weight of the composition, of glucomannan and from about 0.1% to
90% by weight, based upon the weight of the composition of one or
more pharmaceutically acceptable excipients. Generally it is
preferred that the composition of this invention be formulated in a
unit oral dosage form.
[0016] In accordance with another embodiment of this invention
there is provided a method for combating obesity in human patients
by administering to said human patients the lipase inhibitor,
preferably orlistat, in an effective amount to treat said obesity,
in conjunction with glucomannan. In accordance with a preferred
embodiment both the glucomannan and lipase inhibitor can be orally
administered in conventional oral dosage forms such as through the
compositions of this invention. In accordance with this invention,
the glucomannan and lipase inhibitor can be administered
simultaneously, separately or sequentially for carrying out the
method of this invention. Generally, it is preferred, when
separately administered, the two components i.e. the lipase
inhibitor and the glucomannan be administered within two hours of
each other. In accordance with this invention the glucomannan which
is administered in conjunction with lipase inhibitor is
administered in an amount of about 0.5 g to 10 g per day after
administration of lipase inhibitor. In accordance with this
invention the lipase inhibitor is generally administered from 2 to
preferably 3 times per day.
[0017] In accordance with this invention any effective amount of
lipase inhibitors for combating obesity can be administered to
human patients. The use of these lipase inhibitors and their
dosages are well known for combating obesity. By combating obesity,
it is meant that the composition of this invention can be utilized
either for prevention and/or treatment of obesity. In addition the
compositions of this invention can contain any effective amount of
the lipase inhibitor needed for administration to combat
obesity.
[0018] Where the glucomannan is to be separately or simultaneously
administered, in accordance with another embodiment of this
invention, kits can be provided containing the lipase inhibitor,
preferably orlistat as one component, and the glucomannan as the
second component. Preferably, each of the components contains the
glucomannan and lipase inhibitor, such as orlistat, in the
compositions in oral unit dosage forms. The first or lipase
inhibitor component of the kit can contain from 1 to 100 oral
dosage units of the lipase inhibitor, such as orlistat, and the
second or glucomannan component contains from about 1 to 100 oral
dosage units of glucomannan. Lipase inhibitor is present in each
oral unit dosage form in an amount of from 5 to 120 mg and the
glucomannan is provided in a separate oral unit dosage form which
constitutes the second component. In accordance with a preferred
embodiment of this invention, the glucomannan can be provided in
the separate oral unit dosage form in an amount of from about 0.5 g
to about 10 g. Generally it is preferred that the orilstat be
administered in an amount of from 16 mg to 720 mg in each unit oral
dosage form contained within the first component of the kit.
[0019] In accordance with this invention, it has been found that
glucomannan can be administered such as glucomannan itself or in
the form of konjac, e.g. konjac flour, in any amount sufficient to
reduce the gastrointestinal adverse events (GI-AE) commonly
observed after administration of a lipase inhibitor such as
orlistat or artificial fat substitutes. Therefore the method of
this invention involves the use of glucomannan in an amount
sufficient to reduce the gastrointestinal adverse effects observed
after administration of a lipase inhibitor. These effects include
oily spotting, fatty/oily stools, fecal urgency, increased
defecation and fecal incontinence in humans.
[0020] Konjac (Amorphophallus konjac) is a plant, the tuber of
which is the source of a well-known foodstuff in China and Japan,
namely konjac flour. This flour comprises a highly viscous sol of
glucomannan and soluble starches when reconstituted in water. The
principal soluble constituent is glucomannan (formula II), a
polysaccharide comprised of D-glucose and D-mannose, which is
useful as an ingredient in various foodstuffs, as well as in
industrial applications such as films, oil drilling fluids and
paints. 2
[0021] Accordingly, the present invention refers to a composition
comprising a lipase inhibitor and glucomannan. Unless otherwise
indicated the following definitions are set forth to illustrate and
define the meaning and scope of the various terms used to describe
the invention herein.
[0022] The term "lipase inhibitor" refers to compounds which are
capable of inhibiting the action of lipases, for example gastric
and pancreatic lipases. For example, orlistat and lipstatin as
described in U.S. Pat. No. 4,598,089 are potent inhibitors of
lipases. Lipstatin is a natural product of microbial origin, and
orlistat is the result of a hydrogenation of lipstatin. Other
lipase inhibitors include a class of compound commonly referred to
as panclicins. Panclicins are analogues of orlistat (Mutoh et al,
J. Antibiot., 47(12):1369-1375 (1994)). The term "lipase inhibitor"
refers also to polymer bound lipase inhibitors for example
described in International Patent Application WO 99/34786 (Geltex
Pharmaceuticals Inc.). These polymers are characterized in that
they have been substituted with one or more groups that inhibit
lipases. The term "lipase inhibitor" also comprises
pharmaceutically acceptable salts of these compounds. The term
"lipase inhibitor" also refers to 2-oxy-4H-3,1-benzoxazin-4-ones
which have been described in International Patent Application WO
00/40569 (Alizyme Therapeutics Ltd.), e.g.
2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one,
6-methyl-2-tetradecyloxy-4H-- 3,1-benzoxazin-4-one, and
2-hexadecyloxy-6-methyl-4H-3,1-benzoxazin-4-one and other
oxetanones described for example in International Patent
Applications WO 01/32616, WO 01/32669 and WO 01/32670. Most
preferably, the term "lipase inhibitor" refers to orlistat.
[0023] Orlistat is a known compound useful for the control or
prevention of obesity and hyperlipidemia. See, U.S. Pat. No.
4,598,089, issued Jul. 1, 1986, which also discloses processes for
making orlistat and U.S. Pat. No. 6,004,996, which discloses
appropriate pharmaceutical compositions. Further suitable
pharmaceutical compositions are described for example in
International Patent Applications WO 00/09122 and WO 00/09123.
Additional processes for the preparation of orlistat are disclosed
in European Patent Applications Publication Nos. 185,359, 189,577,
443,449, and 524,495.
[0024] Orlistat is preferably orally administered from 60 to 720 mg
per day in divided doses two to three times per day. Preferred is
wherein from 180 to 360 mg, most preferably 360 mg per day of a
lipase inhibitor is administered to a human subject, preferably in
divided doses two or, particularly, three times per day. The
subject is preferably an obese or overweight human, i.e. a human
with a body mass index of 25 or greater. Generally, it is preferred
that the lipase inhibitor be administered within about one or two
hours of ingestion of a meal containing fat.
[0025] Orlistat can be administered to humans in conventional oral
compositions, such as tablets, coated tablets, hard and soft
gelatin capsules, emulsions or suspensions. Examples of carriers
which can be used for tablets, coated tablets, drages and hard
gelatin capsules are lactose, other sugars and sugar alcohols like
sorbitol, mannitol, maltodextrin, or other fillers; surfactants
like sodium lauryl sulfate, Brij 96, or Tween 80; disintegrants
like sodium starch glycolate, maize starch or derivatives thereof;
polymers like povidone and crospovidone; talc; stearic acid or its
salts and the like. Suitable carriers for soft gelatin capsules
are, for example, vegetable oils, waxes, fats, semi-solid and
liquid polyols and the like. Moreover, the pharmaceutical
preparations can contain preserving agents, solubilizers,
stabilizing agents, wetting agents, emulsifying agents, sweetening
agents, coloring agents, flavoring agents, salts for varying the
osmotic pressure, buffers, coating agents and antioxidants. They
can also contain still other therapeutically valuable substances.
The formulations may conveniently be presented in unit dosage form
and may be prepared by any methods known in the pharmaceutical art.
Preferably, orlistat is administered according to the formulation
shown in the Examples and in U.S. Pat. No. 6,004,996,
respectively.
[0026] The term "konjac flour" refers to a hydrocolloidal
polysaccharide obtained from the tubers of species of
Amorphophallus konjac. The perennial tuber is unique to Asia and
especially cultivated in Japan. Konjac flour is a high molecular
weight, nonionic glucomannan consisting primarily of mannose and
glucose molecules combined in a mole ratio of 1.6:1.0. It is a
slightly branched polysaccharide connected by beta 1-4 linkages and
has an average molecular weight ranging from 200,000 to 2,000,000
daltons. Acetyl groups along the glucomannan backbone contribute to
its solubility and are located, on average, at every 9 to 19 sugar
unit. Refined konjac flour is easily soluble in cold water and
forms a highly viscous solution with a pH between 4.0 and 7.0.
Addition of a mild alkaline solution results in the formation of a
heat-stable gel that resists melting, even under extended heating
conditions. The purification process for konjac flour is carried
out in large-scale extraction plants. The konjac tubers are first
pulverized, and then the collected glucomannan particles are
polished in order to dislodge and extract noxious materials
adhering to them. This process yields a refined konjac flour with
high degree of purity that improves product solubility, stability
and overall functionality. The particles are tasteless, odorless
and white in color.
[0027] Konjac flour and glucomannan (PROPOL.RTM., RHEOLEX.RTM.) are
commercially available products (Kyoei Konnyaku, Inc., Behr,
Wunderlich & Co., Provisco, FMC Biopolymers, Naturland,
SiberHegner and Co. Ltd.). The preparation and use have been
described e.g. in U.S. Pat. Nos. 3,767,424, 3,973,007, 4,588,589,
5,486,364, 5,486,364, 5,733,593, 5,536,521, 6,126,906, etc.
[0028] The term "pharmaceutically acceptable" as used herein means
that the corresponding compounds are acceptable from a toxicity
viewpoint.
[0029] In more detail, the present invention relates to a
pharmaceutical composition comprising a lipase inhibitor and
glucomannan. Optionally this composition may contain one or more
pharmaceutically acceptable excipients. The glucomannan may be
provided in form of konjac. Preferably, the konjac contains at
least 80% by weight glucomannan, more preferably at least 90% by
weight glucomannan. The glucomannan or konjac may be provided in
form of konjac powder, e.g. konjac flour. Preferably the lipase
inhibitor is orlistat. These 80% by weight are based on the total
weight of the composition.
[0030] Pharmaceutical compositions incorporating both a compound of
a lipase inhibitor and glucomannan are important embodiments of the
present invention. Such pharmaceutical compositions comprise a
therapeutically effective amount of each of the compounds for the
given purpose. Each dosage unit can obtain the daily doses of both
compounds or may contain a fraction of the daily dose, such as
one-third of the doses. Alternatively, each dosage unit may contain
the entire dose of one of the compounds, and a fraction of the dose
of the other compound. In such case the patient would daily take
one of the combination dosage units, and one or more units
containing only the other compound.
[0031] In a preferred embodiment of the present invention the
composition comprises a) 0.1 to 20% (w/w) lipase inhibitor, b) 10
to 75% (w/w) glucomannan such as konjac, and c) 0.1 to 90% (w/w) of
one or more pharmaceutically acceptable excipients. More
preferably, a composition may comprise a) 0.1 to 10% (w/w) lipase
inhibitor, b) 20 to 75% (w/w) glucomannan and c) 0.1 to 90% (w/w)
of one or more pharmaceutically acceptable excipients. Preferably,
the amount of one or more pharmaceutically acceptable excipients is
from about 5 to 50% (w/w), more preferably 5 to 20%. In more
detail, the composition may contain a) from about 5 to about 1000
mg lipase inhibitor, e.g. orlistat, in an amount of e.g. from about
10 to about 500 mg lipase inhibitor, preferably from about 20 to
about 100 mg lipase inhibitor, e.g. from about 10 to about 360 mg
orlistat, more preferably from about 30 to about 120 mg orlistat,
more preferably from about 40 to about 80 mg orlistat and b) from
about 0.5 to about 10 g glucomannan, preferably from about 0.5 to
about 8 g glucomannan, and more preferably from about 0.5 to about
6 g glucomannan. The weight percent is based upon the total weight
of the composition
[0032] The pharmaceutically acceptable excipients may be selected
from the group consisting of fillers, surfactants, disintegrants,
binders, lubricants, flowability enhancers, sweeteners, and
colorants, e.g. a composition may comprise of a) about 5 to about
1000 mg lipase inhibitor; b) about 0.5 to about 10 g glucomannan;
and optionally pharmaceutically acceptable excipients selected from
the group of about 0.1 to about 10 g fillers, about 0.05 to about
5.0 g surfactants, about 0.05 to about 2.0 g disintegrants, about
0.02 to about 5.0 g binder, about 0.001 to about 1.0 g lubricants,
about 0.1 to about 5.0 g flowability enhancers, about 0.01 to about
4.0 g sweeteners, and about 0.001 to about 0.5 g colorants.
[0033] The pharmaceutically acceptable excipients may be selected
from the group consisting of fillers, e.g. sugars and/or sugar
alcohols, e.g. lactose, sorbitol, mannitol, maltodextrin, etc.;
surfactants, e.g. sodium lauryl sulfate, TPGS, Brij 96 or Tween 80;
disintegrants, e.g. sodium starch glycolate, maize starch or
derivatives thereof; binder, e.g. povidone, crosspovidone,
polyvinylalcohols, hydroxypropylmethylcellulose; lubricants, e.g.
stearic acid or its salts; flowability enhancers, e.g. silicium
dioxide; sweeteners, e.g. aspartame; and/or colorants, e.g.
.beta.-carotene.
[0034] In a preferred embodiment of the present invention the
composition comprises a) about 0.1 to about 20% (w/w) lipase
inhibitor; b) 10 to about 75% (w/w) glucomannan such as konjac; and
optionally pharmaceutically acceptable excipients selected from the
group of about 0.1 to about 20% (w/w) fillers, about 0.1 to about
10% (w/w) surfactants, about 0.1 to about 10% (w/w) disintegrants,
about 0.1 to about 10% (w/w) binder, about 0.1 to about 10% (w/w)
lubricants, about 0.1 to about 10% (w/w) flowability enhancers,
about 0.1 to about 10% (w/w) sweeteners, and about 0.1 to about 5%
(w/w) colorants.
[0035] In more detail, the composition may contain a) from about 5
to about 1000 mg lipase inhibitor, e.g. orlistat, in an amount of
e.g. from about 10 to about 500 mg lipase inhibitor, preferably
from about 20 to about 100 mg lipase inhibitor, e.g. from about 10
to about 360 mg orlistat, more preferably from about 30 to about
120 mg orlistat, more preferably from about 40 to about 80 mg
orlistat and b) from about 0.5 to about 10 g glucomannan,
preferably from about 0.5 to about 8 g glucomannan, and more
preferably from about 0.5 to about 6 g glucomannan.
[0036] Oral dosage forms are the preferred compositions for use in
the present invention and these are the known pharmaceutical forms
for such administration, for example tablets, capsules, bars,
sachets, granules, syrups and aqueous or oily suspensions. The
pharmaceutically acceptable excipients (diluents and carriers) are
known in the pharmacist's art. Tablets may be formed from a mixture
of the active compounds with fillers, for example calcium
phosphate; disintegrating agents, for example maize starch,
lubricating agents, for example magnesium stearate; binders, for
example microcrystalline cellulose or polyvinylpyrrolidone and
other optional ingredients known in the art to permit tabletting
the mixture by known methods. Similarly, capsules, for example hard
or soft gelatin capsules, containing the active compound with or
without added excipients, may be prepared by known methods. The
contents of the capsule may be formulated using known methods so as
to give sustained release of the active compound. For example, the
tablets and capsules may conveniently each contain the amounts of
lipase inhibitor and glucomannan as described above.
[0037] Other dosage forms for oral administration include, for
example, aqueous suspensions containing the active compounds in an
aqueous medium in the presence of a non-toxic suspending agent such
as sodium carboxymethylcellulose, and oily suspensions containing
the active compounds in a suitable vegetable oil, for example
arachis oil, olive oil or myritol 318. The active compounds may be
formulated into granules with or without additional excipients. The
granules may be ingested directly by the patient or they may be
added to a suitable liquid carrier (e.g. water) before ingestion.
The granules may contain disintegrants, e.g. an effervescent pair
formed from an acid and a carbonate or bicarbonate salt to
facilitate dispersion in the liquid medium.
[0038] In the compositions of the present invention the active
compounds may, if desired, be associated with other compatible
pharmacologically active ingredients. Optionally vitamin
supplements may be administered with the compounds in accordance
with the present invention. Both compounds, the lipase inhibitor
and glucomannan, may be administered simultaneously, separately or
sequentially (e.g. orlistat as described above and glucomannan in
the evening). Preferably, the compounds or compositions are
administered during a meal or 1-2 hours before or after a meal. The
amount of glucomannan to be administered will depend on a number of
factors including the age of the patient, the severity of the
condition and the past medical history of the patient and lies
within the discretion of the administering physician.
[0039] The invention will be better understood by reference to the
following examples which illustrate but do not limit the invention
described herein.
EXAMPLES
Example 1
In Vitro Studies
[0040] Surprisingly, it has now been observed that glucomannan is
active in reducing gastro-intestinal adverse events (GI-AE)
commonly observed after administration of a lipase inhibitor such
as orlistat.
[0041] The interaction of konjac (source of glucomannan) with oil
and water was examined by an absorption test. Samples of the
compound were brought into contact with either soya oil or
simulated intestinal fluid (SIF, phosphate buffer without
pancreatin) and incubated for 24 h at 37.degree. C. Remaining
liquid was separated from the solid material by means of
centrifugation (3.times.5 min at 3100 g). Whereas in SIF
significant swelling of the polymer was observed, no swelling
occurred in soya oil. The SIF and soya oil absorption capacity of
konjac was calculated to 4.8 g/g and 0.5 g/g, respectively. The low
amount of oil binding demonstrates its poor lipophilicity.
[0042] The coalescence behavior of emulsions stabilized with konjac
was probed using a centrifugal method. With this in vitro method,
both concentration and pH-depended emulsion stabilities were
examined. The results of these stability studies are listed in
Tables 1 and 2. The use of konjac in less than 0.5% (w/w) revealed
very unstable emulsions resulting in rapid oil/water phase
separation (Table 1). Even at konjac concentrations of 1.0% (w/w),
emulsions remained rather unstable and clear phase separation was
obtained after 10 min centrifugation. Only emulsions containing
more than 1.0% (w/w) konjac exhibited after centrifugation times of
up to t=300 min medium stability with the emulsion partly broken
(FIG. 1).
1TABLE 1 Stability of konjac test emulsions at various
concentrations c and centrifugation times t. Emulsion Stability
Konjac t/min c (% w/w) 1 10 40 70 100 130 160 220 300 0.01 l* l l l
l l l l l 0.1 l l l l l l l l l 0.5 l l l l l l l l l 1.0 m m l l l
l l l l 1.5 h m m m m m m m m 2.0 h m m m m m m m m *l = low
stability: oil and water form two distinct clearly separated
phases; m = medium stability: emulsion partly broken; h = high
stability: no indications of coalescence, optically
non-transparent, stable emulsion
[0043] FIG. 1 displays test emulsions of konjac after
centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. After centrifugation times of t=300 min, only for
emulsions containing konjac in concentrations higher than 1.5%
(w/w) a weak emulsification stabilization is observed.
[0044] In order to investigate emulsion stability at different pH
values, test emulsions with a constant konjac concentration of
c=1.0% (w/w) covering a pH range of 4 to 9 were prepared (Table 2).
At both extreme pH values of 4 and 9 very poor emulsification of
the test emulsions was observed, resulting in instantaneous
layering of the oil phase. Whereas at pH=8 short centrifugation
times of less than 30 min also led to complete emulsion breaking,
emulsions at pH=5 revealed slightly higher stability. Here,
coalescence occurred at centrifugation times higher than 60 min.
The pH optimum in terms of emulsion stability was observed at
slightly acidic to neutral pH values (pH 6-7).
2TABLE 2 Stability of konjac test emulsions at various pH values
and centrifugation times t. Emulsion Stability Konjac t/min pH 1 30
60 120 300 4 l* l l l l 5 m m m l l 6 m m m m m 7 m m m m m 8 m l l
l l 9 l l l l l *l = low stability: oil and water form two distinct
clearly separated phases; m = medium stability: emulsion partly
broken; h = high stability: no indications of coalescence,
optically non-transparent, stable emulsion
[0045] FIG. 2 shows test emulsions of konjac after centrifugation
at 3100 g for t=1 min (a) and t=300 min (b), respectively. The
emulsions contained 1.0% (w/w) konjac at different pH values. After
centrifugation for t=300 min minor emulsions stabilization was
observed at pH 6 and 7, respectively. For all other emulsions
extensive coalescence was observed.
[0046] Solutions of konjac with concentrations of 0.01%, 0.1%,
0.5%, 1.0%, 1.5%, and 2.0% (w/w) in a simulated intestinal fluid
(SIF) without pancreatin according to USP XXII, p. 1789 (pH=7.5,
potassium dihydrogenphosphate buffer) were prepared. To 18 g of
such a solution 2 g of soya oil (FLUKA, 85471) was added yielding a
final oil concentration with respect to the aqueous phase of 10%
w/w. Soya oil was not purified and used as received. Emulsions were
then prepared using a Miccra homogenization apparatus at 28.000 rpm
(level E) and a homogenization time of 1 min. As a reference,
mixtures of soya oil and phosphate buffer were used without
addition of surfactant. Dying of the emulsion with nile red and
subsequent analysis under an optical microscope revealed that the
emulsions were of the oil-in-water type. Median droplet size
analysis immediately after preparation using a Galai CIS-1
apparatus yielded values of typically 20-30 .mu.m. Glass
capillaries of height ca. 95 mm and a diameter of ca. 1.7 mm (glass
thickness ca. 0.8 mm) were filled up to ca. 6.5 cm with the
pre-prepared emulsions by means of a syringe and centrifuged at a
maximum speed of 5000 rpm (Eppendorf, Centrifuge 5403, Rotor No
16A4-44) which corresponds to a centrifugal force of 3100 g (bottom
of glass capillary). In order to record the demulsification
process, the centrifugation process was interrupted at defined time
intervals (t=1, 10, 40, 70, 100, 130, 160, 220, 300 min) and the
capillaries placed on an optical scanner operating in transmission
mode (Bio-Rad GS-700 Imaging Densitometer). The distance between
the capillaries was kept constant by means of a house-made sample
holder. All measurements were conducted at room temperature.
Example 2
In Vivo Studies I
[0047] To test substances that will ameliorate the oil-related side
effects associated with orlistat treatment, an acute human model
was developed. Healthy volunteers received orlistat alone or in
combination with the test substance during 3 consecutive meals
(3-meal test). The modified orlistat formulations used in these
3-meal tests induce 70-80% fat excretion. A questionnaire was given
to the volunteers to record side effects. The most severe oil
related side effect is oily spotting (uncontrolled loss of oil).
This side effect is difficult to quantify accurately in an acute
model, however, in some volunteers a spontaneous separation of fat
from formed stool was observed. This amount of fat, called free oil
(mainly containing triglycerides) was isolated and weighted.
[0048] The amount of free oil was used as a surrogate marker for
the oily spotting as this is considered necessary for the
appearance of oily spotting.
[0049] Two clinical studies have been conducted to investigate the
gastro-intestinal adverse event modifying effects of numerous
substances. It appears that volunteers show an individual
sensitivity to the orlistat-related gastrointestinal side effects.
Therefore, each volunteer was used as his own control (treatment
with orlistat alone). Volunteers showing a weak sensitivity to
orlistat related side effects were excluded from the test
evaluation. For a given volunteer a substance is considered as
positive when the free oil quantity is reduced by at least 50%
compared to the control value (orlistat alone).
[0050] Glucomannan was tested as konjac powder. The konjac powder
is obtained from the root of a tree (Amorphophallus konjac) and
this the natural source of glucomannan. This substance was tested
in the acute side effect model at the dosage of 4 g/meal. Among the
5 tested volunteers 4 had a decrease by at least 50% of the free
oil generated without glucomannan (see table 3). Volunteers treated
with glucomannan/orlistat had no fat excretion decrease (compared
to volunteers treated with orlistat alone, data not shown)
suggesting no interaction of glucomannan with orlistat. No major
AEs associated with the glucomannan treatment has been
reported.
3TABLE 3 Konjac (Glucomannan) results Free oil production
Glucomannan (g/ week) (Konjac; 4 g/meal) orlistat orlistat + Konjac
Test 1 11 8 9 0 Test 2 39 16 17 8 40 6 Positive/total (50%
<control) 4/5
Example 3
In Vivo Studies II
[0051] The results from the in vitro experiments were further
supported by studies carried out with an in vivo mouse model. The
experiment is based on the observation that mice under a high fat
diet with orlistat or other lipase inhibitor treatment distribute
the excreted free oil over their furs while grooming. Several types
and formulations of glucomannan were examined for their ability to
reduce or eliminate the production of free oil. The results
obtained are shown in FIG. 3.
Example 4
Orlistat Pharmaceutical Compositions
[0052] A)
4 Quantity Ingredient mg/Capsule orlistat 120.00 microcrystalline
cellulose (AVICEL PH-101) 93.60 sodium starch glycolate (PRIMOJEL)
7.20 sodium lauryl sulfate 7.20 polyvinylpyrrolidone (Povidone
K-30) 12.00 talc 0.24 Total 240.24 mg
[0053] Procedure:
[0054] 1. Blend orlistat, microcrystalline cellulose, and sodium
starch glycolate in a suitable mixer.
[0055] 2. Granulate with a solution of polyvinylpyrrolidone and
sodium lauryl sulfate in purified water.
[0056] 3. Pass the granulation through an extruder and pass the
extrudate through a spheronizer to form pellets.
[0057] 4. Dry the pellets at 30.degree. C.
[0058] 5. Add talc and mix.
[0059] 6. Fill into hard gelatin capsules.
[0060] B)
5 Quantity Ingredient mg/Capsule orlistat 60 microcrystalline
cellulose 46.8 sodium starch glycolate 3.6 sodium lauryl sulfate
3.6 polyvinylpyrrolidone 6.0 talc 0.12 Total 120.12 mg
[0061] Procedure:
[0062] 1. Blend orlistat, microcrystalline cellulose, and sodium
starch glycolate in a suitable mixer.
[0063] 2. Granulate with solution of polyvinylpyrrolidone and
sodium lauryl sulfate in purified water.
[0064] 3. Pass the granulation through an extruder and pass the
extrudate through a spheronizer to form pellets.
[0065] 4. Dry the pellets at 30.degree. C.
[0066] 5. Add talc and mix.
[0067] 6. Fill into hard gelatin capsules.
[0068] C)
6 Ingredient Quantity mg/Capsule orlistat 60 120 lactose 40 80
microcrystalline cellulose 60 120 sodium lauryl sulfate 5.7 11.4
sodium starch glycolate 20 40 polyvinylpyrrolidone 10 20 talc 0.2
0.4 Total 195.9 mg 391.8 mg
[0069] Procedure:
[0070] 1. Blend orlistat, lactose, microcrystalline cellulose and
sodium starch glycolate in a suitable mixer.
[0071] 2. Granulate with a solution of polyvinylpyrrolidone and
sodium lauryl sulfate in purified water.
[0072] 3. Pass the granulation through an extruder and pass the
extrudate through a spheronizer to form pellets.
[0073] 4. Dry the pellets at 30.degree. C.
[0074] 5. Add talc and mix.
[0075] 6. Fill into hard gelatin capsules.
Example 5
Glucomannan Pharmaceutical Compositions
[0076] Composition:
7 Quantity g/Chewable Ingredient tablet glucomannan 1.5 g sorbitol
1.1 g lactose anhydrous 0.376 g talc 0.16 g sodium stearyl fumarate
0.064 g Total 3.2 g
[0077] Procedure:
[0078] 1. Blend glucomannan, sorbitol and lactose in a suitable
mixer.
[0079] 2. Pass the powder mixture through a sieve.
[0080] 3. Add talc and sodium stearyl fumarate and mix.
[0081] 4. Directly compress the powder mixture to a chewable
tablet.
Example 6
Glucomannan Pharmaceutical Compositions
[0082] Composition:
8 Ingredient Quantity g/Sachet glucomannan 4 g aspartame 0.5 g
beta-carotene 0.001 g Total 4.501 g
[0083] Procedure:
[0084] 1. Fill glucomannan in a suitable high shear mixer.
[0085] 2. Granulate with a solution/colloidal suspension of
Aspartame and beta-carotene in purified water.
[0086] 3. Dry the granules at 60.degree. C.
[0087] 4. Pass the dry granulation through a sieve.
[0088] 5. Fill into sachets.
Example 7
Glucomannan Pharmaceutical Compositions
[0089] Composition:
9 Quantity g/Chewable Ingredient tablet glucomannan 0.5 g lactose
0.5 g microcrystalline cellulose 1.31 g sodium lauryl sulfate 0.09
g sodium starch glycolate 0.3 g polivinylpyrrolidone 0.15 g talc
0.15 g Total 3.0 g
[0090] Procedure:
[0091] 1. Blend glucomannan, lactose, microcrystalline cellulose,
sodium starch glycolate in a suitable mixer.
[0092] 2. Dissolve sodium lauryl sulfate and polivinyl pyrrolidone
in purified water.
[0093] 3. Granulate with the liquid.
[0094] 4. Pass the granulation through an extruder and pass the
extrudate through a spheronizer to form round pellets.
[0095] 5. Dry the pellets at 65.degree. C.
[0096] 6. Add talc and mix
[0097] 7. Compress the pellets to a chewable tablet.
Example 8
Orlistat/Glucomannan Pharmaceutical Compositions
[0098] Composition:
10 Quantity g/Chewable Ingredient tablet orlistat 0.06 g
glucomannan 0.75 g lactose 0.5 g microcrystalline cellulose 1.31 g
sodium lauryl sulfate 0.09 g sodium starch glycolate 0.3 g
polivinylpyrrolidone 0.15 g talc 0.15 g Total 3.31 g
[0099] Procedure:
[0100] 1. Blend orlistat, glucomannan, lactose, microcrystalline
cellulose, sodium starch glycolate in a suitable mixer.
[0101] 2. Dissolve sodium lauryl sulfate and polivinyl pyrrolidone
in purified water.
[0102] 3. Granulate with the liquid.
[0103] 4. Pass the granulation through an extruder and pass the
extrudate through a spheronizer to form round pellets.
[0104] 5. Dry the pellets at maximum 35.degree. C.
[0105] 6. Add talc and mix
[0106] 7. Compress the pellets to a chewable tablet.
Example 9
Orlistat/Glucomannan Pharmaceutical Compositions
[0107] Composition:
11 Ingredient Quantity g/Sachet orlistat 0.12 g glucomannan 4 g
saccharose 2.8 g beta-carotene 0.001 g silicium dioxide 0.5 g Total
7.421 g
[0108] Procedure:
[0109] 1. Blend orlistat, glucomannan, sachharose in a suitable
mixer.
[0110] 2. Mix in several portion with the mixture of beta-carotene
and silicium dioxide.
[0111] 3. Fill into sachets.
Example 10
Orlistat/Glucomannan Pharmaceutical Compositions
[0112] Composition:
12 Quantity g/Chewable Ingredient tablet orlistat 0.12 g
glucomannan 2.0 g sodium starch glycolate 0.1 g microcrystalline
cellulose 0.2 g sodium lauryl sulfate 0.03 g crospovidone 0.1 g
aspartame 0.15 g talc 0.15 g magnesium stearate 0.03 g Total 2.85
g
[0113] Procedure:
[0114] 1. Blend orlistat, glucomannan, microcrystalline cellulose,
sodium starch glycolate and crospovidone in a suitable mixer.
[0115] 2. Granulate with a solution/colloidal suspension of sodium
lauryl sulfate and aspartame in purified water.
[0116] 3. Pass the granulate through a sieve.
[0117] 4. Dry the granules at 30.degree. C.
[0118] 5. Pass the dry granules through a sieve.
[0119] 6. Mix with talc and magnesium stearate.
[0120] 7. Compress to chewable tablet.
* * * * *