U.S. patent application number 10/154494 was filed with the patent office on 2003-02-06 for lipase inhibiting composition.
Invention is credited to Maeder, Karsten, Martin, Rainer Eugen, Raab, Susanne, Scheibler, Lukas Christoph, Schindler, Thomas, Schroeder, Marco.
Application Number | 20030027786 10/154494 |
Document ID | / |
Family ID | 8177654 |
Filed Date | 2003-02-06 |
United States Patent
Application |
20030027786 |
Kind Code |
A1 |
Maeder, Karsten ; et
al. |
February 6, 2003 |
Lipase inhibiting composition
Abstract
Pharmaceutical compositions that contain a lipase inhibitor
having a melting point .gtoreq.37.degree. C., a sucrose fatty acid
ester wherein the sucrose fatty acid ester is a mono-, di-, tri- or
tetra-ester, and optionally one or more pharmaceutically acceptable
excipients, are useful for treatment of obesity.
Inventors: |
Maeder, Karsten; (Freiburg,
DE) ; Martin, Rainer Eugen; (Grenzach-Wyhlen, DE)
; Raab, Susanne; (Leinfelden-Echterdingen, DE) ;
Scheibler, Lukas Christoph; (Augst, CH) ; Schindler,
Thomas; (Loerrach, DE) ; Schroeder, Marco;
(Schopfheim, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8177654 |
Appl. No.: |
10/154494 |
Filed: |
May 23, 2002 |
Current U.S.
Class: |
514/53 ;
514/449 |
Current CPC
Class: |
A61K 47/26 20130101;
A61K 9/0056 20130101; A61P 3/00 20180101; A61P 43/00 20180101; A61P
3/10 20180101; A61P 3/06 20180101; A61K 31/365 20130101; A61P 3/04
20180101 |
Class at
Publication: |
514/53 ;
514/449 |
International
Class: |
A61K 031/335; A61K
031/7016 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 6, 2001 |
EP |
01113793.2 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising a lipase inhibitor
having a melting point .gtoreq.37.degree. C., a sucrose fatty acid
ester wherein the sucrose fatty acid ester is a mono-, di-, tri- or
tetra-ester, and one or more pharmaceutically acceptable
excipients.
2. The composition of claim 1, wherein the ester is a mono-, di-,
or tri-ester.
3. The composition according to claim 2, wherein the ester is a
mono- or di-ester.
4. The composition according to claim 3, wherein the ester is a
mono-ester.
5. The composition according to claim 1, wherein the fatty acid
moieties in the ester are identical.
6. The composition according to claim 1, wherein 0.05 mg to 20 mg
sucrose fatty acid ester is used per 1 mg lipase inhibitor.
7. The composition according to claim 6, wherein 0.1 mg to 10 mg
sucrose fatty acid ester is used per 1 mg lipase inhibitor.
8. The composition according to claim 7, wherein 0.1 to 2 mg
sucrose fatty acid ester is used per 1 mg lipase inhibitor.
9. The composition according to claim 8, wherein 0.15 to 1 mg
sucrose fatty acid ester is used per 1 mg lipase inhibitor.
10. The composition according to claim 1, wherein the lipase
inhibitor is a lipophilic compound.
11. The composition according to 10, wherein the lipase inhibitor
is orlistat.
12. The composition according to claim 1, wherein the fatty acid
moiety of the sucrose fatty acid ester is a C.sub.8 to C.sub.24
saturated or partially non-saturated fatty acid.
13. The composition according to claim 12, wherein the fatty acid
moiety of the sucrose fatty acid ester is a C.sub.12 to C.sub.18
saturated fatty acid.
14. The composition according to claim 13, wherein the fatty acid
ester is selected from the group consisting of sucroselaurate,
sucrosemyristate, sucrosepalmitate, sucrosestearate,
sucrosearachidonate and sucrosebehanate.
15. The composition according to claim 14, wherein the fatty acid
ester is selected from the group consisting of sucroselaurate,
sucrosemyristate, sucrosepalmitate, sucrosestearate.
16. The composition according to claim 15, wherein the fatty acid
ester is sucrosepalmitate.
17. The composition according to claim 15, wherein the fatty acid
ester is sucrosestearate.
18. The composition according to claim 12, wherein the fatty acid
moiety of the sucrose fatty acid ester is a C.sub.12 to C.sub.18
mono- or polyunsaturated fatty acid.
19. The composition of claim 18, wherein the fatty acid moiety is
selected from the group consisting of palmitoleic acid, oleic acid,
elaidic acid, erucic acid, linoleic acid, gamma-linolenic acid,
alpha-linolenic acid and arachidonic acid.
20. The composition of claim 19, wherein the sucrose fatty acid
ester is sucroseoleate.
21. The composition according to claim 1, wherein the fatty acid
moieties in a di-, tri- and tetra-sucrose fatty acid ester is a
mixture of two or more fatty acids.
22. The composition of claim 21, wherein the sucrose fatty acid
ester is sucrosepalmitostearate.
23. The composition according to claim 11, wherein the composition
comprises 10 to 240 mg orlistat.
24. The composition according to claim 23, wherein the composition
comprises 30 to 120 mg orlistat.
25. The composition according to claim 24, wherein the composition
comprises 30, 40, 60, 80, 100, or 120 mg orlistat.
26. The composition according to claim 11, wherein the composition
comprises 60 to 120 mg orlistat and 20 mg to 100 mg sucrose fatty
acid ester.
27. The composition according to claim 26, wherein the composition
comprises 120 mg orlistat and 30 mg sucrose ester.
28. The composition according to claim 26, wherein the composition
comprises 80 to 120 mg orlistat and 10 to 40 mg sucrose fatty acid
ester.
29. The composition according to claim 11, wherein the composition
comprises 20 to 60 mg orlistat and 5 to 15 mg sucrose fatty acid
ester.
30. The composition according to claim 1, wherein the composition
comprises one or more pharmaceutically acceptable excipients
selected from the group consisting of mannitol, lactose, HPMC,
talcum, sorbitol, polyvinylpyrrolidone, lecithin,
polyethylenglycol, polysorbate, polyoxethylenstearate, and
dimethicon.
31. The composition according to claim 30, wherein the
pharmceutically acceptable excipient comprises lactose.
32. The composition according to claim 11, wherein the composition
comprises 10-240 mg orlistat and 0.5-1000 mg sucrose fatty acid
ester.
33. The composition of claim 32, wherein the composition comprises
one or more excipients selected from the group consisting of
maltodextrin, lactose and cellulose.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field
[0002] The present invention relates to lipase inhibiting
compositions having reduced food dependency and decreased formation
of free oil.
[0003] 2. Description
[0004] Lipase inhibitors are well known in the art and include
lipstatin and orlistat. The latter is also known as
tetrahydrolipstatin or THL and is derived from a natural product
excreted by Streptomyces toxytricini. This class of compounds was
found to exhibit in vitro as well as in vivo activity against
various lipases, such as lingual lipase, pancreatic lipase, gastric
lipase, and carboxylester lipase. Its use for the control or
prevention of obesity and hyperlipidemia is described, for
instance, in U.S. Pat. No. 4,598,089.
[0005] Orlistat is currently administered at doses of 120 mg per
meal and dosing is independent of the body mass of the human
subject. Orlistat acts locally in the gastrointestinal ("GI") tract
and prevents lipase from digesting triglycerides and thus inhibits
the formation of absorbable lipid degradation products. For this
reason, systemic availability of the lipase inhibitors is not
required and, instead, local residence in the GI tract is the
preferred mode of delivery.
[0006] Lipase inhibitor compositions currently administered inhibit
around 30% of fat absorption after consumption of a mixed meal;
increasing the concentrations of lipase inhibitors in the
pharmaceutical composition does not increase its clinical efficacy
and/or potency while the intensity of local side effects
increases.
[0007] Anal leakage of oil (oily spotting) is an adverse effect,
which is occasionally observed by patients treated with lipase
inhibitors. This phenomenon reflects physical separation of some
liquid unabsorbed dietary fat from the bulk of solids in the lower
large intestine.
[0008] U.S. Pat. No. 5,447,953 discloses that by combining a lipase
inhibitor with substantial amounts of water insoluble crude fibers,
the inhibiting effect on fat absorption can be increased. Patent
publication WO 00/09123 discloses 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 reduced.
[0009] International Patent Application WO 01/19378 discloses solid
lipid formulations for lipase inhibitors useful to reduce or
prevent fat excretion and unwanted formation of free oil. It has
been found that a higher efficacy (high fat excretion) can be
combined with a lowering of unwanted side effects, e.g. free oil.
Recently it has been recognized that the efficacy of lipase
inhibitors may depend strongly on the kind of the ingested food. A
high efficacy have been found with meals composed of French fries,
sausages and hamburgers, while lower efficacy was observed for
cheese and other dairy products. Strong food dependency of the
formulation efficacy is an unwanted phenomena, because either the
formulation is overdosed in susceptible diets (with the consequence
of free oil formation) or not active in less susceptible diets.
Therefore, the decrease of the food dependency is a prerequisite to
realize scenarios with a low dosage of the inhibitor, a high
efficacy and less fewer side effects.
[0010] Surprisingly, the subject inventors discovered that a
certain sucrose fatty acid ester subgroup can increase the
activities of lipase inhibitors, decrease the food dependency and
decreasing the formation of free oil.
SUMMARY OF THE INVENTION
[0011] The subject invention provides a pharmaceutical composition
comprising a lipase inhibitor having a melting point
.gtoreq.37.degree. C., a sucrose fatty acid ester wherein the
sucrose fatty acid ester is a mono-, di-, tri- or tetra-ester, and
one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE FIGURES
[0012] FIG. 1 is a bar graph that indicates that the sucrose ester
based formulations show an approximate 1.7 times higher efficacy
240 mg SUCROSEESTER P1670: 67.4 (.+-.5.3%, n=5), 30 mg SUCROSEESTER
P1670 66.6 (.+-.13%, n=4) compared to Xenical 39.7 (.+-.8.1%, n=5)
in a double meal test on human volunteers.
[0013] FIG. 2 is a bar graph that indicates the efficacy of Xenical
in the less accessible meal was only 48.4% compared to the
accessible, while the sucrose ester formulation 30 MG SUCROSEESTER
P1670 reached 73.9% (double meal test in human volunteers).
[0014] FIG. 3 displays test emulsions of Surfhope SE Pharma D-1811
after centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. The emulsion containing 2.0% (w/w) sucrose ester
remains even after a centrifugation time of t=300 min stable
(picture (b), right capillary). From left to right: reference
(mixture soy oil/buffer); c=0.01%, c=0.1%; c=0.5%; c=1.0%; c=1.5%;
c=2.0% (w/w).
[0015] FIG. 4 shows test emulsions of Surfhope SE Pharma D-1811
after centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. The emulsions are stabilized with 1.0% (w/w) sucrose
ester at different pH values. Whereas emulsions at pH.ltoreq.7
clearly show phase separation after centrifugation for t=300 min,
emulsions at pH>7 noticeably revealed less free oil.
[0016] FIG. 5 is a bar graph demonstrating the ability of certain
sucrose esters to reduce production of free oil.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The subject invention will now be described in terms of its
preferred embodiments. These embodiments are set forth to aid in
understanding the subject invention but are not to be construed as
limiting.
[0018] The present invention relates to a pharmaceutical
composition comprising a lipase inhibitor, preferably orlistat,
having a melting point .gtoreq.37.degree. C., a sucrose fatty acid
ester wherein the sucrose fatty acid ester is a mono-, di-, tri- or
tetra-ester, and optionally one or more pharmaceutically acceptable
excipients.
[0019] Sucrose fatty acid esters are nonionic surfactants
consisting of sucrose as hydrophilic moiety and one or more fatty
acid moieties as lipophilic group(s). They are manufactured from
purified sugar and vegetable oils. As sucrose has a total of 8
hydroxyl groups, compounds ranging from sucrose mono to octa fatty
acid esters can be produced. The following formula shows as an
example the chemical structure of sucrose monostearate: 1
[0020] The term "sucrose fatty acid ester" comprises one single
sucrose fatty acid ester as well as a mixture of two or more
sucrose ester fatty acids as defined below. In a preferred
embodiment of the present invention the substitution degree of
sucrose ester varies between 1 and 4; e.g. mono-, di-, tri-,
tetra-ester of fatty acids with sucrose. The term includes pure
sucroseesters as well as mixtures of sucroseesters, wherein the
sucroseester might be esterified by different fatty acids and might
have several substitution degrees, e.g. mono-, di-, tri- or
tetra-substituted.
[0021] Sucrose fatty acid ester and mixtures thereof and there
preparation are known in the art and commercially available
[Mitsubishi-Kagaku Foods Corp., Montello Inc., Multi-Kem Corp.,
etc.; see also Garti et al., Sucrose Ester Microemulsions. J. Mol.
Liq., 80(2,3), 253-296 (1999); and Allen et al., Carbohydrate-Alkyl
Ester Derivatives as Biosurfactants, J. Surfactants Deterg., 2(3),
383-390 (1999)].
[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 compounds 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 synthetic 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. In addition,
the term "lipase inhibitor" also refers to
2-oxy-4H-3,1-benzoxazin-4-ones which have been described in
International Patent Application WO00/40569 (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, WO01/32669 and WO 01/32670. Most
preferably, the term "lipase inhibitor" refers to orlistat.
[0023] In German Patent DE 1965133 (Merck) some poly(styrene)
derived polymers are described which exhibit direct lipase
inhibition next to bile acid and triglyceride binding
properties.
[0024] Orlistat is a known compound (formula I) useful for the
control or prevention of obesity and hyperlipidemia. 2
[0025] 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, WO
00/09123, WO 01/19340 and WO 01/19378. Additional processes for the
preparation of orlistat are disclosed in European Patent
Applications Publication Nos. 185,359, 189,577, 443,449, and
524,495.
[0026] In a preferred embodiment of the present invention, the
sucroseester molecules are mono-, di- or tri-ester. More
preferably, the sucrose ester molecules are a mono- or di-ester and
most preferably the sucrose ester are a mono-ester.
[0027] In a di-, tri or tetra-ester the fatty acid moieties may be
identical or different (e.g. sucrosepalmitostearate), preferably
identical.
[0028] The preferred ratio (w/w) between the lipase inhibitor and
the sucrose fatty acid ester is as follows: The composition may
comprise 0.05 mg to 20 mg sucrose fatty acid ester per 1 mg lipase
inhibitor, preferably 0.1 mg to 10 mg sucrose fatty acid ester per
1 mg lipase inhibitor, more preferably 0.1 to 2 mg sucrose fatty
acid ester per 1 mg lipase inhibitor and most preferably 0.15 to 1
mg sucrose fatty acid ester per 1 mg lipase inhibitor.
[0029] Preferably, the lipase inhibitor is a lipophilic compound.
Most preferably, the lipase inhibitor is orlistat.
[0030] In a further preferred embodiment of the present invention,
the fatty acid moiety of the sucrose fatty acid ester is a C.sub.8
to C.sub.24 saturated or partially non-saturated fatty acid.
Preferably, the fatty acid moiety of the sucrose fatty acid ester
is a C.sub.12 to C.sub.18 saturated fatty acid, e.g.
sucroselaurate, sucrosemyristate, sucrosepalmitate,
sucrosestearate, sucrosearachidonate and sucrosebehanate,
preferably sucroselaurate, sucrosemyristate, sucrosepalmitate,
sucrosestearate, more preferably sucrosepalmitate or
sucrosestearate. In a further preferred embodiment of the invention
the fatty acid of the sucrose ester may be selected from C.sub.8 to
C.sub.24, preferably a C.sub.12 to C.sub.18, mono- or
polyunsaturated fatty acids, e.g. selected from the group
consisting of palmitoleic acid, oleic acid, elaidic acid, erucic
acid, linoleic acid, gamma-linolenic acid, alpha-linolenic acid and
arachidonic acid, most preferably oleic acid, i.e. sucrose fatty
acid esters may be sucroseoleate.
[0031] The fatty acid moieties in a di-, tri-, or tetra-sucrose
fatty acid ester may be a mixture of two or more fatty acid, e.g.
sucrosepalmitostearate.
[0032] For lipase inhibitors as described above, e.g. orlistat,
preferred compositions comprise 10 to 240 mg, more preferably 30 to
120 mg, e.g. 30, 40, 60, 80, 100, or 120 g. Especially preferred
compositions comprise 60 to 120 mg orlistat and 20 mg to 100 mg
sucrose fatty acid ester.
[0033] For example a composition as defined above may comprise 120
mg orlistat and 60 mg sucrose ester or 120 mg orlistat and 30 mg
sucrose fatty acid ester. Another composition may comprise 80 to
120 mg orlistat and 10 to 40 mg sucrose fatty acid ester or 20 to
60 mg orlistat and 5 to 15 mg sucrose fatty acid ester.
[0034] Each dosage unit of the above pharmaceutical compositions
can obtain the daily doses of the pharmaceutically active compound
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. Orlistat is preferably orally administered from
30 to 800 mg per day in divided doses two to three times per day
(see above). Other preferred daily doses may range between 120 to
360 mg, more preferred are daily doses between 180 to 270 mg and
most preferably are 180 mg. Daily doses are, preferably divided and
administrated twice or, particularly, three times per day.
Generally, it is preferred that the lipase inhibitor has to be
administered within about one or two hours of ingestion of a meal
containing fat. Generally, for administering a lipase inhibitor as
defined above it is preferred that treatment be administered to a
human who has a strong family history of obesity or has obtained a
body mass index of 25 or greater.
[0035] The compositions of the present invention may be
administered to humans in conventional oral compositions, such as,
tablets, coated tablets, hard and soft gelatin capsules, emulsions,
suspensions, sachets, bars or cracker. Examples of carriers which
can be used for tablets, coated tablets, drages, hard gelatin
capsules and sachets are pharmaceutically acceptable excipients
like lactose, other sugars and sugar alcohols like sorbitol,
mannitol, maltodextrin, or other fillers; surfactants like sodium
lauryl sulfate, Brij 96, Tween 80; disintegrants like sodium starch
glycolate, maize starch or derivatives thereof; polymers like
povidone, crospovidone; lubricants like talc; stearic acid or its
salts and the like. Moreover, the pharmaceutical preparations can
contain preserving agents, solubilizers, stabilizing agents,
wetting agents, binding 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.
[0036] Especially, the above compositions may comprise one or more
pharmaceutically acceptable excipients selected from the group
consisting of mannitol, lactose, HPMC, lecthin, talcum, sorbitol,
polyvinylpyrrolidone, polyethylenglycol, polysorbate,
polyoxethylenstearate, and dimethicon, preferably lactose.
[0037] 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 or sachets.
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 a
pharmaceutically active compound and a sucrose ester as described
above.
[0038] The term "pharmaceutically acceptable" as used herein means
that the corresponding compounds are acceptable from a toxicity
viewpoint.
[0039] The oral dosage form may be a chewable tablet comprising
10-240 mg of orlistat, 0.5-1000 mg of sucrose fatty acid ester and
further excipients such as maltodextrin, lactose or cellulose, for
example 120 mg orlistat, 30 mg sucrosepalmitate e.g.
Sucrosepalmitate P1670, 960 mg maltodextrin, 360 mg Cellactose and
15 mg talcum.
[0040] 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 of the present
invention.
[0041] The invention also refers to a process for preparing a
composition as described above, comprising mixing a
pharmaceutically active compound thereof with sucrose fatty acid
ester and one or more pharmaceutically acceptable diluents and/or
carriers.
[0042] The invention also provides the use of the above combination
of compounds in the manufacture of a medicament for the treatment
and prevention of obesity. Additionally, it provides the above
compositions for use in the treatment and prevention of
obesity.
[0043] In addition, the present invention refers to a method of
treatment of obesity in a human in need of such treatment which
comprises administration to the human of a pharmaceutically active
compound as defined above and a sucrose fatty acid ester, and
optionally additional pharmaceutical acceptable excipients.
[0044] The invention also refers to the use of a composition as
defined above for use in the treatment and prevention of
obesity.
[0045] Another embodiment of the present invention refers to a
process for preparing a composition as defined above, comprising
mixing a pharmaceutically active compound as defined in claim 1
with sucrose ester, and optionally, more pharmaceutically
acceptable diluent and/or carrier.
[0046] Further the invention refers to a kit for treatment of
obesity, said kit comprising a first component which is a lipase
inhibitor and a second component which is sucrose fatty acid ester
unit dosage forms.
[0047] Another embodiment 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 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 sucrose ester defined above. The
invention also refers to a lipase inhibitor and sucrose ester as
defined above for the treatment and prevention of obesity.
[0048] The invention will be better understood by reference to the
following examples which illustrate but do not limit the invention
described herein.
EXAMPLES
[0049] All compounds used in the examples are commercially
available.
1EXAMPLE 1 Orlistat transfer into oil in vitro Transfer in Cream
(%) Transfer in Oliveoil (%) Formulation after 10' after 60' after
10' after 60' Xenical 5 10 35 70 L-1695 55 65 55 80 P-1670 25 45 50
80 S-1670 10 25 60 90 O-1570 55 65 45 80
[0050] Orlistat (4 mg) suspensions stabilized by sucroseesters (2
mg) were transferred into 5 ml of a 10% oil in water emulsion (pH
value 4.5; oil components: olive oil and cream respectively). The
dispersion underwent end-over end mixing for a desired period of
time. The oil phase was separated by cold centrifugation and the
orlistat content in the oil phase was determined by HPLC. For
comparison, an adequate experiment was also performed with a
suspension of XENICAL.RTM. brand of orlistat-containing
pharmaceutical composition. L-1695, P-1670, S-1670, 0-1570 are
commercial sucroseesters (Sucroselaurate, Sucrosepalmitate,
Sucrosestearate, Sucroseoleate respectively) from Mitsubishi-Kagaku
Foods, Japan.
[0051] The results indicate that the sucroseester have a higher
efficacy of the transfer orlistat transfer into oil compared to
XENICAL.RTM.. In addition to a general higher transfer efficacy and
in contrast to XENICAL.RTM., orlistat is transferred into different
kind of oils (cream: emulsified and casein covered oily droplets;
olive oil: unprotected oil) at more comparable rates. The high food
dependency of orlistat is reflected in the fact, that the transfer
after 10 min into olive oil is 7 times more efficient than the
transfer into cream. The sucrose ester show less food dependency.
Therefore, a dose reduction and decreased side effects can be
expected.
Example 2
Tablet Formulation
[0052] Chewable tablets of the following composition were made:
2 Composition 1 Orlistat 120 g Sucrosepalmitate P1670 30 g
Maltodextrin 960 g Cellactose 360 g Talcum 15 g
[0053] Orlistat, sucrosepalmitate and maltodextrin were
homogeneously mixed and 350 g water were added stepwise under
continuous mixing.
[0054] With the help of a syringe the homogeneous dispersion were
spread on a sieve (mesh size 0.5 mm) in tracks. The sieve was put
into a vacuum drying oven (Heraeus VT 5050 EK) which was tempered
to 25.degree. C. Chamber pressure was lowered to 30 Torr (Leybold
Heraeus TRIVAC D8B; COMAT AG DPI 700). After 5 minutes, the
development of a foam structure was completed. The foam was dried
in vacuum for several hours. Care was taken to control that the
temperature of the foam did not exceed 35.degree. C. The resulting
foam was desintegrated and sieved in order to achieve a homogenous
flowable powder. Cellactose and talcum were added and homogeneously
distributed by dry mixing. The resulting composition was tableted
into tablets containing Orlistat 120 mg, Sucrosepalmitate 30 mg,
Maltodextrin 960 mg, Cellactose 360 mg, and Talcum 15 mg.
Example 3
Chewable Tablet Formulation
[0055] Chewable tablets of the following composition were made:
3 Composition 2 Orlistat 120 g Sucrosepalmitate P1670 240 g
Maltodextrin 750 g Cellactose 375 g Talcum 15 g
[0056] The tablets were made by the same procedure as described in
Example 2.
Example 4
Chewable Tablet Formulation
[0057] Chewable tablets of the following composition were made:
4 Composition 3 Orlistat 60 g Sucrosepalmitate P1670 60 g
Maltodextrin 750 g Cellactose 375 g Talcum 15 g
[0058] The tablets were made by the same procedure as described in
Example 2.
Example 5
Chewable Tablet Formulation
[0059] Chewable tablets of the following composition were made:
5 Composition 4 Orlistat 60 g Sucrosestearate S1811 60 g
Maltodextrin 750 g Cellactose 375 g Talcum 15 g
[0060] The tablets were made by the same procedure as described in
Example 2.
Example 6
Chewable Tablet Formulation
[0061] Chewable tablets of the following composition were made:
6 Composition 5 Orlistat 60 g Sucrosemyristate M1695 60 g
Maltodextrin 750 g Cellactose 375 g Talcum 15 g
[0062] The tablets were made by the same procedure as described in
Example 2.
Example 7
Chewable Tablet Formulation
[0063] Chewable tablets of the following composition were made:
7 Composition 6 Orlistat 60 g Sucrosestearate S1816 60 g
Maltodextrin 750 g Cellactose 375 g Talcum 15 g
[0064] The tablets were made by the same procedure as described in
Example 2.
Example 8
Pellet Formulation
[0065]
8 Composition 7 Orlistat 240 g Sucrosepalmitate P1670 60 g Avicel
PH-105 35 g Sodium starch glycolate 60 g Povidone K30 30 g
[0066] The ingredients are dry mixed together in a high speed mixer
Diosna P50). 240 g water are added stepwise and the mixing process
is continued for about 5 minutes. An extruder is fed with this
material (NICA lab E-140; screen 0.8 mm mesh size, thickness 1.0
mm, screen surrounded by cooling device). The material is extruded
to spaghettis of appropriate length. The temperature of the
extrudate does not exceed 35.degree. C. The extrudate is
transferred to a spheronizer ((NICA lab S320) and spheronized for
0.5 to 3 minutes at 700 rpm. The wet pellets are dried in a
fluidized bed dryer (Aeromatic, MP-1) at a temperature of below
35.degree. C. The dried pellets are sieved with sieve inserts of
0.5 and 1.25 mm mesh size, and under- and oversize fractions are
discarded. The pellets are filled into a sachet at doses of 106 mg
(corresponding to 60 mg orlistat).
Example 9
Capsule Formulation
[0067] The above pellets are filled into Gelatin capsules size I at
a dosage of 106 mg (corresponding to 60 mg orlistat).
Example 10
Tablet Formulation
[0068] Magnesium stearate is added to the pellets described in
Example 8 at a level of 1% (w/w) and homogeneously distributed by
appropriate mixing. The mixture is compressed into 107 mg tablets
which correspond to 60 mg orlistat.
Example 11
In vitro Efficacy
[0069] Table: Reduced food-dependent efficacy of sucrose ester
based orlistat formulations in an in vitro lipase inhibition assay
with accessible and resistant fat. Xenical.RTM. pellets and Tablets
from Example 2 and Example 3 were investigated. Water was added to
a dispersed tablet to yield a orlistat concentration of 6.64 mg/ml.
The sample was stirred for 15 min and a geometric dilution series
was prepared. An aliquot from each dilution step was mixed with
substrate and assessed for lipase inhibition. The final emulsion
contained 2.5% (w/v) fat and 10 mg/ml USP pancreatin.
9 Hamburger/ French fries Cream IC.sub.50,Cream IC.sub.50
(.mu.g/ml) IC.sub.50 (.mu.g/ml) IC.sub.50,Hamb. Xenical-Dispersion
2.5 46 5% Dispersion from 2.8 9.0 31% Example 2 (30 mg
Sucrosepalmitate) Dispersion from 1.9 5.5 34% Example 3 (240 mg
Sucrosepalmitate)
[0070] The in vitro lipase test mimics the gastro-intestinal fat
digestion and assesses formulation dependent inhibition of
lipolysis. In this test lipase substrate (cream and grained
hamburger/ french fries, representing resistant and accessible fat,
respectively) is preincubated with a THL-formulation under
simulated gastric conditions (i.e. at pH 4.5 in the presence of 20%
human gastric fluid). During this preincubation, the formulation
can load fat droplets with THL. Lipolysis is then started by adding
artificial intestinal fluid, containing bile salts, phospholipids
and hydrolytic enzymes (pancreatin). After one hour organic solvent
is added to stop the reaction and free fatty acids are quantified.
The dose-response curve is dependent on the formulation as well as
on the type of substrate employed.
[0071] The IC50 value is the concentration which inhibits
triglyceride cleavage by 50%. A high food dependency was observed
for Xenical, the IC50 increased by a factor of 20. The in vitro
food dependency of the sucrose ester based formulations was about
6-times less compared to Xenical.RTM..
Example 12
Efficacy in vivo
[0072] The 120 mg Orlistat tablet formulations described in Example
2 (30 mg Sucrosepalmitate) and Example 3 (240 mg Sucrosepalmitate),
and Xenical.RTM. were tested on human volunteers by means of a
double-meal test, which is composed of accessible fat (Lunch:
Hamburger, French fries and a less accessible fat (Dinner: cheese
meal). The nonabsorbed fat was determined after Bligh & Dyer
[Bligh et al., Can. J. Biochem.Physiol., 37:911(1959)].
[0073] The results indicate (FIG. 1) that the sucrose ester based
formulations show an approximate 1.7 times higher efficacy
formulation with 240 mg SUCROSEESTER P1670: 67.4 (.+-.5.3%, n=5),
formulation with 30 mg SUCROSEESTER P1670 66.6 (.+-.13%, n=4)
compared to Xenical.RTM. 39.7 (.+-.8.1%, n=5).
Example 13
Food Dependency in vivo
[0074] Fatty acid specific analysis of stool permits selective
determination of fat uptake of the lunch and dinner meal
respectively. The results indicate (FIG. 2) that the efficacy of
Xenical.RTM. in the less accessible meal was only 48.4% compared to
the accessible, while the sucrose ester formulation 30 mg
SUCROSEESTER P1670 reached 73.9%. It can be concluded from these
data that the food dependency of orlistat can be substantially
minimized by sucrose ester based formulations.
Example 14
Side Effect in vitro Studies
[0075] Among various other strategies to control anal leakage, the
generation of stable dietary fat emulsion in the colon is of high
importance. Therefore, the emulsification properties of sucrose
esters covering a wide range of hydrophile-lipophile-balance (HLB)
values were investigated using a centrifugal method. This in vitro
method allowed both concentration and pH-depended emulsion
stabilities to examine and thus to select the sucrose esters of
highest potential to control side-effects. The results of the
concentration depended emulsion stability studies are listed in
Tables 1-3.
[0076] Table 1. Stability of Surfhope SE Pharma D-1815 test
emulsions at various concentrations c and centrifugation times
t.
10TABLE 1 Stability of Surfhope SE Pharma D-1815 test emulsions at
various concentrations c and centrifugation times t. Emulsion
Stability Surfhope SE Pharma D-1815 t/min c (% w/w) 10 70 100 160
220 300 0.01 low* low low low low low 0.1 high medium medium medium
medium medium 0.5 high medium medium medium medium medium 1.0 high
medium medium medium medium medium 1.5 high medium medium medium
medium medium 2.0 high medium medium medium medium medium *low: oil
and water form two distinct clearly separated phases; medium:
emulsion partly broken; high: no indications of coalescence,
optically non-transparent, stable emulsion
[0077]
11TABLE 2 Stability of Surfhope SE Pharma D-1811 test emulsions at
various concentrations c and centrifugation times t. Emulsion
Stability Surfhope SE Pharma D-1811 t/min c (% w/w) 10 70 100 160
220 300 0.01 low* low low low low low 0.1 high high medium medium
medium medium 0.5 high high medium medium medium medium 1.0 high
high high medium medium medium 1.5 high high high medium medium
medium 2.0 high high high high high high *low: oil and water form
two distinct clearly separated phases; medium: emulsion partly
broken; high: no indications of coalescence, optically
non-transparent, stable emulsion
[0078]
12TABLE 3 Stability of Surfhope SE Pharma D-1805 test emulsions at
various concentrations c and centrifugation times t. Emulsion
Stability Surfhope SE Pharma D-1805 t/min c (% w/w) 10 70 100 160
220 300 0.01 low* low low low low low 0.1 low low low low low low
0.5 medium medium medium medium medium medium 1.0 medium medium
medium medium medium medium 1.5 high medium medium medium medium
medium 2.0 high high high medium medium medium *low: oil and water
form two distinct clearly separated phases; medium: emulsion partly
broken; high: no indications of coalescence, optically
non-transparent, stable emulsion
[0079] Sucrose esters such as Surfhope SE Pharma D-1811 (Table 2)
with a medium HLB value of 11 proofed to be slightly superior in
their ability to stabilize an emulsion with respect to Surfhope SE
Pharma D-1815 (Table 1) and Surfhope SE Pharma D-1805 (Table 3),
respectively. At concentrations of 2.0% (w/w) Surfhope SE Pharma
D-1811 revealed stable emulsions without any visual signs of
coalescence at centrifugation times up to t=300 min (FIG. 1). Both,
Surfhope SE Pharma D-1815 and Surfhope SE Pharma D-1805 showed only
slightly less stable emulsion stabilities. In addition,
measurements with similarly prepared emulsions stored at room
temperature for 1 week without applying any centrifugal force
revealed that the conditions generated in the centrifugation
experiment correlates to a normal standing period of about 2-3
days, which compares well to the average GI transit time in
humans.
[0080] FIG. 3 displays test emulsions of Surfhope SE Pharma D-1811
after centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. The emulsion containing 2.0% (w/w) sucrose ester
remains even after a centrifugation time of t=300 min stable
(picture (b), right capillary). From left to right: reference
(mixture soy oil/buffer); c=0.01%, c=0.1%; c=0.5%; c=1.0%; c=1.5%;
c=2.0% (w/w).
[0081] Similar emulsion stability tests were conducted using
combinations of sucrose esters and hydrocolloids (e.g., xanthan
gum, gellan gum, carrageenan gum), sphingomyelin, aerosil
derivatives, calcium carboxymethylcellulose, chitosan, bentonites,
whey protein concentrates, pectins, and poly(vinyl alcohol).
Interestingly, these studies showed that 1:1 combinations (w/w) of
Surfhope SE Pharma D-1815 and Aerosil 200, carrageenan gum, and
whey protein concentrates gave emulsions with clearly better
stability than the single compounds alone, due to a yet unknown
synergistic mechanism.
[0082] In order to investigate emulsion stability at various pH
values, test emulsions with a surfactant concentration of c=1.0%
w/w covering the range from pH 4 to 9 were prepared (Table 4-7). At
pH values >7 all sucrose fatty acid esters investigated showed
good emulsification properties. After centrifugation times of 300
min only a small free upper oil phase separated from the optically
non-transparent emulsion phase. Sucrose esters with an HLB value
below 11 gave only poor emulsification at pH values <7 (Table
5-7). Surprisingly, Surfhope SE Pharma D-1815 with an HLB of 15
gave highly stable emulsions. This clearly indicates that sucrose
esters with a rather high HLB value (typically around 15) provide
practically pH-independent superior emulsification stabilities.
[0083] Table 4. Stability of Surfhope SE Pharma D-1815 test
emulsions (c=1.0% w/w) at various pH-values and centrifugation
times t.
13TABLE 4 Stability of Surfhope SE Pharm D-1815 test emulsions (c =
1.0% w/w) at various pH-values and centrifugation times t. Emulsion
Stability Surfhope SE Pharma D-1815 t/min pH 1 30 60 120 300 4
high* high high high high 5 high high high high high 6 high high
high high high 7 high high high high medium 8 high high medium
medium medium 9 high high medium medium medium *low: oil and water
form two distinct clearly separated phases; medium: emulsion partly
broken; high: no indications of coalescence, optically
non-transparent, stable emulsion
[0084]
14TABLE 5 Stability of Surfhope SE Pharma D-1811 test emulsions (c
= 1.0% w/w) at various pH-values and centrifugation times t.
Emulsion Stability Surfhope SE Pharma D-1811 t/min pH 1 30 60 120
300 4 high* medium medium medium low 5 high medium medium medium
low 6 high high medium medium medium 7 high high medium medium
medium 8 high high high high medium 9 high high high high medium
*low: oil and water form two distinct clearly separated phases;
medium: emulsion partly broken; high: no indications of
coalescence, optically non-transparent, stable emulsion
[0085]
15TABLE 6 Stability of Surfhope SE Pharma D-1807 test emulsions (c
= 1.0% w/w) at various pH-values and centrifugation times t.
Emulsion Stability Surfhope SE Pharma D-1807 t/min pH 1 30 60 120
300 4 high* medium medium medium low 5 high medium medium medium
low 6 high high medium medium low 7 high high high medium medium 8
high high high high medium 9 high high high high medium *low: oil
and water form two distinct clearly separated phases; medium:
emulsion partly broken; high: no indications of coalescence,
optically non-transparent, stable emulsion
[0086]
16TABLE 7 Stability of Surfhope SE Pharma D-1805 test emulsions (c
= 1.0% w/w) at various pH-values and centrifugation times t.
Emulsion Stability Surfhope SE Pharma D-1805 t/min pH 1 30 60 120
300 4 low* low low low low 5 medium medium low low low 6 medium
medium medium medium medium 7 high high medium medium medium 8 high
high high high high 9 high high high high high *low: oil and water
form two distinct clearly separated phases; medium: emulsion partly
broken; high: no indications of coalescence, optically
non-transparent, stable emulsion
[0087] FIG. 4 shows test emulsions of Surfhope SE Pharma D-1811
after centrifugation at 3100 g for t=1 min (a) and t=300 min (b),
respectively. The emulsions are stabilized with 1.0% (w/w) sucrose
ester at different pH values. Whereas emulsions at pH<7 clearly
show phase separation after centrifugation for t=300 min, emulsions
at pH>7 noticeably revealed less free oil. From left to right:
reference (mixture soy oil/buffer) at pH=7; pH=4, pH=5; pH=6; pH=7;
pH=8; pH=9.
[0088] In contrast, Sucrose Fatty Acid Ester S-370F revealed very
bad emulsification properties. Due to the high hydrophobicity of
the compound solubility in the continuous aqueous phase was very
low. However, the compound is very easily soluble in soy bean oil
resulting in a significant increase in oil viscosity.
Example 15
Side Effect in vivo Studies
[0089] An in vivo mouse model was developed to investigate the
ability of sucrose esters to reduce the free oil formation after
orlistat treatment. Orlistat was mixed with butter and added to the
feed. The concentration of orlistat administered to the mice was
150 .mu.mol orlistat/kg body weight. The experiment is based on the
observation that mice under a high fat diet treated with orlistat
or other lipase inhibitors distribute the excreted free oil over
their furs while grooming (U.S. Pat. No. 5,431,949). A variety of
sucrose esters as mentioned above were examined for their ability
to reduce or eliminate the production of free oil. The results of
these studies are summarized in FIG. 5.
[0090] In this representation, the excretion of free oil by a
control group which received Orlistat but no gastro-intestinal side
effect controlling agent was taken as background level and
arbitrarily set to zero. Any improvements in free oil production
are given as minus percent value relative to the background. These
experiments revealed that sucrose esters such as Surfhope D-1811 or
Surfhope D-1805 with a medium HLB value show the highest relative
reduction in free oily excretion. In contrast, sucrose esters on
either end of the HLB scale which are either very hydrophilic
(Surfhope D-1815) or very lipophilic (Surfhope D-1803) show less
activity.
Example 16
Pellet Formulation Compressed to Chewable Tablet
[0091]
17 Composition 8 Orlistat 240 g Sucrosepalmitate P1670 60 g Avicel
PH-105 210 g Sodium starch glycolate 60 g Povidone K30 30 g Stearic
acid 6 g
[0092] The ingredients are dry mixed together in a high speed
Aeromatic Fielder GP 1). 240 g water are added stepwise and the
mixing process is continued for about 5 minutes. An extruder is fed
with this material (NICA extruder; screen 0.8 mm mesh size,
thickness 1.0 mm). The material is extruded to spaghettis of
appropriate length. The temperature of the extrudate does not
exceed 35.degree. C. The extrudate is transferred to a spheronizer
((NICA spheronizer) and spheronized for 0.5 to 5 minutes. The wet
pellets are dried in a fluidized bed dryer (Aeromatic, MP-1) at a
temperature of below 35.degree. C. The dried pellets are sieved
with sieve inserts of 0.5 and 1.25 mm mesh size, and under- and
oversize fractions are discarded. Stearic acid is added and
homogeneously distributed by dry mixing. The resulting mixture is
compressed to chewable tablets containing orlistat 120 mg,
sucrosepalmitate 30 mg, Avicel 105 mg, sodium starch glycolate 30
mg, povidone 15 mg and stearic acid 3 mg.
Example 17
Two Layer Chewable Tablet
[0093]
18 Composition 9 a) Orlistat 240 g b) Sucrosepalmitate P1670 60 g
c) Avicel PH-105 210 g d) Sodium starch glycolate 60 g e) Povidone
K30 30 g f) Stearic acid 6 g g) Lactose monohydrate (powder) 1460 g
h) Avicel PH 102 200 g i) Maize starch 1500 100 g k) Sodium starch
glycolate 100 g 1) Povidone 90F 60 g m) Glyceryl benehate 60 g n)
Magnesium Stearate 20 g
[0094] Layer 1: The ingredients a)-e) are dry mixed together in a
high speedAeromatic Fielder GP 1). 240 g water are added stepwise
and the mixing process is continued for about 5 minutes. An
extruder is fed with this material (NICA extruder; screen 0.8 mm
mesh size, thickness 1.0 mm). The material is extruded to
spaghettis of appropriate length. The temperature of the extrudate
does not exceed 35.degree. C. The extrudate is transferred to a
spheronizer ((NICA spheronizer) and spheronized for 0.5 to 5
minutes. The wet pellets are dried in a fluidized bed dryer
(Aeromatic, MP-1) at a temperature of below 35.degree. C. The dried
pellets are sieved with sieve inserts of 0.5 and 1.25 mm mesh size,
and under- and oversize fractions are discarded. Stearic acid is
added and homogeneously distributed by dry mixing. Layer 2: The
excipients g)-m) are mixed together in a high speed mixer
(Aeromatic Fielder GP 1) for 5 minutes, 400 g water added for
granulation. The wet granulate is sieved and dried in a fluidized
bed dryer (Aeromatic, MP-1). The dried granulate is sieved, and
homogeneously mixed with Magnesium stearate.
[0095] The resulting mixtures of layer 1 and 2 are compressed to a
two layer tablet (Kilian compressing equipment) containing orlistat
120 mg, sucrosepalmitate 30 mg, Avicel 105 mg, sodium starch
glycolate 30 mg, povidone 15 mg and stearic acid 3 mg in layer 1
and containing Lactose 730 mg, Avicel 100 mg, maize starch 50 mg,
sodium starch glycolate 50 mg, povidone 30 mg, glyceryl benehate 30
mg and magnesium stearate 10 mg in the second layer.
Example 18
Fast Disintegrating Chewable Tablet
[0096]
19 Composition 10 Orlistat 48 g Sucrosepalmitate P1670 12 g Sodium
starch glycolate 48 g PEG 6000 72 g Xylit 122.4 g Mannit pulvis
122.4 g Myrj 52 12 g Plasdone S630 24 g Magnesium stearate 4.8 g
Talc 24 g
[0097] The ingredients (with exception of magnesium stearate and
talc) were mixed in a high speed mixer (Aeromatic Fielder GP 1) for
5 minutes. 32 g water was added for granulation. The wet granulate
was sieved (Siebschleuder Bergmeier 5.0 mm) and dried in a
fluidized bed dryer (Aeromatic Strea) below 37.degree. C. The dry
granulate was sieved (Fitzpatrick 1.62 mm), mixed with Magnesium
stearate and Talc and compressed to a chewable tablet (Korsch PH
250 tabletting machine).
Example 19
Fast Disintegrating Chewable Tablet
[0098]
20 Composition 11 Orlistat 48 g Sucrosepalmitate P1670 12 g Sodium
starch glycolate 48 g PEG 6000 72 g Xylit 98.4 g Mannit pulvis 98.4
g Myrj 52 12 g Alginic acid 32.64 g Plasdone S630 24 g Magnesium
stearate 4.8 g Talc 14.4 g Calcium carbonate 15.36 g
[0099] The ingredients (with exception of magnesium stearate, talc
and calcium carbonate) were mixed in a high speed mixer (Aeromatic
Fielder GP 1) for 5 minutes. 30 g water was added for granulation.
The wet granulate was sieved (Siebschleuder Bergmeier 5.0 mm) and
dried in a fluidized bed dryer (Aeromatic Strea) below 37.degree.
C. The dry granulate was sieved (Fitzpatrick 1.62 mm),
homogeneously mixed with magnesium stearate, talc and calcium
carbonate and compressed to a chewable tablet (Korsch PH 250
tabletting machine).
[0100] Upon reading the present specification various alternative
embodiments will become obvious to the skilled artisan. These
variations are to be considered within the scope and spirit of the
subject invention which is only to be limited by the claims that
follow and their equivalents.
* * * * *