U.S. patent application number 17/320436 was filed with the patent office on 2021-09-09 for tablet formulation comprising a glp-1 peptide and a delivery agent.
The applicant listed for this patent is Novo Nordisk A/S. Invention is credited to Simon Bjerregaard, Flemming Seier Nielsen, Betty Lomstein Pedersen, Per Sauerberg, Erik Skibsted.
Application Number | 20210275458 17/320436 |
Document ID | / |
Family ID | 1000005598843 |
Filed Date | 2021-09-09 |
United States Patent
Application |
20210275458 |
Kind Code |
A1 |
Bjerregaard; Simon ; et
al. |
September 9, 2021 |
TABLET FORMULATION COMPRISING A GLP-1 PEPTIDE AND A DELIVERY
AGENT
Abstract
The present invention relates to solid compositions comprising a
GLP-1 peptide and a delivery agent, such as SNAC, as well as uses
thereof.
Inventors: |
Bjerregaard; Simon;
(Hilleroed, DK) ; Sauerberg; Per; (Farum, DK)
; Nielsen; Flemming Seier; (Frederikssund, DK) ;
Pedersen; Betty Lomstein; (Glostrup, DK) ; Skibsted;
Erik; (Holbaek, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novo Nordisk A/S |
Bagsvaerd |
|
DK |
|
|
Family ID: |
1000005598843 |
Appl. No.: |
17/320436 |
Filed: |
May 14, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15958236 |
Apr 20, 2018 |
11033499 |
|
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17320436 |
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14409021 |
Dec 18, 2014 |
9993430 |
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PCT/EP2013/062751 |
Jun 19, 2013 |
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15958236 |
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61662456 |
Jun 21, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2072 20130101;
A61K 38/26 20130101; A61K 9/1617 20130101; A61K 9/2013 20130101;
A61K 9/2077 20130101; A61K 9/2004 20130101; A61K 9/2095
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 38/26 20060101 A61K038/26; A61K 9/16 20060101
A61K009/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2012 |
EP |
12172739.0 |
Claims
1. A tablet comprising a granulate comprising: i) no more than 15%
(w/w) GLP-1 peptide, and ii) at least 50%, 55%, or 60% (w/w) salt
of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC).
2. A tablet according to claim 1, wherein said peptide comprises a
substituent comprising a fatty acid or a fatty diacid, of formula
(X) ##STR00006## wherein n is at least 13; and wherein said peptide
optionally comprises one or more 8-amino-3,6-dioxaoctanoic acid
(OEG).
3. A tablet according to claim 1, wherein said GLP-1 peptide is
semaglutide.
4. A tablet according to claim 1, wherein said salt of NAC is
monosodium NAC (SNAC), anhydrous SNAC monosodium salt.
5. A tablet according to claim 1, wherein the amount of said salt
of NAC is 50-90% (w/w), 55-85% (w/w), or 70-80% (w/w).
6. A tablet according to claim 1, wherein said tablet comprises an
intragranular and an extragranular part, wherein said extragranular
part comprises a lubricant and optionally a filler.
7. A tablet according to claim 1, wherein said tablet comprises a)
a granulate comprising i) 1-15% (w/w) GLP-1 peptide, ii) 55-85%
(w/w) salt of NAC, and iii) 1-20% (w/w) binder; b) 10-35% (w/w)
filler; and c) 0.5-3% (w/w) lubricant.
8. A tablet according to claim 1, wherein said tablet does not
comprise a superdisintegrant.
9. A tablet according to claim 1, wherein said tablet is for oral
administration.
10. A tablet according to claim 1, wherein said tablet was prepared
by exerting a compression force of at least 5 kN, such as 5-25 kN,
at least 10 kN or at least 15 kN, or at least 4 kN/cm.sup.2, such
as at least 6 kN/cm.sup.2 or at least 8 kN/cm.sup.2.
11. A method of treating type 2 diabetes or obesity comprising
administering to a subject in need of such treatment a tablet
according to claim 1.
12. A process for the preparation of a tablet comprising a
granulate comprising i) no more than 15% (w/w) GLP-1 peptide, and
ii) at least 50% (w/w) salt of NAC, said method further comprising
the step of exerting a compression force when punching said tablet
of a) at least 5 kN, such as 5-25 kN, at least 10 kN or at least 15
kN, and/or b) at least 4 kN/cm.sup.2, such as at least 6
kN/cm.sup.2 or at least 8 kN/cm.sup.2, wherein said process
optionally comprises a pre-compression step.
13. A method for controlling porosity of the tablet of claim 1,
said method comprising the steps of: a) determining the
near-infrared (NIR) spectrum of one or more of said tablets, b)
comparing said spectrum to a reference NIR spectrum or performing a
statistical analysis of said spectrum to determine the tablet
porosity, c) optionally adjusting the tabletting parameters during
tabletting in order to improve the NIR spectrum or porosity of the
tablets, and d) selecting a subgroup of tablets with a NIR spectrum
or porosity within a predetermined range, wherein said method
optionally is an at-line or an in-line NIR method.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 15/958,236, filed Apr. 20, 2018, which is a Continuation of
U.S. application Ser. No. 14/409,021, filed Dec. 18, 2014, which is
a 35 U.S.C. .sctn. 371 National Stage application of International
Application PCT/EP2013/062751 (WO 2013/189988), filed Jun. 19,
2013, which claimed priority of European Patent Application
12172739.0, filed Jun. 20, 2012; this application claims priority
under 35 U.S.C. .sctn. 119 of U.S. Provisional Application
61/662,456; filed Jun. 21, 2012; the contents of all above-named
applications are incorporated herein by reference.
[0002] The present invention relates to solid compositions
comprising a pharmaceutically active peptide and a delivery agent,
which is a salt of N-(8-(2-hydroxybenzoyl)amino) caprylate (NAC),
as well as processes for their preparation and uses thereof.
SEQUENCE LISTING
[0003] The instant application contains a Sequence Listing which
has been submitted in ASCII format via EFS-Web and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on May 10, 2021 is named 8530US03_SeqList_ST25.txt and is 2
kilobytes in size.
BACKGROUND
[0004] One of the main challenges in oral delivery of proteins and
peptides is the inability of these compounds to be readily
transported across the membranes of the gastrointestinal tract. The
delivery agent SNAC has previously been shown to improve the
bioavailability of orally administered peptides.
[0005] WO 2012/080471 A1, WO 2008/109385 A2 and WO 2010/020978 A1
are related to oral compositions comprising a peptide drug and a
delivery agent. However improved oral compositions are still
needed.
[0006] The present invention relates to further improvements of the
bioavailability by oral administration of compositions of such
peptides, in particular of GLP-1 peptides.
SUMMARY
[0007] In some embodiments the invention relates to a tablet
comprising a granulate comprising i) no more than 15% (w/w) GLP-1
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has a) a bulk density of at least 0.90 g/cm.sup.3, b) a
median pore diameter of no more than 1.5 .mu.m, c) a maximum pore
diameter of no more than 4 .mu.m, and/or d) a crushing strength of
at least 50 N, wherein said bulk density is determined by Assay
(Ia) as described herein, wherein said median pore diameter or
maximum pore diameter is determined by Assay (IIb) as described
herein, wherein said crushing strength is determined by Assay (III)
as described herein, and wherein said disintegration time is
determined by Assay (IV) as described herein.
[0008] In some embodiments the invention relates to a tablet
comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 55% (w/w) salt of NAC, wherein said
tablet has a) a bulk density of at least 0.90 g/cm.sup.3, b) a
median pore diameter of no more than 1.5 .mu.m, c) a maximum pore
diameter of no more than 4 .mu.m, and/or d) a crushing strength of
at least 50 N, wherein said bulk density is determined by Assay
(Ia) as described herein, wherein said median pore diameter or
maximum pore diameter is determined by Assay (IIb) as described
herein, wherein said crushing strength is determined by Assay (III)
as described herein, and wherein said disintegration time is
determined by Assay (IV) as described herein.
[0009] In some embodiments the invention relates to a tablet as
defined herein for use in medicine, such as for treating type 2
diabetes or obesity.
[0010] In some embodiments the invention relates to a granulate as
defined herein. In some embodiments the invention relates to a
process for the preparation of a tablet comprising a granulate
comprising i) no more than 15% (w/w) peptide, such as GLP-1
peptide, and ii) at least 50% (w/w) salt of NAC, said method
comprising the step of exerting a compression force when punching
said tablet of at least 5 kN, such as at least 10 kN or at least 15
kN, or at least 4 kN/cm.sup.2, such as at least 6 kN/cm.sup.2 or at
least 8 kN/cm.sup.2, wherein said process optionally comprises a
pre-compression step, and wherein said tablet optionally is as
defined herein.
[0011] In some embodiments the invention relates to a method for
controlling porosity of a group of tablets, said method comprising
the steps of: a) determining the near-infrared (NIR) spectrum of
one or more of said tablets; b) comparing said spectrum to a
reference NIR spectrum, or performing a statistical analysis of
said spectrum to determine the tablet porosity; c) optionally
adjusting the tabletting parameters during tabletting in order to
improve the NIR spectrum or porosity of the tablets; and d)
selecting a subgroup of tablets with a NIR spectrum or porosity
within a predetermined range; wherein said method optionally is an
at-line or an in-line NIR method, and wherein said tablet
optionally is as defined herein.
BRIEF DESCRIPTION OF DRAWINGS
[0012] FIG. 1 shows surface erosion of Tablet A before (right),
after 5 minutes (middle) and after 10 minutes (left) disintegration
test.
[0013] FIG. 2 shows mercury intrusion into Tablet B (dotted line),
Tablet C (broken line) and tablet E (solid line) (poor, medium and
good performing tablets, respectively).
[0014] FIG. 3 shows NIR reflectance spectra of three tablets
comprising SNAC and Semaglutide with different porosities: 24%
(solid line), 15% (dotted line) and 7% (broken line).
[0015] FIG. 4 shows correlation between measured tablet porosity
and tablet porosity predicted by NIR spectroscopy.
[0016] FIG. 5 shows correlation of semaglutide PK profiles with
tablet erosion at 1 hour after dosing. <=54% tablet erosion at 1
hour (.box-solid.), 55-99% erosion at 1 hour (.circle-solid.), 100%
erosion at 1 hour (.tangle-solidup.).
[0017] FIG. 6 shows correlation of SNAC PK profiles with tablet
erosion at 1 hour after dosing. <=54% erosion at 1 hour
(.box-solid.), 55-99% erosion at 1 hour (.circle-solid.), 100%
erosion at 1 hour (.tangle-solidup.).
DESCRIPTION
[0018] The present invention relates to improved tablets comprising
a peptide, such as a GLP-1 peptide, and a delivery agent, which is
a salt of NAC. The present inventors surprisingly found that the
requirements to physical parameters of tablets, such as density,
porosity and/or crushing strength, as well as the methods of
preparation of tablets according to the present invention provide
tablets with improved bioavailability of peptides, such as acylated
peptides.
[0019] Generally, the term "bioavailability" as used herein refers
to the fraction of an administered dose of an active pharmaceutical
ingredient (API) and/or active moieties, such as a peptide or a
GLP-1 peptide as defined herein, which reaches the systemic
circulation. By definition, when an API and/or active moieties are
administered intravenously, its bioavailability is 100%. However,
when it is administered via other routes (such as orally), its
bioavailability decreases (due to incomplete absorption). Knowledge
about bioavailability is important when calculating dosages for
non-intravenous routes of administration.
[0020] Absolute oral bioavailability is calculated as the relative
exposure of the API and/or active moieties in systemic circulation
following oral administration (estimated as the area under the
plasma concentration versus time curve) compared to the exposure of
the API and/or active moieties following intravenous
administration.
Compositions
[0021] The present invention relates to a composition in the form
of a tablet. In some embodiments the composition of the invention
is for oral administration.
[0022] In some embodiments the tablet comprises a granulate
comprising i) no more than 15% (w/w) peptide, and ii) at least 50%
(w/w) salt of NAC, wherein said tablet has a) a bulk density of at
least 0.90 g/cm.sup.3; b) a median pore diameter of no more than
1.5 .mu.m; and/or c) a maximum pore diameter of no more than 4
.mu.m. In some embodiments the invention relates to a tablet
comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has a) a bulk density of at least 0.90 g/cm.sup.3; b) a
median pore diameter of no more than 1.5 .mu.m; c) a maximum pore
diameter of no more than 4 .mu.m; and/or d) a crushing strength of
at least 50 N.
[0023] In some embodiments the invention relates to a tablet
comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has a) a bulk density, such as a bulk density, of at least
0.90 g/cm.sup.3; b) a median pore diameter of no more than 1.5
.mu.m; c) a maximum pore diameter of no more than 4 .mu.m; d) a
crushing strength of at least 50 N; and/or e) a disintegration time
of 12-18 minutes for a tablet with a total weight of 300-500 mg
comprising at least 60% (w/w) salt of NAC.
[0024] In some embodiments, at tablet of the invention is surface
eroding. By the term "surface eroding" is herein meant that the
material detachment from the tablet is from the surface of the
tablet as e.g. depicted in FIG. 1. A surface eroding tablet is thus
the opposite of a disintegrating type of a tablet, where the tablet
material is disintegrated into primary particles or granules and
hereby accelerating the dissolution process.
[0025] In some embodiments the term "granulate" refers to one or
more granules. In some embodiments the term "granule" refers to
particles gathered into larger particles.
[0026] In some embodiments the tablet comprises a granulate
comprising a peptide, a salt of NAC and optionally a binder. In
some embodiments the composition comprises an intragranular and an
extragranular part, wherein said extragranular part comprises at
least part of a lubricant and optionally a filler.
[0027] In some embodiments the tablet comprises less than 15% (w/w)
peptide, at least 50 (w/w) salt of NAC, less than 10% (w/w) binder,
5-40% (w/w) filler, and less than 10 (w/w) lubricant. In some
embodiments the tablet comprises a) a granulate comprising i) 1-15%
(w/w) peptide, ii) 55-85% (w/w) salt of NAC, and iii) 1-20% (w/w)
binder; b) 10-35% (w/w) filler; and c) 0.5-3% (w/w) lubricant. In
some embodiments the tablet comprises a) a granulate comprising i)
1-100 mg, such as 10 mg, peptide, ii) 100-1000 mg, such as 300 mg,
salt of NAC, and iii) 1-20 mg, such as 8 mg, binder; b) 20-200 mg,
such as 100 mg, filler; and c) 0.5-8 mg, such as 2-8 mg,
lubricant.
[0028] In some embodiments the invention relates to a granulate as
defined herein. In some embodiments the granulate comprises i) no
more than 15% (w/w) peptide, and ii) at least 50% (w/w) salt of
NAC. In some embodiments the granulate comprises i) 1-15% (w/w)
peptide, ii) 55-85% (w/w) salt of NAC, and iii) 1-20% (w/w) binder.
In some embodiments the granulate comprises i) 1-100 mg, such as 10
mg, peptide, ii) 100-1000 mg, such as 300 mg, salt of NAC, and iii)
1-20 mg, such as 8 mg, povidone. In some embodiments the granulate
comprises at least 80% (w/w) delivery agent, less than 10% (w/w)
lubricant, and optionally less than 20% filler. In some embodiments
the granulate comprises a peptide, at least 10 (w/w) filler and
less than 40% (w/w) binder.
[0029] In some embodiments the composition or granulate comprises
at least one pharmaceutically acceptable excipient. The term
"excipient" as used herein broadly refers to any component other
than the active therapeutic ingredient(s). The excipient may be an
inert substance, which is inert in the sense that it substantially
does not have any therapeutic and/or prophylactic effect per se.
The excipient may serve various purposes, e.g. as a delivery agent,
absorption enhancer, vehicle, filler (also known as diluents),
binder, lubricant, glidant, disintegrant, crystallization
retarders, acidifying agent, alkalizing agent, preservative,
antioxidant, buffering agent, chelating agent, complexing agents,
surfactant agent, emulsifying and/or solubilizing agents,
sweetening agents, wetting agents stabilizing agent, colouring
agent, flavouring agent, and/or to improve administration, and/or
absorption of the active substance. A person skilled in the art may
select one or more of the aforementioned excipients with respect to
the particular desired properties of the solid oral dosage form by
routine experimentation and without any undue burden. The amount of
each excipient used may vary within ranges conventional in the art.
Techniques and excipients which may be used to formulate oral
dosage forms are described in Handbook of Pharmaceutical
Excipients, 6th edition, Rowe et al., Eds., American
Pharmaceuticals Association and the Pharmaceutical Press,
publications department of the Royal Pharmaceutical Society of
Great Britain (2009); and Remington: the Science and Practice of
Pharmacy, 21th edition, Gennaro, Ed., Lippincott Williams &
Wilkins (2005).
[0030] In some embodiments the composition or granulate comprises a
filler, such as lactose (e.g. spray-dried lactose, .alpha.-lactose,
.beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM.,
Microtose.RTM. or Fast-FloC.RTM.), microcrystalline cellulose
(various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming
Tai.RTM. or Solka-Floc.RTM.), other cellulose derivatives, sucrose,
sorbitol, mannitol, dextrins, dextrans, maltodextrins, dextrose,
fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starches or
modified starches (including potato starch, maize starch and rice
starch), calcium phosphate (e.g. basic calcium phosphate, calcium
hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate,
calcium carbonate, or sodium alginate. In some embodiments the
filler is microcrystalline cellulose, such as Avicel PH 101, Avicel
PH 102, or Avicel PH 200. In some embodiments the composition
comprises 5-40% (w/w), such as 10-30% (w/w) or 5-25% (w/w), filler.
In some embodiments said filler is in the intragranular and/or
extragranular part of the composition.
[0031] In some embodiments the composition or granulate comprises a
binder, such as lactose (e.g. spray-dried lactose, .alpha.-lactose,
.beta.-lactose, Tabletose.RTM., various grades of Pharmatose.RTM.,
Microtose.RTM. or Fast-FloC.RTM.), microcrystalline cellulose
(various grades of Avicel.RTM., Elcema.RTM., Vivacel.RTM., Ming
Tai.RTM. or Solka-Floc.RTM.), hydroxypropylcellulose,
L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC)
(e.g. Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as,
e.g., the 4,000 cps grades of Methocel E and Metolose 60 SH, the
4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000,
15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000,
39,000 and 100,000 grades of Metolose 90 SH), methylcellulose
polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C,
Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium
carboxymethylcellulose, other cellulose derivatives, sucrose,
dextrins, maltodextrins, starches or modified starches (including
potato starch, maize starch and rice starch), calcium lactate,
calcium carbonate, acacia, sodium alginate, agar, carrageenan,
gelatin, guar gum, pectin, PEG, or povidone. In some embodiments
the binder is povidone, such as povidone K 90. In some embodiments
the amount of binder is 0.1-10% (w/w), such as 0.2-4% (w/w) or
0.5-3% (w/w), or such as 1.0-2.5% (w/w). In some embodiments the
binder is in the intragranular and/or extragranular part of the
composition.
[0032] In some embodiments the tablet or granulate does not contain
a superdisintegrant, i.e. an ingredient improving disintegrant
efficiency such as e.g. sodium starch glycolate, sodium
carboxymethyl starch, crospovidone and croscarmellose sodium. In
some embodiments the composition or granulate comprises a
disintegrant, such as alginic acid, alginates, microcrystalline
cellulose, hydroxypropyl cellulose, other cellulose derivatives,
polacrillin potassium, starch, or pregelatinized starch.
[0033] In some embodiments the composition or granulate comprises a
lubricant, such as stearic acid, magnesium stearate, calcium
stearate or other metallic stearate, talc, waxes, glycerides, light
mineral oil, glyceryl behenate, hydrogenated vegetable oils, sodium
stearyl fumarate, polyethylene glycols, alkyl sulfates, or sodium
benzoate. In some embodiments the composition or granulate
comprises a lubricant, such as magnesium silicate, talc, or
colloidal silica. In some embodiments the lubricant is magnesium
stearate. In some embodiments the amount of lubricant is 0.1-10%
(w/w) or 0.5-5% (w/w), such as 1-3.5% (w/w), 0.5-3% (w/w) or
1.0-2.5% (w/w). In some embodiments the lubricant is in the
intragranular and/or extragranular part of the composition.
[0034] Still further, the composition or granulate of the invention
may be formulated as is known in the art of oral formulations of
insulinotropic compounds.
[0035] In some embodiments the weight of the tablet is in the range
of 150 mg to 1000 mg, such as in the range of 300-600 mg or such as
300-500 mg.
Methods of Preparation of Pharmaceutical Compositions
[0036] In some embodiments the invention relates to a process for
the preparation of a tablet comprising a granulate comprising i) no
more than 15% (w/w) peptide, such as GLP-1 peptide, and ii) at
least 50% (w/w) salt of NAC, said method comprising the step of
exerting a compression force when punching said tablet of at least
5 kN, such as 5-25 kN, and/or at least 4 kN/cm.sup.2. In some
embodiments the compression force is in the range of 5-25 kN. In
some embodiments the compression force is at least 5 kN, such as at
least 10 kN or at least 15 kN. In some embodiments the compression
force is no more than 25 kN, such as no more than 20 kN. In some
embodiments the compression force is at least 4 kN/cm.sup.2, such
as at least 6 kN/cm.sup.2 or at least 8 kN/cm.sup.2. In some
embodiments the process comprises a pre-compression step. In some
embodiments the tablet or granulate is as defined herein.
[0037] The composition of the invention may be prepared as is known
in the art. In some embodiments the composition or the granulate
may be prepared as described in the examples herein. The
composition may comprise one or more intragranular parts and an
extragranular part, wherein the intragranular parts have been
granulated, and wherein the extragranular part has been added after
granulation. The extragranular part may comprise a lubricant.
[0038] In some embodiments two or more ingredients of the
composition are blended. To prepare a dry blend of tabletting
material, the various components are weighed, optionally delumped
and then combined. The mixing of the components may be carried out
until a homogeneous blend is obtained.
[0039] In some embodiments at least a part of the composition is
dry granulated or wet granulated. A granulate may be produced in a
manner known to a person skilled in the art, for example by dry
granulation techniques in which the pharmaceutically active agent
and/or delivery agents are compacted with the excipients to form
relatively large moldings, for example slugs or ribbons, which are
comminuted by grinding, and the ground material serves as the
tabletting material to be later compressed into tablets. Suitable
equipment for dry granulation includes but is not limited to roller
compaction equipment from Gerteis, such as Gerteis MINI-PACTOR. In
some embodiments the granulate is prepared by roller compaction. In
some embodiments the moldings from the roller compactions process
are comminuted into granules. Alternatively, a granulate can be
obtained by wet granulation which may be carried out by mixing the
pharmaceutically active agent dissolved in water with a dry blend
of the delivery agents and optionally one or more excipients
followed by drying of the granulate.
[0040] To compress the tabletting material into a solid oral dosage
form, for example a tablet, a tablet press may be used. In a
tabletting press, the tabletting material is filled (e.g. force fed
or gravity fed) into a die cavity. The tabletting material is then
compressed by a punch with pressure. Subsequently, the resulting
compact, or tablet is ejected from the tabletting press. The above
mentioned compression process is subsequently referred to herein as
the "compression process". Suitable tablet presses include, but are
not limited to, rotary tablet presses and eccentric tablet presses.
Examples of tablet presses include, but are not limited to, the
Fette 102i (Fette GmbH), the Korsch XL100, the Korsch PH 106 rotary
tablet press (Korsch AG, Germany), the Korsch EK-O eccentric
tabletting press (KorschA G, Germany), the DIAF TM20 press
(Denmark) and the Manesty F-Press (Manesty Machines Ltd., United
Kingdom). By the term "exerting a compression force" is thus meant
compressing the tabletting material with a specified force as e.g.
measured in Newton such as e.g. at least 5 kN or at least 4
kN/cm.sup.2.
[0041] As used herein "pre-compression" is intended to mean the
application of a preliminary compression force just before a second
main compression force is applied. During the pre-compression step
the height of the powder compact is reduced to no more than 2 times
the height of the final tablet, such as no more than 2 times or no
more than 1.3 times the final height of the tablet.
[0042] In some embodiments the invention relates to a
pharmaceutical composition obtained by the process as defined
herein.
[0043] In some embodiments the tablet is prepared by exerting a
compression force in the range of 5-25 kN. In some embodiments the
tablet is prepared by exerting a compression force of at least 5
kN, such as at least 10 kN or at least 15 kN. In some embodiments
the tablet is prepared by exerting a compression force of no more
than 25 kN, such as no more than 20 kN. In some embodiments the
term "resistance to crushing of tablets" or "crushing strength" has
the meaning defined in section 2.9.8 in the European Pharmacopoeia
7.5, 7th edition 2012; crushing strength may be measured inter alia
in Newton (N) or kilopond (kP) using a jaw speed of 20 N/s (1 kP
equals 9.807 N).
[0044] In some embodiments the term "roller compaction force" means
the force between the rolls of the roller compactor when compacting
materials into a continuous strip of compressed material as
determined by a pressure transducer that converts the hydraulic
pressure into electrical signal; the roller compaction force may be
measured in kiloNewton (kN) or in kiloNewton per roll width
(kN/cm).
Physical Properties and In Vitro Methods
[0045] Density is the ratio of mass to volume. Powder compression
is defined as the reduction of a powder volume due to the
application of a mechanical force. Bonds are formed between
granules during compression because of the increased proximity of
particle surface accomplished during compression, which provide
coherence and mechanical resistance to the powder compact. During
compression repacking and deformation of granules (elastic or
plastic deformation) will occur. Bulk density is the mass of the
tablet divided by total volume of the tablet defined by the outer
boundary of the tablet. This volume is determined by the dimension
of the punches (cup volume), die hole surface area and tablet band
thickness used for compression into a tablet. The bulk density can
be calculated as (tablet mass/(2.times.(cup volume)+(die hole
surface area).times.((tablet thickness)-2.times.(cup depth)))).
Alternatively, the bulk density can be determined by submerging the
tablet into a non-wetting liquid at atmospheric pressure, like
mercury, and determining the displaced volume. In some embodiments
the tablet of the invention has a bulk density of at least 0.90
g/cm.sup.3, such as at least 0.95 g/cm.sup.3 or at least 1.0
g/cm.sup.3, or such as at least 1.1 g/cm.sup.3 or at least 1.2
g/cm.sup.3. In some embodiments the bulk density is 1.10-1.19
g/cm.sup.3, such as 1.13-1.18 g/cm.sup.3, such as about 1.14, about
1.15, about 1.16, or about 1.17 g/cm.sup.3. In some embodiments the
bulk density is no more than 1.19 g/cm.sup.3. Bulk density of
compositions of the invention may be determined as described in
Assay (I) or (IIb) herein.
[0046] The microstructure of pharmaceutical solid dosage forms
(porosity, pore volume-size distribution, specific surface area)
can be investigated by different methods, e.g. mercury porosimetry.
Porosity is a measure of the void spaces in a tablet, and is a
fraction of the volume of voids (i.e. volume of pores) over the
total volume, between 0-1, or as a percentage between 0-100%.
Porosity can be calculated as (1-(tablet bulk density/granule
density)) or (1-(tablet bulk density/tablet skeletal density)).
Alternatively, the pore volume can be determined by mercury
intrusion into the tablet. Since mercury does not wet most
substances and will not spontaneously penetrate pores by capillary
action, it must be forced into the pores by the application of
external pressure. In practice, the tablet is evacuated, and then
immersed in mercury. At laboratory pressures mercury will not enter
the pores of the tablet. The pressure on the mercury is then raised
in a stepwise fashion, forcing the mercury into the pores of the
tablet. When the pressure is sufficiently high, the mercury will
invade all the pores. A measurement of the volume of mercury
intruded into the tablets provides the pore volume directly. The
pore diameter is the average or effective diameter of the openings
in the tablet. There is a direct relation between pore size and
amount of mercury intrusion at a given pressure. At any pressure,
the pores into which mercury has intruded have diameters greater
than
D=-4.gamma. cos .theta./P (1)
wherein D is the diameter, .gamma. is surface tension of mercury
and .theta. is the contact angle between the sample and mercury, P
is pressure. By measuring the volume of mercury that intrudes into
the sample material with each pressure change, the volume of pores
in the corresponding size class is known. The contact angle of
mercury with most solids is between 135.degree. and 142.degree., so
an average of 140.degree. can be taken without much error. The
surface tension of mercury at 20.degree. C. under vacuum is 480
mN/m. Then equation 1 can be reduced to:
D=(1470 kPa.times..mu.m)/P (2)
Total intrusion volume (ml mercury per gram of tablet) is the total
volume on mercury intruded into the sample at the highest applied
pressure and is a measure of pore volume from which porosity can be
calculated. The median pore diameter can be determined from the
cumulative mercury intrusion volume as the pore diameter where 50%
of the total volume has been added. The maximum pore diameter can
be determined from the cumulative mercury intrusion volume as the
pore diameter where mercury starts to intrude into the sample. In
some embodiments the tablet has a median pore diameter of no more
than 1.5 .mu.m, such as no more than 1.3 .mu.m or no more than 1.0
.mu.m. In some embodiments the tablet has a maximum pore diameter
of no more than 4 .mu.m, such as no more than 3.5 .mu.m or no more
than 3 .mu.m. Porosity of compositions, including median pore
diameter and maximum pore diameter, of the invention may be
determined as described in Assay (IIa) or (IIb) herein.
[0047] Crushing strength of a tablet is the compressive stress
(diametrally applied) required to cause the tablet to fail by
fracture. In some embodiments the tablet has a crushing strength of
50-400 N, such as 50-300 N. In some embodiments the tablet has a
crushing strength of at least 50 N, such as at least 75 N or at
least 100 N. In some embodiments the tablet has a crushing strength
of no more than 300 N, such as no more than 250 N. Crushing
strength of compositions of the invention may be determined as
described in Assay (III) herein.
[0048] Disintegration time of compositions of the invention may be
determined as described in Assay (IV) herein. In some embodiments
the tablet has a disintegration time of 11-18 minutes, such as
12-18 minutes, 12-17 minutes or 13-15 minutes. In some embodiments
the tablet has a disintegration time of 11-18 minutes, such as
12-18 minutes, 12-17 minutes or 13-15 minutes, and wherein said
tablet has a total weight of 300-500 mg, such as 250-750 mg, and
comprises at least 60% (w/w) salt of NAC. In some embodiments the
disintegration time is no more than 22 minutes and/or the bulk
density is no more than 1.19 g/cm.sup.3. In some embodiments the
disintegration time is no more than 21 minutes, such as no more
than 20 minutes. In some embodiments the tablet of the invention
the active ingredient(s) and the delivery agent are released by
surface erosion; hence, the tablets becomes smaller and smaller
with time by dissolution primarily from the surface from
non-disintegrated tablets. Surface erosion can be shown by visual
inspection during the disintegration test; the tablets are surface
eroding if the tablet does not break into smaller parts during the
first 8 minutes of the disintegration test.
[0049] Dissolution of compositions of the invention may be
determined as described in Assay (V) herein. In some embodiments
the peptide and the salt of NAC are co-released from the tablet as
determined by Assay (V) as described herein. In some embodiment
co-release of two or more ingredients is defined as dissolved
relative amounts of said ingredients within +/-50%, such as +/-25%
or +/-10%, of the ingredient having the highest dissolved relative
amount compared to the ingredient having the lowest dissolved
relative amount at any point in time during the dissolution test
according to Assay (V) as described herein; wherein the dissolved
relative amount is the amount of an ingredient in solution relative
to the total amount of said ingredient.
[0050] Oral bioavailability and absorption kinetics of the
composition of the invention may be determined according to Assay
(VI) as described herein.
[0051] Cmax is herein used in connection with salt of NAC for the
maximum concentration of salt of NAC in blood plasma after
administration and prior to the administration of a second dose,
i,e. the peak plasma concentration of salt of NAC after
administration.
Peptides
[0052] In some embodiments the composition of the invention
comprises a peptide. In some embodiments the peptide comprises a
lipophilic side chain, such as a peptide comprising an alkyl moiety
with at least 14 carbon atoms. In some embodiments the peptide is
an acylated peptide. In some embodiments the peptide comprises
substituent comprising a fatty acid or a fatty diacid, such as
formula (X)
##STR00001##
wherein n is at least 13. In some embodiments the peptide comprises
one or more 8-amino-3,6-dioxaoctanoic acid (OEG).
[0053] The systemic appearance in plasma of peptides comprising a
lipophilic side chain following oral administration is often
significantly prolonged relative to the same peptides without
lipophilic side chain. In some embodiments a peptide comprising a
lipophilic side chain has a protracted mode of action. In some
embodiments it is particularly advantageous when a peptide
comprising a lipophilic side chain is comprised in a tablet of the
invention. It has surprisingly been found by the inventors that a
tablet of the invention is particularly suitable when the active
component is a peptide comprising a lipophilic side chain. The
inventors thus surprisingly found that gradual release of a salt of
NAC from the tablet by surface erosion extend the absorption
profile of a peptide comprising a lipophilic side chain. In some
embodiment tablets of the invention cause a gradual release of salt
of NAC leading to a low Cmax in plasma of said salt of NAC in
subjects, such as a Cmax of less than 900 ng/ml upon oral
administration of a tablet comprising approximately 1 mmol salt of
NAC.
[0054] In some embodiments the amount of peptide is no more than
15% (w/w) or no more than 10% (w/w), such as 1-5% (w/w). In some
embodiments the peptide is in the intragranular part of the
composition.
[0055] In some embodiments the composition of the invention
comprises a GLP-1 peptide. The term "GLP-1 peptide" as used herein
refers to a compound, which fully or partially activates the human
GLP-1 receptor. In some embodiments the "GLP-1 peptide" binds to a
GLP-1 receptor, e.g., with an affinity constant (K.sub.D) or
activate the receptor with a potency (EC.sub.50) of below 1 .mu.M,
e.g. below 100 nM as measured by methods known in the art (see e.g.
WO98/08871) and exhibits insulinotropic activity, where
insulinotropic activity may be measured in vivo or in vitro assays
known to those of ordinary skill in the art. For example, the GLP-1
peptide may be administered to an animal with increased blood
glucose (e.g. obtained using an Intravenous Glucose Tolerance Test
(IVGTT), a person skilled in the art will be able to determine a
suitable glucose dosage and a suitable blood sampling regime, e.g.
depending on the species of the animal, for the IVGTT) and the
plasma insulin concentration measured over time.
[0056] In some embodiments the GLP-1 peptide is a GLP-1 analogue,
optionally comprising one substituent. The term "analogue" as used
herein referring to a GLP-1 peptide (hereafter "peptide") means a
peptide wherein at least one amino acid residue of the peptide has
been substituted with another amino acid residue and/or wherein at
least one amino acid residue has been deleted from the peptide
and/or wherein at least one amino acid residue has been added to
the peptide and/or wherein at least one amino acid residue of the
peptide has been modified. Such addition or deletion of amino acid
residues may take place at the N-terminal of the peptide and/or at
the C-terminal of the peptide. In some embodiments a simple
nomenclature is used to describe the GLP-1 peptide, e.g., [Aib8]
GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein the
naturally occurring Ala in position 8 has been substituted with
Aib. In some embodiments the GLP-1 peptide comprises a maximum of
twelve, such as a maximum of 10, 8 or 6, amino acids which have
been alterered, e.g., by substitution, deletion, insertion and/or
modification, compared to e.g. GLP-1(7-37). In some embodiments the
analogue comprises up to 10 substitutions, deletions, additions
and/or insertions, such as up to 9 substitutions, deletions,
additions and/or insertions, up to 8 substitutions, deletions,
additions and/or insertions, up to 7 substitutions, deletions,
additions and/or insertions, up to 6 substitutions, deletions,
additions and/or insertions, up to 5 substitutions, deletions,
additions and/or insertions, up to 4 substitutions, deletions,
additions and/or insertions or up to 3 substitutions, deletions,
additions and/or insertions, compared to e.g. GLP-1(7-37). Unless
otherwise stated the GLP-1 comprises only L-amino acids.
[0057] In some embodiments the term "GLP-1 analogue" or "analogue
of GLP-1" as used herein refers to a peptide, or a compound, which
is a variant of the human Glucagon-Like Peptide-1 (GLP-1(7-37)).
GLP-1(7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ
ID No: 1). In some embodiments the term "variant" refers to a
compound which comprises one or more amino acid substitutions,
deletions, additions and/or insertions.
[0058] In some embodiments the GLP-1 peptide exhibits at least 60%,
65%, 70%, 80% or 90% sequence identity to GLP-1(7-37) over the
entire length of GLP-1(7-37). As an example of a method for
determination of sequence identity between two analogues the two
peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) are aligned. The
sequence identity of [Aib8]GLP-1(7-37) relative to GLP-1(7-37) is
given by the number of aligned identical residues minus the number
of different residues divided by the total number of residues in
GLP-1(7-37). Accordingly, in said example the sequence identity is
(31-1)/31.
[0059] In some embodiments the C-terminal of the GLP-1 peptide is
an amide.
[0060] In some embodiments the GLP-1 peptide is GLP-1(7-37) or
GLP-1(7-36)amide. In some embodiments the GLP-1 peptide is
exendin-4, the sequence of which is
HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID No: 2).
[0061] In some embodiments the GLP-1 peptide comprises one
substituent which is covalently attached to the peptide. In some
embodiments the substituent comprises a fatty acid or a fatty
diacid. In some embodiments the substituent comprises a C16, C18 or
C20 fatty acid. In some embodiments the substituent comprises a
C16, C18 or C20 fatty diacid. In some embodiments the substituent
comprises formula (X)
##STR00002##
wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or
19. In some embodiments the substituent comprises formula (X),
wherein n is in the range of 13 to 19, such as in the range of 13
to 17. In some embodiments the substituent comprises formula (X),
wherein n is 13, 15 or 17. In some embodiments the substituent
comprises formula (X), wherein n is 13. In some embodiments the
substituent comprises formula (X), wherein n is 15. In some
embodiments the substituent comprises formula (X), wherein n is 17.
In some embodiments the substituent comprises one or more
8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEG.
[0062] In some embodiments the substituent is
[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryla-
mino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].
[0063] In some embodiments the substituent is
[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamin-
o)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}-ethoxy)acetylamino-
]ethoxy}ethoxy)acetyl].
[0064] In some embodiments the GLP-1 peptide is semaglutide, also
known as
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylam-
ino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg-
34]GLP-1(7-37), which may be prepared as described in
WO2006/097537, Example 4.
[0065] In some embodiments the composition comprises the GLP-1
peptide or a pharmaceutically acceptable salt, amide, or ester
thereof. In some embodiments the composition comprises the GLP-1
peptide one or more pharmaceutically acceptable counter ions.
[0066] In some embodiments the dosage of GLP-1 is in the range of
0.01 mg to 100 mg. In some embodiments the composition or granulate
comprises an amount of a GLP-1 peptide in the range of at least 1
mg, such as at least 5 mg or at least 10 mg. In some embodiments
the composition or granulate comprises 10 mg GLP-1 peptide.
[0067] In some embodiments the composition comprises an amount of a
GLP-1 peptide in the range of 0.05 to 25 .mu.mol, such as in the
range of 0.5 to 20 .mu.mol.
[0068] In some embodiments the GLP-1 peptide is selected from one
or more of the GLP-1 peptides mentioned in WO93/19175, WO96/29342,
WO98/08871, WO99/43707, WO99/43706, WO99/43341, WO99/43708,
WO2005/027978, WO2005/058954, WO2005/058958, WO2006/005667,
WO2006/037810, WO2006/037811, WO2006/097537, WO2006/097538,
WO2008/023050, WO2009/030738, WO2009/030771 and WO2009/030774.
[0069] In some embodiments the GLP-1 peptide is selected from the
group consisting of
N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxponadecanoyl)pip-
eridine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]e-
thoxy}acetyl-[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;
N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)pi-
peridine-4-carbonyl]amino}propionylamino)-ethoxy]ethoxy}acetylamino)ethoxy-
]ethoxy}acetyl[desaminoHis7,Arg34]GLP-1-(7-37);
N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)p-
iperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy-
]ethoxy}acetyl-[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidi-
n-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)-ethoxy]acetylamino)eth-
oxy]ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-(7-37-
)amide;
N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylam-
ino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)m-
ethyl]-cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-
-37);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadec-
anoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)ac-
etyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]-cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethox-
y)acetylamino]ethoxy}ethoxy)acetyl]-[Aib8,Arg34]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}-ethox-
y)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7--
37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-ca-
rboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]etho-
xy}ethoxy)-acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg3-
4,Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-non-
adecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy-
)-acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(-
7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)-methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethox-
y)acetylamino]ethoxy}ethoxy)-acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]-
GLP-1-(7-37);
N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecano-
ylamino)methyl]cyclohexanecarbonyl}amino)-butyrylamino]ethoxy}ethoxy)acety-
lamino]ethoxy}ethoxy)acetyl[Aib8,Lys26]GLP-1 (7-37)amide;
N-epsilon26
[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxponadecanoylamino]-methyl)cyc-
lohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)-et-
hoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1 (7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]cyclohexane-carbonyl}
amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]
[DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]cyclohexanecarbonyl}
amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Desami-
noHis7,Glu22, Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetr-
azol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)
butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamin-
o) butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}
butyrylamino)butyrylamino]ethoxy}ethoxy)
acetyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoylsulfamoyl)butyrylamino]
butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]G-
LP-1-(7-34);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamin-
o) butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoylsulfamoyl)
butyrylamino]hexanoylamino}butyrylamino)
butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}
butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}
butyrylamino)butyrylamino]
ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoylsulfamoyl)butyrylamino]
hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]-
GLP-1-(7-36)amide;
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetr-
azol-5-yl)hexadecanoylsulfamoyl)
butyrylamino]hexanoylamino}butyrylamino)
butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-ami-
no)butyrylamino]ethoxy}
ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);
N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoylsulfamoyl)butyrylamino]
dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg3-
4]GLP-1-(7-36)amide;
N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4--
carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfam-
oyl) butyrylamino]dodecanoylamino}butyrylamino)
butyrylamino]ethoxy}ethoxy)
acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}et-
hoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys2-
6,Arg34]GLP-1-(7-36)amide;
N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoylsulfamoyl)butyrylamino]
dodecanoylamino}butyrylamino)
butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7--
37)amide;
N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(1-
6-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}but-
yrylamino) butyrylamino]
ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)am-
ide;
N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecano-
yl) piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}
acetylamino)ethoxy] ethoxy}acetyl
[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;
N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxponadecanoyl)
piperidine-4-carbonyl]amino} propionylamino)
ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,
Arg26,Arg34, Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperid-
in-4-ylcarbonylamino]3-carboxy-propionylamino) ethoxy)ethoxy]
acetylamino) ethoxy] ethoxy)acetyl] [DesaminoHis7, Glu22,Arg26,
Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl] cyclohexanecarbonyl}
amino)butyrylamino]ethoxy} ethoxy)acetylamino]
ethoxy}ethoxy)acetyl]
[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]cyclohexane-carbonyl}
amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl]
[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino)methyl]
cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)
acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,
Lys37]GLP-1-(7-37);
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-non-
adecanoylamino) methyl]cyclohexane-carbonyl}amino)
butyrylamino]ethoxy}ethoxy) acetylamino] ethoxy}ethoxy)acetyl]
[DesaminoHis7,Glu22,Arg26,Glu30,Arg34, Lys37]GLP-1-(7-37);
N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoyl-sulfamoyl) butyrylamino]dodecanoylamino}
butyrylamino) butyrylamino] ethoxy}ethoxy)acetyl]
[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tet-
razol-5-yl)hexadecanoylsulfamoyl)
butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]
ethoxy}ethoxy)acetyl]
[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy)
ethoxy) ethoxy))
propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amid-
e;
N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-a-
mino)ethoxy) ethoxy]
acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,
Glu30,Arg34,Lys37] GLP-1-(7-37)amide;
N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-am-
ino) ethoxy)ethoxy]acetyl)ethoxy)ethoxy)
acetyl)}-[desaminoHis7,Glu22, Arg26, Arg34,Lys37]GLP-1-(7-37)amide;
N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)
acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)
acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;
N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl)
butyryl] [DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylami-
no) butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy} ethoxy)acetyl]
[DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);
N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(-
19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}
butyrylamino)ethoxy]ethoxy}
acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);
N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-
-yl)-hexadecanoylsulfamoyl]
butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamin-
o} ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]
GLP-1 (7-37);
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptad-
ecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-a-
cetyl] [Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);
N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylami-
no)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]
[Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoyla-
mino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]
[desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);
N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoyla-
mino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]
[desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1-(7-37)-Glu-Lys
peptide;
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-ca-
rboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]etho-
xy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]G-
LP-1-(7-37);
N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoyla-
mino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[-
Aib8,Glu22, Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);
N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylam-
ino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino)
butyryl] [Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);
N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]
[ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);
N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)
decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)
ethoxy]acetyl},
N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)
decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)
ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26
(17-carboxyhepta-decanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;
N-epsilon26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyhamino]meth-
yl}benzoyl[Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy] acetylamino)
ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carbo-
xybutyrylamino]ethoxy)ethoxy]
acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy]
acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1--
(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(c-
arboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)ace-
tyl][Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-Sulf-
opropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34-
]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34-
] GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34-
]GLP-1-(7-37)-amide;
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carb-
oxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]
[Aib8,Arg34,Pro37]GLP-1-(7-37)amide;
Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carbox-
ybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy) ethoxy)acetyl)}),
Arg34)GLP-1 H(7-37)-OH;
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptad-
ecanoyl)amino]methyl}benzoyl)amino]ethoxy)
ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);
N-alpha7-formyl,
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-car-
boxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]
[Arg34]GLP-1-(7-37);
N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-ca-
rboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,
Glu22, Arg34] GLP-1-(7-37);
N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N--((S)-1,3-dicarboxypropyl-
) carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino]
ethoxy)ethoxy] ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}
[Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-hepta-
decanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)
ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);
N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-car-
boxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamin-
o) butyrylamino} [Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,A-
rg34]GLP-1-(7-37);
N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)--
4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}
ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);
N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxy-
butyrylamino)
ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37-
, Lys26] GLP-1 (7-37)amide;
N-epsilon26-[2-(2-[2-[4-(21-carboxpneicosanoylamino)-4(S)-carboxybutyryla-
mino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); and
N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxpneicosanoylamino)-4(S)-carbox-
ybutyrylamino]
ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).
[0070] In some embodiments the GLP-1 peptide is
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylam-
ino)butyrylamino]ethoxy}ethoxy)acetylamino]-ethoxy}ethoxy)acetyl][Aib8,Arg-
34]GLP-1(7-37), also known as semaglutide.
Salt of NAC
[0071] The delivery agent used in the present invention is a salt
of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC). In some
embodiments the delivery agent is an absorption enhancer. The
structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is
shown in formula (I).
##STR00003##
[0072] In some embodiments the amount of salt of NAC is at least
50% (w/w) or at least 60% (w/w), such as 50-90% (w/w), 55-85% (w/w)
or 70-80% (w/w), or such as 65-75 (w/w), 60-80% (w/w), or 50-90%
(w/w). In some embodiments the salt of NAC is in the intragranular
part of the composition.
[0073] In some embodiments the salt of NAC comprises one monovalent
cation, two monovalent cations or one divalent cation. In some
embodiments the salt of NAC is selected from the group consisting
of the sodium salt, potassium salt and calcium salt of NAC.
[0074] The salts of NAC may be prepared using the method described
in e.g. WO96/030036, WO00/046182, WO01/092206 or WO2008/028859.
[0075] The salt of NAC may be crystalline and/or amorphous. In some
embodiments the delivery agent comprises any hydrate, solvate
and/or anhydrate form of the salt of NAC, such as the anhydrate,
monohydrate, dihydrate, trihydrate, a solvate or one third of a
hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino) caprylic acid
as well as combinations thereof. In some embodiments the delivery
agent is a salt of NAC as described in WO2007/121318.
[0076] In some embodiments the delivery agent is sodium NAC
(referred to as "SNAC" herein), also known as sodium
8-(salicyloylamino)octanoate.
[0077] In some embodiments the amount of the salt of
N-(8-(2-hydroxybenzoyl)amino)-caprylic acid in the composition is
in the range of 0.6-3.5 mmol. In some embodiments the amount of the
salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the
composition is at least 0.6 mmol, such as selected from the group
at least 0.8 mmol or at least 0.9 mmol. In some embodiments the
amount of the salt of NAC in the composition is up to 2.5 mmol. In
some embodiments the amount of the salt of NAC is 1 mmol, such as
1.08 mmol.
[0078] In some embodiments the amount of SNAC in the composition is
in the range of 100-1000 mg. In some embodiments the amount of SNAC
in the composition is at least 150 mg, such as or at least 250 mg.
In some embodiments the amount of SNAC in the composition is up to
800 mg, such as up to 700 mg or up to 600 mg. In some embodiments
the amount of SNAC in the composition is 300 mg.
[0079] In some embodiments the molar ratio between the peptide and
the salt of NAC in the tablet is 1:10 or more, i.e. the salt of NAC
is in 10 fold excess of the peptide or more when measured in moles,
such as 1:50 or more, or 1:100 or more.
Method of Controlling Tablet Porosity
[0080] In some embodiments the invention relates to a method for
controlling porosity of a group of tablets, said method comprising
the steps of: a) determining the near-infrared (NIR) spectrum of a
selection of tablets, b) comparing said spectrum to a reference NIR
spectrum or performing a statistical analysis of said spectrum to
determine the tablet porosity, and c) selecting a subgroup of
tablets with a NIR spectrum or porosity within a predetermined
range. In some embodiments said method for controlling porosity is
an at-line NIR method. As used herein, the term "at-line NIR
method" is intended to mean a method wherein a NIR spectrometer is
placed next to tabletting press and measurement needs an operator
to remove and analyse tablets. In some embodiments said method for
controlling porosity is an in-line NIR method. As used herein, the
term "in-line NIR method" is intended to mean a method wherein a
NIR spectrometer is attached to the tabletting press and
measurement is performed automatically. In some embodiments said
method for controlling porosity comprises continuous measurement of
porosity. In some embodiments said method for controlling porosity
comprises comparison of said spectrum to a reference spectrum. In
some embodiments said method for controlling porosity comprises
adjustment of tabletting parameters during tabletting in order to
improve the porosity of the tablets. In some embodiments said
method for controlling porosity comprises obtaining a subgroup of
tablets with the desired porosity. In some embodiments said method
for controlling porosity said tablet is as defined herein. In some
embodiments the term "a group of tablets" is intended to mean at
least two tablets, such as at least 10 tablets, 5-100 or 20-50
tablets.
Pharmaceutical Indications
[0081] The present invention also relates to a composition or a
granulate of the invention for use as a medicament. In some
embodiments the composition or the granulate is administered
orally.
[0082] In particular embodiments, the composition or a granulate of
the invention may be used for the following medical treatments, all
preferably relating one way or the other to diabetes:
[0083] (i) prevention and/or treatment of all forms of diabetes,
such as hyperglycemia, type 2 diabetes, impaired glucose tolerance,
type 1 diabetes, non-insulin dependent diabetes, MODY (maturity
onset diabetes of the young), gestational diabetes, and/or for
reduction of HbA1C;
[0084] (ii) delaying or preventing diabetic disease progression,
such as progression in type 2 diabetes, delaying the progression of
impaired glucose tolerance (IGT) to insulin requiring type 2
diabetes, and/or delaying the progression of non-insulin requiring
type 2 diabetes to insulin requiring type 2 diabetes;
[0085] (iii) improving .beta.-cell function, such as decreasing
.beta.-cell apoptosis, increasing .beta.-cell function and/or
.beta.-cell mass, and/or for restoring glucose sensitivity to
.beta.-cells;
[0086] (iv) prevention and/or treatment of cognitive disorders;
[0087] (v) prevention and/or treatment of eating disorders, such as
obesity, e.g. by decreasing food intake, reducing body weight,
suppressing appetite, inducing satiety; treating or preventing
binge eating disorder, bulimia nervosa, and/or obesity induced by
administration of an antipsychotic or a steroid; reduction of
gastric motility; and/or delaying gastric emptying;
[0088] (vi) prevention and/or treatment of diabetic complications,
such as neuropathy, including peripheral neuropathy; nephropathy;
or retinopathy;
[0089] (vii) improving lipid parameters, such as prevention and/or
treatment of dyslipidemia, lowering total serum lipids; lowering
HDL; lowering small, dense LDL; lowering VLDL: lowering
triglycerides; lowering cholesterol; increasing HDL; lowering
plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting
generation of apolipoprotein a (apo(a)) in vitro and/or in
vivo;
[0090] (iix) prevention and/or treatment of cardiovascular
diseases, such as syndrome X; atherosclerosis; myocardial
infarction; coronary heart disease; stroke, cerebral ischemia; an
early cardiac or early cardiovascular disease, such as left
ventricular hypertrophy; coronary artery disease; essential
hypertension; acute hypertensive emergency; cardiomyopathy; heart
insufficiency; exercise tolerance; chronic heart failure;
arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis; mild
chronic heart failure; angina pectoris; cardiac bypass reocclusion;
intermittent claudication (atheroschlerosis oblitterens); diastolic
dysfunction; and/or systolic dysfunction;
[0091] (ix) prevention and/or treatment of gastrointestinal
diseases, such as inflammatory bowel syndrome; small bowel
syndrome, or Crohn's disease; dyspepsia; and/or gastric ulcers;
[0092] (x) prevention and/or treatment of critical illness, such as
treatment of a critically ill patient, a critical illness
poly-nephropathy (CIPNP) patient, and/or a potential CIPNP patient;
prevention of critical illness or development of CIPNP; prevention,
treatment and/or cure of systemic inflammatory response syndrome
(SIRS) in a patient; and/or for the prevention or reduction of the
likelihood of a patient suffering from bacteraemia, septicaemia,
and/or septic shock during hospitalisation; and/or
[0093] (xi) prevention and/or treatment of polycystic ovary
syndrome (PCOS).
[0094] In a particular embodiment, the indication is selected from
the group consisting of (i)-(iii) and (v)-(iix), such as
indications (i), (ii), and/or (iii); or indication (v), indication
(vi), indication (vii), and/or indication (iix).
[0095] In another particular embodiment, the indication is (i). In
a further particular embodiment the indication is (v). In a still
further particular embodiment the indication is (iix).
[0096] In some embodiments the invention relates to a composition
or a granulate of the invention for treatment of diabetes or
obesity, wherein said granulate is administered orally. In some
embodiments the invention relates to a method for treatment of
diabetes or obesity comprising oral administration of a composition
comprising a composition or a granulate of the invention to a
patient in need thereof.
[0097] The following indications are particularly preferred: Type 2
diabetes, and/or obesity.
Embodiments of the Invention
[0098] The following are non-limiting examples of embodiments of
the invention:
1. A tablet comprising a granulate comprising i) no more than 15%
(w/w) peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0099] a) a bulk density of at least 0.90 g/cm.sup.3;
[0100] b) a median pore diameter of no more than 1.5 .mu.m; and/or
[0101] c) a maximum pore diameter of no more than 4 .mu.m. 2. A
tablet comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0102] a) a bulk density of at least 0.90 g/cm.sup.3;
[0103] b) a median pore diameter of no more than 1.5 .mu.m; [0104]
c) a maximum pore diameter of no more than 4 .mu.m; and/or [0105]
d) a crushing strength of at least 50 N, such as 50-400 N. 3. A
tablet comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0106] a) a bulk density, such as a bulk density, of at
least 0.90 g/cm.sup.3; [0107] b) a median pore diameter of no more
than 1.5 .mu.m; [0108] c) a maximum pore diameter of no more than 4
.mu.m; [0109] d) a crushing strength of at least 50 N, such as
50-400 N; and/or [0110] e) a disintegration time of 12-18 minutes
for a tablet with a total weight of 300-500 mg comprising at least
60% (w/w) salt of NAC.4. A tablet according to any one of the
preceding embodiments, wherein said tablet does not contain a
disintegrant.5. A tablet according to any one of the preceding
embodiments, wherein said disintegration time is no more than 22
minutes and/or said bulk density is no more than 1.19 g/cm.sup.3.
6. A tablet according to any one of the preceding embodiments,
wherein said peptide comprises substituent comprising a fatty acid
or a fatty diacid, such as formula (X)
##STR00004##
[0110] wherein n is at least 13. 7. A tablet according to any one
of the preceding embodiments, wherein said peptide comprises one or
more 8-amino-3,6-dioxaoctanoic acid (OEG). 8. A tablet according to
any one of the preceding embodiments, wherein said peptide is an
acylated peptide or a GLP-1 peptide, such as an acylated GLP-1
peptide. 9. A tablet according to any one of the preceding
embodiments, wherein said tablet is for oral administration. 10. A
tablet according to any one of the preceding embodiments, wherein
the amount of peptide is no more than 10% (w/w), such as 1-5%
(w/w). 11. A tablet according to any one of the preceding
embodiments, wherein the amount of said salt of NAC is 50-90%
(w/w), such as 55-85% (w/w) or 70-80% (w/w). 12. A tablet according
to any one of the preceding embodiments, wherein said tablet
comprises a lubricant, such as magnesium stearate. 13. A tablet
according to any one of the preceding embodiments, wherein the
amount of said lubricant is no more than 3% (w/w), such as 1.5-3.0%
(w/w). 14. A tablet according to any one of the preceding
embodiments, wherein said tablet comprises a binder, such as
povidone. 15. A tablet according to any one of the preceding
embodiments, wherein said granulate comprises a filler, such as
microcrystalline cellulose. 16. A tablet according to any one of
the preceding embodiments, wherein said tablet comprises a
granulate comprising said peptide, said salt of NAC and optionally
a binder. 17. A tablet according to any one of the preceding
embodiments, wherein said tablet comprises an intragranular and an
extragranular part, wherein said extragranular part comprises said
lubricant and optionally a filler. 18. A tablet according to any
one of the preceding embodiments, wherein said peptide is a GLP-1
peptide, such as semaglutide. 19. A tablet according to any one of
the preceding embodiments, wherein said salt of NAC is monosodium
NAC (SNAC), such as anhydrous SNAC monosodium salt. 20. A tablet
according to any one of the preceding embodiments, wherein said
tablet comprises
[0111] a) a granulate comprising [0112] i) 1-15% (w/w) peptide,
[0113] ii) 55-85% (w/w) salt of NAC, and [0114] iii) 1-20% (w/w)
binder;
[0115] b) 10-35% (w/w) filler; and
[0116] c) 0.5-3% (w/w) lubricant.
21. A tablet according to any one of the preceding embodiments,
wherein said tablet comprises
[0117] a) a granulate comprising [0118] i) 1-100 mg, such as 10 mg,
peptide, [0119] ii) 100-1000 mg, such as 300 mg, salt of NAC, and
[0120] iii) 1-20 mg, such as 8 mg, binder;
[0121] b) 20-200 mg, such as 100 mg, filler; and
[0122] c) 0.5-8 mg, such as 2-8 mg, lubricant.
22. A tablet according to any one of the preceding embodiments,
wherein said tablet was prepared by exerting a compression force of
at least 5 kN, such as at least 10 kN or at least 15 kN, or no more
than 25 kN, such as no more than 20 kN or 5-25 kN. 23. A tablet
according to any one of the preceding embodiments, wherein said
tablet has a weight of 300-500 mg. 24. A tablet according to any
one of the preceding embodiments, wherein said tablet has a bulk
density of at least 0.90 g/cm.sup.3, such as at least 0.95
g/cm.sup.3 or at least 1.0 g/cm.sup.3, or such as at least 1.1
g/cm.sup.3 or at least 1.2 g/cm.sup.3. 25. A tablet according to
any one of the preceding embodiments, wherein said tablet has a
median pore diameter of no more than 1.5 .mu.m, such as no more
than 1.3 .mu.m or no more than 1.0 .mu.m. 26. A tablet according to
any one of the preceding embodiments, wherein said tablet has a
maximum pore diameter of no more than 4 .mu.m, such as no more than
3.5 .mu.m or no more than 3 .mu.m. 27. A tablet according to any
one of the preceding embodiments, wherein said tablet has a
crushing strength of at least 50 N, such as at least 100 N. 28. A
tablet according to any one of the preceding embodiments, wherein
said tablet has a disintegration time of 11-18 minutes, such as
12-18 minutes, 12-17 minutes or 13-15 minutes, and wherein said
tablet has a total weight of 300-500 mg and comprises at least 60
(w/w) salt of NAC. 29. A tablet according to any one of the
preceding embodiments, wherein said density is determined by Assay
(Ia) as described herein. 30. A tablet according to any one of the
preceding embodiments, wherein said median pore diameter or maximum
pore diameter is determined by Assay (IIb) as described herein. 31.
A tablet according to any one of the preceding embodiments, wherein
said crushing strength is determined by Assay (III) as described
herein. 32. A tablet according to any one of the preceding
embodiments, wherein said disintegration time is determined by
Assay (IV) as described herein. 33. A tablet as defined in any one
of the preceding embodiments for use in medicine. 34. A tablet as
defined in any one embodiments 1-32 for treating type 2 diabetes or
obesity. 35. A method for treating type 2 diabetes or obesity
comprising administering a tablet as defined in any one of
embodiments 1-32 to a patient in need thereof. 36. Use of a tablet
as defined in any one of embodiments 1-32 for the preparation of a
medicament. 37. Use of a tablet as defined in any one of
embodiments 1-32 for the preparation of a medicament for treating
type 2 diabetes or obesity. 38. A granulate comprising i) no more
than 15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC. 39.
A granulate according to embodiment 38, wherein said granulate
comprises i) 1-5% (w/w) peptide, ii) 55-85% (w/w) salt of NAC, and
iii) 1-20% (w/w) binder. 40. A granulate according to embodiment 38
or 39, wherein said granulate comprises i) 1-100 mg, such as 10 mg,
peptide, ii) 100-1000 mg, such as 300 mg, salt of NAC, and iii)
1-20 mg, such as 8 mg, povidone. 41. A granulate according to any
one of embodiments 38-40, wherein said granulate is as defined in
any one of embodiments 1-32. 42. A process for the preparation of a
tablet comprising a granulate comprising i) no more than 15% (w/w)
peptide, such as GLP-1 peptide, and ii) at least 50% (w/w) salt of
NAC, said process comprising the step of exerting a compression
force when punching said tablet of [0123] a) at least 5 kN, such as
5-25 kN, or [0124] b) at least 4 kN/cm.sup.2. 43. A process
according to embodiment 42, wherein said compression force is at
least 5 kN, such as 5-25 kN, at least 10 kN or at least 15 kN, orb)
at least 4 kN/cm.sup.2, such as at least 6 kN/cm.sup.2 or at least
8 kN/cm.sup.2. 44. A process according to embodiment 42 or 43,
wherein said compression force is no more than 25 kN, such as no
more than 20 kN. 45. A process according to any one of embodiments
42-44, wherein said process comprises a pre-compression step. 46. A
process according to any one of embodiments 42-45, wherein said
tablet is as defined in any one of embodiments 1-32. 47. A method
for controlling porosity of a group of tablets, said method
comprising the steps of: [0125] a) determining the near-infrared
(NIR) spectrum of a selection of tablets; [0126] b) comparing said
spectrum to a reference NIR spectrum, or performing a statistical
analysis of said spectrum to determine the tablet porosity; and
[0127] c) selecting a subgroup of tablets with a NIR spectrum or
porosity within a predetermined range. 48. A method according to
embodiment 47, wherein said method is an at-line NIR method. 49. A
method according to embodiment 47, wherein said method is an
in-line NIR method. 50. A method according to 49, wherein said
method comprises continuous measurement of porosity. 51. A method
according to any one of embodiments 47-50, wherein said spectrum is
compared to a reference spectrum. 52. A method according to any one
of embodiments 47-51, wherein tabletting parameters are adjusted
during tabletting in order to improve the porosity of the tablets.
53. An method according to any one of embodiments 47-52, wherein a
subgroup of tablets with the desired porosity is obtained. 54. A
method according to any one of embodiments 47-53, wherein said
tablet is as defined in any one of embodiments 1-32.
Further Embodiments of the Invention
[0128] The following are further non-limiting examples of
embodiments of the invention:
1. A tablet comprising a granulate comprising i) no more than 15%
(w/w) peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0129] a) a bulk density of at least 0.90 g/cm.sup.3;
[0130] b) a median pore diameter of no more than 1.5 .mu.m; and/or
[0131] c) a maximum pore diameter of no more than 4 .mu.m. 2. A
tablet comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0132] a) a bulk density of at least 0.90 g/cm.sup.3;
[0133] b) a median pore diameter of no more than 1.5 .mu.m; [0134]
c) a maximum pore diameter of no more than 4 .mu.m; and/or [0135]
d) a crushing strength of at least 50 N, such as 50-400 N. 3. A
tablet comprising a granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC, wherein said
tablet has [0136] a) a bulk density, such as a bulk density, of at
least 0.90 g/cm.sup.3; [0137] b) a median pore diameter of no more
than 1.5 .mu.m; [0138] c) a maximum pore diameter of no more than 4
.mu.m; [0139] d) a crushing strength of at least 50 N, such as
50-400 N; and/or [0140] e) a disintegration time of 12-18 minutes
for a tablet with a total weight of 300-500 mg comprising at least
60% (w/w) salt of NAC. 4. A tablet comprising a granulate
comprising i) no more than 15% (w/w) peptide, and ii) at least 60%
(w/w) salt of NAC, wherein said tablet has [0141] a) a bulk
density, such as a bulk density, of at least 0.90 g/cm.sup.3;
[0142] b) a median pore diameter of no more than 1.5 .mu.m; [0143]
c) a maximum pore diameter of no more than 4 .mu.m; [0144] d) a
crushing strength of at least 50 N, such as 50-400 N; and/or [0145]
e) a disintegration time of 12-18 minutes for a tablet with a total
weight of 300-500 mg comprising at least 60% (w/w) salt of NAC. 5.
A tablet comprising a granulate comprising i) no more than 15%
(w/w) peptide, and ii) at least 50% (w/w) salt of NAC, which has a
bulk density of at least 0.90 g/cm.sup.3; wherein said tablet
further has [0146] a) a median pore diameter of no more than 1.5
.mu.m; and/or [0147] b) a maximum pore diameter of no more than 4
.mu.m. 6. A tablet comprising a granulate comprising i) no more
than 15% (w/w) peptide, and ii) at least 50% (w/w) salt of NAC,
which has a bulk density of at least 0.90 g/cm.sup.3; wherein said
tablet further has [0148] a) a median pore diameter of no more than
1.5 .mu.m; [0149] b) a maximum pore diameter of no more than 4
.mu.m; and/or [0150] c) a crushing strength of at least 50 N, such
as 50-400 N. 7. A tablet comprising a granulate comprising i) no
more than 15% (w/w) peptide, and ii) at least 50% (w/w) salt of
NAC, which has a bulk density of at least 0.90 g/cm.sup.3; [0151]
wherein said tablet further has [0152] a) a median pore diameter of
no more than 1.5 .mu.m; [0153] b) a maximum pore diameter of no
more than 4 .mu.m; and/or [0154] c) a crushing strength of at least
50 N, such as 50-400 N; and/or [0155] d) a disintegration time of
12-18 minutes for said tablet with a total weight of 300-500 mg. 8.
A tablet according to any one of the preceding embodiments which is
surface eroding. 9. A tablet according to any one of the preceding
embodiments, wherein said tablet does not contain a
superdisintegrant. 10. A tablet according to any one of the
preceding embodiments, wherein said tablet does not contain sodium
starch glycolate, sodium carboxymethyl starch, crospovidone or
croscarmellose sodium. 11. A tablet according to any one of the
preceding embodiments, wherein the tablet is dry granulated. 12. A
tablet according to any one of the preceding embodiments, wherein
said disintegration time is no more than 22 minutes and/or said
bulk density is no more than 1.19 g/cm.sup.3. 13. A tablet
according to any one of the preceding embodiments, wherein said
peptide comprises substituent comprising a fatty acid or a fatty
diacid, such as formula (X)
##STR00005##
[0155] wherein n is at least 13. 14. A tablet according to any one
of the preceding embodiments, wherein said peptide comprises one or
more 8-amino-3,6-dioxaoctanoic acid (OEG). 15. A tablet according
to any one of the preceding embodiments, wherein said peptide is an
acylated peptide or a GLP-1 peptide, such as an acylated GLP-1
peptide. 16. A tablet according to any one of the preceding
embodiments, wherein said tablet is for oral administration. 17. A
tablet according to any one of the preceding embodiments, wherein
the amount of peptide is no more than 10% (w/w), such as 1-5%
(w/w). 18. A tablet according to any one of the preceding
embodiments, wherein the amount of said salt of NAC is 50-90%
(w/w), such as 55-85% (w/w) or 70-80% (w/w). 19. A tablet according
to any one of the preceding embodiments, wherein said tablet
comprises a lubricant, such as magnesium stearate. 20. A tablet
according to any one of the preceding embodiments, wherein the
amount of said lubricant is no more than 3% (w/w), such as 1.5-3.0%
(w/w). 21. A tablet according to any one of the preceding
embodiments, wherein said tablet comprises a binder, such as
povidone. 22. A tablet according to any one of the preceding
embodiments, wherein said granulate comprises a filler, such as
microcrystalline cellulose. 23. A tablet according to any one of
the preceding embodiments, wherein said tablet comprises a
granulate comprising said peptide, said salt of NAC and optionally
a binder. 24. A tablet according to any one of the preceding
embodiments, wherein said tablet comprises an intragranular and an
extragranular part, wherein said extragranular part comprises said
lubricant and optionally a filler. 25. A tablet according to any
one of the preceding embodiments, wherein said peptide is a GLP-1
peptide. 26. A tablet according to any one of the preceding
embodiments, wherein said peptide is
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylam-
ino)butyrylamino]-ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg-
34]GLP-1(7-37). 27. A tablet according to any one of the preceding
embodiments, wherein said salt of NAC is monosodium NAC (SNAC),
such as anhydrous SNAC monosodium salt. 28. A tablet according to
any one of the preceding embodiments, wherein said tablet comprises
[0156] a) a granulate comprising [0157] i) 1-15% (w/w) peptide,
[0158] ii) 55-85% (w/w) salt of NAC, and [0159] iii) 1-20% (w/w)
binder; [0160] b) 10-35% (w/w) filler; and [0161] c) 0.5-3% (w/w)
lubricant. 29. A tablet according to any one of the preceding
embodiments, wherein said tablet comprises [0162] a) a granulate
comprising [0163] i) 1-100 mg, such as 10 mg, peptide, [0164] ii)
100-1000 mg, such as 300 mg, salt of NAC, and [0165] iii) 1-20 mg,
such as 8 mg, binder; [0166] b) 20-200 mg, such as 100 mg, filler;
and [0167] c) 0.5-8 mg, such as 2-8 mg, lubricant. 30. A tablet
according to any one of the preceding embodiments, wherein said
tablet was prepared by exerting a compression force of at least 5
kN, such as at least 10 kN or at least 15 kN, or no more than 25
kN, such as no more than 20 kN or 5-25 kN. 31. A tablet according
to any one of the preceding embodiments, wherein said tablet has a
weight of 300-500 mg. 32. A tablet according to any one of the
preceding embodiments, wherein said tablet has a weight of 300-400
mg. 33. A tablet according to any one of the preceding embodiments,
wherein said tablet has a weight of about 300 mg. 34. A tablet
according to any one of the preceding embodiments, wherein said
tablet has a weight of about 400 mg. 35. A tablet according to any
one of the preceding embodiments, wherein said tablet has a weight
of about 430 mg, such as 427 mg. 36. A tablet according to any one
of the preceding embodiments, wherein said tablet has a bulk
density of at least 0.90 g/cm.sup.3, such as at least 0.95
g/cm.sup.3 or at least 1.0 g/cm.sup.3, or such as at least 1.1
g/cm.sup.3 or at least 1.2 g/cm.sup.3. 37. A tablet according to
any one of the preceding embodiments, wherein said tablet has a
bulk density of no more than 1.2 g/cm.sup.3, such as no more than
1.19 g/cm.sup.3. 38. A tablet according to any one of the preceding
embodiments, wherein said tablet has a bulk density of about 1.2
g/cm.sup.3, such as about 1.15 g/cm.sup.3. 39. A tablet according
to any one of the preceding embodiments, wherein said tablet has a
median pore diameter of no more than 1.5 .mu.m, such as no more
than 1.3 .mu.m or no more than 1.0 .mu.m. 40. A tablet according to
any one of the preceding embodiments, wherein said tablet has a
median pore diameter of about 92 nm. 41. A tablet according to any
one of the preceding embodiments, wherein said tablet has a maximum
pore diameter of no more than 4 .mu.m, such as no more than 3.5
.mu.m or no more than 3 .mu.m. 42. A tablet according to any one of
the preceding embodiments, wherein said tablet has a maximum pore
diameter of no more than 2.5 .mu.m, such as no more than 2 .mu.m,
no more than 1.5 .mu.m, or no more than 1 .mu.m. 43. A tablet
according to any one of the preceding embodiments, wherein said
tablet has a maximum pore diameter of about 0.1 .mu.m. 44. A tablet
according to any one of the preceding embodiments, wherein said
tablet has a crushing strength of at least 50 N, such as at least
100 N. 45. A tablet according to any one of the preceding
embodiments, wherein said tablet has a crushing strength of no more
than 400 N. 46. A tablet according to any one of the preceding
embodiments, wherein said tablet has a crushing strength of about
120 N. 47. A tablet according to any one of the preceding
embodiments, wherein said tablet has a disintegration time of 10-18
minutes, such as 10-17 minutes or 10-13 minutes, and wherein said
tablet has a total weight of 300-500 mg and comprises at least 60%
(w/w) salt of NAC. 48. A tablet according to any one of the
preceding embodiments, wherein said tablet has a disintegration
time of 11-18 minutes, such as 12-18 minutes, 12-17 minutes or
13-15 minutes, and wherein said tablet has a total weight of
300-500 mg and comprises at least 60 (w/w) salt of NAC. 49. A
tablet according to any one of the preceding embodiments, wherein
said tablet has a disintegration time of 9-11 minutes for a tablet
with a total weight of 300-500 mg and comprises at least 60% (w/w)
salt of NAC. 50. A tablet according to any one of the preceding
embodiments, which causes gradual release of said salt of NAC in
vivo. 51. A tablet according to any one of the preceding
embodiments, wherein Cmax in plasma of said salt of NAC is less
than 900 ng/ml upon oral administration of said tablet. 52. A
tablet according to any one of the preceding embodiments comprising
approximately 1 mmol salt of NAC, wherein Cmax in plasma of said
salt of NAC is less than 900 ng/ml upon oral administration of said
tablet. 53. A tablet according to any one of the preceding
embodiments, wherein said density is determined by Assay (Ia) as
described herein. 54. A tablet according to any one of the
preceding embodiments, wherein said median pore diameter or maximum
pore diameter is determined by Assay (IIb) as described herein. 55.
A tablet according to any one of the preceding embodiments, wherein
said crushing strength is determined by Assay (III) as described
herein. 56. A tablet according to any one of the preceding
embodiments, wherein said disintegration time is determined by
Assay (IV) as described herein. 57. A tablet comprising a granulate
comprising i) about 5% (w/w)
N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylam-
ino)butyrylamino]ethoxy}ethoxy)-acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg-
34]GLP-1(7-37), and ii) about 70% (w/w) salt of NAC, wherein said
tablet has [0168] a) a bulk density of about 1.15 g/cm.sup.3;
[0169] b) a median pore diameter of about 92 nm; [0170] c) a
maximum pore diameter of about 0.1 .mu.m; [0171] d) a crushing
strength of about 120 N; and [0172] e) a disintegration time of
9-11 minutes for a tablet with a total weight of about 430 mg, such
as 427 mg. 58. A tablet as defined in any one of the preceding
embodiments for use in medicine. 59. A tablet as defined in any one
of embodiments 1-57 for treating type 2 diabetes or obesity. 60. A
method for treating type 2 diabetes or obesity comprising
administering a tablet as defined in any one of embodiments 1-57 to
a patient in need thereof. 61. Use of a tablet as defined in any
one of embodiments 1-57 for the preparation of a medicament. 62.
Use of a tablet as defined in any one of embodiments 1-57 for the
preparation of a medicament for treating type 2 diabetes or
obesity. 63. A granulate comprising i) no more than 15% (w/w)
peptide, and ii) at least 50% (w/w) salt of NAC. 64. A granulate
according to embodiment 63, wherein said granulate comprises i)
1-5% (w/w) peptide, ii) 55-85% (w/w) salt of NAC, and iii) 1-20%
(w/w) binder. 65. A granulate according to embodiment 63 or 64,
wherein said granulate comprises i) 1-100 mg, such as 10 mg,
peptide, ii) 100-1000 mg, such as 300 mg, salt of NAC, and iii)
1-20 mg, such as 8 mg, povidone. 66. A granulate according to any
one of embodiments 63-65, wherein said granulate is as defined in
any one of embodiments 1-57. 67. A granulate according to any one
of embodiments 63-65 for use in a tablet according to any one of
embodiments 1-57. 68. A process for the preparation of a tablet
comprising a granulate comprising i) no more than 15% (w/w)
peptide, such as GLP-1 peptide, and ii) at least 50% (w/w) salt of
NAC, said process comprising the step of exerting a compression
force when punching said tablet of [0173] a) at least 5 kN, such as
5-25 kN, or [0174] b) at least 4 kN/cm.sup.2. 69. A process
according to embodiment 68, wherein said compression force is at
least 5 kN, such as 5-25 kN, at least 10 kN or at least 15 kN, orb)
at least 4 kN/cm.sup.2, such as at least 6 kN/cm.sup.2 or at least
8 kN/cm.sup.2. 70. A process according to embodiment 68 or 69,
wherein said compression force is no more than 25 kN, such as no
more than 20 kN. 71. A process according to any one of embodiments
68-70, wherein said process comprises a pre-compression step. 72. A
process according to any one of embodiments 68-71, wherein said
tablet is as defined in any one of embodiments 1-57. 73. A method
for controlling porosity of a group of tablets, said method
comprising the steps of:
[0175] a) determining the near-infrared (NIR) spectrum of a
selection of tablets;
[0176] b) comparing said spectrum to a reference NIR spectrum, or
performing a statistical analysis of said spectrum to determine the
tablet porosity; and
[0177] c) selecting a subgroup of tablets with a NIR spectrum or
porosity within a predetermined range.
74. A method according to embodiment 73, wherein said method is an
at-line NIR method. 75. A method according to embodiment 73,
wherein said method is an in-line NIR method. 76. A method
according to 75, wherein said method comprises continuous
measurement of porosity. 77. A method according to any one of
embodiments 73-76, wherein said spectrum is compared to a reference
spectrum. 78. A method according to any one of embodiments 73-77,
wherein tabletting parameters are adjusted during tabletting in
order to improve the porosity of the tablets. 79. A method
according to any one of embodiments 73-78 having a further step
between step b) and c), wherein tablet compression force is
adjusted based on results from step b) to obtain a group of tables
with the desired porosity. 80. A method according to embodiment 79,
wherein tablet compression force in said further step between step
b) and c) is reduced if results from step b) show that porosity of
the tablets is lower than desired, or increased if results from
step b) show that porosity of the tablets is higher than desired.
81. A method according to any one of embodiments 73-78, wherein a
subgroup of tablets with the desired porosity is obtained. 82. A
method according to any one of embodiments 73-81, wherein said
tablet is as defined in any one of embodiments 1-57.
Examples
Materials and Methods
[0178] The GLP-1 compound semaglutide may be prepared using the
method described in WO2006/097537, Example 4.
[0179] The delivery agent SNAC may be prepared using the method
described in WO00/046182 or WO2008/028859.
General Methods of Preparation
[0180] The manufacturing process of tablets comprised of 3 major
unit processes, i.e. granulation, blending and compression. The
manufacturing process additionally comprised a number of secondary
unit operations such as dry-sieving of granulate and sieving of
excipients, which may be carried out according to common general
knowledge of a skilled person.
Wet Granulation
[0181] For a batch size of 160 tablets (48 g SNAC) typically 13.8
ml water was used for wet granulation. Approximately 80% (w/w) of
the total amount of water was filled into a vial and peptide (e.g.
GLP-1) was added. The vial was placed on a Boule mixer, which
gently tumbled the vial until all the material was dissolved. Then
pH was adjusted to 8.5 with 1-2 N NaOH solution or 0.2 N HCl
solution. Finally, water was added in order to obtain 100% of the
total amount of water.
[0182] SNAC and Povidone were blended in a high-shear mixer, such
as Diosna high-shear mixer or Rowenta mixer, for 1-3 minutes. Then
the granulation solution with dissolved peptide (e.g. GLP-1) was
added with a uniform rate over 1-2 minutes using a pipette or
syringe. Purified water was added if more granulation fluid was
needed. The wet granulation was stopped 10-15 seconds after
addition of the granulation solution. The granulate was dried in an
oven for minimum 16 hours at 45.degree. C. to a moisture content
lower than 2.5% as determined by Karl Fisher titration or loss on
drying. The dried granulate was passed through a 0.5 mm sieve.
[0183] This method is also referred to as "wet" herein.
Dry Granulation--Method A
[0184] Dry granulation was performed by roller compaction of a
blend of SNAC, semaglutide, povidone, microcrystalline cellulose
and magnesium stearate on a Gerteis Micro-Pactor.RTM.. Ribbons were
milled with a KitchenAid mill and sieved through a 500 .mu.m mesh.
The granulated powder was further blended with extragranular
magnesium stearate (2.3 mg per tablet) for 3 minutes on a Turbula
mixer before compression into tablets.
[0185] This method is also referred to as "dry A" herein.
Dry Granulation--Method B
[0186] A blend of SNAC and magnesium stearate in the mass ratio
195:5 (SNAC:magnesium stearate) was dry granulated. The remaining
magnesium stearate was added extragranularly during blending
subsequent to dry granulation. Dry granulation was carried out by
roller compaction on a Gerteis MINI-PACTOR using smooth rolls, a
0.63 mm wire mesh screen, and a granulator speed of 60 rpm. The
roll speed was set at 1.5 or 3.0 rpm and roller compaction forces
around 1 to 13 kN/cm were applied at a gap of 1.0 mm. Subsequent to
dry granulation comminution of the moldings into granules was
carried out.
[0187] This method is also referred to as "dry B" herein.
Blending
[0188] The granules were blended with extragranular excipients
(e.g. filler and lubricant) in several sub-steps before
compression. Blending was first done with microcrystalline
cellulose for 8-10 minutes and then with extragranular magnesium
stearate for 3 minutes on a Turbula mixer at 32 rpm in an equal
volume to volume manner.
Compression
[0189] The powder blend was compressed into tablets on e.g. a Fette
102i rotary tablet press, a Korsch PH 100 tablet press, or a DIAF
single punch press. An optional pre-compression step was applied
before the main compression to reduce the amount of entrapped air
during the main compression.
General Methods of Detection and Characterisation
Assay (I): Density
[0190] The tablet volume and weight was measured. From these
measures, the bulk density could be calculated as the mass of the
tablet divided by the volume.
Assay (IIa): Calculated Porosity
[0191] The tablet volume and weight was measured. From these
measures, the bulk density could be calculated as the mass of the
tablet divided by the volume. Assuming a skeletal density of the
tablet of 1.38 g/cm.sup.3 the solid fraction could be calculated as
tablet bulk density divided by tablet skeletal density. The
porosity is then 1 minus the solid fraction.
Assay (IIb): Mercury Porosimetry
[0192] The porosity analysis utilized a Micromeritics Autopore IV
model 9520 with Autopore IV 9500 software version 1.06. The sample
amount was adjusted in order to use 10-90% of the stem volume. The
sample was evacuated to 50 .mu.mHg for 5 minutes. The sample cell
was then filled with mercury at a filling pressure of 0.0032 MPa,
Mercury intrusion was performed in the pressure range from 0.0007
to 420 MPa
Assay (III): Crushing Strength
[0193] The crushing strength of the tablets was measured with a
Pharma Test apparatus (33AA02). The test measures the force
required to disrupt the tablet, and the test was based on the
pharmacopeia method Ph Eur 2.9.8.
Assay (IV): Disintegration Test
[0194] The disintegration test was carried out using a Pharma Test
PTZ AUTO disintegration test apparatus. The setup is based on
pharmacopeia method Ph Eur 2.09.01, Test A (Basket-rack assembly).
The disintegration apparatus consists of a basket rack holding
2.times.6 plastic tubes, open at the top and bottom, the bottom of
the tube is covered by a screen. SNAC tablets are placed in the
tubes and on top of the tablets are placed discs for automated
disintegration detection. The basket is immersed in 800 ml purified
water held at 37.degree. C., in a 1 L beaker. Time for complete
disintegration was measured. Furthermore, tablets were observed
visually for surface eroding behaviour during the disintegration
test.
Assay (V): Dissolution Test
[0195] The dissolution test was conducted with apparatus 2 in
accordance with United States Pharmacopoeia 35 using a paddle
rotation speed of 50 rpm. The 500 mL dissolution medium of
phosphate buffer (pH 6.8) was used at a temperature of 37.degree.
C. The dissolution media had a content of 0.1% Tween80. Sample
aliquots were removed at appropriate intervals. Release was
determined using a RP-HPLC method for dual detection of SNAC and
semaglutide. The content was calculated based on the peak area of
the SNAC and semaglutide peaks in the chromatogram relative to the
peak areas of the SNAC and semaglutide references, respectively.
The HPLC method was based on gradient elution on a C8 column. The
solvent system was trifluoroacetic acid and acetonitrile with UV
detection at 210 nm.
Assay (VI): Oral Administration to Beagle Dogs
[0196] Animals, Dosing and Blood Sampling: Beagle dogs, weighing
6-17 kg during the study period were included in the study. The
dogs were dosed in fasting state. The compositions were
administered by a single oral dosing to the dogs in groups of 8
dogs. Blood samples were taken at the following time points:
predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72,
96, 120, 144, 192 and 240 hours post dosing. The i.v. solution (20
nmol/mL in a pH 7.4 solution comprising 0.1 mg/ml Tween 20, 5.5
mg/ml Phenol, 1.42 mg/ml Na2HPO4 and 14 mg/ml Propylene Glycol) was
dosed in a dose volume of 0.1 mL/kg in the same dog colony in one
dosing group (n=8). Blood samples were taken at the following time
points: predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24,
48, 72, 96, 120, 144, 192 and 240 hours post dosing.
[0197] Preparation of Plasma: All blood samples were collected into
test tubes containing EDTA for stabilisation and kept on ice until
centrifugation. Plasma was separated from whole blood by
centrifugation and the plasma was stored at -20.degree. C. or lower
until analysis.
[0198] Analysis of Plasma Samples: The plasma was analysed for
semaglutide using a Luminescence Oxygen Channeling Immunoassay
(LOCI). The LOCI assay employs donor beads coated with streptavidin
and acceptor beads conjugated with a monoclonal antibody binding to
a mid-molecular region of semaglutide. The other monoclonal
antibody, specific for an N-terminal epitope, was biotinylated. In
the assay the three reactants were combined with the semaglutide
which form a two-sited immuno-complex. Illumination of the complex
releases singlet oxygen atoms from the donor beads which channels
into the acceptor beads and trigger chemiluminescence which was
measured in the EnVision plate reader. The amount of light was
proportional to the concentration of semaglutide and the lower
limit of quantification (LLOQ) in plasma was 100 .mu.M.
Example 1: Preparation of Tablets
[0199] Tablets comprising GLP-1 and SNAC with compositions as
described in Table 1 were prepared by granulation, blending, and
compression as described in the section General Methods of
Preparation, wherein [0200] during compression of composition A the
compression force was varied to obtain tablets with varying
disintegration times by adjusting the height of the tablets; [0201]
tablets from composition D were prepared by direct compression of a
granulate formed by dry granulation by exerting a compression force
of 5.2, 10.2, 14.9, 20.9, or 25.9 kN; and [0202] for tablets from
composition E a pre-compression step was applied setting the tablet
band height to 3.5 mm, tablets were prepared by exerting a
compression force of 4.0, 5.5, 7.0, or 10.5 kN, and the tablet band
height of the final tablets was set between 1.24 and 1.89 mm.
TABLE-US-00001 [0202] TABLE 1 Composition of tablets (amounts are
expressed as "per tablet") Composition A B C D E F Semaglutide 10
10 20 10 10 10 (mg) SNAC (mg) 300 300 600 300 300 300 Povidone K 90
8-16 8 16 8 8 8 (mg) Microcrystalline 78-156 78 156 100 100 78
cellulose (mg) Magnesium 4 4 8 7.7 7.7 7.7 Stearate (mg) (intragr.)
(intragr.) (intragr.) 2.3 1.6 2.0 (extragr.) (extragr.) (extragr.)
Sodium na na na na na 1-20 mg polystyrene sulfonate resin with 1
MBq 111Indium chloride Tablet weight 400-498 400 800 428 427 408.7-
(mg) 427.7 Granulation type wet wet wet dry A dry B dry B (wet, dry
A, or dry B) Tablet tooling 10 13 .times. 7.5 18.9 .times. 10 10
8.5 .times. 16 7.5 .times. 13 (mm) Tablet shape round, oval, oval,
round, oval, oval, deep convex convex flat convex convex convex
Tablet press DIAF Korsch Korsch Fette Fette Carver PH 100 PH 100
model C Pre-compression no no no no yes no
Example 2: Effect on Tablet Disintegration Time on Oral
Bioavailability of Semaglutide in Beagle Dogs
[0203] Tablets with various crushing strengths and disintegration
times were prepared from composition A as described in Example 1
and with an amount of microcrystalline cellulose and povidone as
shown in Table 2. Oral bioavailability and absorption kinetics of
GLP-1 after administration of the tablets to beagle dogs were
determined according to Assay (VI) as described herein. The bulk
density was estimated according to Assay (Ia) as described herein.
The results are shown in Table 2.
TABLE-US-00002 TABLE 2 Oral bioavailability and absorption kinetics
of semaglutide after administration of tablets of composition A
with various disintegration times to beagle dogs. Content of
microcrystalline Content of Disintegration Oral Estimated cellulose
povidone time Total tablet bioavailability Tmax bulk density (mg)
(mg) (min:sec) weight (mg) (%) (hours) (g/cm.sup.3) 78 8 11:30 416
0.5 0.8 1.02 78 8 13:25 404 1.3 1.5 1.16 78 8 14:12 415 2.4 1.2
1.17 120 8 16:34 445 1.0 1.6 1.16 156 16 19:14 498 0.2 1.1 1.00 156
16 23:25 497 0.3 1.7 1.20
[0204] The results demonstrate that 10 mm round tablets with a deep
convex face and a total weight of 404-445 mg with a disintegration
time of 13-17 minutes are to be preferred, however, this is
expected only to apply for tablets of similar composition and
weight, i.e. tablets with a total weight of 300-500 mg comprising
at least 60% (w/w) salt of NAC.
[0205] The results further demonstrate that Tmax for plasma
semaglutide was minimum 1 hour for the best performing tablets in
contrast to published studies with SNAC and human GLP-1 showing a
Tmax of 20-30 minutes. Hence, a somewhat more protracted release of
SNAC is desired for peptides with longer oral absorption
half-lives, such as acylated GLP-1 peptides.
[0206] FIG. 1 shows tablet A before (right), after 5 minutes
(middle) and after 10 minutes (left) in a disintegration test
according to Assay (IV) as described herein on tablets from the
batch having an oral availability of 2.4% in Table 2. The results
show that Tablet A has surface eroding properties.
Example 3: Porosity Measurements on Good and Poor Performing
Tablets
[0207] Tablets were prepared from compositions B,C and E (hereafter
referred to as Tablet batch B, Tablet batch C and Tablet batch D,
respectively) as described in Example 1 and subjected to mercury
porosimetry according to Assay (IIb) as described herein. Tablet
batch E (comprising 10 mg semaglutide and 300 mg SNAC) gave the
best result in a clinical trial, tablet batch B gave intermediate
results, while Tablet batch C (comprising the 20 mg semaglutide and
600 mg SNAC) gave poor results with respect to oral
bioavailability. The results are shown in Table 3 and FIG. 2.
TABLE-US-00003 TABLE 3 Porosimetry results from mercury intrusion
into Tablet batch B, C and E Tablet Tablet Tablet batch B batch C
batch E Total Intrusion 0.27 0.41 0.15 Volume (mL/g) Total Pore
Area 29.5 24.5 31.6 (m.sup.2/g) Median Pore 0.84 2.06 0.09 Diameter
(Volume) (.mu.m) Bulk Density at 1.00 0.88 1.15 0.1000 MPa
(g/cm.sup.3) Apparent (skeletal) 1.37 1.38 1.38 Density
(g/cm.sup.3) Porosity (%) 27.1 36.5 17.4
[0208] FIG. 2 shows cumulative mercury intrusion into Tablet batch
B, C and E depending on pore diameter. FIG. 2 shows that Tablet
batch B has a maximum pore diameter of 2.5 .mu.m whereas Tablet
batch C has a maximum pore diameter of 5 .mu.m. FIG. 2 shows a
sharp increase in liquid mercury intrusion volume at a pore
diameter of 5 .mu.m for Tablet batch C and a more gradual increase
of mercury intrusion at a pore diameter of 2.5 .mu.m for Tablet
batch B, whereas Tablet batch E prepared by a dry granulation
technique showed low amount of pores above 0.1 .mu.m. This shows
that especially larger pores are reduced as compression pressure
increases, whereas the smaller pores remain intact. Furthermore,
dry granulation provides tablets with very low pore size and
porosity.
[0209] These results show that preferred tablets providing an
improved bioavailability can be identified by having a porosity of
less than 36.5%, a bulk density larger than 0.90 g/cm.sup.3, a
median pore diameter less than 2 .mu.m, and/or a maximum pore
diameter less than 5 .mu.m.
Example 4: Compactability of Granulate without a Pre-Compression
Step
[0210] Tablets were prepared from composition D (round and flat
faced tablets with a diameter of 10 mm) as described in Example 1.
The density, porosity, and crushing strength was determined
according to Assay (Ia), (IIa), and (III) as described herein,
respectively. The results are shown in Table 4.
TABLE-US-00004 TABLE 4 Compression profile and resulting tablet
properties Compression Compression Crushing Tablet bulk Porosity
pressure pressure/cm.sup.2 strength density (1-solid (kN) (kN) (N)
(g/cm.sup.3) fraction) 5.2 6.6 73 1.02 0.26 10.2 13.0 156 1.16 0.16
14.9 19.0 197 1.22 0.12 20.9 26.6 221 1.25 0.09 25.9 33.0 234 1.27
0.08
[0211] These results show that the compression pressure should be
higher than 5.2 kN or the compression pressure per area should be
higher than 6.6 kN/cm.sup.2 in order to obtain tablets with a
density above 1.0 g/cm.sup.3 and a porosity of no more than
26%.
Example 5: Compactability of a Granulate with a Pre-Compression
Step
[0212] Tablets were prepared from composition E (16 mm.times.8.5 mm
oval tablets with a convex face) as described in Example 1.
Determination of density, porosity, crushing strength, and
disintegration time was carried according to Assay (Ia), (IIa),
(III), and (IV) as described herein, respectively. The results are
shown in Table 5.
TABLE-US-00005 TABLE 5 Compression profile and resulting tablet
properties Compression Compression Crushing Disintegration Tablet
bulk pressure pressure/cm.sup.2 strength time density Porosity (kN)
(kN) (N) (min:sec) (g/cm.sup.3) (fraction) 4.0 3.8 48 9:20 1.08
0.22 5.5 5.2 75 11:30 1.21 0.12 7.0 6.6 95 12:00 1.20 0.13 10.5 9.9
135 12:30 1.30 0.06
[0213] The results show that SNAC tablets with low porosity
(<37%) and high density (>1.0 g/cm.sup.3) can be prepared at
a compression pressure >4.0 kN or at a compression pressure per
area of more than 3.8 kN/cm.sup.2 when a pre-compression step is
included in the tabletting step.
Example 6: Control of Tablet Porosity by Near-Infrared (NIR)
Reflectance Spectroscopy
[0214] NIR reflectance has been demonstrated to be a fast and
precise method to control the porosity of tablets comprising SNAC
and Semaglutide. Tablets with varying porosity were manufactured by
varying the compression force as described in Example 4. A NIR
reflectance spectrum was acquired from a group of tablets from each
of the applied compressions forces by scanning twice on each side
with a Bruker MPA 01 Multi Purpose FT-NIR Analyzer. Subsequently,
the spectrum was compared to the porosity value for the tablet,
which was determined as described in Example 4, using projections
to latent structures (PLS) regression.
[0215] FIG. 3 shows the NIR reflectance spectrum of three tablets
with porosity of 24%, 15 and 7%. At wavelengths from 12.000
cm.sup.-1 to 6.000 cm.sup.-1 is the spectral absorbance increasing
with increasing porosity. At wavelengths from 5.000 cm.sup.-1 to
4.000 cm.sup.-1 is the spectral absorbance decreasing with
increasing porosity.
[0216] A statistical regression model was established between the
spectra of fifty tablets comprising SNAC and Semaglutide and their
corresponding porosity values. With such a regression model is it
possible to predict the porosity of future tablet samples based on
their NIR reflectance spectrum. The results are shown in FIG. 4
where tablet porosity values (x-axis) for the fifty tablets
comprising SNAC and Semaglutide were compared to the tablet
porosity predicted by the regression model (y-axis) based on the
NIR reflectance spectrum. There was found to be a high correlation
between the two methods (R.sup.2=0.99).
[0217] Accordingly, this method provides a fast and easy
determination of tablet porosity on individual tablets with NIR
spectroscopy during tabletting. This allows NIR spectroscopy to be
used for in-line monitoring of porosity of individual tablets and
for adjustment of the tabletting process to achieve tablets with a
highly specific porosity.
[0218] Furthermore, based on these results it is possible to
interface NIR technology with the tabletting machine in three
distinct ways and thereby enable real-time control of tablet
porosity during tabletting (Table 6).
TABLE-US-00006 TABLE 6 Interface opportunity. Interface opportunity
Instrumentation Control At-line, Off-the shelf NIR The spectrometer
is full spectrometer. placed next to the spectrum Analysis time
~10- tabletting press. 20 seconds/tablet During the tabletting plus
sample removal process are samples and time for manual removed,
analysed and control adjustments. the porosity determined.
Commercially available. The operator can adjust the tabletting
press to optimize the porosity during manufacturing. In-line, The
NIR spectrometer The spectrometer pc is full is attached to the
interfaced with the spectrum tabletting press. A tabletting press
and robotic arm removes signals for adjustment samples and places
of the tabletting press them in the NIR is transferred spectrometer
for automatically to analysis. optimize the porosity Analysis time
~30 during manufacturing seconds/tablet. Commercially available.
In-line, The tablets pass a The spectrometer pc is single measuring
point when interfaced with the wavenumber leaving the tabletting
tabletting press and press. A light emitting signals for adjustment
diode (LED) based of the tabletting press instrument measures is
transferred the NIR reflectance at automatically to one specific
wavelength optimize the porosity from the surface of the during
manufacturing tablets as they pass the measuring point. Analysis
time ~ milliseconds. Not commercially available. Needs to be
designed.
Example 7: Dissolution of Tablets
[0219] Tablets were prepared from compositions B and C (hereafter
referred to as Tablet batch B and Tablet batch C, respectively) as
described in Example 1 and their dissolution profile was determined
according to Assay (V) as described herein. The results are shown
in Table 7.
TABLE-US-00007 TABLE 7 Dissolution profile Tablet batch B Tablet
batch C Time from Semaglutide SNAC Semaglutide SNAC test start (%
(w/w) of (% (w/w) of (% (w/w) of (% (w/w) of (min) 10 mg) 300 mg)
20 mg) 600 mg) 15 62 65 63 62 30 86 87 105 100 45 91 90 106 100 60
93 92 106 100
[0220] These results show that GLP-1 and SNAC are co-released in
Tablet batch B and Tablet batch C.
[0221] While certain features of the invention have been
illustrated and described herein, many modifications,
substitutions, changes, and equivalents will now occur to those of
ordinary skill in the art. It is, therefore, to be understood that
the appended claims are intended to cover all such modifications
and changes as fall within the true spirit of the invention.
Example 8: In Vivo Location and Duration of Tablet Erosion
[0222] The in vivo location and duration of tablet erosion was
investigated in a clinical study using gamma-scintigraphy. The
study also assessed the pharmacokinetic parameters of oral
semaglutide and SNAC. In order to employ gamma scintigraphy, a
gamma emitting isotope was incorporated into formulation F (Table
1), where indium-111 (111In) was used to label a sodium polystyrene
sulfonate resin, which was incorporated into the tablets.
Manufacturing Process
[0223] The manufacturing process was a three-stage process whereby
simple blending was undertaken to prepare the SNAC/magnesium
stearate blend, the Amberlite.RTM. resin was radiolabelled and the
final tablet was compressed by individually weighing out the
aforementioned components as well as the semaglutide granules.
[0224] The SNAC/magnesium stearate blend was prepared by manual
volumetric doubling of the magnesium stearate with the SNAC
granules, followed by blending using an inflated plastic bag.
Magnesium stearate was pre-screened before use through a 355 .mu.m
sieve.
[0225] Before compression the lubricated SNAC blend, semaglutide
granules and radiolabelled Amberlite.RTM. IRP-69A resin were
individually weighed out for each tablet and manually mixed until
visually uniform.
[0226] The radiolabelled tablets were compressed using a manual
Carver Model C tablet press (L145) at a compression force of 6.7 kN
(8.8 kN/cm.sup.2). Tablets were compressed with a 7.5.times.13 mm
radial oval convex tablet tooling. The tablet thickness was 6.4 mm.
Hardness varied from 91-104 N, and bulk density was 1.07
g/cm.sup.3
Dosing
[0227] 24 Subjects were treated in a cross-over trial design so
that all subjects received one period with dosing of 10 mg
semaglutide and 50 ml water and one period with dosing of 10 mg
semaglutide and 240 mL water. Dosing was performed with the
subjects positioned in a sitting position in front of the gamma
camera to provide an anterior view and permit measurement of
oesophageal transit. Blood samples for pharmacokinetic profiles
were collected and the pharmacokinetic assessments included
24-hours semaglutide profiles and 6-hours SNAC profiles.
Scintigraphy dynamic imaging was performed (until 4 hour
post-dosing) and safety and tolerability was assessed. The dynamic
imaging was performed with the subjects sitting. Subjects remained
in the camera room until completion of the rapid imaging phase (30
minutes post-dose). Static imaging was performed with subjects
standing. Thereafter, subjects were permitted to leave the camera
room. Subjects were permitted to sit or remain moderately active
(walk around the clinical unit) and imaging continued until 4 hours
post dosing. Initial tablet erosion (ITE) was defined as the first
sign of sustained release of radioactive marker from the tablet.
Complete tablet erosion (CTE) was defined as the time at which the
entire radioactive marker had dispersed into the gastrointestinal
tract and no signs of a distinct `core` remain. The anatomical
location of the capsule at the time of each event (ITE and CTE) was
determined. Quantitative assessment of tablet erosion was performed
to generate the tablet erosion time profile. A region of interest
was drawn around the tablet and amount of radioactive marker
retained within that region was quantified. Data was corrected for
depth of radioactivity in the body, radioactive decay and
background.
[0228] Blood samples were collected at -30, 0, 10, 20, 30, 40, 50
minutes, 1, 1.5, 2, 3, 4, 6 12 and 24 hours post dosing.
Bioanalysis of semaglutide was performed using a validated assay
and bioanalysis of SNAC was performed using a liquid chromatography
mass spectrometry (LC/MS/MS) assay.
TABLE-US-00008 TABLE 8 Tablet erosion of tablets after dosing with
50 or 240 ml water 50 ml*.sup.) 240 ml*.sup.) Time (min) to initial
6.0 (7.7) 9.7 (18.4) tablet erosion (SD) (min post-dose) Time (min)
to complete 95.4 (49.4) 66.2 (48.8) tablet erosion (SD) Duration
(min) of 89.9 (48.8) 56.4 (43.1) tablet erosion (SD)
*.sup.)Standard deviation shown in brackets
[0229] The anatomical location of ITE and CTE was the stomach for
all subjects, for both volumes of water tested. The duration of
tablet erosion was to some degree influenced by water volume,
however even with a large volume of water the duration of tablet
erosion was surprisingly long (56.+-.43 minutes). The long erosion
time is a central aspect of the tablet technology.
[0230] A negative correlation between tablet erosion at 1 hour post
dosing and semaglutide plasma exposure is shown in FIG. 5. Full
tablet erosion at 1 hour resulted in very low plasma exposure of
semaglutide, whereas less than 54% tablet erosion resulted in high
plasma exposure of semaglutide. It is seen that slow tablet erosion
correlated with higher plasma semaglutide exposure and longer tmax
of semaglutide.
[0231] FIG. 6 shows that a higher degree of tablet erosion for a
tablet containing 300 mg SNAC at 1 hour after dosing correlated
with higher peak exposure to SNAC. Hence, plasma exposure and Cmax
of SNAC correlated negatively with the efficacy of the tablet.
Sequence CWU 1
1
2131PRTHomo sapiens 1His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser
Ser Tyr Leu Glu Gly1 5 10 15Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu
Val Lys Gly Arg Gly 20 25 30240PRTHeloderma suspectum 2His Gly Glu
Gly Thr Phe Ile Thr Ser Asp Leu Ser Lys Gln Met Glu1 5 10 15Glu Glu
Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro 20 25 30Ser
Ser Gly Ala Pro Pro Pro Ser 35 40
* * * * *