U.S. patent application number 10/564259 was filed with the patent office on 2007-03-22 for orally dosed pharmaceutical compositions comprising a delivery agent in micronized form.
Invention is credited to Moise Azria, Simon David Bateman, Anasuya Ashok Ghosh, Shoufeng Li, Alan Edwar Royce.
Application Number | 20070065505 10/564259 |
Document ID | / |
Family ID | 34062133 |
Filed Date | 2007-03-22 |
United States Patent
Application |
20070065505 |
Kind Code |
A1 |
Li; Shoufeng ; et
al. |
March 22, 2007 |
Orally dosed pharmaceutical compositions comprising a delivery
agent in micronized form
Abstract
Solid pharmaceutical compositions and methods of their use
suitable for the oral delivery of pharmacologically active agents,
e.g. peptides, comprising a therapeutically-effective amount of a
pharmacologically active agent; a crospovidone or povidone; and a
delivery agent for said pharmacologically active agent are
disclosed. The compositions utilize micronized forms of the
delivery agent which provides enhanced bioavailability of
pharmacologically active agents, particularly calcitonin.
Inventors: |
Li; Shoufeng; (Bridgewater,
NJ) ; Ghosh; Anasuya Ashok; (Randolph, NJ) ;
Bateman; Simon David; (Randolph, NJ) ; Azria;
Moise; (Basel, CH) ; Royce; Alan Edwar;
(Saylorsburg, PA) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
34062133 |
Appl. No.: |
10/564259 |
Filed: |
July 9, 2004 |
PCT Filed: |
July 9, 2004 |
PCT NO: |
PCT/EP04/07584 |
371 Date: |
August 11, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60486495 |
Jul 11, 2003 |
|
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Current U.S.
Class: |
424/464 ;
514/10.3; 514/10.8; 514/10.9; 514/11.2; 514/11.4; 514/11.8;
514/11.9; 514/12.4; 514/2.3; 514/20.5; 514/3.3; 514/7.7; 514/7.8;
514/8.5; 514/8.6; 514/9.9 |
Current CPC
Class: |
A61P 19/00 20180101;
A61K 9/2013 20130101; A61K 47/183 20130101; A61P 19/08 20180101;
A61K 9/1617 20130101; A61K 38/23 20130101; A61K 47/18 20130101 |
Class at
Publication: |
424/464 ;
514/012 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 38/23 20060101 A61K038/23 |
Claims
1. A solid pharmaceutical composition suitable for the oral
delivery of a pharmacologically active agent comprising a. a
therapeutically-effective amount of a pharmacologically active
agent; b. pharmaceutically acceptable inactive excipients, and c. a
delivery agent for said pharmacologically active agent, wherein
said delivery agent is in micronized form.
2. A composition according to claim 1 wherein the active agent is a
peptide.
3. A composition according to claim 2 wherein the peptide is a
calcitonin.
4. A composition according to claim 3 wherein the calcitonin is
salmon calcitonin.
5. A composition according to claim 1 wherein said inactive
excipients are selected from the group consisting of crospovidone
and povidone.
6. A composition according to claim 1 wherein the delivery agent is
selected from the group consisting of 5-CNAC, SNAD, and SNAC.
7. A composition according to claim 1 wherein the delivery agent is
selected from the group consisting of a disodium salt of 5-CNAC, a
disodium salt of SNAD, and a disodium salt of SNAC.
8. A composition according to claim 1 which additionally includes a
diluent.
9. A composition according to claim 8 wherein the diluent is
microcrystalline cellulose.
10. A composition according to claim 1 which additionally includes
a lubricant.
11. A composition according to claim 10 wherein the lubricant is
magnesium stearate.
12. A method for enhancing the oral bioavailability of a
pharmacologically active agent, said method comprising
administering to a patient in need of a pharmacologically active
agent, an effective amount of a pharmaceutical composition
according to claim 1.
13. A method of treatment of bone related diseases and calcium
disorders comprising administering to a patient in need of such
treatment a therapeutically effective amount of a composition
according to claim 1, wherein said pharmacologically active agent
is a bone active agent.
14. A method according to claim 13, wherein said pharmacologically
active agent is calcitonin.
15. A method according to claim 14 wherein said calcitonin is
salmon calcitonin.
16. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to oral compositions for the
delivery of pharmacologically active agents, to methods of
enhancing the bioavailability of orally administered
pharmacologically active agents, and to methods of treating and/or
preventing disease in mammals, particularly humans, by orally
administering a pharmacologically active agent in accordance with
the invention.
[0003] 2. Description of the Related Art
[0004] Oral delivery of pharmacologically active agents is
generally the delivery route of choice since it is convenient,
relatively easy and generally painless, resulting in greater
patient compliance relative to other modes of delivery. However,
biological, chemical and physical barriers such as varying pH in
the gastrointestinal tract, powerful digestive enzymes, and active
agent impermeable gastrointestinal membranes, makes oral delivery
of some pharmacologically active agents to mammals problematic,
e.g. the oral delivery of calcitonins, which are long-chain
polypeptide hormones secreted by the parafollicular cells of the
thyroid gland in mammals and by the ultimobranchial gland of birds
and fish, has proven difficult due, at least in part, to the
insufficient stability of calcitonin in the gastrointestinal tract
as well as the inability of calcitonin to be readily transported
through the intestinal walls into the blood stream.
[0005] U.S. Pat. Nos. 5,773,647 and 5,866,536 describe compositions
for the oral delivery of active agents, such as heparin and
calcitonin, with modified amino acids, such as,
N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC),
N-(10-[2-hydroxybenzoyl]aminodecanoic acid (SNAD), and
N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC) In addition, WO
00/059863 discloses the disodium salts of formula I ##STR1##
[0006] wherein [0007] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently hydrogen, --OH, --NR.sup.6R.sup.7, halogen,
C.sub.1-C.sub.4alkyl, or C.sub.1-C.sub.4alkoxy; [0008] R.sup.5 is a
substituted or unsubstituted C.sub.2-C.sub.16alkylene, substituted
or unsubstituted C.sub.2-C.sub.16alkenylene, substituted or
unsubstituted C.sub.1-C.sub.12alkyl(arylene), or substituted or
unsubstituted aryl(C.sub.1-C.sub.12alkylene); and [0009] R.sup.6
and R.sup.7 are independently hydrogen, oxygen, or C.sub.1-C.sub.4
alkyl; and hydrates and solvates thereof as particularly
efficacious for the oral delivery of active agents, such as
calcitonin, cyclosporin and heparin.
[0010] The present invention describes pharmaceutical compositions
which provide still greater oral bioavailability of
pharmacologically active agents, e.g. peptides such as
calcitonin.
SUMMARY OF THE INVENTION
[0011] Accordingly, the present invention is directed to
pharmaceutical compositions which, quite surprisingly, greatly
enhance the oral bioavailability of active agents, particularly
peptides. Specifically, the invention provides solid pharmaceutical
compositions suitable for the oral delivery of pharmacologically
active agents, comprising [0012] 1. a therapeutically-effective
amount of a pharmacologically active agent; [0013] 2.
pharmaceutically acceptable inactive excipients; and [0014] 3. a
delivery agent for said pharmacologically active agent, wherein
said delivery agent is in micronized form.
[0015] In another embodiment the present invention provides solid
pharmaceutical compositions suitable for the oral delivery of
calcitonin, comprising [0016] 1. a therapeutically-effective amount
of a calcitonin; and [0017] 2. pharmaceutically acceptable inactive
excipients, and [0018] 3. a delivery agent for said calcitonin,
wherein said delivery agent is in micronized form.
[0019] In an additional embodiment of the present invention the
pharmaceutically acceptable inactive excipient may be either or
both of the polymers crospovidone or povidone.
[0020] In a still further embodiment of the present invention the
solid pharmaceutical composition suitable for oral delivery may
also comprise a diluent.
[0021] In addition in another embodiment of the present invention
the solid pharmaceutical composition suitable for oral delivery may
also comprise a lubricant.
[0022] In a further embodiment, the invention is directed to a
method for enhancing the oral bioavailability of a
pharmacologically active agent, said method comprising
administering to a subject in need of said pharmacologically active
agent an effective amount of a pharmaceutical composition according
to the instant invention.
[0023] In a still further embodiment, the invention is directed to
a method of treatment of bone related diseases and calcium
disorders comprising administering to a patient in need of such
treatment a therapeutically effective amount of a composition
according to the instant invention, wherein said pharmacologically
active agent is calcitonin.
[0024] Further features and advantages of the invention will become
apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The pharmacologically active agents suitable for use in the
instant invention include both therapeutic as well as preventative
agents and is directed particularly to agents which by themselves
do not pass or which pass only a small amount of the administered
dose through the gastrointestinal mucosa and/or are susceptible to
cleavage by acids and enzymes in the gastro-intestinal tract. The
pharmacologically active agents include, but are not limited to
proteins; polypeptides; hormones; polysaccharides including
mixtures of muco-polysaccharides; carbohydrates; lipids; and
combinations thereof.
[0026] Specific examples of pharmacologically active agents
include, but are not limited to, the following, including
synthetic, natural or recombinant sources thereof: growth hormone,
including human growth hormones (hGH), recombinant human growth
hormones (rhGH), bovine growth hormones, and porcine growth
hormones; growth hormone-releasing hormones; interferons, including
.alpha., .beta., and .gamma.-interferon; interleukin-1;
interleukin-2; insulin, including porcine, bovine, human, and human
recombinant, optionally having counter ions including sodium, zinc,
calcium and ammonium; insulin-like growth factor, including IGF-1;
heparin, including unfractionated heparin, heparinoids, dermatans,
chondroitins, low, very low and ultra low molecular weight
heparins; calcitonin, including salmon, porcine, eel, chicken and
human; erythopoietein; atrial naturetic factor; antigens;
monoclonal antibodies; somatostatin; protease inhibitors;
adrenocorticotropin, gonadotropin releasing hormone; oxytocin;
leutinizing-hormone-releasing hormone; follicle stimulating
hormone; glucocerebrosidase; thrombopoietin; filgrastim;
prostaglandins; cyclosporin; vasopressin; cromolyn sodium (sodium
or disodium chromoglycate); vancomycin; desferrioxamine (DFO);
parathyroid hormone (PTH), including its fragments; antimicrobials,
including anti-fungal agents; vitamins; analogs, fragments,
mimetics or polyethylene glycol (PEG)-modified derivatives of these
compounds; or any combination thereof.
[0027] An interesting pharmacologically active agent is a
pharmacologically active peptide, particularly bone active agents,
and even more particularly calcitonin.
[0028] Bone active agents include classes of agents which display
in vivo pharmacological activity in animals such as stabilization,
healing, or growth of bone, deceleration or inhibition of bone
turnover, deceleration or inhibition of bone resorption, inhibition
of osteoclast activity, and stimulation of osteoblast activity.
Some of these agents may be peptidic, for example calcitonins,
parathyroid hormone (PTH), PTH fragments, analogs and releasers,
and Transforming Growth Factors (TGFs) fragments, analogs and
releasers. The bone active agents may also be small molecule
non-peptidic structures which show in vivo pharmacological bone
activities as described above in this paragraph.
[0029] A known class of such pharmacologically active agents,
calcitonins, have varying pharmaceutical utility and are commonly
employed in the treatment of e.g. Paget's disease, hypercalcemia
and postmenopausal osteoporosis. Various calcitonins, including
salmon, pig and eel calcitonin are commercially available and
commonly employed for the treatment of e.g. Paget's disease,
hypercalcemia of malignancy and osteoporosis. The calcitonin can be
any calcitonin, including natural, synthetic or recombinant sources
thereof, as well as calcitonin derivatives such as 1,7-Asu-eel
calcitonin. The compositions can comprise a single calcitonin or
any combination of two or more calcitonins. The preferred
calcitonin is synthetic salmon calcitonin.
[0030] The calcitonins are commercially available or may be
synthesized by known methods.
[0031] The amount of pharmacologically active agent is generally an
amount effective to accomplish the intended purpose, e.g. a
therapeutically effective amount. However, the amount can be less
than that amount when a plurality of the compositions are to be
administered, i.e., the total effective amount can be administered
in cumulative dosage units. The amount of active agent can also be
more than the effective amount when the composition provides
sustained release of the pharmacologically active agent. The total
amount of active agent to be used can be determined by methods
known to those skilled in the art. However, because the
compositions may deliver the active agent more efficiently than
prior compositions, less amounts of active agent than those used in
prior dosage unit forms or delivery systems can be administered to
a subject while still achieving the same blood levels and/or
therapeutic effects.
[0032] When the pharmacologically active agent is salmon
calcitonin, the appropriate dosage will, of course, vary depending
upon, for example, the host and the nature and severity of the
condition being treated. However, in general, satisfactory results
will be obtained systemically at daily dosages of from about 0.5
.mu.g/kg to about 10 .mu.g/kg animal body weight, preferably 1
.mu.g/kg to about 6 .mu.g/kg body weight.
[0033] The pharmacologically active agent generally comprises from
0.05 to 70 percent by weight relative to the total weight of the
overall pharmaceutical composition, preferably an amount of from
0.01 to 50 percent by weight, more preferably 0.3 to 30 percent by
weight relative to the total weight of the overall pharmaceutical
composition.
[0034] The pharmaceutically acceptable inactive excipients may
include polymers and inactive compounds which for example, aid the
formulation or manufacturing of the solid oral dosage form
contemplated by the present invention or which may aid the release
of the solid oral composition in the gastrointestinal
environment.
[0035] The pharmaceutically inactive ingredients, referred to
above, for example optionally include crospovidones and povidones,
which may be any crospovidone and povidone. Crospovidone is a
synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidone, also
called 1-ethenyl-2-pyrrolidinone, having a molecular weight of
1,000,000 or more. Commercially available crospovidones include
Polyplasdone XL, Polyplasdone XL-10, Polyplasdone INF-10 available
from ISP, Kollidon CL, available from BASF Corporation. The
preferred crospovidone is Polyplasdone XL.
[0036] Povidone is a synthetic polymer consisting of linear
1-vinyl-2-pyrrolidinone groups having a molecular weight generally
between 2,500 and 3,000,000. Commercially available povidones
include Kollidon K-30, Kollidon K-90F available from BASF
Corporation and Plasdone K-30 and Plasdone K-29/32, available from
ISP.
[0037] As mentioned above, the crospovidones and povidones are
commercially available. Alternatively, they may be synthesized by
known processes.
[0038] The crospovidone, povidone or combination thereof is
generally present in the compositions in an amount of from 0.5 to
50 percent by weight relative to the total weight of the overall
pharmaceutical composition, preferably an amount of from 2 to 25
percent, more preferably 5 to 20 percent by weight relative to the
total weight of the pharmaceutical composition.
[0039] The delivery agents useful in the present invention are any
agents useful for delivering the particular pharmacologically
active agent. Suitable delivery agents are any one of the 123
modified amino acids disclosed in aforementioned U.S. Pat. No.
5,866,536 or any one of the 193 modified amino acids described in
the aforementioned U.S. Pat. No. 5,773,647 or any combination
thereof. The contents of the aforementioned U.S. Pat. Nos.
5,773,647 and 5,866,536 are hereby incorporated by reference in
their entirety. In addition, the delivery agent can be the disodium
salt of any of the aforementioned modified amino acids as well as
ethanol solvates and hydrates thereof. Suitable compounds include
compounds of the following formula I ##STR2## wherein
[0040] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
hydrogen, --OH, --NR.sup.6R.sup.7, halogen, C.sub.1-C.sub.4alkyl,
or C.sub.1-C.sub.4alkoxy;
[0041] R.sup.5 is a substituted or unsubstituted
C.sub.2-C.sub.16alkylene, substituted or unsubstituted
C.sub.2-C.sub.16alkenylene, substituted or unsubstituted
C.sub.1-C.sub.12alkyl(arylene), or substituted or unsubstituted
aryl(C.sub.1-C.sub.12alkylene); and
[0042] R.sup.6 and R.sup.7 are independently hydrogen, oxygen, or
C.sub.1-C.sub.4 alkyl; and hydrates and alcohol solvates thereof.
The compounds of formula I as well as their disodium salts and
alcohol solvates and hydrates thereof are described in WO
00/059863, along with methods for preparing them.
[0043] The disodium salt may be prepared from the ethanol solvate
by evaporating or drying the ethanol solvate by methods known in
the art to form the anhydrous disodium salt. Drying is generally
carried out at a temperature of from about 80 to about 120.degree.
C., preferably from about 85 to about 90.degree. C., and most
preferably at about 85.degree. C. The drying step is generally
performed at a pressure of 26'' Hg or greater. The anhydrous
disodium salt generally contains less than about 5% by weight of
ethanol and preferably less than about 2% by weight of ethanol,
based on 100% total weight of anhydrous disodium salt.
[0044] The disodium salt of the delivery agent can also be prepared
by making a slurry of the delivery agent in water and adding two
molar equivalents of aqueous sodium hydroxide, sodium alkoxide or
the like. Suitable sodium alkoxides include, but are not limited
to, sodium methoxide, sodium ethoxide, and combinations
thereof.
[0045] A still further method of preparing the disodium salt is by
reacting the delivery agent with one molar equivalent of sodium
hydroxide to yield the disodium salt.
[0046] The disodium salt can be isolated as a solid by
concentrating the solution containing the disodium salt to a thick
paste by vacuum distillation. This paste may be dried in a vacuum
oven to obtain the disodium salt of the delivery agent as a solid.
The solid can also be isolated by spray drying an aqueous solution
of the disodium salt.
[0047] The delivery agents may be prepared by methods known in the
art, e.g., as mentioned above, by methods described in U.S. Pat.
Nos. 5,773,647 and 5,866,536.
[0048] The ethanol solvates, as described in the aforementioned WO
00/059863, include, but are not limited to, a molecular or ionic
complex of molecules or ions of ethanol solvent with molecules or
ions of the disodium salt of the delivery agent. Typically, the
ethanol solvate contains about one ethanol molecule or ion for
every molecule of disodium salt of the delivery agent.
[0049] The ethanol solvate of the disodium salt of the delivery
agent can be prepared by dissolving the delivery agent in ethanol.
Typically, each gram of delivery agent is dissolved in from about 1
to about 50 mL of ethanol and generally, from about 2 to about 10
mL of ethanol. The delivery agent/ethanol solution is then reacted
with a molar excess of a sodium containing salt, such as a
monosodium containing salt, relative to delivery agent, i.e. for
every mole of delivery agent there is more than one mole of sodium
cations, yielding the ethanol solvate. Suitable monosodium salts
include, but are not limited to, sodium hydroxide; sodium
alkoxides, such as sodium methoxide and sodium ethoxide; and any
combination of the foregoing. Preferably, at least about two molar
equivalents of the monosodium containing salt are added to the
ethanol solution, i.e. for every mole of delivery agent there is at
least about two moles of sodium cations. Generally, the reaction is
performed at or below the reflux temperature of the mixture, such
as at ambient temperature. The ethanol solvate is then recovered by
methods known is the art, such as, concentration of the resulting
slurry at atmospheric distillation, cooling the concentrated slurry
and filtering the solid. The recovered solid can then be vacuum
dried to obtain the ethanol solvate.
[0050] The hydrates of the disodium salts of the delivery agents
may be prepared by drying the ethanol solvate to from an anhydrous
disodium salt, as described above, and hydrating the anhydrous
disodium salt. Preferably, the monohydrate of the disodium salt is
formed. Since the anhydrous disodium salt is very hydroscopic, the
hydrate forms upon exposure to atmospheric moisture. Generally, the
hydrating step is performed at from about ambient temperature to
about 50.degree. C., preferably ambient temperature to about
30.degree. C. and in an environment having at least 50% relative
humidity. Alternatively, the anhydrous disodium salt may be
hydrated with steam.
[0051] The preferred delivery agents are
N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC),
N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),
N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC)and their
monosodium and disodium salts, ethanol solvates of their sodium
salts and the monohydrates of their sodium salts and any
combinations thereof. The most preferred delivery agent is the
disodium salt of 5-CNAC and the monohydrate thereof.
[0052] The delivery agent, 5 CNAC, SNAD, and SNAC are very water
soluble and nearly fully, i.e. greater than 90%, absorbed by the
gastrointestinal tract whether it is ingested in micronized or
coarse form. However, it has been found, surprisingly, that when a
micronized form of one of these carrier agents is employed in the
composition, the absorption of the pharmacologically active agent
of the present composition is more completely absorbed into the
blood stream. Therefore, the use of micronized carrier agent is a
required element of the present invention.
[0053] A micronized form of the carrier agent, which is utilized in
preparation of the solid oral dosage form of the present invention,
is defined as a carrier agent which, when added to the present
composition mixture of pharmacologically active agent and
pharmaceutically inactive ingredients, has an average particle size
of less than 40 micrometers. Desirably the carrier agent of the
present invention has a micronized form which is defined as an
average particle size of less than 20 microns. More interestingly,
the carrier agent for the present invention has a micronized form
which is defined as an average particle size of less than 10
microns.
[0054] Micronized forms of the carrier agent of the present
invention may be prepared by grinding it in a grinding mill which
is acceptable for grinding pharmaceutical ingredients and which is
capable of grinding the pharmaceutical ingredients and/or carrier
agent to a fine and uniform micronized particle size. An example of
such a grinding mill is an Air Jet Mill Gem T.RTM. (Copley
Scientific, Ltd., Nottingham, UK). The finely ground carrier agent
either separately or finely ground carrier agent plus any
combination of finely ground additional ingredients of the present
invention may then be screened, for example, over a mesh screen
having the appropriate openings, in order to allow only those
ingredients which have the required particle size to pass through
and be collected for use in the present invention.
[0055] The pharmaceutical compositions of the present invention
typically contain a delivery effective amount of one or more of the
delivery agents, i.e. an amount sufficient to deliver the active
agent for the desired effect. Generally, the delivery agent is
present in an amount of 2.5% to 99.4% by weight, more preferably
25% to 50% by weight.
[0056] The pharmaceutical compositions of the present invention may
be provided as a capsule including a soft-gel capsule, tablet,
caplet or other solid oral dosage form, all of which can be
prepared by methods well known in the art.
[0057] The compositions may additionally comprise additives in
amounts customarily employed including, but not limited to, a pH
adjuster, a preservative, a flavorant, a taste-masking agent, a
fragrance, a humectant, a tonicifier, a colorant, a surfactant, a
plasticizer, a lubricant such as magnesium stearate, a flow aid, a
compression aid, a solubilizer, an excipient, a diluent such as
microcrystalline cellulose, e.g. Avicel PH 102.RTM. (supplied by
FMC corporation 1735 Market Street Philadelphia, Pa. 19103, USA),
or any combination thereof. Other additives may include phosphate
buffer salts, citric acid, glycols, and other dispersing
agents.
[0058] The composition may also include one or more enzyme
inhibitors, such as actinonin or epiactinonin and derivatives
thereof; aprotinin, Trasylol and Bowman-Birk inhibitor.
[0059] Further, a transport inhibitor, i.e. a .rho.-glycoprotein
such as Ketoprofin, may be present in the compositions of the
present invention.
[0060] Preferably, the solid pharmaceutical compositions of the
instant invention include a diluent, such as Avicel.RTM., and a
lubricant, such as magnesium stearate.
[0061] The solid pharmaceutical compositions of the instant
invention can be prepared by first grinding either the carrier
agent or the carrier agent with any combination of the additional
ingredients of the present composition to a micronized particle
size. The micronized carrier agent or micronized carrier agent plus
micronized additional ingredients of the present invention may then
be further processed by conventional methods e.g. by blending a
mixture of the active agent or active agents, the delivery agent,
the crospovidone or povidone and other ingredients, kneading, and
filling into capsules or, instead of filling into capsules, molding
followed by further tableting or compression-molding to give
tablets. In addition, a solid dispersion may be formed by known
methods followed by further processing to form a tablet or
capsule.
[0062] Preferably, the ingredients in the pharmaceutical
compositions of the instant invention are homogeneously or
uniformly mixed throughout the solid dosage form.
[0063] The compositions of the present invention may be
administered to deliver an active agent to any animal in need
thereof, including, but not limited to, mammals, such as rodents,
cows, pigs, dogs, cats, and primates, particularly humans.
[0064] The following examples serve to further illustrate the
invention and will be readily understood by one of ordinary skill
in the art. The examples are not meant to be limiting of the
present invention in any way.
EXAMPLE 1
[0065] Micronized 5-CNAC and tablets of salmon calcitonin plus
micronized 5-CNAC may be prepared in accordance with the present
invention as follows:
Preparation of Micronized 5-CNAC
[0066] Coarse 5-CNAC, which is to be micronized, is added to a jet
mill (Air Jet Mill Gem T.RTM. Copley Scientific, Ltd., Nottingham,
UK) using a 80 ceramic pan cake jet mill, 8 cm diameter, 6 bar N2,
0.5 mm nozzles with manual feed of about 700 g/h. The coarse 5-CNAC
is jet milled and periodically sampled under microscope with
reference ruler measurements to identify when the average desired
micronized particle size is obtained. Three different batches are
ground to create 6 um, 35 um, and 46 um batches. Individual sieving
of the separate micronized batches is then done by using a conical
sieve mill (Quadro Comil, Quadro Engineering Incorporated 613 Colby
Drive, Waterloo, Ontario, Canada N2V 1A1) with a U10, 813 um
conical sieve, round beater, operating at 1500 upm with throughput
of about 150 kg/h. TABLE-US-00001 Formulation I. Salmon Calcitonin
Formulation with 5-CNAC of Different Particle Size Ingredient
Amount (mg) Percent (%) Salmon Calcitonin 1 0.25 Micronized 5-CNAC
228 57 Avicel PH 102 .RTM. 147 36.75 Crospovidone, NF 20 5
Magnesium stearate 4 1 Total 400 100
Preparation of Formulation 1
[0067] Three different batches of tablets are prepared using the
three different batches of micronized 5-CNAC disodium, one tablet
batch having an average 5-CNAC disodium particle size of 46 microns
(Batch A), a second tablet batch having an average 5-CNAC disodium
particle size of 6 microns (Batch B), and a third tablet batch
having an average 5-CNAC disodium particle size of 35 microns
(Batch C).
[0068] 0.50 g of salmon calcitonin, pre-screened through a 40 mesh
screen, 57. g of micronized 5-CNAC disodium salt, screened through
a 35 mesh screen, and 10 g of Polyplasdone XL (crospovidone, NF,
International Specialty Products, 1361 Alps Road, Wayne, N.J.,
07470, USA) is combined in a 500 mL jar and is mixed using a
Turbula mixer for 100 revolutions at a speed of 46 RPM. An
additional 57. g of micronized 5-CNAC disodium salt, screened
through a 35 mesh screen, and 36.75 g of Avicel PH 102 .RTM. is
added to the jar and mixed for 500 revolutions at a speed of 46
RPM. A further 36.75 g of Avicel PH 102 .RTM. is added to the jar
and is mixed for an additional 100 revolutions at a speed of 46
RPM. 4.0 g of magnesium stearate is screened into the jar using a
35 mesh screen and is blended for 1 minute at a speed of 46 RPM.
The final blend is compressed into tablets using a Manesty B3B
tablet press. The tablet weight is approximately 400 mg.
[0069] The bioavailability of the tablets created in Example 1 may
be tested as follows:
EXAMPLE 2
Primate Administration
[0070] The tablets are prepared as in Example 1 using three
different batches of micronized 5-CNAC disodium, one tablet batch
having an average 5-CNAC disodium particle size of 46 microns
(Batch A), a second tablet batch having an average 5-CNAC disodium
particle size of 6 microns (Batch B), and a third tablet batch
having an average 5-CNAC disodium particle size of 35 microns
(Batch C). The tablets prepared from each of the three different
batches are administered to the same four Rhesus monkeys separately
on different days as follows:
[0071] The Rhesus monkeys fast overnight prior to dosing and are
restrained in chairs fully conscious, for the duration of the study
period. One tablet from Batch A or Batch B or Batch C is
administered to each monkey via a gavage tube followed by 10 mL of
water.
[0072] Rhesus monkey blood samples are collected immediately before
administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, and 6
hours after administration. A tablet from each of the remaining two
tablet batches is dosed and blood samples are collected in a
similar manner but on a separate day for each of the remaining
tablet batches. Resulting plasma salmon calcitonin for each dose
and for each monkey is determined by radioimmunoassay. For each
monkey, the primate plasma salmon calcitonin (SCt) for one batch
and one time period, mean plasma SCt concentrations for all monkeys
for one batch and one time period, Standard Deviation (SD) of
plasma SCt concentrations for one batch and one time period, and
Standard Error of the Mean (SEM) for plasma SCt concentrations for
all monkeys for one batch and one time period are calculated and
reported in Tables 1, 2, and 3 as follows. TABLE-US-00002 TABLE 1
BATCH A: AVERAGE 5-CNAC PARTICLE SIZE 46 MICROMETERS Salmon
Calcitonin (SCt) Plasma Concentrations [pg/mL] (Single Oral Tablet
(200 mg 5-CNAC + 1 mg SCt) to the Rhesus Monkey) Animal Time
[hours] no. 0 0.25 0.50 0.75 1 1.5 2 3 4 5 6 1 0.0 17.8 91.7 279.7
449.2 278.8 48.0 10.5 5.3 3.3 0.0 2 0.0 117.4 535.0 430.8 981.4
1718.0 2396.4 719.5 253.6 102.1 62.9 3 0.0 113.9 754.5 1502.0
2351.0 2066.0 2684.4 1310.0 649.6 280.6 156.5 4 0.0 46.0 127.0
425.5 765.8 1102.0 1599.0 1022.0 419.3 87.0 23.4 Mean 0.0 73.8
377.1 659.5 1136.9 1291.2 1682.0 765.5 332.0 118.3 60.7 SD 0.0 49.7
322.2 566.0 838.4 783.8 1182.1 558.1 271.6 116.6 68.9 SEM 0.0 24.9
161.1 283.0 419.2 391.9 591.0 279.0 135.8 58.3 34.5 Lower Limit of
Quantification (LLOQ) = 2.5 pg/mL, concentrations below LLOQ were
set to zero for Table 1
[0073] TABLE-US-00003 TABLE 2 BATCH B: AVERAGE 5-CNAC PARTICLE SIZE
6 MICROMETERS Salmon Calcitonin (SCt) Plasma Concentrations [pg/mL]
(Single Oral Tablet (200 mg 5-CNAC + 1 mg SCt) to the Rhesus
Monkey) Animal Time [hours] no. 0 0.25 0.50 0.75 1 1.5 2 3 4 5 6 1
0.0 265.6 315.8 245.6 357.2 1927.0 3010.0 863.2 139.4 48.5 20.8 2
0.0 607.0 777.0 1336.0 1602.0 4146.0 7521.0 2681.0 420.8 73.9 43.2
3 0.0 80.9 225.5 325.6 655.6 1478.0 3979.0 2775.0 520.2 91.5 41.3 4
0.0 286.4 155.3 237.7 241.0 269.7 294.2 321.0 179.8 67.5 13.6 Mean
0.0 310.0 368.4 536.2 714.0 1955.2 3701.1 1660.1 315.1 70.4 29.7 SD
0.0 218.5 280.2 534.7 617.2 1619.6 2986.3 1253.5 184.8 17.8 14.8
SEM 0.0 109.2 140.1 267.3 308.6 809.8 1493.1 626.7 92.4 8.9 7.4
Lower Limit of Quantification (LLOQ) = 2.5 pg/mL, concentrations
below LLOQ were set to zero for Table 2
[0074] TABLE-US-00004 TABLE 3 BATCH C: AVERAGE 5-CNAC PARTICLE SIZE
35 MICROMETERS Salmon Calcitonin (SCt) Plasma Concentrations
[pg/mL] (Single Oral Tablet (200 mg 5-CNAC + 1 mg SCt) to the
Rhesus Monkey) Animal Time [hours] no. 0 0.25 0.50 0.75 1 1.5 2 3 4
5 6 1 0.0 36.1 94.7 428.0 739.4 2568.0 4025.0 1348.0 499.6 218.4
98.1 2 0.0 10.9 55.0 168.9 248.2 507.3 654.0 434.8 177.3 68.8 38.9
3 0.0 172.3 336.6 409.5 584.9 1487.0 2087.0 1479.0 162.0 52.0 17.2
4 0.0 7.9 46.9 208.1 390.1 1237.0 2347.0 1342.0 192.3 42.3 19.2
Mean 0.0 56.8 133.3 303.6 490.7 1449.8 2278.3 1151.0 257.8 95.4
43.4 SD 0.0 78.0 137.1 134.1 215.8 853.5 1382.1 481.6 161.7 82.7
37.8 SEM 0.0 39.0 68.6 67.1 107.9 426.7 691.1 240.8 80.8 41.4 18.9
Lower Limit of Quantification (LLOQ) = 2.5 pg/mL, concentrations
below LLOQ were set to zero for Table 3
[0075] The foregoing clearly shows that the compositions according
to the instant invention allow considerably improved oral
bioavailability of active agent. The improved bioavailability
results in high in vivo concentrations of active agent,
particularly calcitonin, being achieved via oral delivery, and in
correlation to the particle sizes of 5-CNAC in the oral
formulations of the Examples.
[0076] The foregoing embodiments and examples are given merely to
illustrate the instant invention and are not intended to be
limiting. Numerous other embodiments and variations are within the
scope of the invention and readily accessible to those skilled in
the art.
* * * * *