U.S. patent application number 11/443528 was filed with the patent office on 2006-09-28 for 5-cnac as oral delivery agent for parathyroid hormone fragments.
Invention is credited to Moise Azria, Simon David Bateman.
Application Number | 20060217313 11/443528 |
Document ID | / |
Family ID | 23214149 |
Filed Date | 2006-09-28 |
United States Patent
Application |
20060217313 |
Kind Code |
A1 |
Azria; Moise ; et
al. |
September 28, 2006 |
5-CNAC as oral delivery agent for parathyroid hormone fragments
Abstract
Pharmaceutical compositions for the effective oral delivery of a
parathyroid hormone, PTH, as well as methods for administration of
the compositions are provided. Additionally, methods for
stimulating new bone formation and treating and/or preventing
osteoporosis are also provided.
Inventors: |
Azria; Moise; (Basel,
CH) ; Bateman; Simon David; (Randolph, NJ) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
23214149 |
Appl. No.: |
11/443528 |
Filed: |
May 30, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10484331 |
Jun 3, 2004 |
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PCT/EP02/09181 |
Aug 16, 2002 |
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11443528 |
May 30, 2006 |
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60313048 |
Aug 17, 2001 |
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Current U.S.
Class: |
514/11.8 ;
514/159; 514/16.9; 562/450 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 47/183 20130101; A61P 19/00 20180101; A61K 2300/00 20130101;
A61P 19/10 20180101; A61K 9/4858 20130101; A61P 5/18 20180101; A61K
31/198 20130101; A61K 38/29 20130101; A61P 19/08 20180101 |
Class at
Publication: |
514/012 ;
514/159; 562/450 |
International
Class: |
A61K 38/29 20060101
A61K038/29; A61K 31/60 20060101 A61K031/60 |
Claims
1. A pharmaceutical composition for oral delivery comprising a PTH
fragment and N-(5-chlorosalicviovl)-8-aminocaprylic acid and
pharmaceutically acceptable salts and esters thereof, said PTH
fragment selected from PTH (1-28) to PTH (1-41).
2. A pharmaceutical composition according to claim 1 wherein the
PTH fragment is selected from PTH (1-28), PTH (1-31), PTH (1-34),
PTH (1-37), PTH (1-38) and PTH (1-41).
3. A pharmaceutical composition according to claim 1 wherein the
PTH fragment is PTH (1-34).
4. A pharmaceutical composition according to claim 1 wherein the
PTH fragment is recombinant PTH.
5. A pharmaceutical composition according to claim 3 wherein the
PTH fragment is recombinant PTH.
6. A pharmaceutical composition according to claim 1 wherein the
PTH fragment is human parathyroid hormone.
7. A pharmaceutical composition according to claim 6 wherein the
human parathyroid hormone is hPTH (1-34).
8. A pharmaceutical composition for oral delivery comprising a PTH
fragment and a compound selected from the free acid, the disodium
salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid and the
monohydrate thereof, said PTH fragment selected from PTH (1-28) to
PTH (1-41).
9. A pharmaceutical composition according to claim 8 wherein the
compound is N-(5-chloro-salicyloyl)-8-aminocaprylic acid.
10. A pharmaceutical composition for oral delivery comprising a PTH
fragment and the disodium salt of
N-(5-chloro-salicyloyl)-8-aminocaprylic acid.
11. A method for orally administering an effective dose of PTH
comprising orally administering to a patient in need of PTH a
pharmaceutical composition comprising a therapeutically effective
amount of a PTH fragment and 5-CNAC, said PTH fragment selected
from PTH (1-28)-PTH (1-41).
12. A method according to claim 11 wherein the PTH is selected from
PTH (1-28), PTH (1-31), PTH (1-34), PTH (1-37), PTH (1-38) and PTH
(1-41).
13. A method according to claim 11 wherein the PTH is hPTH
(1-34).
14. A method according to claim 11 wherein the PTH is recombinant
PTH.
15. A method according to claim 11 wherein the PTH is recombinant
hPTH.
16. A method according to claim 11 wherein the 5-CNAC is selected
from the free acid, the disodium salt of
N-(5-chlorosalicyloyl)-8-aminocaprylic acid and the monohydrate
thereof.
17. A method according to claim 11 wherein the 5-CNAC is
N-(5-chloro-salicyloyl)-8-aminocaprylic acid.
18. A method according to claim 11 wherein the 5-CNAC is the
disodium salt of N-(5-chloro-salicyloyl)-8-aminocaprylic acid.
19. A method of stimulating new bone formation comprising orally
administering to a patient in need of new bone formation a
pharmaceutical composition comprising a therapeutically effective
amount of a PTH fragment and 5-CNAC, said PTH fragment selected
from PTH (1-28)-PTH (1-41).
20. A method of treatment or prevention of osteoporosis comprising
orally administering to a patient in need of said treatment or
prevention a pharmaceutical composition comprising a
therapeutically effective amount of a PTH fragment and 5-CNAC, said
PTH fragment selected from PTH (1-28)-PTH (1-41).
21. The use of 5-CNAC for the preparation of a pharmaceutical
composition suitable for the oral delivery of PTH fragments
selected from PTH (1-28)-PTH (1-41).
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to the oral delivery of
parathyroid hormone (PTH). The mammalian parathyroid hormones, e.g.
human (hPTH), bovine (bPTH) and porcine (pPTH), are single
polypeptide chains of 84 amino acid residues having molecular
weights of approximately 9500. Specifically, the present invention
relates to PTH fragments incorporating at least the first 28
N-terminal amino acid residues (PTH (1-28)) up to and including the
first 41 N-terminal amino acid residues (PTH (1-41)). More
particularly, the invention is directed to pharmaceutical
compositions for the oral delivery of PTH, said compositions
comprising PTH (1-28) to (1-41) and
N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC).
[0003] 2. Description of the Related Art
[0004] PTH studies done in animals and humans with PTH, PTH-related
peptides, and PTH analogues have demonstrated its usefulness in
increasing bone formation and bone resorption and have prompted
interest in its use for the treatment of osteoporosis and related
bone disorders. However, the oral delivery of PTH in mammals has
proven difficult due, at least in part, to the insufficient
stability of PTH in the gastrointestinal tract as well as the
inability of PTH to be readily transported through the intestinal
walls into the blood stream.
[0005] U.S. Pat. No. 5,773,647 (the '647 patent) describes 193
carrier compounds useful for the delivery of active agents,
including PTH. One of the carrier compounds expressly described
therein is N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC)
having the formula ##STR1## Example 2 in Column 6 of the '647
patent describes the preparation of 11 different dosing
compositions some intracolonic (IC) and some oral gavage (PO) each
containing parathyroid hormone and a carrier, the carrier being
different for each composition. An IC dosing composition was
prepared using 5-CNAC as the carrier. Example 3 therein describes
in vivo tests carried out dosing male Sprague-Dawley rats with the
dosing solutions prepared in Example 2. Blood samples were
collected and the serum PTH concentration was quantified for each
rat.
[0006] Surprisingly, it has now been found that 5-CNAC in
combination with specific PTH fragments, i.e. PTH fragments
incorporating at least the first 28 N-terminal aminoacid residues
(PTH (1-28)) up to and including the first 41 N-terminal amino acid
residues (PTH (1-41)) when orally administered gives unexpectedly
high PTH serum levels relative to other PTHs and other carriers and
provide a sharp C.sub.max allowing for a bone formation effect.
SUMMARY OF THE INVENTION
[0007] Accordingly, the present invention is directed to
pharmaceutical compositions suitable for oral delivery of PTH
fragments and to methods of administering such compositions.
[0008] Specifically, the instant invention is directed to a
pharmaceutical composition for oral delivery comprising a
therapeutically effective amount of a PTH fragment and 5-CNAC, said
PTH fragment selected from PTH (1-28) to PTH (1-41). Preferably,
the PTH is human parathyroid hormone, hPTH.
[0009] In another embodiment, the invention is directed to a method
for orally administering an effective dose of PTH comprising orally
administering to a patient in need of PTH a pharmaceutical
composition comprising a therapeutically effective amount of a PTH
fragment and 5-CNAC, said PTH fragment selected from PTH (1-28) to
PTH (1-41).
[0010] The invention is also directed to a method of stimulating
new bone formation comprising orally administering to a patient in
need of new bone formation a pharmaceutical composition comprising
a therapeutically effective amount of a PTH fragment and 5-CNAC,
said PTH fragment selected from PTH (1-28) to PTH (1-41).
[0011] In a further embodiment, the invention is directed to a
method of treatment or prevention of osteoporosis comprising orally
administering to a patient in need of said treatment or prevention
a pharmaceutical composition comprising a therapeutically effective
amount of a PTH fragment and 5-CNAC, said PTH fragment selected
from PTH (1-28) to PTH (1-41).
[0012] In a still further embodiment, the invention is directed to
the use of 5-CNAC for the preparation of a pharmaceutical
composition suitable for the oral delivery of PTH fragments
selected from PTH (1-28) to PTH (1-41).
[0013] Further features and advantages of the invention will become
apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The PTH fragments can be of any parathyroid hormone,
particularly mammalian parathyroid hormone, e.g. human (hPTH),
bovine (bPTH), and porcine (pPTH) and particularly hPTH and will
incorporate at least the first 28 N-terminal residues (PTH (1-28))
up to and including the first 41 N-terminal residues (PTH (1-41))
and include without limitation PTH (1-28), PTH (1-31) PTH (1-34),
PTH (1-37), PTH (1-38) and PTH (141). Human parathyroid hormone
(1-34) is particularly preferred. These parathyroid hormone
fragments are commercially available or can be obtained
recombinantly or by peptide synthesis.
[0015] For purposes of the instant invention, the 5-CNAC, i.e.
N-(5-chlorosalicyloyl)-8-aminocaprylic acid, can be the free acid,
analogs thereof, its monosodium and disodium salts, ethanol
solvates of the sodium salts and the monohydrates of the sodium
salts and any combinations thereof. The free acid, the disodium
salt of 5-CNAC and the monohydrate thereof are particularly useful.
N-(5-chlorosalicyloyl)-8-aminocaprylic acid is described in the
aforementioned '647 patent, the contents of which are hereby
incorporated by reference, and can be made by methods described
therein. The sodium salts and alcohol solvates and hydrates thereof
are described in WO 00/059863, along with methods for preparing
them.
[0016] 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.
[0017] The disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic
acid can also be prepared by making a slurry of
N-(5-chlorosalicyloyl)-8-aminocaprylic acid 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.
[0018] A still further method of preparing the disodium salt is by
reacting N-(5-chlorosalicyloyl)-8-aminocaprylic acid with one molar
equivalent of sodium hydroxide to form a monosodium salt and then
adding an additional one molar equivalent of sodium hydroxide to
yield the disodium salt.
[0019] 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
N-(5-chlorosalicyloyl)-8-aminocaprylic acid as a solid. The solid
can also be isolated by spray drying an aqueous solution of the
disodium salt.
[0020] 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 N-(5-chlorosalicyloyl)-8-aminocaprylic
acid. Typically, the ethanol solvate contains about one ethanol
molecule or ion for every molecule of disodium salt of
N-(5-chlorosalicyloyl)-8-aminocaprylic acid.
[0021] The ethanol solvate of the disodium salt of
N-(5-chlorosalicyloyl)-8-aminocaprylic acid can be prepared by
dissolving N-(5-chlorosalicyloyl)8-aminocaprylic acid in ethanol.
Typically, each gram of N-(5-chlorosalicyloyl)-8-aminocaprylic acid
is dissolved in from about 1 to about 50 mL of ethanol and
generally, from about 2 to about 10 mL of ethanol. The
N-5-chlorosalicyloyl)-8-aminocaprylic acid/ethanol solution is then
reacted with a molar excess of a sodium containing salt, such as a
monosodium containing salt, relative to
N-(5-chlorosalicyloyl)8-aminocaprylic acid, i.e. for every mole of
N-(5-chlorosalicyloyl)-8-aminocaprylic acid 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
N-(5-chlorosalicyloyl)-8-aminocaprylic acid 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.
[0022] The hydrates of the disodium salts of the
N-(5-chlorosalicyloyl)-8-aminocaprylic acid may be prepared by
drying the ethanol solvate to form 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.
[0023] The amount of PTH fragment to be administered is generally
an amount effective to stimulate new bone formation i.e. a
therapeutically effective amount. This amount will necessarily vary
with the age, size, sex and condition of the subject to be treated,
the nature and severity of the disorder to be treated and the like.
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 PTH can also be more than the effective amount when
the composition provides sustained release of the pharmacologically
active agent. The total amount of PTH to be used can be determined
by methods known to those skilled in the art. However, in general,
satisfactory results will be obtained systemically at daily dosages
of from about 0.001 .mu.g/kg to about 10 mg/kg animal body weight,
preferably 1 .mu.g/kg to about 6 .mu.g/kg body weight.
[0024] The pharmaceutical compositions of the present invention
typically contain a delivery effective amount of 5-CNAC, i.e. an
amount sufficient to deliver the PTH for the desired effect
Generally, the 5-CNAC is present in an amount of 2.5% to 99.4% by
weight, more preferably 25% to 50% by weight of the total
composition.
[0025] Oral administration of the pharmaceutical compositions
according to the invention can be accomplished regularly, e.g. once
or more on a daily or weekly basis; intermittently, e.g.
irregularly during a day or week; or cyclically, e.g. regularly for
a period of days or weeks followed by a period without
administration.
[0026] The dosage form of the pharmaceutical compositions of the
instant invention can be any known form, e.g. liquid or solid
dosage forms.
[0027] The liquid dosage forms include solution emulsions,
suspensions, syrups and elixirs. In addition to the PTH and 5-CNAC,
the liquid formulations may also include inert excipients commonly
used in the art such as, solubilizing agents e.g. ethanol; oils
such as cottonseed, castor and sesame oils; wetting agents;
emulsifying agents; suspending agents; sweeteners; flavorings; and
solvents such as water.
[0028] The solid dosage forms include capsules, soft-gel capsules,
tablets, caplets, powders, granules or other solid oral dosage
forms, all of which can be prepared by methods well known in the
art.
[0029] The pharmaceutical 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 supplied by FMC corporation, or any combination
thereof. Other additives may include phosphate buffer salts, citric
acid, glycols, and other dispersing agents.
[0030] The composition may also include one or more enzyme
inhibitors, such as actinonin or epiactinonin and derivatives
thereof; aprotinin, Trasylol and Bowman-Birk inhibitor.
[0031] Further, a transport inhibitor, i.e. a .rho.-glycoprotein
such as Ketoprofin, may be present in the compositions of the
present invention.
[0032] The solid pharmaceutical compositions of the instant
invention can be prepared by conventional methods e.g. by blending
a mixture of the PTH fragment, the 5-CNAC, and any 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.
[0033] Preferably, the ingredients in the pharmaceutical
compositions of the instant invention are homogeneously or
uniformly mixed throughout the solid dosage form.
[0034] Parathyroid hormones are indicated for preventing or
treating all bone conditions which are associated with increased
calcium depletion or resorption or in which stimulation of bone
formation and calcium fixation in the bone is desirable, e.g.
osteoporosis of various genesis (e.g. juvenile, menopausal,
post-menopausal, post-traumatic, caused by old age or by
corticoid-steroid therapy a or inactivity), fractures, osteopathy,
including acute and chronic states associated with skeletal
demineralization, osteo-malacia, periodontal bone loss or bone loss
due to arthritis or osteoarthritis or cancer (e.g. bone; metastis)
or for treating hypoparathyroidism.
[0035] Parathyroid hormones are particularly indicated for
preventing or treating osteoporosis of various genesis.
[0036] According to a further embodiment of the invention, the PTH
may, be employed as adjunct or adjuvant to other therapy, e.g. a
therapy using a bone resorption inhibitor, for example as in
osteoporosis therapy, in particular a therapy employing calcium, a
calcitonin or an analogue or derivative thereof, e.g. salmon, eel
or human calcitonin, a steroid hormone, e.g. an estrogen, a partial
estrogen agonist or estrogen-gestagen combination, a SERM
(Selective Estrogen Receptor Modulator) e.g. raloxifene,
lasofoxifene, TSE-424, FC1271, Tibolone (Livial.RTM.), vitamin D or
an analogue thereof or an activator of PTH release, or
bisphosphonates, e.g. clodronic acid, etidronic acid, pamidronic
acid, aledronic acid, ibandronic acid, zoledronic acid, risedronic
acid or tiludronic acid and salts and hydrates thereof.
[0037] When the PTH is administered in conjunction with, e.g. as an
adjuvant to bone resorption inhibition therapy, dosages for the
co-administered inhibitor will of course vary depending on the type
of inhibitor drug employed, e.g. whether it is a steroid or a
calcitonin, on the condition to be treated, whether it is a
curative or preventive therapy, on the regimen and so forth.
[0038] The oral administration of the present invention may be to
any animal in need thereof, including, but not limited to, mammals,
such as rodents, cows, pigs, dogs, cats, and primates, particularly
humans.
[0039] The following examples serve to further illustrate the
invention.
EXAMPLE 1
[0040] The following capsules are prepared as follows:
Capsules prepared from 800 .mu.g hPTH* (Capsule 1A)
Capsules prepared from 400 mg 5-CNAC**/800 .mu.g hPTH* (Capsule
1B)
*The PTH fragment is human parathyroid hormone, fragment 1-34
commercially available from Sigma. **The 5-CNAC is the disodium
salt of N-(5-chlorosalicyloyl)8-aminocaprylic acid.
[0041] The hPTH only capsules are prepared by weighing out 400
.mu.g of the hPTH and placing it directly into each capsule. The
hPTH/5-CNAC capsules are prepared as dry blends by weighing out the
individual components blending them together to make a homogeneous
mix and then hand filling 400 mg of the mix into each capsule.
EXAMPLE 2
Primate Administration
[0042] The capsules prepared in Example 1 are administered to
Rhesus monkeys as follows: four monkeys in a group are each dosed
with one capsule prepared as in Example 1 as follows:
[0043] The Rhesus monkeys fast overnight prior to dosing and are
restrained in chairs fully conscious, for the duration of the study
period. The capsules are orally administered via a gavage tube
followed by 10 mL of water.
[0044] Blood samples are collected at 0, 0.25, 0.5, 0.75, 1, 1.5,
2, 3, 4, 5, and 6 hours after administration. Plasma hPTH levels
are determined by radioimmunoassay. The primate plasma PTH results
from each group of monkeys are averaged and the maximum mean plasma
calculated. The results for the PTH only group are reported in
Table 1 and the results for the hPTH/5-CNAC group are reported in
Table 2. TABLE-US-00001 TABLE 1 hPTH ONLY hPTH PLASMA
CONCENTRATIONS (pg/mL) AFTER ORAL ADMINISTRATION TO THE RHESUS
MONKEY Dose: 1 Capsule 1D Animal Time [hours] no. 0 0.25 0.50 0.75
1 1.5 2 3 4 5 6 R927 0 0 0 0 0 0 0 0 0 0 0 S982 0 0 0 0 0 0 0 0 0 0
0 Mean 0 0 0 0 0 0 0 0 0 0 0 SD 0 0 0 0 0 0 0 0 0 0 0 SEM 0 0 0 0 0
0 0 0 0 0 0 LLOQ = 25 pg/mL, concentrations below LLOQ were set to
zero.
[0045] TABLE-US-00002 TABLE 2 hPTH/5-CNAC hPTH PLASMA
CONCENTRATIONS (pg/mL) AFTER ORAL ADMINISTRATION TO THE RHESUS
MONKEY Dose: 1 Capsule 1B Ani- mal Time [hours] no. 0 0.25 0.50
0.75 1 1.5 2 3 4 5 6 R944 0 83 191 300 360 262 154 35 0 0 0 S963 0
127 332 663 1258 150 34 0 0 0 0 Mean 0 105 262 482 809 206 94 17 0
0 0 SD 0 31 100 257 635 79 85 25 0 0 0 SEM 0 22 71 182 449 56 60 17
0 0 0
[0046] As can be seen from the data in Tables-1 and 2, the 5-CNAC
significantly facilitates the oral 4 delivery of the hPTH fragment
In addition, the data in Table 2 indicate a sharp C.sub.max in the
PTH plasma profile allowing for a bone formation effect.
[0047] 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.
* * * * *