U.S. patent application number 15/549425 was filed with the patent office on 2018-02-01 for treatment of osteoporosis.
The applicant listed for this patent is Entera Bio Ltd.. Invention is credited to Gregory BURSHTEIN, Hillel GALITZER, Ariel ROTHNER, Phillip M. SCHWARTZ.
Application Number | 20180028622 15/549425 |
Document ID | / |
Family ID | 56614456 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028622 |
Kind Code |
A1 |
BURSHTEIN; Gregory ; et
al. |
February 1, 2018 |
TREATMENT OF OSTEOPOROSIS
Abstract
A pharmaceutical composition for use in the treatment of
osteoporosis by oral administration of the composition is provided
herein. The composition comprises parathyroid hormone or a fragment
thereof; and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).
Further disclosed are uses of the composition in the preparation of
a medicament and methods of treating osteoporosis utilizing the
composition.
Inventors: |
BURSHTEIN; Gregory; (Modiin,
IL) ; ROTHNER; Ariel; (Jerusalem, IL) ;
SCHWARTZ; Phillip M.; (Jerusalem, IL) ; GALITZER;
Hillel; (Yad Binyamin, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Entera Bio Ltd. |
Jerusalem |
|
IL |
|
|
Family ID: |
56614456 |
Appl. No.: |
15/549425 |
Filed: |
February 9, 2016 |
PCT Filed: |
February 9, 2016 |
PCT NO: |
PCT/IL2016/050154 |
371 Date: |
August 8, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62113600 |
Feb 9, 2015 |
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62113629 |
Feb 9, 2015 |
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62113604 |
Feb 9, 2015 |
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62113673 |
Feb 9, 2015 |
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62113638 |
Feb 9, 2015 |
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62113625 |
Feb 9, 2015 |
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62113619 |
Feb 9, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 2300/00 20130101; A61P 19/10 20180101; A61K 9/2054 20130101;
A61K 38/55 20130101; A61K 9/28 20130101; A61K 9/0053 20130101; A61P
5/18 20180101; A61K 31/05 20130101; A61K 31/19 20130101; A61K 38/22
20130101; A61K 47/12 20130101; A61K 9/2009 20130101; A61K 9/2086
20130101; A61K 31/20 20130101; A61K 9/2886 20130101; A61K 31/166
20130101; A61K 9/20 20130101; A61K 9/2013 20130101; A61K 38/29
20130101; A61K 38/55 20130101; A61K 2300/00 20130101; A61K 38/29
20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 38/29 20060101
A61K038/29; A61K 9/20 20060101 A61K009/20; A61K 45/06 20060101
A61K045/06; A61K 31/20 20060101 A61K031/20; A61K 9/00 20060101
A61K009/00 |
Claims
1-14. (canceled)
15. A method of treating osteoporosis in a subject in need thereof,
the method comprising administering to the subject via oral
ingestion a composition comprising: parathyroid hormone or a
fragment thereof; and SNAC (sodium
8-N-(2-hydroxybenzoyl)aminocaprylate).
16. The method of claim 15, wherein said fragment comprises
teriparatide.
17. The method of claim 15, wherein the composition further
comprises at least one protease inhibitor.
18. The method of claim 17, wherein said at least one protease
inhibitor comprises at least one trypsin inhibitor.
19. The method of claim 18, wherein said at least one trypsin
inhibitor is selected from the group consisting of lima bean
trypsin inhibitor, aprotinin, soybean trypsin inhibitor and
ovomucoid trypsin inhibitor.
20. The method of claim 18, wherein said at least one trypsin
inhibitor comprises soybean trypsin inhibitor.
21. The method of claim 15, comprising administering via oral
ingestion said parathyroid hormone or said fragment thereof in an
amount in a range of from 200 to 3000 .mu.g.
22. The method of claim 15, wherein said administration via oral
ingestion is effected once per day.
23. The method of claim 15, wherein the composition is formulated
such that absorption of said parathyroid hormone or said fragment
thereof following administration of the composition via oral
ingestion is characterized by an average Cmax in a range of from 30
pg/ml to 700 pg/ml.
24. (canceled)
25. The method of claim 15, wherein the composition is formulated
such that absorption of said parathyroid hormone or said fragment
thereof following administration of the composition via oral
ingestion is characterized by an average ratio of AUC to Cmax which
is 3 hours or lower.
26. The method of claim 25, wherein said average ratio of AUC to
Cmax is 60 minutes or lower.
27. The method of claim 15, wherein the composition is formulated
as a tablet.
28. The method of claim 16, wherein the composition further
comprises at least one protease inhibitor.
29. The method of claim 28, wherein said at least one protease
inhibitor comprises at least one trypsin inhibitor.
30. The method of claim 29, wherein said at least one trypsin
inhibitor is selected from the group consisting of lima bean
trypsin inhibitor, aprotinin, soybean trypsin inhibitor and
ovomucoid trypsin inhibitor.
31. The method of claim 29, wherein said at least one trypsin
inhibitor comprises soybean trypsin inhibitor.
32. The method of claim 16, comprising administering via oral
ingestion said teriparatide in an amount in a range of from 200 to
3000 .mu.g.
33. The method of claim 16, wherein said administration via oral
ingestion is effected once per day.
34. The method of claim 16, wherein the composition is formulated
such that absorption of said parathyroid hormone or said fragment
thereof following administration of the composition via oral
ingestion is characterized by an average Cmax in a range of from 50
pg/ml to 450 pg/ml.
35. The method of claim 16, wherein the composition is formulated
such that absorption of said teriparatide following administration
of the composition via oral ingestion is characterized by an
average ratio of AUC to Cmax which is 3 hours or lower.
36. The method of claim 35, wherein said average ratio of AUC to
Cmax is 60 minutes or lower.
37. The method of claim 16, wherein the composition is formulated
as a tablet.
Description
FIELD AND BACKGROUND OF THE INVENTION
[0001] The present invention, in some embodiments thereof, relates
to therapy, and more particularly, but not exclusively, to
compositions and methods for the treatment of osteoporosis by oral
administration.
[0002] Parathyroid hormone (PTH) is secreted by the parathyroid
gland as a polypeptide containing 84 amino acids. PTH regulates
serum calcium levels by enhancing release of calcium from bones
(bone resorption), and by enhancing absorption of calcium in the
intestines.
[0003] Teriparatide is a recombinant form of the first 34 amino
acids of human PTH (PTH (1-34)), and is used for treatment of
osteoporosis. Administration is by subcutaneous injection once per
day at a dose of 20 .mu.g [Riek & Towler, Mo Med 2011,
108:118-123].
[0004] PTH (including PTH (1-34)) has been reported to enhance bone
growth provided that it is administered intermittently, with
circulating levels returning to control levels within 3 hours
[Martin, J Bone Metab 2014, 21:8-20]. In contrast, prolonged
elevated PTH levels deplete bones by enhancing bone resorption.
[0005] Oral administration of peptide pharmaceuticals is
problematic due to degradation of peptides in the digestive system
and poor absorption of large molecules.
[0006] U.S. Patent Application Publication No. 2007/0087957
describes compositions for oral administration of a protein, the
compositions comprising a protein and an omega-3 fatty acid, as
well as the use of such compositions for oral administration of
insulin.
[0007] Qi & Ping [J Microencapsulation 2004, 21:37-45] describe
administration of enteric microspheres containing insulin with SNAC
(sodium 8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric
microspheres are for protecting the insulin from digestive enzymes
of the stomach and small intestine, and the SNAC is for enhancing
absorption.
[0008] U.S. Patent Application Publication No. 2011/0142800
describes compositions for oral administration of a protein,
comprising a protein having a molecular weight of up to 100,000 Da,
a protease inhibitor, and an absorption enhancer, such as SNAC,
N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD),
8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC),
8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC) and
4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB) and
sodium salts thereof.
[0009] U.S. Pat. No. 8,110,547 describes compositions for buccal
administration of parathyroid hormone (PTH). The composition
comprises PTH or a fragment or analog thereof, as well as a
delivery agent such as 4-MOAC, SNAC, SNAD, 5-CNAC and 4-CNAB.
[0010] Additional background art includes Qi et al. [Acta Pharm
Sinica 2004, 39:844-848]; International Patent Application
Publications WO 00/50386, WO 01/32130, WO 01/32596, WO 03/045306
and WO 2007/121471; Japanese Patent Application Nos. 2005281231 and
2006111558; and U.S. Patent Application Publication Nos.
2006/0234913 and 2013/0224300.
SUMMARY OF THE INVENTION
[0011] According to an aspect of some embodiments of the invention,
there is provided a pharmaceutical composition for use in the
treatment of osteoporosis by oral administration of the composition
to a subject in need thereof, the composition comprising:
[0012] parathyroid hormone of a fragment thereof; and
[0013] SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).
[0014] According to an aspect of some embodiments of the invention,
there is provided a use of a composition in the preparation of a
medicament for the treatment of osteoporosis by oral administration
of the composition to a subject in need thereof, the composition
comprising:
[0015] parathyroid hormone or a fragment thereof; and
[0016] SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).
[0017] According to some embodiments of the invention, the
treatment comprises oral administration of the parathyroid hormone
or fragment thereof in an amount in a range of from 200 to 3000
.mu.g.
[0018] According to some embodiments of the invention, the
composition and/or medicament is for oral administration once per
day.
[0019] According to an aspect of some embodiments of the invention,
there is provided a method of treating osteoporosis in a subject in
need thereof, the method comprising orally administering to the
subject a composition comprising:
[0020] parathyroid hormone or a fragment thereof; and
[0021] SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).
[0022] According to some embodiments of the invention, the method
comprises orally administering the parathyroid hormone or fragment
thereof in an amount in a range of from 200 to 3000 .mu.g.
[0023] According to some embodiments of the invention, the oral
administration is effected once per day.
[0024] According to some embodiments of the invention, the fragment
comprises teriparatide.
[0025] According to some embodiments of the invention, the
composition further comprises at least one protease inhibitor.
[0026] According to some embodiments of the invention, the at least
one protease inhibitor comprises at least one trypsin
inhibitor.
[0027] According to some embodiments of the invention, the at least
one trypsin inhibitor is selected from the group consisting of lima
bean trypsin inhibitor, aprotinin, soybean trypsin inhibitor and
ovomucoid trypsin inhibitor.
[0028] According to some embodiments of the invention, the at least
one trypsin inhibitor comprises soybean trypsin inhibitor.
[0029] According to some embodiments of the invention, the
composition is formulated such that absorption of the parathyroid
hormone or fragment thereof following oral administration of the
composition is characterized by a Cmax in a range of from 30 pg/ml
to 700 pg/ml.
[0030] According to some embodiments of the invention, the
composition comprises teriparatide and is formulated such that
absorption of teriparatide following oral administration of the
composition is characterized by a Cmax in a range of from 30 pg/ml
to 300 pg/ml.
[0031] According to some embodiments of the invention, the
composition is formulated such that absorption of the parathyroid
hormone or fragment thereof following oral administration of the
composition is characterized by a ratio of AUC to Cmax which is 3
hours or lower.
[0032] According to some embodiments of the invention, the ratio of
AUC to Cmax is 60 minutes or lower.
[0033] According to some embodiments of the invention, the
composition is formulated as a tablet.
[0034] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0035] Some embodiments of the invention are herein described, by
way of example only, with reference to the accompanying drawings.
With specific reference now to the drawings in detail, it is
stressed that the particulars shown are by way of example and for
purposes of illustrative discussion of embodiments of the
invention. In this regard, the description taken with the drawings
makes apparent to those skilled in the art how embodiments of the
invention may be practiced.
[0036] In the drawings:
[0037] FIGS. 1A-1C are graphs showing plasma concentrations of
parathyroid hormone(1-34) as a function of time after oral
administration of a tablet according to some embodiments of the
invention; each of FIGS. 1A-1C presents data for a different
subject, and each subject was administered a tablet on two separate
occasions (two weeks apart);
[0038] FIG. 2 is a bar graph showing maximal plasma concentrations
(Cmax) of parathyroid hormone(1-34) as a function of time after
oral administration of 200, 400, 680, 1400 or 1800 .mu.g
teriparatide according to some embodiments of the invention, and
after subcutaneous administration of 20 .mu.g teriparatide;
[0039] FIG. 3 is a graph showing plasma concentrations of
parathyroid hormone(1-34) as a function of time after oral
administration of 1800 .mu.g teriparatide according to some
embodiments of the invention, after subcutaneous administration of
20 .mu.g teriparatide, or after administration of a placebo;
[0040] FIG. 4 is a graph showing plasma concentrations of cAMP as a
function of time after oral administration of 680 .mu.g
teriparatide according to some embodiments of the invention, or
after subcutaneous administration of 20 .mu.g teriparatide;
[0041] FIGS. 5A-5C depict exemplary unit dosage forms for use
according to some embodiments of the invention;
[0042] FIGS. 6A-6C depict exemplary coated unit dosage forms for
oral administration according to some embodiments of the
invention;
[0043] FIG. 7 depicts an exemplary tablet for oral administration
according to some embodiments of the invention;
[0044] FIG. 8 depicts an exemplary coated tablet for oral
administration according to some embodiments of the invention;
[0045] FIG. 9 depicts an exemplary external layer of unit dosage
forms for oral administration according to some embodiments of the
invention;
[0046] FIG. 10 depicts an exemplary external layer of a unit dosage
form for oral administration according to some embodiments of the
invention;
[0047] FIG. 11 depicts an exemplary core of a unit dosage form for
oral administration according to some embodiments of the
invention;
[0048] FIG. 12 depicts an exemplary drug delivery system according
to some embodiments of the invention;
[0049] FIGS. 13A-13C depict an exemplary drug delivery system
according to some embodiments of the invention, prior to oral
administration (FIG. 13A), and subsequent to oral administration in
the stomach (FIG. 13B) and in the intestines (FIG. 13C);
[0050] FIG. 14 depicts a casing of an exemplary drug delivery
system according to some embodiments of the invention;
[0051] FIG. 15 presents a graph showing the release of SNAC, as a
function of time, from an exemplary tablet formulation comprising
sodium bicarbonate in comparison with an exemplary tablet
formulation without sodium bicarbonate; and
[0052] FIG. 16 presents a bar graph showing relative absorption of
teriparatide from an exemplary oral formulation co-administered
with 150 ml of water (H.sub.2O) or with an aqueous solution of 3
mg/ml sodium bicarbonate (H.sub.2O+NaCO3) (absorption upon
co-administration with water defined as 100%).
DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION
[0053] The present invention, in some embodiments thereof, relates
to therapy, and more particularly, but not exclusively, to
compositions and methods for the treatment of osteoporosis by oral
administration.
[0054] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not
necessarily limited in its application to the details set forth in
the following description or exemplified by the Examples. The
invention is capable of other embodiments or of being practiced or
carried out in various ways.
[0055] As discussed hereinabove, parathyroid hormone (PTH) and
fragments thereof have been known as effective in the treatment of
osteoporosis, and have been used to this effect by subcutaneous
injection of PTH or a fragment thereof.
[0056] The present inventors have now uncovered that osteoporosis
can be advantageously treated using oral administration of
parathyroid hormone (and/or a fragment thereof) rather than
subcutaneous injection, by utilizing compositions designed for
overcoming the poor absorption of parathyroid hormone upon oral
administration.
[0057] While investigating the enhancement of absorption of
parathyroid hormone by SNAC (sodium
8-N-(2-hydroxybenzoyl)aminocaprylate) upon oral administration, the
present inventors have uncovered that compositions comprising SNAC
can be used to obtain pharmacokinetic profiles which are desirable
for treating osteoporosis. Thus, such compositions are
characterized by relatively rapid increase in levels of parathyroid
hormone, followed by a relatively rapid decrease in levels of
parathyroid hormone. The present inventors have envisioned that
oral administration of such compositions would be particularly
useful for treating osteoporosis, as the desired enhancement of
bone growth in osteoporosis treatment is associated with transient
elevation, rather than chronic elevation of parathyroid
hormone.
[0058] Referring now to the drawings, FIGS. 1A-1C show that oral
administration of exemplary compositions according to some
embodiments of the present invention, results in an increase in
plasma levels of a PTH (teriparatide), followed almost immediately
by a rapid decrease in plasma levels of the PTH. FIG. 2 shows that
the plasma levels of the PTH are proportional to the orally
administered dose. FIG. 3 shows that the time during which the
orally administered PTH is absorbed into the blood is considerably
shorter than when the PTH is administered subcutaneously. FIG. 4
shows that the absorbed PTH exhibits a biological effect.
[0059] These results indicate that oral administration of
compositions comprising PTH as described herein is both an
effective and convenient route for administering PTH, as well as
being associated with a characteristic pharmacokinetic profile
which is suitable, for example, for treating osteoporosis.
[0060] According to an aspect of some embodiments of the invention,
there is provided a pharmaceutical composition for use in the
treatment of osteoporosis.
[0061] According to some embodiments of the present invention, the
compositions are suitable for treating osteoporosis by oral
administration of the composition. That is, the compositions
provide a therapeutic effect when administered orally.
[0062] A pharmaceutical composition according to embodiments of the
present invention comprises:
[0063] parathyroid hormone or a fragment thereof; and SNAC (sodium
8-N-(2-hydroxybenzoyl)aminocaprylate).
[0064] According to an aspect of some embodiments of the invention,
there is provided a use of a composition as described herein in the
preparation of a medicament for the treatment of osteoporosis,
wherein the treatment is effected by oral administration of the
medicament to a subject in need thereof.
[0065] According to an aspect of some embodiments of the invention,
there is provided a method of treating osteoporosis in a subject in
need thereof.
[0066] According to some embodiments of the present invention, the
method is effected by orally administering to the subject a
composition as described herein.
[0067] In some embodiments according to any of the aspects of
embodiments described herein, the composition for oral
administration is formulated as one or more unit dosage form(s), as
defined herein.
[0068] Herein and in the art, the term "parathyroid hormone" refers
to an 84-amino acid polypeptide hormone secreted by the parathyroid
glands.
[0069] Herein, a "fragment" of parathyroid hormone refers to a
polypeptide comprising a portion of the abovementioned 84 amino
acids of parathyroid hormone. Preferably, the fragment is a
fragment which exhibits a biological activity of parathyroid
hormone.
[0070] Teriparatide is an example of a parathyroid hormone
fragment, composed of amino acids 1-34 (i.e., an N-terminal
portion) of the full parathyroid hormone polypeptide. The term
"teriparatide" is used interchangeably herein with the terms
"PTH(1-34)" and "parathyroid hormone(1-34)".
[0071] Herein, for the sake of brevity, the term "parathyroid
hormone" or its abbreviation "PTH" encompasses parathyroid hormone
(having a naturally occurring amino acid sequence, e.g., in
humans), fragments thereof and homologs of the parathyroid hormone
or the fragment thereof, except where indicated otherwise. For
example, the terms "PTH(1-84)" and "parathyroid hormone(1-84)"
refer herein in particular to the full 84-amino acid parathyroid
hormone polypeptide, whereas the terms "PTH(1-34)" and "parathyroid
hormone(1-34)" refer herein to a particular fragment of parathyroid
hormone (teriparatide).
[0072] Without being bound by any particular theory, it is believed
that PTH tend to be poorly absorbed upon oral administration due to
their relatively large molecular weight and/or due to their
polarity; and therefore, their absorption is particularly
susceptible to enhancement by SNAC activity.
[0073] Methods and Compositions:
[0074] As used herein, the phrase "pharmaceutical composition"
(also referred to herein, for brevity, as "composition") refers to
a preparation of a parathyroid hormone (PTH) described herein
(e.g., PTH(1-34), PTH(1-84)) with other chemical components such as
SNAC, and optionally additional ingredients such as described
herein. The purpose of a pharmaceutical composition is to
facilitate administration of the PTH.
[0075] In some embodiments of any one of the embodiments described
herein, the composition for oral administration further comprises
at least one protease inhibitor. Optional species and amounts of
protease inhibitor are described in detail herein.
[0076] In some embodiments of any one of the embodiments described
herein, a treatment or method according to any of the respective
embodiments described herein comprises oral administration of at
least 100 .mu.g of PTH (e.g., PTH(1-34)). In some embodiments, the
treatment or method comprises oral administration of at least 200
.mu.g of PTH (e.g., PTH(1-34)). In some embodiments, the treatment
or method comprises oral administration of at least 500 .mu.g of
PTH (e.g., PTH(1-34)). In some embodiments, the amount of SNAC is
in accordance with any one of the ratios of SNAC to PTH (e.g.,
PTH(1-34)) described herein. In some embodiments, the composition
further comprises at least one protease inhibitor in an amount
which is in accordance with any one of the ratios of protease
inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0077] In some embodiments of any one of the embodiments described
herein, a treatment or method according to any of the respective
embodiments described herein comprises oral administration of 20 mg
or less of PTH (e.g., PTH(1-34)). In some embodiments, the
treatment or method comprises oral administration of 10 mg or less
of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or
method comprises oral administration of 5 mg or less of PTH (e.g.,
PTH(1-34)). In some embodiments, the treatment or method comprises
oral administration of 3 mg (3000 .mu.g) or less of PTH (e.g.,
PTH(1-34)). In some embodiments, the treatment or method comprises
oral administration of 2000 .mu.g or less of PTH (e.g., PTH(1-34)).
In some embodiments, the treatment or method comprises oral
administration of 1000 .mu.g or less of PTH (e.g., PTH(1-34)). In
some embodiments, the amount of SNAC is in accordance with any one
of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In
some embodiments, the composition further comprises at least one
protease inhibitor in an amount which is in accordance with any one
of the ratios of protease inhibitor to PTH (e.g., PTH(1-34))
described herein.
[0078] In some embodiments of any one of the embodiments described
herein, a treatment or method according to any of the respective
embodiments described herein comprises oral administration of 200
.mu.g to 20 mg of PTH (e.g., PTH(1-34)). In some embodiments, the
treatment or method comprises oral administration of 200 .mu.g to
10 mg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment
or method comprises oral administration of 200 .mu.g to 5 mg of PTH
(e.g., PTH(1-34)). In some embodiments, the treatment or method
comprises oral administration of from 200 to 3000 .mu.g of PTH
(e.g., PTH(1-34)). In some embodiments, the treatment or method
comprises oral administration of from 200 to 2000 .mu.g of PTH
(e.g., PTH(1-34)). In some embodiments, the treatment or method
comprises oral administration of from 500 to 1000 .mu.g of PTH
(e.g., PTH(1-34)). In some embodiments, the treatment or method
comprises oral administration of about 750 .mu.g of PTH (e.g.,
PTH(1-34)). In some embodiments, the amount of SNAC is in
accordance with any one of the ratios of SNAC to PTH (e.g.,
PTH(1-34)) described herein. In some embodiments, the composition
further comprises at least one protease inhibitor in an amount
which is in accordance with any one of the ratios of protease
inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0079] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected from 1 to 3 times per day.
In some embodiments, the composition (e.g., formulated as a unit
dosage form) is for oral administration from 1 to 3 times per
day.
[0080] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected once or twice per day. In
some embodiments, the composition (e.g., formulated as a unit
dosage form) is for oral administration once or twice per day.
[0081] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected once per day. In some
embodiments, the composition (e.g., formulated as a unit dosage
form) is for oral administration once per day.
[0082] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected by oral administration of
from 1 to 3 pharmaceutical composition unit dosage forms.
[0083] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected by oral administration of
from 1 to 2 pharmaceutical composition unit dosage forms.
[0084] In some embodiments of any one of the embodiments described
herein, the oral administration according to any of the respective
embodiments described herein is effected by oral administration of
one pharmaceutical composition unit dosage form.
[0085] In some embodiments of any one of the embodiments described
herein, a composition for administration as described herein (e.g.,
a composition unit dosage form according to any of the respective
embodiments described herein) comprises at least 100 .mu.g of PTH
(e.g., PTH(1-34)). In some embodiments, the composition comprises
at least 200 .mu.g of PTH (e.g., PTH(1-34)). In some embodiments,
the composition comprises at least 500 .mu.g of PTH (e.g.,
PTH(1-34)). In some embodiments, the amount of SNAC is in
accordance with any one of the ratios of SNAC to PTH (e.g.,
PTH(1-34)) described herein. In some embodiments, the composition
further comprises at least one protease inhibitor in an amount
which is in accordance with any one of the ratios of protease
inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0086] In some embodiments of any one of the embodiments described
herein, a composition for administration as described herein (e.g.,
a composition unit dosage form according to any of the respective
embodiments described herein) comprises 20 mg or less of PTH (e.g.,
PTH(1-34)). In some embodiments, the composition comprises 10 mg or
less of PTH (e.g., PTH(1-34)). In some embodiments, the composition
comprises 5 mg or less of PTH (e.g., PTH(1-34)). In some
embodiments, the composition comprises 3 mg (3000 .mu.g) or less of
PTH (e.g., PTH(1-34)). In some embodiments, the composition
comprises 2000 .mu.g or less of PTH (e.g., PTH(1-34)). In some
embodiments, the composition comprises 1000 .mu.g or less of PTH
(e.g., PTH(1-34)). In some embodiments, the amount of SNAC is in
accordance with any one of the ratios of SNAC to PTH (e.g.,
PTH(1-34)) described herein. In some embodiments, the composition
further comprises at least one protease inhibitor in an amount
which is in accordance with any one of the ratios of protease
inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0087] In some embodiments of any one of the embodiments described
herein, the composition (e.g., a composition unit dosage form
according to any of the respective embodiments described herein)
comprises from 200 .mu.g to 20 mg of PTH (e.g., PTH(1-34)). In some
embodiments, the composition comprises 200 .mu.g to 10 mg of PTH
(e.g., PTH(1-34)). In some embodiments, the composition comprises
200 .mu.g to 5 mg of PTH (e.g., PTH(1-34)). In some embodiments,
the composition comprises from 200 to 3000 .mu.g of PTH (e.g.,
PTH(1-34)). In some embodiments, the composition comprises from 200
to 2000 .mu.g of PTH (e.g., PTH(1-34)). In some embodiments, the
composition comprises from 500 to 1000 .mu.g of PTH (e.g.,
PTH(1-34)). In some embodiments, the composition comprises about
750 .mu.g of PTH (e.g., PTH(1-34)). In some embodiments, the amount
of SNAC is in accordance with any one of the ratios of SNAC to PTH
(e.g., PTH(1-34)) described herein. In some embodiments, the
composition further comprises at least one protease inhibitor in an
amount which is in accordance with any one of the ratios of
protease inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0088] Parathyroid hormone is characterized in that acute exposure
to the hormone results in a substantially different biological
effect than does chronic exposure, as acute exposure causes a net
enhancement of bone growth, whereas chronic exposure causes a net
enhancement of bone resorption (effectively the opposite of
enhancing bone growth). Enhancement of bone growth may optionally
be used for treating, for example, osteoporosis, whereas
enhancement of bone resorption may relatively undesirable in
treating osteoporosis.
[0089] Herein, the phrase "substantially different biological
effect" means that at least a portion of the effects differ in type
rather than in magnitude. For example, net enhancement of bone
growth is effectively the opposite of net enhancement of bone
resorption.
[0090] Without being bound by any particular theory, it is believed
that a pharmacokinetic profile of compositions described herein can
provide particularly pronounced and/or consistent effects
associated with acute exposure to PTH, suitable, for example, for
promoting pronounced and consistent enhancement of bone growth in
the treatment of osteoporosis.
[0091] In some embodiments, the composition (e.g., composition unit
dosage form) is formulated such that absorption of the PTH
following oral administration of the composition is characterized
by a ratio of AUC to Cmax which is 3 hours or lower.
[0092] In some embodiments, the ratio of AUC to Cmax is 2 hours or
lower.
[0093] In some embodiments, the ratio of AUC to Cmax is 90 minutes
or lower.
[0094] In some embodiments, the ratio of AUC to Cmax is 60 minutes
or lower.
[0095] In some embodiments, the ratio of AUC to Cmax is 50 minutes
or lower.
[0096] In some embodiments, the ratio of AUC to Cmax is 40 minutes
or lower.
[0097] In some embodiments, the ratio of AUC to Cmax is 30 minutes
or lower.
[0098] In some embodiments, the ratio of AUC to Cmax is 20 minutes
or lower.
[0099] In some embodiments, the ratio of AUC to Cmax is 15 minutes
or lower.
[0100] In some embodiments, the ratio of AUC to Cmax is 10 minutes
or lower.
[0101] As used herein the term "AUC" refers to the area under a
curve which represents levels of an administered agent (e.g., PTH)
in the blood (e.g., plasma levels) as a function of time following
administration, and can be determined by measuring plasma levels of
the agent (e.g., PTH) at various time points following
administration, as exemplified herein.
[0102] As used herein the term "Cmax" refers to the maximal
concentration of an administered agent (e.g., PTH) in the blood
(e.g., plasma levels), and can be determined by measuring levels of
the agent (e.g., PTH) at various time points following
administration, as exemplified herein.
[0103] As PTH is normally present to some degree in the blood prior
to administration, the area under the baseline levels are excluded
from the AUC and Cmax (e.g., by subtracting the baseline level from
the measured levels at each time point), such that the AUC and Cmax
each represent an aspect of the increase above baseline levels
which occurs following administration. The baseline can optionally
be determined by measuring levels prior to administration and/or by
determining (e.g., by curve-fitting) the baseline to which levels
decay after administration. Alternatively or additionally, in
embodiments wherein the administered PTH species (e.g.,
teriparatide) is distinct from endogenous PTH, the measurement of
PTH may be selective for the administered PTH species (e.g., using
the assay described in the Examples section herein).
[0104] The ratio of AUC to Cmax (i.e., AUC divided by Cmax) will
depend on the nature of the pharmacokinetic profile of the
composition, particularly on the shape of the curve which
represents levels of the PTH in the blood (e.g., plasma levels) as
a function of time following administration. Pharmacokinetic
profiles characterized by a sharp increase and decrease within a
brief period of time will tend to have a relatively low ratio of
AUC to Cmax, whereas pharmacokinetic profiles characterized by a
more gradual increase and decrease over a broader period of time
will tend to have a relatively high ratio of AUC to Cmax.
[0105] Thus, without being bound by any particular theory, it is
believed that a ratio of AUC to Cmax which is 3 hours or lower, as
described herein according to any of the respective embodiments, is
associated with a relatively sharp increase and decrease of levels
of PTH in the blood.
[0106] The ratio of AUC to Cmax is optionally calculated based on
data from multiple administrations of the composition. In such
cases, a ratio of AUC to Cmax is preferably calculated for each
administration, and then the ratios calculated for each
administration may be averaged.
[0107] Similarly, the Cmax is optionally calculated based on data
from multiple administrations of the composition. In such cases, a
Cmax value is preferably calculated for each administration, and
then the Cmax values calculated for each administration may be
averaged.
[0108] Without being bound by any particular theory, it is believed
that averaging data (e.g., measured blood levels of PTH) from
different administrations of PTH will frequently result in a
broader curve, a lower Cmax value, and larger ratio of AUC to Cmax,
than that which is observed after a single administration. Hence, a
Cmax value and a ratio of AUC to Cmax calculated for averaged data
(as opposed to an average of ratios calculated for each
administration, as described hereinabove) is a less accurate
indicator of the effect of the composition following
administration.
[0109] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form) is
formulated such that absorption of the PTH following oral
administration of the composition is characterized by a Cmax of
from 30 pg/ml PTH to 700 pg/ml PTH. In some embodiments, the Cmax
is from 50 pg/ml PTH to 450 pg/ml PTH. In some embodiments, the PTH
is PTH(1-84). In some embodiments, the PTH is PTH(1-34).
[0110] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises parathyroid hormone(1-34) and is formulated such that
absorption of the parathyroid hormone(1-34) following oral
administration of the composition is characterized by a Cmax of
from 30 pg/ml parathyroid hormone(1-34) to 300 pg/ml parathyroid
hormone(1-34). In some embodiments, the Cmax is from 50 pg/ml
parathyroid hormone(1-34) to 200 pg/ml parathyroid
hormone(1-34).
[0111] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises parathyroid hormone(1-84) and is formulated such that
absorption of the parathyroid hormone(1-84) following oral
administration of the composition is characterized by a Cmax of
from 70 pg/ml parathyroid hormone(1-84) to 700 pg/ml parathyroid
hormone(1-84). In some embodiments, the Cmax is from 100 pg/ml
parathyroid hormone(1-84) to 450 pg/ml parathyroid
hormone(1-84).
[0112] In some embodiments of any one of the embodiments described
herein, a Cmax (in pg/ml) of any PTH (e.g., including a fragment or
homolog according to any of the respective embodiments described
herein) is a molar equivalent to a Cmax for PTH(1-34) and/or
PTH(1-84) according to any of the respective embodiments described
herein. A Cmax according to such embodiments may be determined by
multiplying the Cmax for PTH(1-34) and/or PTH(1-84) by the ratio of
molecular weight of the PTH to be administered according to such an
embodiment to the molecular weight of the PTH(1-34) and/or
PTH(1-84).
[0113] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form) is
formulated such that absorption of the PTH following oral
administration of the composition is characterized by a Cmax of
from 100 pg/ml PTH to 450 pg/ml PTH.
[0114] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-34) and is formulated such that absorption of the
PTH(1-34) following oral administration of the composition is
characterized by a Cmax of from 100 pg/ml PTH(1-34) to 200 pg/ml
PTH(1-34).
[0115] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-84) and is formulated such that absorption of the
PTH(1-84) following oral administration of the composition is
characterized by a Cmax of from 225 pg/ml PTH(1-84) to 450 pg/ml
PTH(1-84).
[0116] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form) is
formulated such that absorption of the PTH following oral
administration of the composition is characterized by a Cmax of
from 30 pg/ml PTH to 225 pg/ml PTH.
[0117] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-34) and is formulated such that absorption of the
PTH(1-34) following oral administration of the composition is
characterized by a Cmax of from 30 pg/ml PTH(1-34) to 100 pg/ml
PTH(1-34).
[0118] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-84) and is formulated such that absorption of the
PTH(1-84) following oral administration of the composition is
characterized by a Cmax of from 70 pg/ml PTH(1-84) to 225 pg/ml
PTH(1-84).
[0119] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form) is
formulated such that absorption of the PTH following oral
administration of the composition is characterized by a Cmax of
from 200 pg/ml PTH to 700 pg/ml PTH.
[0120] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-34) and is formulated such that absorption of the
PTH(1-34) following oral administration of the composition is
characterized by a Cmax of from 200 pg/ml PTH(1-34) to 300 pg/ml
PTH(1-34).
[0121] In some embodiments of any one of the embodiments described
herein, the composition (e.g., composition unit dosage form)
comprises PTH(1-84) and is formulated such that absorption of the
PTH(1-84) following oral administration of the composition is
characterized by a Cmax of from 450 pg/ml PTH(1-84) to 700 pg/ml
PTH(1-84).
[0122] In some embodiments of any one of the embodiments described
herein, a bioavailability of the PTH (e.g., PTH(1-34)) upon oral
administration of the composition is in a range of from 0.05 to
50%. In some embodiments, the bioavailability is in a range of from
0.1 to 15%. In some embodiments, the bioavailability is in a range
of from 0.2 to 5%. In some embodiments, the bioavailability is in a
range of from 0.5 to 3%.
[0123] Without being bound by any particular theory, it is believed
that SNAC enhances the bioavailability of the PTH considerably.
[0124] In some embodiments of any one of the embodiments described
herein, a bioavailability of the PTH (e.g., PTH(1-34)) upon oral
administration of the composition is at least 50% higher than (150%
of the level of) a bioavailability of the PTH (e.g., PTH(1-34))
upon oral administration of an equivalent composition which lacks
SNAC (e.g., being identical in all aspects except for the absence
of SNAC). In some embodiments, the bioavailability is at least
twice (200% of the level of) the bioavailability upon oral
administration of an equivalent composition which lacks SNAC. In
some embodiments, the bioavailability is at least four-fold (400%
of the level of) the bioavailability upon oral administration of an
equivalent composition which lacks SNAC. In some embodiments, the
bioavailability is at least ten-fold (1000% of the level of) the
bioavailability upon oral administration of an equivalent
composition which lacks SNAC. In some embodiments, the
bioavailability is at least twenty-fold (2000% of the level of) the
bioavailability upon oral administration of an equivalent
composition which lacks SNAC. In some embodiments, the
bioavailability is at least fifty-fold (5000% of the level of) the
bioavailability upon oral administration of an equivalent
composition which lacks SNAC.
[0125] Some of the administered agents according to various
embodiments described herein comprise polypeptides or proteins, for
example, PTH and many of the protease inhibitors described herein.
Any of these polypeptides are to be interpreted in line the
definition of the term "polypeptide" hereinafter.
[0126] Any formulation which provides desired pharmacokinetic
parameters according to any of the respective embodiments described
herein is suitable for use according to embodiments of the
invention in the treatment of the indicated medical conditions, and
is encompassed by the terms "pharmaceutical composition",
"medicament" and "drug delivery system" recited herein.
[0127] Such formulations may include ingredients or combinations of
ingredients known to a person skilled in the art as providing the
desired pharmacokinetic parameters according to any of the
respective embodiments described herein.
[0128] Any of the compositions and unit dosage forms described
herein may optionally consist essentially of the ingredients
described herein (e.g., PTH, SNAC, and optionally at least one
protease inhibitor), or alternatively, the composition further
comprises suitable pharmaceutically acceptable carriers or
excipients.
[0129] Hereinafter, the phrases "physiologically acceptable
carrier" and "pharmaceutically acceptable carrier", which may be
interchangeably used, refer to a carrier or a diluent that does not
cause significant irritation to an organism and does not abrogate
the biological activity and properties of the administered
compound. An adjuvant is included under these phrases.
[0130] Herein the term "excipient" refers to an inert substance
added to a pharmaceutical composition to further facilitate
administration of an active ingredient. Examples, without
limitation, of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils and polyethylene glycols.
[0131] The term "unit dosage form", as used herein, describes
physically discrete units, each unit containing a predetermined
quantity of one or more active ingredient(s) calculated to produce
the desired therapeutic effect, in association with at least one
pharmaceutically acceptable carrier, diluent, excipient, or
combination thereof.
[0132] In some embodiments of any one of the embodiments described
herein, the composition is formulated as a solid composition. In
some embodiments, the composition is formulated as a tablet.
[0133] In some embodiments of any one of the embodiments described
herein, the composition consists primarily of the combination of
PTH, SNAC, and optional at least one protease inhibitor described
herein, that is, at least 50 weight percents of the composition
consists of ingredients selected from the group consisting of a
PTH, SNAC and (optional) at least one protease inhibitor. In some
embodiments, at least 60 weight percents of the composition
consists of a PTH, SNAC and (optional) at least one protease
inhibitor. In some embodiments, at least 70 weight percents of the
composition consists of a PTH, SNAC and (optional) at least one
protease inhibitor. In some embodiments, at least 80 weight
percents of the composition consists of a PTH, SNAC and (optional)
at least one protease inhibitor. In some embodiments, at least 90
weight percents of the composition consists of a PTH, SNAC and
(optional) at least one protease inhibitor. In some embodiments, at
least 95 weight percents of the composition consists of a PTH, SNAC
and (optional) at least one protease inhibitor. In some
embodiments, at least 98 weight percents of the composition
consists of a PTH, SNAC and (optional) at least one protease
inhibitor. In some embodiments, the composition is formulated as a
tablet.
[0134] As exemplified in the Examples section herein, compositions
which readily dissolve in the stomach--including, without
limitation, compositions comprising a large proportion (e.g., at
least 50 weight percents) of PTH and SNAC and (optional) protease
inhibitor (e.g., as described herein according to any of the
respective embodiments)--can provide pharmacokinetic profiles
characterized by rapid increase in levels of absorbed PTH, followed
almost immediately by a rapid decrease in levels of absorbed
PTH.
[0135] Without being bound by any particular theory, it is believed
that dissolution, and particularly relatively rapid dissolution, in
gastric fluid facilitates rapid absorption of PTH, because both the
PTH and the SNAC which can enhance absorption of the PTH become
available in the stomach soon after oral administration (e.g.,
prior to passage of the composition to the intestines). It is
further believed that dissolution, and particularly relatively
rapid dissolution, in gastric fluid facilitates control over the
time during which PTH is absorbed, because the SNAC is inactivated
upon exposure to acidic conditions of the stomach due to
protonation of SNAC (e.g., conversion of the carboxylate salt to a
carboxylic acid), such that soon after full dissolution of the
composition in the stomach, little or no SNAC remains capable of
enhancing absorption of PTH.
[0136] It is further believed that a pharmacokinetic profile
characterized by rapid increase in levels of absorbed PTH, followed
almost immediately by a rapid decrease in levels of absorbed PTH is
particularly useful for treating osteoporosis, as brief exposure to
PTH is associated with bone growth enhancement as is generally
desirable when treating osteoporosis, in contrast to bone
resorption enhancement associated with chronic exposure to PTH,
which is generally undesirable when treating osteoporosis.
[0137] In some embodiments of any of the embodiments described
herein, the composition is soluble in gastric fluid. In some
embodiments, the composition dissolves in gastric fluid in no more
than 60 minutes. In some embodiments, the composition dissolves in
gastric fluid in no more than 50 minutes. In some embodiments, the
composition dissolves in gastric fluid in no more than 40 minutes.
In some embodiments, the composition dissolves in gastric fluid in
no more than 30 minutes. In some embodiments, the composition
dissolves in gastric fluid in no more than 20 minutes. In some
embodiments, the composition dissolves in gastric fluid in no more
than 15 minutes. In some embodiments, the composition dissolves in
gastric fluid in no more than 10 minutes. In some embodiments, the
composition dissolves in gastric fluid in no more than 5
minutes.
[0138] Herein, the phrases "soluble in gastric fluid", "dissolves
in gastric fluid" and the like refer to solubility in simulated
gastric fluid without pepsin, at pH 2.0, under conditions according
to USP 23 Apparatus 2 (paddle) (e.g., 800 ml volume, 50 rotations
per minute). Dissolution is indicated by absence of visible
composition at the bottom of the fluid. However, visible material
suspended in the liquid is not excluded by the terms "soluble" and
"dissolution". The phrase "soluble in gastric fluid" refers herein
to dissolution within a period of 6 hours. A liquid composition
miscible with simulated gastric fluid is considered herein to be
"soluble in gastric fluid", wherein the dissolution is the mixing
of the liquid composition with the simulated gastric fluid.
[0139] Techniques for formulation and administration of drugs may
be found in "Remington's Pharmaceutical Sciences," Mack Publishing
Co., Easton, Pa., latest edition, which is incorporated herein by
reference.
[0140] Pharmaceutical compositions of some embodiments of the
invention may be manufactured by processes well known in the art,
e.g., by means of conventional mixing, dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping
or lyophilizing processes.
[0141] Pharmaceutical compositions for use in accordance with some
embodiments of the invention thus may be formulated in conventional
manner using one or more physiologically acceptable carriers
comprising excipients and auxiliaries, which facilitate processing
of the active ingredients into preparations which, can be used
pharmaceutically.
[0142] The pharmaceutical composition can be formulated readily by
combining the active compounds with pharmaceutically acceptable
carriers well known in the art as being suitable for oral
administration. Such carriers optionally facilitate formulation of
the pharmaceutical composition as tablets, pills, dragees,
capsules, liquids, gels, syrups, slurries, suspensions, and the
like, for oral ingestion by a patient. Pharmacological preparations
for oral use can be made using a solid excipient, optionally
grinding the resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries if desired, to obtain
tablets or dragee cores.
[0143] Suitable excipients are, in particular, fillers such as
sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth, methyl
cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose; and/or physiologically acceptable polymers
such as polyvinylpyrrolidone (PVP). If desired, disintegrating
agents may be added, such as cross-linked polyvinyl pyrrolidone,
agar, or alginic acid or a salt thereof such as sodium alginate;
and/or lubricants such as talc or magnesium stearate.
[0144] In some embodiments of any one of the embodiments described
herein, the composition (e.g., formulated as a tablet) further
comprises a lubricant. In some embodiments, the lubricant is
included in a concentration of 5 weight percents or less,
optionally 2 weight percents or less, and optionally about 1 weight
percent. In some embodiments, the composition (e.g., formulated as
a tablet) consists essentially of the PTH (as described herein),
SNAC, lubricant and optionally at least one protease inhibitor (as
described herein). In some embodiments, the lubricant is magnesium
stearate.
[0145] Dragee cores are optionally provided with suitable coatings.
For this purpose, concentrated sugar solutions may be used which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, titanium dioxide, lacquer
solutions and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0146] Pharmaceutical compositions which can be used orally include
push-fit capsules made of gelatin as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules may contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active ingredients may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added.
[0147] In some embodiments of any of the embodiments described
herein, the composition comprising PTH and SNAC (according to any
of the respective embodiments described herein) is coated by an
enteric coating. In some embodiments, the enteric coating increases
bioavailability of the PTH by reducing inactivation of SNAC and/or
PTH which is induced by exposure to gastric conditions.
[0148] Herein, the phrase "enteric coating" refers to a coating
which dissolves under conditions in the intestines (e.g., in an
aqueous environment having a pH of at least 5.5 and/or in the
presence of colonic bacteria), but does not dissolve under
conditions in the stomach (e.g., in an aqueous environment having a
pH in a range of from 1 to 3.5). An enteric coating may optionally
dissolve in the duodenum, optionally in the jejunum, optionally in
the ileum, and optionally in the colon, thereby exposing the
core.
[0149] In some embodiments of any of the embodiments described
herein relating to an enteric coating, the enteric coating
comprises at least one enteric polymer. In some such embodiments, a
concentration of enteric polymer in the enteric coating is at least
20 weight percents. In some such embodiments, a concentration of
the enteric polymer(s) in the enteric coating is at least 30 weight
percents. In some such embodiments, a concentration of the enteric
polymer(s) in the enteric coating is at least 40 weight percents.
In some such embodiments, a concentration of the enteric polymer(s)
in the enteric coating is at least 50 weight percents. In some such
embodiments, a concentration of the enteric polymer(s) in the
enteric coating is at least 60 weight percents. In some such
embodiments, a concentration of the enteric polymer(s) in the
enteric coating is at least 70 weight percents. In some such
embodiments, a concentration of the enteric polymer(s) in the
enteric coating is at least 80 weight percents. In some such
embodiments, a concentration of the enteric polymer(s) in the
enteric coating is at least 90 weight percents. In some such
embodiments, the enteric coating consists essentially of the
enteric polymer(s).
[0150] As used herein, the term "enteric polymer" refers to a solid
polymer or mixture of polymers which is soluble in an aqueous
solution at a pH in a range of from 5.5 to 8 (i.e., soluble in at
least a portion of the aforementioned pH range), but not soluble in
an aqueous solution at any pH in a range of from 1 to 3.5, and
preferably insoluble at any pH in a range of from 1 to 5.5. When an
enteric polymer is a mixture of polymers, the mixture is considered
herein to be soluble under any given conditions if at least a
portion of the polymers in the mixture are soluble under such
conditions, provided that dissolution of the soluble polymer(s)
results in full disintegration of the mixture (optionally
disintegration to particles of no more than 1 mm in diameter, and
optionally no more than 0.1 mm in diameter).
[0151] The pH dependency of solubility of an enteric polymer allows
the enteric polymer to be in a form of a solid coating in the
stomach, as well as under dry conditions (e.g., prior to oral
administration), while becoming soluble in at least a portion of
the intestines.
[0152] Many enteric polymers are known in the art, and the skilled
person will be readily capable of selecting and preparing a
suitable enteric polymer for dissolving at a pre-determined pH
and/or in a pre-determined region of the intestines.
[0153] Examples of enteric polymers include, without limitation,
copolymers of one or more hydrophobic monomers and one or more
anionic monomers (e.g., monomers containing a carboxylic acid
and/or carboxylate salt group), optionally with about a 1:1 ratio
of hydrophobic monomers to anionic monomers). Such copolymers are
anionic, and consequently water-soluble, at a pH of about 7, but
relatively non-ionic and hydrophobic, and consequently
water-insoluble, at a pH which is sufficiently to result in
protonation of almost all of the anionic groups.
[0154] Examples of such copolymers used in the art (e.g.,
commercially available as Eudragit.RTM. products) include, without
limitation, copolymers wherein anionic monomers are acrylic acid
and/or methacrylic acid monomers, and hydrophobic monomers are
esters (e.g., alkyl esters) of acrylic acid and/or methacrylic acid
monomers, for example, ethyl acrylate, methyl acrylate, ethyl
methacrylate and/or methyl methacrylate monomers. For example,
poly(methacrylic acid-co-ethyl acrylate) (with about a 1:1 ratio of
methacrylic acid to ethyl acrylate) is commercially available,
e.g., as Eudragit.RTM. L100-55.
[0155] Further examples of enteric polymers include, without
limitation, polyvinyl acetate phthalate, cellulose acetate
succinate, cellulose acetate phthalate, hydroxypropyl methyl
cellulose phthalate, hydroxypropyl methyl cellulose acetate
succinate, and cellulose acetate trimellitate.
[0156] In some embodiments of any one of the embodiments described
herein relating to an enteric polymer, the enteric polymer is
soluble in an aqueous solution at pH 5.5. In some such embodiments,
dissolution of the enteric polymer commences soon after the drug
delivery system reaches the intestines, for example, in the
duodenum.
[0157] In some embodiments of any one of the embodiments described
herein relating to an enteric coating, the enteric coating is
soluble in an aqueous solution at pH 5.5. In some such embodiments,
dissolution of the enteric coating commences soon after the drug
delivery system reaches the intestines, for example, in the
duodenum.
[0158] In some embodiments of any one of the embodiments described
herein relating to an enteric polymer, the enteric polymer is not
soluble in an aqueous solution at pH 5.5, and is soluble in an
aqueous solution at pH 6.0. In some such embodiments, dissolution
of the enteric polymer commences relatively soon after the drug
delivery system reaches the intestines, for example, in the
duodenum.
[0159] In some embodiments of any one of the embodiments described
herein relating to an enteric coating, the enteric coating is not
soluble in an aqueous solution at pH 5.5, and is soluble in an
aqueous solution at pH 6.0. In some such embodiments, dissolution
of the enteric coating commences relatively soon after the drug
delivery system reaches the intestines, for example, in the
duodenum.
[0160] In some embodiments of any one of the embodiments described
herein relating to an enteric polymer, the enteric polymer is not
soluble in an aqueous solution at pH 5.5 or 6.0, and is soluble in
an aqueous solution at pH 6.5. In some such embodiments,
dissolution of the enteric polymer commences in the small
intestines (e.g., in the jejunum), although optionally not in the
duodenum.
[0161] In some embodiments of any one of the embodiments described
herein relating to an enteric coating, the enteric coating is not
soluble in an aqueous solution at pH 5.5 or 6.0, and is soluble in
an aqueous solution at pH 6.5. In some such embodiments,
dissolution of the enteric coating commences in the small
intestines (e.g., in the jejunum), although optionally not in the
duodenum.
[0162] In some embodiments of any one of the embodiments described
herein relating to an enteric polymer, the enteric polymer is not
soluble in an aqueous solution at either pH 5.5, 6.0 or 6.5, and is
soluble in an aqueous solution at pH 7.0 and/or at pH 7.5. In some
such embodiments, dissolution of the enteric polymer commences in
the ileum or colon, and optionally not in the duodenum or
jejunum.
[0163] In some embodiments of any one of the embodiments described
herein relating to an enteric coating, the enteric coating is not
soluble in an aqueous solution at either pH 5.5, 6.0 or 6.5, and is
soluble in an aqueous solution at pH 7.0 and/or at pH 7.5. In some
such embodiments, dissolution of the enteric coating commences in
the ileum or colon, and optionally not in the duodenum or
jejunum.
[0164] It is to be appreciated that in some embodiments when
dissolution of an enteric polymer and/or enteric coating commences
at any given pH and/or location in the gastrointestinal tract
(e.g., as described herein), a significant amount of time may pass
until a composition coated by the coating is exposed and/or the
coating is disintegrated and/or completely dissolved, as the
dissolution of enteric polymer and/or enteric coating is not
necessarily a very rapid process. The time until the core is
exposed and/or the coating is disintegrated and/or completely
dissolved may optionally be controlled, for example, in accordance
with the thickness of the enteric coating, wherein thicker enteric
coatings are associated with longer dissolution times.
[0165] Pharmaceutical compositions suitable for use in context of
some embodiments of the invention include compositions wherein the
PTH is contained in an amount effective to achieve the intended
purpose. More specifically, the composition preferably comprises a
therapeutically effective amount of PTH, that is, an amount of PTH
effective to prevent, alleviate or ameliorate symptoms of
osteoporosis. Furthermore, an amount of SNAC is preferably
effective for enhancing absorption of the PTH (e.g., in a manner
described herein); and an amount of protease inhibitor is
preferably effective for inhibiting degradation of the PTH by a
protease.
[0166] Determination of a therapeutically effective amount is well
within the capability of those skilled in the art, especially in
light of the detailed disclosure provided herein.
[0167] For any preparation used in the methods of the invention,
the therapeutically effective amount or dose can be estimated
initially from in vitro and cell culture assays. For example, a
dose can be formulated in animal models to achieve a desired
concentration or titer. Such information can be used to more
accurately determine useful doses in humans.
[0168] Toxicity and therapeutic efficacy of the PTH described
herein can be determined by standard pharmaceutical procedures in
vitro, in cell cultures or experimental animals. The data obtained
from these in vitro and cell culture assays and animal studies can
be used in formulating a range of dosage for use in human. The
dosage may vary depending upon the dosage form employed and the
route of administration utilized. The exact formulation and dosage
can be chosen by the individual physician in view of the patient's
condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological
Basis of Therapeutics", Ch. 1 p. 1).
[0169] Dosage amount and interval may be adjusted individually to
provide levels (e.g., plasma levels) of PTH sufficient to induce or
suppress a biological effect (minimal effective concentration,
MEC). The MEC will vary for each preparation, but can be estimated
from in vitro data. Dosages necessary to achieve the MEC will
depend on individual characteristics. Detection assays for PTH are
known in the art and can be used to determine plasma concentrations
of PTH.
[0170] Depending on the severity and responsiveness of the
condition to be treated, dosing can be of a single or a plurality
of administrations, with course of treatment lasting from several
hours to several weeks or until cure is effected or diminution of
the disease state is achieved.
[0171] The amount of a composition to be administered will, of
course, be dependent on the subject being treated, the severity of
the affliction, the manner of administration, the judgment of the
prescribing physician, etc.
[0172] Compositions of some embodiments of the invention may, if
desired, be presented in a pack or dispenser device, such as an FDA
approved kit, which may contain one or more unit dosage forms
containing the active ingredient(s). The pack may, for example,
comprise metal or plastic foil, such as a blister pack. The pack or
dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accommodated by a
notice associated with the container in a form prescribed by a
governmental agency regulating the manufacture, use or sale of
pharmaceuticals, which notice is reflective of approval by the
agency of the form of the compositions or human or veterinary
administration. Such notice, for example, may be of labeling
approved by the U.S. Food and Drug Administration for prescription
drugs or of an approved product insert. Compositions comprising a
preparation of the invention may also be prepared (e.g., as
described herein), placed in an appropriate container, and labeled
for treatment of osteoporosis, as is further detailed herein.
[0173] In some embodiments of any one of the embodiments described
herein, treatment according to any of the aspects described herein
is effected by orally administering the composition on a relatively
empty stomach and small intestines.
[0174] In some embodiments of any one of the embodiments described
herein, oral administration of the composition is effected at least
2 hours after the most recent food intake. In some embodiments,
oral administration of the composition is effected at least 4 hours
after the most recent food intake. In some embodiments, oral
administration of the composition is effected at least 6 hours
after the most recent food intake. In some embodiments, oral
administration of the composition is effected at least 8 hours
after the most recent food intake. In some embodiments, oral
administration of the composition is effected at least 10 hours
after the most recent food intake.
[0175] In some embodiments of any one of the embodiments described
herein, oral administration of the composition is effected at least
2 hours after the most recent intake of food or drink. In some
embodiments, oral administration of the composition is effected at
least 4 hours after the most recent intake of food or drink. In
some embodiments, oral administration of the composition is
effected at least 6 hours after the most recent intake of food or
drink. In some embodiments, oral administration of the composition
is effected at least 8 hours after the most recent intake of food
or drink. In some embodiments, oral administration of the
composition is effected at least 10 hours after the most recent
intake of food or drink.
[0176] In some embodiments of any one of the embodiments described
herein, oral administration of the composition is effected in the
morning prior to eating. In some embodiments, oral administration
of the composition is effected in the morning prior to eating or
drinking. Such administration of the unit dosage form and/or drug
delivery device in the morning (e.g., after sleeping) may
optionally be the most convenient way for a subject to ensure that
a considerable period of time has passed between oral
administration and the most recent intake of food (and optionally
drink).
[0177] In some embodiments of any one of the embodiments described
herein, oral administration of the composition is effected at least
10 minutes prior to eating (e.g., a subject should abstain from
eating for at least 10 minutes after administration). In some
embodiments, oral administration of the composition is effected at
least 20 minutes prior to eating. In some embodiments, oral
administration of the composition is effected at least 30 minutes
prior to eating. In some embodiments, oral administration of the
composition is effected at least 60 minutes (1 hour) prior to
eating. In some embodiments, oral administration of the composition
is effected at least 2 hours prior to eating. In some embodiments,
oral administration of the composition is effected at least 3 hours
prior to eating. In some embodiments oral administration of the
composition is effected at least 4 hours prior to eating.
[0178] In some embodiments of any one of the embodiments described
herein, oral administration of the composition is effected at least
10 minutes prior to eating or drinking (e.g., a subject should
abstain from eating or drinking for at least 10 minutes after
administration). In some embodiments, oral administration of the
composition is effected at least 20 minutes prior to eating or
drinking. In some embodiments, oral administration of the
composition is effected at least 30 minutes prior to eating or
drinking. In some embodiments, oral administration of the
composition is effected at least 60 minutes (1 hour) prior to
eating or drinking. In some embodiments, oral administration of the
composition is effected at least 2 hours prior to eating or
drinking. In some embodiments, oral administration of the
composition is effected at least 3 hours prior to eating or
drinking. In some embodiments, oral administration of the
composition is effected at least 4 hours prior to eating or
drinking.
[0179] Without being bound by any particular theory, it is believed
that food (and optionally drink) in the stomach and small
intestines may interact with the SNAC and/or PTH in a manner which
is detrimental to absorption of the PTH in an efficient and
predictable manner. It is further believed that oral administration
of a composition as described herein on an empty stomach (e.g., in
the morning) allows the release of PTH and SNAC at various
locations in the intestines, while food ingested after the oral
administration (e.g., during the day after administration of the
composition in the morning) generally remains "behind" the PTH and
SNAC in the gastrointestinal tract, thereby reducing interactions
between ingested food and the SNAC and/or PTH.
[0180] As the composition passes through the gastrointestinal tract
after oral administration, the therapeutically active agent and
SNAC may optionally be released in a controlled manner (e.g.,
according to any of the respective embodiments described herein),
thereby providing control over the pharmacokinetic profile of the
PTH.
[0181] In some embodiments of any one of the embodiments described
herein, the composition is formulated so as to be characterized by
a rate of release of PTH and SNAC (as a function of time)
characterized by at least two peaks (multi-modal rate of release),
e.g., as described herein in any of the respective embodiments. In
some such embodiments, the multi-modal rate of release is effected
by oral administration of a unit dosage form comprising a plurality
of populations of particles with enteric coatings (e.g., with
different enteric coatings for each population), as described
herein according to any of the respective embodiments.
[0182] In some embodiments, a multi-modal release rate is
associated with intermittent controlled periods of time in which
levels of PTH in the blood are in an optimal range (e.g., high
enough to exert a beneficial effect, but without reaching toxic
levels), for example, wherein each peak in the release rate is
associated with an intermittent time period of a level in an
optimal range. Such a pharmacokinetic profile may optionally mimic,
for example, the profile upon oral administration of multiple doses
at different times.
[0183] Without being bound by any particular theory, it is believed
that using a single oral administration to achieve absorption
during multiple controlled periods of time is advantageous for use
of PTH with SNAC in the treatment of osteoporosis, as compared with
the use of multiple oral administrations of PTH with SNAC, for
which it is not realistic to perform all such administrations on a
relatively empty stomach (e.g., as described herein).
[0184] Protease Inhibitor:
[0185] In some embodiments of any of the embodiments described
herein, the composition further comprises at least one protease
inhibitor.
[0186] Herein throughout, the term "protease inhibitor" refers to a
compound which reduces a proteolytic activity of a protease, for
example, a proteolytic activity which inactivates a PTH described
herein. The term "protease inhibitor" encompasses, for example,
both large molecules (e.g., proteins) and small molecules, as well
as both naturally occurring compounds and synthetic compounds.
[0187] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
trypsin inhibitor. In some embodiments, the at least one protease
inhibitor consists essentially of one or more trypsin
inhibitor(s).
[0188] Examples of trypsin inhibitors which may be utilized in any
one of the embodiments described herein, include, without
limitation, lima bean trypsin inhibitor, aprotinin, soybean trypsin
inhibitor, ovomucoid trypsin inhibitor and any combination thereof.
In some embodiments, the at least one trypsin inhibitor comprises
soybean trypsin inhibitor (SBTI). In some embodiments, the at least
one trypsin inhibitor (an optionally the at least one protease
inhibitor) consists essentially of SBTI.
[0189] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
serpin. In some embodiments, the at least one protease inhibitor
consists essentially of one or more serpin(s).
[0190] Examples of serpins which may be utilized in any one of the
embodiments described herein, include, without limitation, alpha
1-antitrypsin, antitrypsin-related protein, alpha
1-antichymotrypsin, kallistatin, protein C inhibitor, cortisol
binding globulin, thyroxine-binding globulin, angiotensinogen,
centerin, protein Z-related protease inhibitor, vaspin,
monocyte/neutrophil elastase inhibitor, plasminogen activator
inhibitor-2, squamous cell carcinoma antigen-1 (SCCA-1), squamous
cell carcinoma antigen-2 (SCCA-2), maspin, proteinase inhibitor 6
(PI-6), megsin, serpin B8 (PI-8), serpin B9 (PI-9), bomapin,
yukopin, hurpin/headpin, antithrombin, heparin cofactor II,
plasminogen activator inhibitor 1, glia-derived nexin, pigment
epithelium derived factor, alpha 2-antiplasmin, complement
1-inhibitor, 47 kDa heat shock protein (HSP47), neuroserpin and
pancpin.
[0191] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
cysteine protease inhibitor. In some embodiments, the at least one
protease inhibitor consists essentially of one or more cysteine
protease inhibitor(s).
[0192] Examples of cysteine protease inhibitors which may be
utilized in any one of the embodiments described herein, include,
without limitation, type 1 cystatins, type 2 cystatins, human
cystatins C, D, S, SN, and SA, cystatin E/M, cystatin F, and type 3
cystatins (including kininogens).
[0193] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
threonine protease inhibitor. In some embodiments, the at least one
protease inhibitor consists essentially of one or more threonine
protease inhibitor(s).
[0194] Examples of threonine protease inhibitors which may be
utilized in any one of the embodiments described herein, include,
without limitation, bortezomib, MLN-519, ER-807446 and TMC-95A.
[0195] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
aspartic protease inhibitor. In some embodiments, the at least one
protease inhibitor consists essentially of one or more aspartic
protease inhibitor(s).
[0196] Examples of aspartic protease inhibitors which may be
utilized in any one of the embodiments described herein, include,
without limitation, .alpha..sub.2-macroglobulin, pepstatin A,
aspartic protease inhibitor 11, aspartic protease inhibitor 1,
aspartic protease inhibitor 2, aspartic protease inhibitor 3,
aspartic protease inhibitor 4, aspartic protease inhibitor 5,
aspartic protease inhibitor 6, aspartic protease inhibitor 7,
aspartic protease inhibitor 8, aspartic protease inhibitor 9,
pepsin inhibitor Dit33, and protease A inhibitor 3.
[0197] In some embodiments of any of the embodiments described
herein, the at least one protease inhibitor comprises at least one
metalloprotease inhibitor. In some embodiments, the at least one
protease inhibitor consists essentially of one or more
metalloprotease inhibitor(s).
[0198] Examples of metalloprotease inhibitors which may be utilized
in any one of the embodiments described herein, include, without
limitation, angiotensin-1-converting enzyme inhibitory peptide,
antihemorrhagic factor BJ46a, beta-casein, proteinase inhibitor
CeKI, venom metalloproteinase inhibitor DM43, carboxypeptidase A
inhibitor, smpI, IMPI, alkaline proteinase, latexin,
carboxypeptidase inhibitor, antihemorrhagic factor HSF, testican-3,
SPOCK3, TIMP1, metalloproteinase inhibitor 1, metalloproteinase
inhibitor 2, TIMP2, metalloproteinase inhibitor 3, TIMP3,
metalloproteinase inhibitor 4, TIMP4, putative metalloproteinase
inhibitor tag-225, tissue inhibitor of metalloprotease, WAP, kazal
inhibitor, immunoglobulin, and kunitz and NTR domain-containing
protein 1.
[0199] Examples of protease inhibitors which may be utilized in any
one of the embodiments described herein also include, without
limitation, AEBSF-HCl, .epsilon.-aminocaproic acid,
.alpha.1-antichymotypsin, antipain, antithrombin III,
.alpha.1-antitrypsin, APMSF (4-amidinophenyl-methane
sulfonyl-fluoride), sprotinin, benzamidine, chymostatin, DFP
(diisopropylfluoro-phosphate), leupeptin,
4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride, PMSF
(phenylmethyl sulfonyl fluoride), TLCK
(1-chloro-3-tosylamido-7-amino-2-heptanone), TPCK
(1-chloro-3-tosylamido-4-phenyl-2-butanone), pentamidine
isothionate, pepstatin, guanidium, .alpha.2-macroglobulin, a
chelating agent of zinc, and iodoacetate.
[0200] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is at least about 0.1 mg. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 0.2 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 0.3 mg. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 0.4 mg. In some embodiments, the amount of
a protease inhibitor in a composition for administration as
described herein is at least about 0.6 mg. In some embodiments, the
amount of a protease inhibitor in a composition for administration
as described herein is at least about 0.8 mg. In some embodiments,
the amount of a protease inhibitor in a composition for
administration as described herein is at least about 1 mg. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is at least about 1.5 mg. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 2 mg. In some embodiments, the amount of a protease inhibitor
in a composition for administration as described herein is at least
about 2.5 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 3 mg. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 5 mg. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 7 mg. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 10 mg. In some embodiments, the amount of
a protease inhibitor in a composition for administration as
described herein is at least about 12 mg. In some embodiments, the
amount of a protease inhibitor in a composition for administration
as described herein is at least about 15 mg. In some embodiments,
the amount of a protease inhibitor in a composition for
administration as described herein is at least about 20 mg. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is at least about 30 mg. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 50 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 70 mg. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 100 mg.
[0201] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 0.1 to 1
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 0.2 to 1 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 0.3 to 1 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 0.5 to 1 mg.
[0202] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 0.1 to 2
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 0.2 to 2 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 0.3 to 2 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 0.5 to 2 mg. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is in a range of from 1 to 2
mg.
[0203] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 1 to 10
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 2 to 10 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 3 to 10 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 5 to 10 mg.
[0204] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 1 to 20
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 2 to 20 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 3 to 20 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 5 to 20 mg. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is in a range of from 10 to
20 mg.
[0205] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 10 to 100
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 20 to 100 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 30 to 100 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 50 to 100 mg.
[0206] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is in a range of from 10 to 200
mg. In some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is in a range of
from 20 to 200 mg. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is in a range of from 30 to 200 mg. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is in a range of from 50 to 200 mg. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is in a range of from 100 to
200 mg.
[0207] In some embodiments of any one of the embodiments described
herein, the amount of a protease inhibitor in a composition for
administration as described herein is at least about 10 kallikrein
inactivator units (k.i.u.). In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 12 k.i.u. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is at least about 15 k.i.u. In some embodiments,
the amount of a protease inhibitor in a composition for
administration as described herein is at least about 20 k.i.u. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 30 k.i.u. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 40 k.i.u. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 50 k.i.u. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is at least about 70 k.i.u. In some embodiments,
the amount of a protease inhibitor in a composition for
administration as described herein is at least about 100 k.i.u. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 150 k.i.u. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 200 k.i.u. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 300 k.i.u. In some embodiments, the amount
of a protease inhibitor in a composition for administration as
described herein is at least about 500 k.i.u. In some embodiments,
the amount of a protease inhibitor in a composition for
administration as described herein is at least about 700 k.i.u. In
some embodiments, the amount of a protease inhibitor in a
composition for administration as described herein is at least
about 1000 k.i.u. In some embodiments, the amount of a protease
inhibitor in a composition for administration as described herein
is at least about 1500 k.i.u. In some embodiments, the amount of a
protease inhibitor in a composition for administration as described
herein is at least about 3000 k.i.u. In some embodiments, the
amount of a protease inhibitor in a composition for administration
as described herein is at least about 4000 k.i.u. In some
embodiments, the amount of a protease inhibitor in a composition
for administration as described herein is at least about 5000
k.i.u.
[0208] Herein and in the art, a "kallikrein inactivating unit"
(k.i.u) refers to an amount of protease inhibitor that has the
ability to inhibit 2 units of kallikrein by 50% (e.g., in aqueous
solution at an optimal pH and solution volume for activity of the
protease inhibitor).
[0209] In some embodiments of any one of the embodiments described
herein, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 1:1 to 5:1 (protease inhibitor:
PTH). In some embodiments, a weight ratio of protease inhibitor PTH
(e.g., PTH(1-34)) is in a range of from 5:1 to 10:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 10:1 to 20:1. In some embodiments,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 20:1 to 30:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 30:1 to 40:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 40:1 to
50:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 50:1 to 75:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 75:1 to 100:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 200:1 to 300:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 300:1 to 400:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 400:1 to 500:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0210] SNAG:
[0211] In some embodiments of any one of the embodiments described
herein, the SNAC may optionally be replaced with a similar
compound, such as SNAD (sodium 10-N-(2-hydroxybenzoyl)aminodecanoic
acid). As shown below, the structure of SNAD differs from that of
SNAC only in the length of the fatty acid moiety.
##STR00001##
[0212] In some embodiments of any one of the embodiments described
herein, the SNAC may optionally be replaced with a similar
compound, wherein the caprylic acid moiety of SNAC is replaced by
another fatty acid moiety at least 6 carbon atoms in length, for
example, from 6 to 20 carbon atoms in length, optionally from 6 to
18 carbon atoms in length, optionally from 6 to 16 carbon atoms in
length, optionally from 6 to 14 carbon atoms in length, optionally
from 6 to 12 carbon atoms in length and optionally from 6 to 10
carbon atoms in length. The fatty acid moiety may be saturated
(e.g., as are caprylic acid in SNAC and decanoic acid in SNAD) or
unsaturated (i.e., comprising at least one unsaturated
carbon-carbon bond).
[0213] In some embodiments of any one of the embodiments described
herein, a concentration of SNAC in a composition described herein
is in a range of from 2.5 to 99.4 weight percents. In some of the
aforementioned embodiments, the concentration of SNAC is in a range
of from 2.5 to 10 weight percents. In some of the aforementioned
embodiments, the concentration of SNAC is in a range of from 8 to
15 weight percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 10 to 20 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 15 to 30 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 20 to 40 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 30 to 50 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 40 to 60 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 50 to 70 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 2.5 to 10 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 2.5 to 10 weight
percents. In some of the aforementioned embodiments, the
concentration of SNAC is in a range of from 70 to 99.4 weight
percents.
[0214] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to the PTH (e.g., PTH(1-34)) is in a
range of from 5:1 to 10:1 (SNAC: PTH). In some embodiments, the
ratio is about 7.5:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0215] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 10:1 to 20:1 (SNAC: PTH). In some embodiments, the
ratio is about 15:1. In some of the aforementioned embodiments, the
composition further comprises a protease inhibitor. In some of the
aforementioned embodiments wherein the composition comprises a
protease inhibitor, a weight ratio of protease inhibitor to PTH
(e.g., PTH(1-34)) is in a range of from 1:1 to 5:1 (protease
inhibitor: PTH), optionally about 3:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 5:1 to 10:1, optionally about 7.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 10:1 to 20:1, optionally about
15:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 20:1 to 30:1,
optionally about 25:1. In some embodiments, a weight ratio of
protease inhibitor PTH (e.g., PTH(1-34)) is in a range of from 30:1
to 40:1, optionally about 35:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 40:1 to 50:1, optionally about 45:1. In some embodiments, a
weight ratio of protease inhibitor PTH (e.g., PTH(1-34)) is in a
range of from 50:1 to 75:1, optionally about 62.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 75:1 to 100:1, optionally about
87.5:1. In some embodiments, a weight ratio of protease inhibitor
to PTH (e.g., PTH(1-34)) is in a range of from 100:1 to 200:1,
optionally about 150:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
200:1 to 300:1, optionally about 250:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 300:1 to 400:1, optionally about 350:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 400:1 to 500:1, optionally about
450:1. In some embodiments, the protease inhibitor is soybean
trypsin inhibitor.
[0216] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1 (SNAC: PTH). In some embodiments, the
ratio is about 25:1. In some of the aforementioned embodiments, the
composition further comprises a protease inhibitor. In some of the
aforementioned embodiments wherein the composition comprises a
protease inhibitor, a weight ratio of protease inhibitor to PTH
(e.g., PTH(1-34)) is in a range of from 1:1 to 5:1 (protease
inhibitor: PTH), optionally about 3:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 5:1 to 10:1, optionally about 7.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 10:1 to 20:1, optionally about
15:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 20:1 to 30:1,
optionally about 25:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
30:1 to 40:1, optionally about 35:1. In some embodiments, a weight
ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range
of from 40:1 to 50:1, optionally about 45:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 50:1 to 75:1, optionally about 62.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 75:1 to 100:1, optionally about
87.5:1. In some embodiments, a weight ratio of protease inhibitor
to PTH (e.g., PTH(1-34)) is in a range of from 100:1 to 200:1,
optionally about 150:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
200:1 to 300:1, optionally about 250:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 300:1 to 400:1, optionally about 350:1. In some
embodiments, a weight ratio of protease inhibitor PTH (e.g.,
PTH(1-34)) is in a range of from 400:1 to 500:1, optionally about
450:1. In some embodiments, the protease inhibitor is soybean
trypsin inhibitor.
[0217] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 30:1 to 50:1 (SNAC: PTH). In some embodiments, the
ratio is about 40:1. In some of the aforementioned embodiments, the
composition further comprises a protease inhibitor. In some of the
aforementioned embodiments wherein the composition comprises a
protease inhibitor, a weight ratio of protease inhibitor to PTH
(e.g., PTH(1-34)) is in a range of from 1:1 to 5:1 (protease
inhibitor: PTH), optionally about 3:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 5:1 to 10:1, optionally about 7.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 10:1 to 20:1, optionally about
15:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 20:1 to 30:1,
optionally about 25:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
30:1 to 40:1, optionally about 35:1. In some embodiments, a weight
ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range
of from 40:1 to 50:1, optionally about 45:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 50:1 to 75:1, optionally about 62.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 75:1 to 100:1, optionally about
87.5:1. In some embodiments, a weight ratio of protease inhibitor
to PTH (e.g., PTH(1-34)) is in a range of from 100:1 to 200:1,
optionally about 150:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
200:1 to 300:1, optionally about 250:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 300:1 to 400:1, optionally about 350:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 400:1 to 500:1, optionally about
450:1. In some embodiments, the protease inhibitor is soybean
trypsin inhibitor.
[0218] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 50:1 to 100:1 (SNAC: PTH). In some embodiments, the
ratio is about 75:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0219] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 100:1 to 200:1 (SNAC: PTH). In some embodiments, the
ratio is about 150:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0220] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 200:1 to 300:1 (SNAC: PTH). In some embodiments, the
ratio is about 250:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0221] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 300:1 to 500:1 (SNAC: PTH). In some embodiments, the
ratio is about 400:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0222] In some embodiments of any one of the embodiments described
herein, a weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in a
range of from 500:1 to 1000:1 (SNAC: PTH). In some embodiments, the
ratio is about 750:1. In some embodiments, the composition further
comprises a protease inhibitor. In some of the aforementioned
embodiments wherein the composition comprises a protease inhibitor,
a weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in
a range of from 1:1 to 5:1 (protease inhibitor: PTH), optionally
about 3:1. In some embodiments, a weight ratio of protease
inhibitor to PTH (e.g., PTH(1-34)) is in a range of from 5:1 to
10:1, optionally about 7.5:1. In some embodiments, a weight ratio
of protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of
from 10:1 to 20:1, optionally about 15:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 20:1 to 30:1, optionally about 25:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 30:1 to 40:1, optionally about
35:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 40:1 to 50:1,
optionally about 45:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
50:1 to 75:1, optionally about 62.5:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 75:1 to 100:1, optionally about 87.5:1. In some
embodiments, a weight ratio of protease inhibitor to PTH (e.g.,
PTH(1-34)) is in a range of from 100:1 to 200:1, optionally about
150:1. In some embodiments, a weight ratio of protease inhibitor to
PTH (e.g., PTH(1-34)) is in a range of from 200:1 to 300:1,
optionally about 250:1. In some embodiments, a weight ratio of
protease inhibitor to PTH (e.g., PTH(1-34)) is in a range of from
300:1 to 400:1, optionally about 350:1. In some embodiments, a
weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is in a
range of from 400:1 to 500:1, optionally about 450:1. In some
embodiments, the protease inhibitor is soybean trypsin
inhibitor.
[0223] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is at least about 0.1 mg. In some embodiments, the
amount of SNAC in a composition for administration as described
herein is at least about 0.2 mg. In some embodiments, the amount of
SNAC in a composition for administration as described herein is at
least about 0.3 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 0.4 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 0.6 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 0.8 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 1 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 1.5 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 2 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 2.5 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 3 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 5 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 7 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 10 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 12 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 15 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 20 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 30 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 50 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 70 mg. In some embodiments, the amount of SNAC in a
composition for administration as described herein is at least
about 100 mg. In some embodiments, the amount of PTH (e.g.,
PTH(1-34)) is in accordance with any one of the ratios of SNAC to
PTH (e.g., PTH(1-34)) described herein. In some embodiments, the
composition further comprises at least one protease inhibitor in an
amount which is in accordance with any one of the ratios of
protease inhibitor to PTH (e.g., PTH(1-34)) described herein.
[0224] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 0.1 to 1 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.2 to 1 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.3 to 1 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.5 to 1 mg.
[0225] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 0.1 to 2 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.2 to 2 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.3 to 2 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 0.5 to 2 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 1 to 2 mg.
[0226] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 1 to 10 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 2 to 10 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 3 to 10 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 5 to 10 mg.
[0227] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 1 to 20 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 2 to 20 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 3 to 20 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 5 to 20 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 10 to 20 mg.
[0228] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 100 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 100 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 100 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 100 mg.
[0229] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 200 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 200 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 200 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 200 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 100 to 200 mg.
[0230] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 500 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 500 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 500 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 500 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 100 to 500 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 200 to 500 mg.
[0231] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 100 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 200 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 500 to 1000 mg.
[0232] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 100 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 200 to 1000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 500 to 1000 mg.
[0233] In some embodiments of any one of the embodiments described
herein, the amount of SNAC in a composition for administration as
described herein is in a range of from 10 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 20 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 30 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 50 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 100 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 200 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 500 to 2000 mg. In some
embodiments, the amount of SNAC in a composition for administration
as described herein is in a range of from 1000 to 2000 mg.
[0234] In some embodiments of any one of the embodiments described
herein, at least 50 weight percents of the composition consists of
SNAC. In some embodiments, at least 60 weight percents of the
composition consists of SNAC. In some embodiments, at least 70
weight percents of the composition consists of SNAC. In some
embodiments, at least 80 weight percents of the composition
consists of SNAC. In some embodiments, at least 90 weight percents
of the composition consists of SNAC.
[0235] Without being bound by any particular theory, it is believed
that compositions having a large proportion of SNAC, which is a
salt, tend to be readily soluble in aqueous solution, including in
gastric fluid, as is desirable according to some embodiments of the
invention.
[0236] The following describes exemplary compositions and/or
methods or treatments employing same, which may provide the desired
pharmacokinetic properties as described herein in any one of the
respective embodiments and any combinations thereof.
[0237] Protective Agents:
[0238] In some embodiments according to any of the aspects of the
embodiments described herein, the method or treatment further
comprises oral administration of a protective agent.
[0239] In some embodiments according to any of the aspects of the
embodiments described herein, the composition for oral
administration of PTH further comprises a protective agent. In some
embodiments, the composition is formulated as one or more unit
dosage forms (e.g., according to any of the respective embodiments
described herein). The unit dosage form(s) may be formulated in any
form suitable for oral administration, including solid and/or
liquid forms. In some embodiments, the unit dosage form is a solid
unit dosage form. In some embodiments, the composition is
formulated as a tablet.
[0240] Herein, the term "protective agent" refers to an agent
capable of protecting the PTH and/or SNAC against enzymes and/or
acid in the gastrointestinal tract. For example, a protease
inhibitor can protect PTH from activity of a protease, and an
antacid can protect SNAC (e.g., by reducing conversion of SNAC from
a carboxylate salt to a carboxylic acid form) and/or PTH from
stomach acid (e.g., acid-induced denaturation).
[0241] In some embodiments, of any of the embodiments described
herein, the composition comprises at least one antacid compound
(e.g., according to any of the respective embodiments described
herein). In some such embodiments, the composition further
comprises at least one protease inhibitor (e.g., according to any
of the respective embodiments described herein).
[0242] Without being bound by any particular theory, it is believed
that compositions comprising PTH and SNAC are significantly
affected by inactivation of the SNAC upon contact with stomach
acid, which converts SNAC from a soluble carboxylate salt to an
insoluble carboxylic acid. The inactivation of SNAC reduces the
absorption of the PTH, thereby potentially reducing the efficacy of
the composition. In addition, protease inhibitors used to protect
PTH from proteolysis may also be at least partially inactivated
upon contact with stomach acid, which may further reduce the
efficacy of such compositions. It is further believed that the
ability of protease inhibitors to protect PTH against protease
activity in the digestive system is limited, because much of the
PTH is inactivated by proteases before the proteases are inhibited
by the protease inhibitor.
[0243] In some embodiments, of any of the embodiments described
herein, the composition is in a form of a homogeneous mixture, such
that a protective agent (optionally an antacid compound) is
uniformly dispersed among the SNAC and therapeutically active agent
(and optionally any additional ingredient present).
[0244] The present inventors have further designed unit dosage
forms so as to release a protective agent prior to release of the
compound which the protective agent is intended to protect, for
example, releasing an antacid for reducing acidity in a vicinity of
an orally administered composition prior to exposure of SNAC and/or
PTH to stomach acid, and/or releasing a protease inhibitor for
inhibiting proteases prior to exposure of PTH to proteases.
[0245] In some embodiments, of any of the embodiments described
herein, the composition is formulated as a unit dosage form
comprising a core and an external layer. The core comprises PTH and
SNAC; and the external layer comprises at least one protective
agent.
[0246] In some of any of the embodiments described herein, the
protective agent is a protease inhibitor, according to any of the
respective embodiments described herein.
[0247] In some of any of the embodiments described herein, the
protective agent is an antacid compound, according to any of the
respective embodiments described herein.
[0248] In some of any of the embodiments described herein, the unit
dosage form comprises at least one protective agent which is an
antacid compound (according to any of the respective embodiments
described herein) and at least one protective agent which is a
protease inhibitor (according to any of the respective embodiments
described herein).
[0249] Herein throughout, the term "antacid compound" refers to any
pharmaceutically acceptable compound capable of neutralizing
stomach acid (e.g., HCl in aqueous solution), preferably wherein
one mole of antacid compound is capable of neutralizing at least
0.5 mole of HCl, and more preferably capable of neutralizing at
least 1 mole of HCl. The PTH, SNAC and protease inhibitors
described herein are excluded from the scope of the phrase "antacid
compound", even though they may exhibit some ability to neutralize
stomach acid, in some embodiments of the invention.
[0250] Examples of antacid compounds which may be used in any one
of the embodiments described herein relating to one or more antacid
compounds (in accordance with any of the aspects of embodiments of
the invention described herein), include, without limitation,
calcium carbonate, calcium gluconate, calcium citrate, sodium
carbonate, sodium bicarbonate, sodium gluconate, sodium citrate,
sodium hydroxide, potassium carbonate, potassium bicarbonate,
potassium gluconate, potassium citrate, potassium hydroxide,
magnesium carbonate, magnesium gluconate, magnesium citrate,
magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum
gluconate, aluminum citrate, and aluminum hydroxide.
[0251] The unit dosage form may have any shape suitable for orally
administered pharmaceutical dosage forms, including, without
limitation, any 3-dimensional shape having a substantially
rectangular (including substantially square), substantially
circular and/or substantially oval cross-section along at least one
axis. For example, the unit dosage form may have a substantially
box-like shape, having a substantially rectangular cross-section
(optionally with rounded corners) along 3 axes; a substantially
cylindrical shape, having substantially circular and/or
substantially oval cross-section along one axis, and a
substantially rectangular cross-section (optionally with rounded
corners) along 2 axes; or a substantially spherical or ovoid shape,
having a substantially circular and/or substantially oval
cross-section along 3 axes.
[0252] In some of any one of the embodiments described herein, the
external layer comprises one or more protease inhibitors and one or
more antacid compounds. In some such embodiments, the external
layer consists essentially of one or more protease inhibitors and
one or more antacid compounds. Alternatively, in some such
embodiments, the external layer comprises a combination of one or
more excipients with the protease inhibitor(s) and antacid
compound(s).
[0253] In some of any one of the embodiments described herein, the
external layer comprises one or more protease inhibitors, and is
devoid of antacid compounds. In some such embodiments, the external
layer consists essentially of one or more protease inhibitors.
Alternatively, in some such embodiments, the external layer
comprises a combination of one or more excipients with the protease
inhibitor(s).
[0254] In some of any one of the embodiments described herein, the
external layer comprises one or more antacid compounds, and is
devoid of protease inhibitors. In some such embodiments, the
external layer consists essentially of one or more antacid
compounds. Alternatively, in some such embodiments, the external
layer comprises a combination of one or more excipients with the
antacid compound(s).
[0255] Herein throughout, the phrase "devoid of" encompasses the
presence of minute amounts of the indicated substance (for example,
less than 0.1 weight percent, optionally less than 0.05 weight
percent, optionally less than 0.02 weight percent, and optionally
less than 0.01 weight percent) as well as the complete absence of
the indicated substance.
[0256] In some of any one of the embodiments described herein, a
concentration (as a weight percentage) of PTH in the external layer
is lower than a concentration of PTH in the core. In some of any
one of the embodiments described herein, a concentration (as a
weight percentage) of PTH in the external layer is less than 50% of
a concentration of PTH in the core. In some embodiments, the
concentration in the external layer is less than 20% of the
concentration in the core. In some embodiments, the concentration
in the external layer is less than 10% of the concentration in the
core. In some embodiments, the concentration in the external layer
is less than 5% of the concentration in the core. In some
embodiments, the concentration in the external layer is less than
2% of the concentration in the core. In some embodiments, the
concentration in the external layer is less than 1% of the
concentration in the core. In some embodiments, the external layer
is devoid of PTH.
[0257] In some of any one of the embodiments described herein, a
concentration (as a weight percentage) of SNAC in the external
layer is lower than a concentration of SNAC in the core. In some of
any one of the embodiments described herein, a concentration (as a
weight percentage) of SNAC in the external layer is less than 50%
of a concentration of SNAC in the core. In some embodiments, the
concentration in the external layer is less than 20% of the
concentration in the core. In some embodiments, the concentration
in the external layer is less than 10% of the concentration in the
core. In some embodiments, the concentration in the external layer
is less than 5% of the concentration in the core. In some
embodiments, the concentration in the external layer is less than
2% of the concentration in the core. In some embodiments, the
concentration in the external layer is less than 1% of the
concentration in the core. In some embodiments, the external layer
is devoid of SNAC. In some embodiments, the external layer is
devoid of PTH and devoid of SNAC.
[0258] In some of any one of the embodiments described herein, the
external layer covers the whole surface of the core.
[0259] In some of any one of the embodiments described herein, the
external layer does not cover the whole surface of the core. In
some embodiments wherein the external layer does not cover the
whole surface of the core, the external layer is separated into a
plurality of unconnected layers (e.g., 2 layers, 3 layers, 4
layers, or more than 4 layers), each of the unconnected layers
covering a different region of the surface of the core. In such
embodiments, the phrase "external layer" refers collectively to all
such unconnected layers. In some embodiments, the external layer is
separated into two unconnected layers which cover opposite sides of
the core. In alternative embodiments wherein the external layer
does not cover the whole surface of the core, the external layer is
in a form of a single continuous layer.
[0260] In some of any one of the embodiments described herein, the
external layer covers at least 30% of the surface area of the core.
In some embodiments, the external layer covers at least 40% of the
surface area of the core. In some embodiments, the external layer
covers at least 50% of the surface area of the core. In some
embodiments, the external layer covers at least 60% of the surface
area of the core. In some embodiments, the external layer covers at
least 70% of the surface area of the core. In some embodiments, the
external layer covers at least 80% of the surface area of the core.
In some embodiments, the external layer covers at least 90% of the
surface area of the core.
[0261] In some embodiments of any one of the embodiments described
herein, the protease inhibitor(s) and/or antacid compound(s) in the
external layer are distributed homogeneously throughout the
external layer.
[0262] In some embodiments of any one of the embodiments described
herein, the protease inhibitor(s) and/or antacid compound(s) in the
external layer are distributed inhomogeneously throughout the
external layer.
[0263] In some such embodiments, the protease inhibitor(s) and/or
antacid compound(s) are within particles (e.g., microspheres
containing the protease inhibitor(s) and/or antacid compound(s)),
and the external layer further comprises a material (e.g., a filler
and/or binder) between the particles.
[0264] Alternatively or additionally, in some embodiments, the
external layer comprises two or more layers (e.g., concentric
layers), wherein each layer within the external layer has a
different composition. For example, the external layer may
optionally comprise a first layer which comprises one of the
protease inhibitor(s) and/or antacid compound(s), a second layer
which comprises another of the protease inhibitor(s) and/or antacid
compound(s), and optionally one or more additional layers, each
comprising different inhibitor(s) and/or antacid compound(s).
[0265] In some embodiments of any one of the embodiments described
herein, the core further comprises one or more protease inhibitors
and/or antacid compounds, in addition to PTH and SNAC.
[0266] In some embodiments of any one of the embodiments described
herein, the core consists essentially of the PTH and SNAC or a
combination of the PTH, SNAC and the protease inhibitor(s) and/or
antacid compound(s).
[0267] In some embodiments of any one of the embodiments described
herein, the core comprises a combination of one or more excipients
with the PTH and SNAC (and optionally the protease inhibitor(s)
and/or antacid compound(s)).
[0268] In some embodiments of any one of the embodiments described
herein, the core comprises PTH, SNAC and one or more antacid
compounds. In some embodiments, the core consists essentially of a
combination of PTH, SNAC and the antacid compound(s).
Alternatively, in some embodiments, the core comprises a
combination of one or more excipients with PTH, SNAC and antacid
compound(s).
[0269] In some embodiments of any one of the embodiments described
herein, the core comprises PTH, SNAC and one or more protease
inhibitors. In some embodiments, the core consists essentially of a
combination of PTH, SNAC and the protease inhibitor(s).
Alternatively, in some embodiments, the core comprises a
combination of one or more excipients with PTH, SNAC and protease
inhibitor(s).
[0270] In some embodiments of any one of the embodiments described
herein, the PTH and/or SNAC in the core are distributed
homogeneously throughout the core.
[0271] In some embodiments of any one of the embodiments described
herein, the PTH and/or SNAC in the core are distributed
inhomogeneously throughout the core.
[0272] In some such embodiments, the PTH and/or SNAC are within
particles (e.g., microspheres containing the PTH and/or SNAC), and
the core comprises a material (e.g., a filler and/or binder)
between the particles.
[0273] Alternatively or additionally, in some embodiments, the core
comprises an inner portion and an outer portion (e.g., configured
concentrically), wherein each portion within the core has a
different composition. For example, the core may optionally
comprise an outer portion which comprises PTH and an inner portion
which comprises SNAC, or vice versa.
[0274] In some of any one of the embodiments described herein, the
unit dosage form further comprises a coating which coats the outer
surface of the external layer described herein, and optionally also
a region of a core surface which is not covered by an external
layer (in embodiments wherein the external layer does not cover the
whole core). In some embodiments, the coating is formed from
material which dissolves in at least a portion of the
gastrointestinal tract.
[0275] In some embodiments of any one of the embodiments described
herein, the coating is an enteric coating (e.g., an enteric coating
according to any of the respective embodiments described
herein).
[0276] In some embodiments of any one of the embodiments described
herein, the coating dissolves under conditions in the stomach
(e.g., in an aqueous environment, optionally only when a low pH is
present), thereby exposing the external layer. Such a coating is
optionally adapted for altering an appearance of the unit dosage
form (e.g., for aesthetic enhancement and/or labeling), to provide
flavor and/or mask flavor, and/or to protect the external layer
and/or core (e.g., from mechanical insult, air, light and/or
liquids).
[0277] Dissolution of the unit dosage form in the gastrointestinal
system initially comprises primarily dissolution of the external
layer (optionally after dissolution of a coating, if present),
thereby releasing the protease inhibitor(s) and/or antacid
compound(s) in the external layer prior to release of PTH and SNAC
from the core.
[0278] In some embodiments of any one of the embodiments described
herein, the unit dosage form is formulated as a tablet. In some
embodiments, the unit dosage form is formulated as a multi-layered
tablet (e.g., a 3-layered tablet), in which the external layer
forms an upper layer and a lower layer, and the core is formulated
as a middle layer sandwiched between the upper layer and a lower
layer. Exemplary tablets are shown in FIGS. 7 and 8 herein. Any of
the multi-layered tablets described herein may optionally prepared
according to any technique known in the art for preparing
multi-layered tablets (e.g., 3-layered tablet), including, without
limitation a technique described by Shende et al. [Int J Drug
Delivery 2012, 4:418-426], the contents of which are incorporated
herein by reference.
[0279] In some embodiments of any one of the embodiments described
herein, the unit dosage form consists primarily of the combination
of PTH, SNAC, and at least one protective agent (protease
inhibitor(s) and/or antacid compound(s)) described herein, that is,
at least 50 weight percents of the unit dosage form consists of
ingredients selected from the group consisting of PTH, SNAC and at
least one protective agent. In some embodiments, at least 60 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, at least 70 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, at least 80 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, at least 90 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, at least 95 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, at least 98 weight
percents of the unit dosage form consists of PTH, SNAC and at least
one protective agent. In some embodiments, the unit dosage form is
formulated as a tablet.
[0280] In some embodiments of any one of the embodiments described
herein, the external layer and core described herein consist
primarily of the combination of PTH, SNAC, and at least one
protective agent (protease inhibitor(s) and/or antacid compound(s))
described herein, that is, at least 50 weight percents of the total
weight of the external layer and core consists of ingredients
selected from the group consisting of PTH, SNAC and at least one
protective agent. In some embodiments, at least 60 weight percents
of the total weight of the external layer and core consists of PTH,
SNAC and at least one protective agent. In some embodiments, at
least 70 weight percents of the total weight of the external layer
and core consists of PTH, SNAC and at least one protective agent.
In some embodiments, at least 80 weight percents of the total
weight of the external layer and core consists of PTH, SNAC and at
least one protective agent. In some embodiments, at least 90 weight
percents of the total weight of the external layer and core
consists of PTH, SNAC and at least one protective agent. In some
embodiments, at least 95 weight percents of the total weight of the
external layer and core consists of PTH, SNAC and at least one
protective agent. In some embodiments, at least 98 weight percents
of the total weight of the external layer and core consists of PTH,
SNAC and at least one protective agent. In some embodiments, the
external layer and core are formulated as parts of a tablet. In
some embodiments, the tablet is a multi-layered tablet (e.g.,
3-layered tablet).
[0281] Referring now to the drawings, FIGS. 5A-5C show the
structure, in cross-section, of an exemplary unit dosage form 100
according to some related embodiments of the invention. Unit dosage
form 100 comprises a core 110 and an external layer 120. The
embodiments shown in FIGS. 5A-5C differ only in that FIG. 5A shows
exemplary embodiments in which external layer 120 covers all of
core 110; FIG. 5B shows exemplary embodiments in which external
layer 120 is separated into unconnected layers which cover
different regions of core 110 (such that external layer 120 does
not cover all of core 110); and FIG. 5C shows exemplary embodiments
in which external layer 120 is a single continuous layer which does
not cover all of core 110. Unit dosage form 100 is optionally
substantially rectangular in cross-section (as depicted in FIGS.
5A-5C) along at least one axis. However, the cross-section may have
a differently shape (e.g., substantially circular and/or
substantially oval), and it is to be understood that the shapes
depicted in FIGS. 5A-5C are not intended to be limiting.
[0282] External layer 120 comprises one or more protease inhibitors
and/or antacid compounds, in accordance with any of one of the
embodiments described herein relating to a composition of an
external layer, and optionally consists essentially of one or more
protease inhibitors and/or antacid compounds (e.g., in accordance
with one of the respective embodiments described herein).
Alternatively, external layer 120 comprises a combination of one or
more excipients with the protease inhibitor(s) and/or antacid
compound(s) (e.g., in accordance with one of the respective
embodiments described herein).
[0283] In some embodiments, external layer 120 comprises one or
more protease inhibitors (e.g., in accordance with one of the
respective embodiments described herein), is optionally devoid of
antacid compounds, and optionally consists essentially of one or
more protease inhibitors (e.g., in accordance with one of the
respective embodiments described herein). Alternatively, external
layer 120 comprises a combination of one or more excipients with
the protease inhibitor(s) (e.g., in accordance with one of the
respective embodiments described herein).
[0284] In some embodiments, external layer 120 comprises one or
more antacid compounds (e.g., in accordance with one of the
respective embodiments described herein), is optionally devoid of
protease inhibitors, and optionally consists essentially of one or
more antacid compounds (e.g., in accordance with one of the
respective embodiments described herein). Alternatively, external
layer 120 comprises a combination of one or more excipients with
the antacid compound(s) (e.g., in accordance with one of the
respective embodiments described herein).
[0285] In some embodiments, a concentration (as a weight
percentage) of PTH in external layer 120 is less than a
concentration of PTH in core 110 (e.g., in accordance with one of
the respective embodiments described herein). In some embodiments,
external layer 120 is devoid of PTH.
[0286] In some embodiments, a concentration (as a weight
percentage) of SNAC in external layer 120 is less than a
concentration of SNAC in core 110 (e.g., in accordance with one of
the respective embodiments described herein). In some embodiments,
external layer 120 is devoid of SNAC. In some embodiments, external
layer 120 is devoid of PTH and devoid of SNAC.
[0287] FIGS. 6A-6C show the structure, in cross-section, of an
exemplary unit dosage form 200 according to some related
embodiments of the invention. Unit dosage form 200 as shown in
FIGS. 6A-6C, corresponds to unit dosage form 100 (in any one of the
respective embodiments described herein) as shown, respectively, in
FIGS. 5A-5C, differing from unit dosage form 100 in that unit
dosage form 200 further comprises coating 230. Unit dosage form 200
comprises a core 210 and an external layer 220, which correspond,
respectively, to core 110 and an external layer 120 of unit dosage
form 100, as described herein, in any one of the respective
embodiments.
[0288] The embodiments shown in FIGS. 6A-6C differ only in that
FIG. 6A shows exemplary embodiments in which external layer 220
covers all of core 210; FIG. 6B shows exemplary embodiments in
which external layer 220 is separated into unconnected layers which
cover different regions of core 210 (such that external layer 220
does not cover all of core 210); and FIG. 6C shows exemplary
embodiments in which external layer 220 is a single continuous
layer which does not cover all of core 210.
[0289] Unit dosage form 200 is optionally substantially rectangular
in cross-section (as depicted in FIGS. 6A-6C) along at least one
axis. However, the cross-section may have a differently shape
(e.g., substantially circular and/or substantially oval), and it is
to be understood that the shapes depicted in FIGS. 6A-6C are not
intended to be limiting.
[0290] Coating 230 has a composition in accordance with any one of
the embodiments described herein relating to a coating, and is
optionally formed from material which dissolves in at least a
portion of the gastrointestinal tract (e.g., in accordance with one
of the respective embodiments described herein).
[0291] In some embodiments of any one of the embodiments described
herein, coating 230 is an enteric coating, as described herein
(e.g., in accordance with one of the respective embodiments).
[0292] In some embodiments of any one of the embodiments described
herein, coating 230 dissolves under conditions in the stomach
(e.g., in accordance with one of the respective embodiments
described herein), thereby exposing external layer 220. Coating 230
is optionally adapted for altering an appearance of unit dosage
form 200 (e.g., for aesthetic enhancement and/or labeling), to
provide flavor and/or mask flavor, and/or to protect external layer
220 and/or core 210 (e.g., from mechanical insult, air, light
and/or liquids), e.g., in accordance with one of the respective
embodiments described herein).
[0293] In some embodiments of any one of the embodiments described
herein, coating 230 is an enteric coating (e.g., in accordance with
one of the respective embodiments described herein), external layer
220 comprises one or more protease inhibitors (e.g., in accordance
with one of the respective embodiments described herein), and core
210 comprises PTH and SNAC, and optionally one or more protease
inhibitors (e.g., in accordance with one of the respective
embodiments described herein). In some such embodiments, unit
dosage form 200 is formulated as a tablet (e.g., optionally as
depicted in FIG. 8).
[0294] In embodiments wherein coating 230 is an enteric coating,
dissolution of the unit dosage form 200 in the gastrointestinal
system comprises dissolution of enteric coating 230 in the
intestines, followed primarily by dissolution of external layer
220, thereby releasing the protease inhibitor(s) in the external
layer prior to release of PTH and SNAC from core 210.
[0295] In some of any of the embodiments wherein coating 230 is an
enteric coating, external layer 220 and/or core 210 is devoid of an
antacid.
[0296] In some embodiments of any one of the embodiments described
herein, coating 230 is a coating which dissolves under gastric
conditions (e.g., in accordance with one of the respective
embodiments described herein), external layer 220 comprises one or
more antacid compounds (e.g., in accordance with one of the
respective embodiments described herein), and core 210 comprises
PTH and SNAC, and optionally one or more antacid compounds (e.g.,
in accordance with one of the respective embodiments described
herein). In such embodiments, initial dissolution of the unit
dosage form 200 in the gastro-intestinal tract primarily comprises
dissolution of coating 230 and external layer 220 in the stomach,
thereby releasing the antacid compound(s) in the external layer and
reducing an acidity in the stomach (e.g., in a vicinity of the unit
dosage form) prior to release of PTH and SNAC from core 210.
[0297] In some embodiments of any one of the embodiments wherein
coating 230 is a coating which dissolves under gastric conditions,
external layer 220 and/or core 210 is devoid of a protease
inhibitor.
[0298] In some embodiments of any one of the embodiments described
herein, unit dosage form 200 is formulated as a coated tablet. In
some embodiments, the unit dosage form 200 is formulated as a
coated multi-layered tablet (e.g., 3-layered tablet), in which
external layer 220 forms an upper layer and a lower layer, and core
210 is formulated as a middle layer sandwiched between the upper
layer and a lower layer. An exemplary coated tablet is shown in
FIG. 8. Any of the coated multi-layered tablets described herein
may optionally prepared using any technique known in the art for
preparing multi-layered tablets, followed by coating the tablet
using any tablet-coating technique known in the art.
[0299] FIG. 7 shows the structure of an exemplary unit dosage form
according to some embodiments of the invention, in a form of tablet
300. Tablet 300 comprises a core 310 and an external layer 320,
which correspond, respectively, to core 110 and external layer 120
of unit dosage form 100, as described herein in any one of the
respective embodiments (e.g., with respect to FIG. 5B).
[0300] Tablet 300 is optionally has a substantially circular or
substantially oval cross-section in cross-section (as depicted in
FIG. 7). However, the tablet may have a differently shape, and it
is to be understood that the shape depicted in FIG. 7 is not
intended to be limiting.
[0301] External layer 320 includes layer 330 on an obverse face
(e.g., a circular or oval face) and layer 340 on a reverse face
(e.g., a circular or oval face) of tablet 300. Layers 330 and 340
are optionally unconnected, such that external layer 320 is
separated into two unconnected layers, corresponding to external
layer 120 in FIG. 5B).
[0302] External layer 320 optionally covers at least 50% of a
surface area of core 310, optionally at least 60%, optionally at
least 70%, optionally at least 80%, and optionally at least 90% of
the surface of core 310.
[0303] External layer 320 comprises one or more protease inhibitors
and/or antacid compounds, as described for external layer 120
according to any one of the respective embodiments described
herein. In some embodiments, external layer 320 comprises one or
more antacid compounds (e.g., in accordance with one of the
respective embodiments described herein).
[0304] In some embodiments of any one of the embodiments described
herein, external layer 320 is devoid of protease inhibitors.
Optionally, external layer 320 consists essentially of one or more
antacid compounds. Alternatively, external layer 320 comprises a
combination of one or more excipients with the antacid compound(s)
(e.g., in accordance with one of the respective embodiments
described herein).
[0305] In some embodiments of any one of the embodiments described
herein, external layer 320 comprises one or more protease
inhibitors in addition to one or more antacid compounds (e.g., in
accordance with one of the respective embodiments described
herein). Optionally, external layer 320 consists essentially of one
or more protease inhibitors and one or more antacid compounds.
Alternatively, external layer 320 comprises a combination of one or
more excipients with the protease inhibitor(s) and antacid
compound(s) (e.g., in accordance with one of the respective
embodiments described herein).
[0306] Core 310 comprises PTH of the tablet and SNAC, and
optionally further comprises one or more protease inhibitors and/or
antacid compounds, as described for core 110 according to any one
of the respective embodiments described herein. In some
embodiments, core 310 comprises one or more antacid compounds
(e.g., in accordance with one of the respective embodiments
described herein).
[0307] Initial dissolution of tablet 300 in the gastrointestinal
system primarily comprises dissolution of external layer 320,
thereby releasing the protease inhibitor(s) and/or antacid
compound(s) in the external layer prior to release of PTH and SNAC
from core 310.
[0308] FIG. 8 shows the structure, in cross-section, of an
exemplary unit dosage form according to some embodiments of the
invention, in a form of coated tablet 400. Tablet 400 corresponds
to tablet 300 (in any one of the respective embodiments described
herein), differing in that tablet 400 further comprises enteric
coating 430. Tablet 400 comprises a core 410, an external layer
420, and an enteric coating 430, which correspond, respectively, to
core 210, external layer 220 and coating 230 of unit dosage form
200, as described herein, in any one of the respective embodiments
(e.g., with respect to FIG. 6B).
[0309] Enteric coating 430 may optionally be an enteric coating
according to any one of the embodiments described herein relating
to an enteric coating, for example, with respect to coating 230
(e.g., in accordance with one of the respective embodiments).
[0310] Tablet 400 optionally has a substantially circular or
substantially oval cross-section in cross-section (as depicted in
FIG. 8). However, the tablet may have a differently shape, and it
is to be understood that the shape depicted in FIG. 8 is not
intended to be limiting.
[0311] External layer 420 includes layer 440 on an obverse face
(e.g., a circular or oval face) and layer 450 on a reverse face
(e.g., a circular or oval face) of tablet 400. Layers 440 and 450
are optionally unconnected, such that external layer 420 is
separated into two unconnected layers, corresponding to external
layer 220 in FIG. 6B).
[0312] External layer 420 optionally covers at least 50% of a
surface area of core 410, optionally at least 60%, optionally at
least 70%, optionally at least 80%, and optionally at least 90% of
the surface of core 410.
[0313] External layer 420 comprises one or more protease inhibitors
and/or antacid compounds, as described for external layer 120
and/or external layer 220 according to any one of the respective
embodiments described herein. In some embodiments of any one of the
embodiments described herein, external layer 420 is devoid of
antacid compounds. Optionally, external layer 420 consists
essentially of one or more protease inhibitors. Alternatively,
external layer 420 comprises a combination of one or more
excipients with the protease inhibitor(s).
[0314] Core 410 comprises PTH of the tablet and SNAC, and
optionally further comprises one or more protease inhibitors and/or
antacid compounds, as described for core 110 and/or core 210
according to any one of the respective embodiments described
herein. In some embodiments, core 410 comprises one or more
protease inhibitors. In some embodiments, core 410 is devoid of
antacid compounds.
[0315] Dissolution of tablet 400 in the gastrointestinal system
comprises dissolution of enteric coating 430 in the intestines,
followed primarily by dissolution of external layer 420, thereby
releasing the protease inhibitor(s) in the external layer prior to
release of PTH and SNAC from core 410.
[0316] FIG. 9 shows a composition of an exemplary external layer
500 according to some of any one of the embodiments of the
invention. External layer 500 corresponds to any external layer
described herein (e.g., external layer 120, 220, 320 and/or 420),
in any one of the respective embodiments described herein, and has
an inner face 510 which faces a core as described herein, and an
outer face 520, which faces a coating described herein and/or
surface of a unit dosage form described herein. External layer 500
comprises a first compound 530 (optionally a single compound, and
optionally a combination of compounds) depicted as rectangles, and
a second compound 540 (optionally a single compound, and optionally
a combination of compounds) depicted as circles. Additional
compounds (not shown) may optionally also be comprised by external
layer 500.
[0317] The distribution of compounds 530 and 540 is optionally
inhomogeneous, such that compound 530 is more concentrated in the
vicinity of outer face 520 than in the vicinity of inner face 510,
and/or compound 540 is more concentrated in the vicinity of inner
face 510 than in the vicinity of outer face 520, as depicted in
FIG. 9. Thus, a gradient in concentration exists between faces 510
and 520. In some embodiments, dissolution of external layer 500
results in dissolution of compound 530 preceding dissolution of
compound 540.
[0318] Alternatively, the distribution of compounds 530 and 540 is
homogeneous, such that no gradient in concentration exists between
faces 510 and 520.
[0319] In some of any of the embodiments described herein, compound
530 is one or more antacid compounds (e.g., in accordance with one
of the respective embodiments described herein), and compound 540
is one or more protease inhibitor(s) and/or excipient(s) (e.g., in
accordance with one of the respective embodiments described
herein).
[0320] In some of any of the embodiments described herein, compound
530 is one or more protease inhibitors (e.g., in accordance with
one of the respective embodiments described herein), and compound
540 is one or more antacid compound(s) and/or excipient(s) (e.g.,
in accordance with one of the respective embodiments described
herein).
[0321] FIG. 10 shows a composition of an exemplary external layer
600 according to some of any one of the embodiments of the
invention. External layer 600 corresponds to any external layer
described herein (e.g., external layer 120, 220, 320, 420 and/or
520), in any one of the respective embodiments described herein,
and has an inner face 610 which faces a core as described herein,
and an outer face 620, which faces a coating described herein
and/or surface of a unit dosage form described herein. External
layer 600 comprises a first compound 630 (optionally a single
compound, and optionally a combination of compounds) depicted as
rectangles, and a second compound 640 (optionally a single
compound, and optionally a combination of compounds) depicted as
circles. Additional compounds (not shown) may optionally also be
comprised by external layer 600.
[0322] As depicted in FIG. 10, the distribution of compounds 630
and 640 is optionally inhomogeneous, such that compound 630 is more
concentrated in the vicinity of one or more regions of the unit
dosage form surface (e.g., the right-hand side of FIG. 10) than in
the vicinity of other regions of the unit dosage form surface
(e.g., the left-hand side of FIG. 10), and/or compound 540 is more
concentrated in the vicinity of one or more regions of the unit
dosage form surface (e.g., the left-hand side of FIG. 10) than in
the vicinity of other regions of the unit dosage form surface
(e.g., the right-hand side of FIG. 10). Thus, a gradient in
concentration exists in the plane of external layer 600.
[0323] Alternatively, the distribution of compounds 630 and 640 is
homogeneous, such that no gradient in concentration exists in the
plane of external layer 600.
[0324] In some of any of the embodiments described herein, compound
630 is one or more antacid compounds (e.g., in accordance with one
of the respective embodiments described herein), and compound 640
is one or more protease inhibitor(s) and/or excipient(s) (e.g., in
accordance with one of the respective embodiments described
herein).
[0325] In some of any of the embodiments described herein, compound
630 is one or more protease inhibitors (e.g., in accordance with
one of the respective embodiments described herein), and compound
640 is one or more antacid compound(s) and/or excipient(s) (e.g.,
in accordance with one of the respective embodiments described
herein).
[0326] FIG. 11 shows a composition of an exemplary core 700
according to some of any one of the embodiments of the invention.
Core 700 corresponds to any external layer described herein (e.g.,
core 110, 210, 310 and/or 410), in any one of the respective
embodiments described herein, and may optionally be combined with
any external layer described herein.
[0327] As depicted in FIG. 11, the distribution of one or more
compounds in core 700 is optionally inhomogeneous, such that the
one or more compounds are concentrated within particles 710
separated at least in part by an interstitial material 720.
[0328] Particles 710 optionally comprise PTH and/or SNAC (e.g., in
accordance with one of the respective embodiments described
herein), at a concentration which is higher than a concentration of
PTH and/or SNAC in interstitial material 720. Particles 710 may
include different species of particles, having different
compositions (e.g., one species comprising SNAC, and one species
comprising PTH). Particles 710 are optionally in a form of granules
and/or microspheres.
[0329] Interstitial material 720 is optionally devoid of PTH and/or
SNAC. Interstitial material 720 optionally comprises on or more
excipients (e.g., in accordance with one of the respective
embodiments described herein), such as a filler and/or binder, and
optionally consists essentially of one or more excipients.
[0330] Alternatively, the distribution of compounds in core 700 is
homogeneous.
[0331] In some embodiments of any one of the embodiments described
herein, at least 50 weight percents of a core described herein
(e.g., any one of cores 110, 210, 310 and 410) consists of SNAC. In
some embodiments, at least 60 weight percents of a core described
herein (e.g., any one of cores 110, 210, 310 and 410) consists of
SNAC. In some embodiments, at least 70 weight percents of a core
described herein (e.g., any one of cores 110, 210, 310 and 410)
consists of SNAC. In some embodiments, at least 80 weight percents
of a core described herein (e.g., any one of cores 110, 210, 310
and 410) consists of SNAC. In some embodiments, at least 90 weight
percents of a core described herein (e.g., any one of cores 110,
210, 310 and 410) consists of SNAC.
[0332] Without being bound by any particular theory, it is believed
that compositions (e.g., unit dosage forms and/or cores described
herein) having a large proportion of SNAC, which is a salt, tend to
be readily soluble in aqueous solution, including in gastric fluid,
as is desirable according to some embodiments of the invention.
[0333] In some embodiments of any one of the embodiments described
herein, the unit dosage form (e.g., any one of unit dosage form
100, unit dosage form 200, and tablet 300) is soluble in gastric
fluid (as defined herein). In some such embodiments, the unit
dosage form does not comprise an enteric coating, thereby
facilitating dissolution in gastric fluid. In some embodiments, the
unit dosage form dissolves in gastric fluid in no more than 60
minutes. In some embodiments, the unit dosage form dissolves in
gastric fluid in no more than 50 minutes. In some embodiments, the
unit dosage form dissolves in gastric fluid in no more than 40
minutes. In some embodiments, the unit dosage form dissolves in
gastric fluid in no more than 30 minutes. In some embodiments, the
unit dosage form dissolves in gastric fluid in no more than 20
minutes. In some embodiments, the unit dosage form dissolves in
gastric fluid in no more than 15 minutes. In some embodiments, the
unit dosage form dissolves in gastric fluid in no more than 10
minutes. In some embodiments, the unit dosage form dissolves in
gastric fluid in no more than 5 minutes.
[0334] In some embodiments of any one of the embodiments described
herein, the unit dosage form (e.g., any one of unit dosage form
100, unit dosage form 200, and tablet 300) is not soluble in
gastric fluid.
[0335] In some embodiments of any one of the embodiments described
herein, the unit dosage form is formulated such that absorption of
the PTH following oral administration of the unit dosage form is
characterized by a bioavailability of the PTH which is at least 10%
higher than a bioavailability of the PTH following oral
administration of a unit dosage form composition consisting of the
core of the aforementioned unit dosage form, without the external
layer described herein. In some embodiments, the bioavailability is
at least 20% higher than (120% of the level of) the bioavailability
upon oral administration of the core. In some embodiments, the
bioavailability is at least 50% higher than (150% of the level of)
the bioavailability upon oral administration of the core. In some
embodiments, the bioavailability is at least twice (200% of the
level of) the bioavailability upon oral administration of the core.
In some embodiments, the bioavailability is at least four-fold
(400% of the level of) the bioavailability upon oral administration
of the core. In some embodiments, the bioavailability is at least
ten-fold (1000% of the level of) the bioavailability upon oral
administration of the core. In some embodiments, the
bioavailability is at least twenty-fold (2000% of the level of) the
bioavailability upon oral administration of the core.
[0336] Without being bound by any particular theory, it is believed
that the protective agent significantly enhances bioavailability by
protecting SNAC and thereby increasing the amount of active SNAC
which remains available for enhancing absorption of the PTH; and/or
by protecting the PTH and thereby increasing the amount of PTH
which remains active upon absorption.
[0337] In some embodiments of any one of the embodiments described
herein relating to a composition comprising an antacid compound,
the composition consists primarily of the combination of PTH, SNAC,
and at least one antacid compound described herein, that is, at
least 50 weight percents of the composition consists of ingredients
selected from the group consisting of a PTH, SNAC and at least one
antacid compound. In some embodiments, at least 60 weight percents
of the composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, at least 70 weight percents of the
composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, at least 80 weight percents of the
composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, at least 90 weight percents of the
composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, at least 95 weight percents of the
composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, at least 98 weight percents of the
composition consists of PTH, SNAC and at least one antacid
compound. In some embodiments, the composition is formulated as a
tablet.
[0338] In some embodiments of any one of the embodiments described
herein relating to a composition comprising an antacid compound,
the composition optionally further comprises at least one protease
inhibitor, and at least 50 weight percents of the composition
consists of ingredients selected from the group consisting of PTH,
SNAC, at least one antacid compound and at least one protease
inhibitor. In some embodiments, at least 60 weight percents of the
composition consists of PTH, SNAC, at least one antacid compound
and at least one protease inhibitor. In some embodiments, at least
70 weight percents of the composition consists of PTH, SNAC, at
least one antacid compound and at least one protease inhibitor. In
some embodiments, at least 80 weight percents of the composition
consists of PTH, SNAC, at least one antacid compound and at least
one protease inhibitor. In some embodiments, at least 90 weight
percents of the composition consists of PTH, SNAC, at least one
antacid compound and at least one protease inhibitor. In some
embodiments, at least 95 weight percents of the composition
consists of PTH, SNAC, at least one antacid compound and at least
one protease inhibitor. In some embodiments, at least 98 weight
percents of the composition consists of PTH, SNAC, at least one
antacid compound and at least one protease inhibitor. In some
embodiments, the composition is formulated as a tablet.
[0339] In some embodiments of any one of the embodiments described
herein relating to a composition comprising an antacid compound,
the composition is formulated such that a bioavailability of the
PTH upon oral administration of the composition is at least 10%
higher than a bioavailability of the PTH upon oral administration
of a composition comprising the PTH and SNAC without the at least
one antacid compound (e.g., being identical in all aspects except
for the absence of the antacid compound(s)). In some embodiments,
the bioavailability is at least 20% higher than (120% of the level
of) the bioavailability upon oral administration of a composition
comprising the PTH and SNAC without the at least one antacid
compound. In some embodiments, the bioavailability is at least 50%
higher than (150% of the level of) the bioavailability upon oral
administration of a composition comprising the PTH and SNAC without
the at least one antacid compound. In some embodiments, the
bioavailability is at least twice (200% of the level of) the
bioavailability upon oral administration of a composition
comprising the PTH and SNAC without the at least one antacid
compound. In some embodiments, the bioavailability is at least
four-fold (400% of the level of) the bioavailability upon oral
administration of a composition comprising the PTH and SNAC without
the at least one antacid compound. In some embodiments, the
bioavailability is at least ten-fold (1000% of the level of) the
bioavailability upon oral administration of a composition
comprising the PTH and SNAC without the at least one antacid
compound. In some embodiments, the bioavailability is at least
twenty-fold (2000% of the level of) the bioavailability upon oral
administration of a composition comprising the PTH and SNAC without
the at least one antacid compound.
[0340] An antacid may be utilized advantageously in combination
with PTH and SNAC, without necessarily combining all of the
ingredients in a single composition.
[0341] In some embodiments of any one of the embodiments described
herein, the method or treatment according any of the respective
embodiments described herein further comprises co-administering to
the subject, an antacid composition comprising at least one antacid
compound, as defined herein (e.g., at least one antacid compound
described herein), and/or at least one gastric acid secretion
inhibitor; and the composition comprising PTH and SNAC (e.g., as
described herein according to any of the respective
embodiments).
[0342] As used herein, the phrase "gastric acid secretion
inhibitor" refers to any agent which reduces secretion of acid into
the stomach, although it does not necessarily have any effect on
acid which has already been secreted. Examples of gastric acid
secretion inhibitors which may be used in any of the embodiments
described herein relating to an antacid composition include,
without limitation, H.sub.2 receptor antagonists, such as
cimetidine, famotidine, nizatidine and ranitidine; and proton pump
inhibitors, such as omeprazole, lansoprazole, dexlansoprazole,
esomeprazole, rabeprazole and ilaprazole.
[0343] In some embodiments of any one of the embodiments described
herein relating to co-administering an antacid composition, the
antacid composition is optionally any antacid composition known in
the art (e.g., a commercially available antacid composition).
[0344] In some embodiments of any one of the embodiments described
herein relating to co-administering an antacid composition, the
co-administering comprises administering the antacid composition
prior to or concomitantly with the composition comprising PTH and
SNAC.
[0345] In some embodiments of any one of the embodiments described
herein relating to co-administering an antacid composition
concomitantly with the composition comprising PTH and SNAC, the
antacid composition comprises at least one antacid compound, as
defined herein (e.g., in accordance with any of the respective
embodiments described herein).
[0346] In some embodiments of any one of the embodiments described
herein relating to co-administering an antacid composition
comprising at least one gastric acid secretion inhibitor, the
co-administering comprises administering the antacid composition
prior to the composition comprising PTH and SNAC (e.g., in
accordance with any of the respective embodiments described
herein).
[0347] Without being bound by any particular theory, it is believed
that antacid compounds as defined herein (compounds capable of
neutralizing stomach acid) are generally effective at reducing
acidity in the stomach and/or in a region thereof immediately (as
neutralization of acid occurs as a relatively rapid chemical
reaction) but may have a limited long-term effect due to secretion
of additional acid into the stomach, and are therefore particularly
effective when administered concomitantly with or shortly (e.g., no
more than 90 minutes) prior to the composition comprising PTH and
SNAC.
[0348] It is further believed that gastric acid secretion
inhibitors are generally effective at reducing stomach acidity for
a relatively long duration (due to long-term inhibition of gastric
acid secretion) but may have a limited effect on acidity
immediately after administration due to an absence of a significant
effect on acid which is already present in the stomach, and are
therefore particularly effective when administered prior to the
composition comprising PTH and SNAC.
[0349] Herein, the term "concomitantly" refers to an events (e.g.,
administration of an antacid composition) being within a time
period of from 5 minutes before to 5 minutes after another event
(e.g., administration of a composition comprising PTH and SNAC),
and in some embodiments, within a time period of from one minute
before to one minute after the other event.
[0350] In some embodiments, concomitant co-administration is
effected by swallowing the two compositions simultaneously.
[0351] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, administering the antacid composition prior to the
composition comprising PTH and SNAC comprises administering the
antacid composition no more than 5 days prior to the composition
comprising PTH and SNAC. In some embodiments, the antacid
composition is administered no more than 4 days prior to the
composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 3 days prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 2 days prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 1 day (24 hours)
prior to the composition comprising PTH and SNAC. In some
embodiments, the antacid composition comprises a proton-pump
inhibitor.
[0352] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, the antacid composition is administered at least about
1 day (e.g., at least about 24 hours) prior to the composition
comprising PTH and SNAC, for example, from about 1 to about 5 days
(e.g., about 2 days to about 4 days, optionally about 3 days) prior
to the composition comprising PTH and SNAC. In some embodiments,
the antacid composition comprises a proton-pump inhibitor.
[0353] In some of any of the embodiments described herein in which
the antacid composition is optionally administered at least 12
hours prior to the composition comprising PTH and SNAC, the antacid
composition comprises a proton-pump inhibitor.
[0354] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, administering the antacid composition prior to the
composition comprising PTH and SNAC comprises administering the
antacid composition no more than 16 hours prior to the composition
comprising PTH and SNAC. In some embodiments, the antacid
composition is administered no more than 12 hours prior to the
composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 10 hours prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 8 hours prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 6 hours prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 4 hours prior to
the composition comprising PTH and SNAC. In some embodiments, the
antacid composition comprises an H.sub.2 receptor antagonist.
[0355] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, the antacid composition is administered at least about
2 hours prior to the composition comprising PTH and SNAC, for
example, from about 2 to about 10 hours (e.g., 2 to 8 hours, 2 to 6
hours, 2 to 4 hours) prior to the composition comprising PTH and
SNAC. In some embodiments, the antacid composition comprises an
H.sub.2 receptor antagonist or a proton pump inhibitor. In some
embodiments, the antacid composition comprises an H.sub.2 receptor
antagonist.
[0356] In some of any of the embodiments described herein in which
the antacid composition is optionally administered at least 2 hours
prior to, but less than 12 hours prior to, the composition
comprising PTH and SNAC, the antacid composition comprises an
H.sub.2 receptor antagonist.
[0357] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, administering the antacid composition prior to the
composition comprising PTH and SNAC comprises administering the
antacid composition no more than 90 minutes prior to the
composition comprising PTH and SNAC. In some embodiments, the
antacid composition is administered no more than 60 minutes prior
to the composition comprising PTH and SNAC. In some embodiments,
the antacid composition is administered no more than 30 minutes
prior to the composition comprising PTH and SNAC. In some
embodiments, the antacid composition is administered no more than
20 minutes prior to the composition comprising PTH and SNAC. In
some embodiments, the antacid composition is administered no more
than 10 minutes prior to the composition comprising PTH and SNAC.
In some embodiments, the antacid composition comprises an antacid
compound (as defined herein).
[0358] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, the composition comprising PTH and SNAC is essentially
the same as any one of the compositions described herein comprising
PTH, SNAC and antacid compound(s), with the exception that no
antacid compound is present.
[0359] In some embodiments, the composition comprising PTH and SNAC
and/or the antacid composition further comprises at least one
protease inhibitor (e.g., one or more protease inhibitors as
described herein).
[0360] In some embodiments, the composition comprising PTH and SNAC
and/or the antacid composition is formulated as a unit dosage form.
The unit dosage form may be formulated in any form suitable for
oral administration, including solid and/or liquid forms. In some
embodiments, the unit dosage form (e.g., a unit dosage form of the
composition comprising PTH and SNAC) is a solid unit dosage form.
In some embodiments, the unit dosage form (e.g., a unit dosage form
of the composition comprising PTH and SNAC) is formulated as a
tablet.
[0361] In some embodiments, the composition comprising PTH and SNAC
and the antacid composition (e.g., in solid form) are each soluble
in gastric fluid (as defined herein). In some embodiments, the
compositions each dissolve in gastric fluid in no more than 60
minutes. In some embodiments, the compositions each dissolve in
gastric fluid in no more than 50 minutes. In some embodiments, the
compositions each dissolve in gastric fluid in no more than 40
minutes. In some embodiments, the compositions each dissolve in
gastric fluid in no more than 30 minutes. In some embodiments, the
compositions each dissolve in gastric fluid in no more than 20
minutes. In some embodiments, the compositions each dissolve in
gastric fluid in no more than 15 minutes. In some embodiments, the
compositions each dissolve in gastric fluid in no more than 10
minutes. In some embodiments, the compositions each dissolve in
gastric fluid in no more than 5 minutes.
[0362] In some embodiments, neither the composition comprising the
therapeutically active agent and SNAC nor the antacid composition
(e.g., in solid form) are soluble in gastric fluid (as defined
herein).
[0363] In some embodiments of any one of the embodiments described
herein relating to co-administering at least one antacid
composition, absorption of PTH following the co-administration is
characterized by a bioavailability of the PTH which is at least 10%
higher than a bioavailability of the PTH following oral
administration of the composition comprising the PTH and SNAC
without co-administering the antacid composition. In some
embodiments, the bioavailability is at least 20% higher than (120%
of the level of) the bioavailability without co-administering the
antacid composition. In some embodiments, the bioavailability is at
least 50% higher than (150% of the level of) the bioavailability
without co-administering the antacid composition. In some
embodiments, the bioavailability is at least twice (200% of the
level of) the bioavailability without co-administering the antacid
composition. In some embodiments, the bioavailability is at least
four-fold (400% of the level of) the bioavailability without
co-administering the antacid composition. In some embodiments, the
bioavailability is at least ten-fold (1000% of the level of) the
bioavailability without co-administering the antacid composition.
In some embodiments, the bioavailability is at least twenty-fold
(2000% of the level of) the bioavailability without
co-administering the antacid composition.
[0364] Any one or more of the antacid compounds described herein
may be used in any one of the embodiments described herein which
utilize an antacid compound.
[0365] In some embodiments, the at least one antacid compound is
selected from the group consisting of calcium carbonate, calcium
gluconate, calcium citrate, sodium carbonate, sodium bicarbonate,
sodium gluconate, sodium citrate, sodium hydroxide, potassium
carbonate, potassium bicarbonate, potassium gluconate, potassium
citrate, potassium hydroxide, magnesium carbonate, magnesium
gluconate, magnesium citrate, magnesium oxide and magnesium
hydroxide.
[0366] In some embodiments, the at least one antacid compound is
selected from the group consisting of calcium carbonate, calcium
gluconate, sodium carbonate, sodium bicarbonate, sodium citrate,
sodium hydroxide, potassium carbonate, potassium bicarbonate,
potassium citrate, potassium hydroxide, magnesium carbonate,
magnesium hydroxide, magnesium oxide, aluminum carbonate, and
aluminum hydroxide.
[0367] In some embodiments, the at least one antacid compound the
at least one antacid compound is selected from the group consisting
of calcium carbonate, calcium citrate, sodium bicarbonate, sodium
hydroxide, magnesium carbonate, magnesium citrate, magnesium
hydroxide, magnesium oxide, aluminum carbonate, and aluminum
hydroxide.
[0368] In some embodiments, the at least one antacid compound is
selected from the group consisting of calcium carbonate, sodium
carbonate, sodium bicarbonate, potassium bicarbonate, magnesium
carbonate, magnesium hydroxide, and aluminum hydroxide.
[0369] In some embodiments of any one of the embodiments described
herein relating to an antacid compound, a total amount of antacid
compound(s) administered according to any of the respective
embodiments of a method or treatment described herein (e.g., in a
core of a unit dosage form described herein and/or in a unit dosage
form described herein), is such that the at least one antacid
compound comprises at least 0.00001 molar equivalent of base. In
some embodiments, the at least one antacid compound comprises at
least 0.00003 molar equivalent of base. In some embodiments, the at
least one antacid compound comprises at least 0.0001 molar
equivalent of base. In some embodiments, the at least one antacid
compound comprises at least 0.0003 molar equivalent of base. In
some embodiments, the at least one antacid compound comprises at
least 0.001 molar equivalent of base. In some embodiments, the at
least one antacid compound comprises at least 0.002 molar
equivalent of base. In some embodiments, the at least one antacid
compound comprises at least 0.003 molar equivalent of base. In some
embodiments, the at least one antacid compound comprises at least
0.005 molar equivalent of base. In some embodiments, the at least
one antacid compound comprises at least 0.01 molar equivalent of
base. In some embodiments, the at least one antacid compound
comprises no more than 0.03 molar equivalent of base.
[0370] Herein, 1 molar equivalent of base refers to an amount of a
basic compound (e.g., an antacid compound described herein) capable
of neutralizing 1 mole of HCl (e.g., in an aqueous solution). In
determining molar equivalents of base in antacid compounds
described herein, each mole of hydroxide ion and/or bicarbonate ion
is considered to be capable of neutralizing 1 mole of HCl, each
mole of carbonate ion is considered to be capable of neutralizing 2
moles of HCl, and each mole of citrate ion (if fully deprotonated)
is considered to be capable of neutralizing 3 moles of HCl.
[0371] In some embodiments of any one of the embodiments described
herein relating to an antacid compound, a total amount of antacid
compound(s) administered according to any of the respective
embodiments of a method or treatment described herein (e.g., in a
core of a unit dosage form described herein and/or in a unit dosage
form described herein), is at least 0.5 mg. In some embodiments,
the amount of antacid compound(s) is at least 1 mg. In some
embodiments, the amount of antacid compound(s) is at least 2 mg. In
some embodiments, the amount of antacid compound(s) is at least 5
mg. In some embodiments, the amount of antacid compound(s) is at
least 10 mg. In some embodiments, the amount of antacid compound(s)
is at least 25 mg. In some embodiments, the amount of antacid
compound(s) is at least 50 mg. In some embodiments, the amount of
antacid compound(s) is at least 100 mg. In some embodiments, the
amount of antacid compound(s) is at least 200 mg. In some
embodiments, the amount of antacid compound(s) is at least 300 mg.
In some embodiments, the amount of antacid compound(s) is at least
400 mg. In some embodiments, the amount of antacid compound(s) is
at least 500 mg. In some embodiments, the amount of antacid
compound(s) is at least 750 mg. In some embodiments, the amount of
antacid compound(s) is at least 1 gram.
[0372] Casing:
[0373] In some embodiments of any one of the embodiments described
herein, the composition comprising PTH and SNAC (according to any
of the respective embodiments described herein) forms a part of a
drug delivery system comprising a casing and the composition
comprising PTH and SNAC contained within the casing.
[0374] The casing according to such embodiments of the invention
comprises at least two components being in conjunction, and at
least one retainer for maintaining the conjunction of the
aforementioned components under gastric conditions, the casing
being configured such that upon removal of the retainer, the casing
is breached.
[0375] Herein, the term "casing" refers to a structure which
encloses an inner volume and separates the inner volume from a
surrounding environment. The term "casing" encompasses structures
of any shape, including deformable structures which readily change
shape (e.g., casings formed from a soft substance, for example, in
the form of a soft pouch), as well as rigid structures, provided
that the ability to separates the inner volume from a surrounding
environment is maintained.
[0376] Herein, the term "retainer" refers to a component of the
casing which is characterized by a structure and chemical
composition suitable for performing the abovementioned function of
maintaining the conjunction of the aforementioned components under
gastric conditions. The casing may optionally comprise one retainer
or a plurality of retainers (e.g., 2 retainers, 3 retainers, 4
retainers, more than 4 retainers). By maintaining conjunction of
the aforementioned components under gastric conditions, the
retainer optionally provides control over release of the PTH in the
composition by, inter alia, preventing release in the stomach,
while allowing release in the intestines.
[0377] For simplicity, a retainer is described herein throughout in
the singular (e.g., "a retainer", "the retainer"). Use of the
singular should not be interpreted as meaning that only one
retainer is present and/or that only one retainer is referred to by
any given description, unless this is explicitly indicated. Rather,
in the absence of any indication to the contrary, a description of
a retainer (in the singular) according to any one of the
embodiments described herein is to be interpreted as referring to
any one or more retainer(s) in a casing, and optionally to each
retainer in the casing (in embodiments wherein the casing has more
than one retainer).
[0378] Herein, the abovementioned at least two components being in
conjunction are also referred to herein, for the sake of brevity,
as the "casing components". This use of the phrase "casing
components" is not intended to suggest in any way that the casing
does not comprise other components. For example, the casing
comprises at least one component, e.g., the retainer described
herein, which is not referred to herein as a "casing
component".
[0379] Herein, the phrase "conjunction" refers to a state wherein
two or more objects meet in a form of physical contact, overlapping
and/or close proximity.
[0380] The components in conjunction may optionally be different
portions of a single component, wherein the different portions can
be separated from one another upon removal of a retainer. For
example, in some embodiments, the components in conjunction form
different edges of a flexible component which is folded upon
itself, such that breaching of the casing (e.g., upon removal of a
retainer) can be effected by unfolding of the flexible component,
to thereby separate the edges.
[0381] In some embodiments, a conjunction is such that casing
components in conjunction are linked to one another.
[0382] In some embodiments, the casing components in conjunction
form a capsule shell. The casing components may optionally be
formed from any substance known in the art to be suitable for
forming a capsule shell for pharmaceutical use. In some
embodiments, the casing comprises two casing components which fit
together to form a capsule shell, for example, wherein each casing
component is one half of a capsule shell. In some embodiments,
casing comprises more than two casing components (e.g., 3 or 4
casing components) which fit together to form a capsule shell.
[0383] Examples of mechanisms by which a conjunction may optionally
be maintained by one or more retainers include, without limitation,
adhering to casing components, optionally to each of the casing
components (e.g., such that casing components are linked by
adhesion to the same retainer); blocking movement of casing
components, optionally blocking movement of each of the casing
components (e.g., wherein casing components are not necessarily
linked, but are physically restrained from separating from one
another); and clamping casing components.
[0384] Herein, the term "clamping" refers to an act of holding
objects together by applying a pressure which presses an object
against another object.
[0385] Clamping may maintain casing components in conjunction, for
example, by opposing movement of a casing component in a direction
perpendicular to a surface of another casing component (e.g., by
pressing a casing component in the opposite direction, namely,
towards the surface), and/or by opposing movement (e.g., sliding)
of a casing component in a direction parallel to a surface of
another casing component (e.g., by increasing friction between the
two components).
[0386] In some of any of the embodiments described herein, a
retainer is an adhesive (e.g., a glue) which maintains at least two
casing components in conjunction (e.g., in the form of a capsule
shell) by adhering to the casing components. Optionally the
adhesive is present at an interface between the casing components.
Alternatively or additionally, the adhesive adheres to the casing
components at a location other than an interface between the casing
components, for example, at an external and/or internal surface of
the casing (e.g., a capsule shell surface).
[0387] Herein, the terms "breach" and "breached", and variations
thereof, refer to formation of an opening in the casing which
connects the inner volume of the casing to a surrounding
environment, and which is sufficiently large to allow escape of the
PTH contained within the casing.
[0388] In some embodiments, breaching of the casing upon removal of
the retainer(s) of the casing is such that a breach formed in the
casing has an area which is at least 10% of an area of the surface
of the casing prior to breaching of the casing. In some
embodiments, a breach formed in the casing has an area which is at
least 20% of an area of the surface of the casing prior to
breaching of the casing. In some embodiments, a breach formed in
the casing has an area which is at least 30% of an area of the
surface of the casing prior to breaching of the casing. In some
embodiments, a breach formed in the casing has an area which is at
least 40% of an area of the surface of the casing prior to
breaching of the casing. In some embodiments, a breach formed in
the casing has an area which is at least 50% of an area of the
surface of the casing prior to breaching of the casing.
[0389] Herein, "removal" of a retainer refers to a hypothetical
situation in which the casing is altered only in that the retainer
is absent. Although such a situation is hypothetical, rather than a
real-world physical process, it is useful for describing the
structure of the casing herein according to many embodiments of the
invention.
[0390] It is to be appreciated that a retainer may be partially
degraded or otherwise altered without being removed, in a manner
which results in breaching of the casing, optionally essentially
the same extent of breaching as would occur upon removal of the
retainer. When such cases are described herein, the partial
degradation and/or alteration of the retainer is not referred to as
"removal" of the retainer.
[0391] In some of any of the embodiments described herein,
breaching of the casing upon removal of a retainer is effected by
separation of casing components.
[0392] In some of any of the embodiments described herein, a
retainer forms an integral part of the casing, such that absence of
the retainer per se (i.e., without any additional change in the
casing, such as movement of the casing components) forms a breach
in the casing. In some embodiment, further breaching of the casing
is effected by separation of casing components.
[0393] In some of any of the embodiments described herein, absence
of a retainer per se (i.e., without any additional change in the
casing, such as movement of the casing components) does not form a
breach in the casing, but rather, removal of the retainer effects
breaching of the casing, for example, by allowing separation of
casing components.
[0394] In some of any of the embodiments described herein, absence
of a retainer per se (i.e., without any additional change in the
casing, such as movement of the casing components) does not form a
breach in the casing which is at least 30% of an area of the
surface of the casing prior to breaching of the casing (e.g., no
breach is formed, or a breach is formed which is less than 30% of
the area of the casing surface). In some embodiments, absence of a
retainer per se does not form a breach in the casing which is at
least 20% of an area of the surface of the casing prior to
breaching of the casing. In some embodiments, absence of a retainer
per se does not form a breach in the casing which is at least 10%
of an area of the surface of the casing prior to breaching of the
casing. In some embodiments, absence of a retainer per se does not
form a breach in the casing which is at least 5% of an area of the
surface of the casing prior to breaching of the casing. In some
embodiments, absence of a retainer per se does not form a breach in
the casing which is at least 2% of an area of the surface of the
casing prior to breaching of the casing.
[0395] Optionally, each of the casing components is in conjunction
with each of the other casing component(s) in the casing.
[0396] Alternatively, the casing components may be divided into a
plurality of sets (e.g., 2 sets, 3 sets, 4 sets, or more than 4
sets), wherein each of the casing components in each set is in
conjunction with each of the other casing component(s) in the same
set, but not necessarily in conjunction with casing components of
other sets. Any one casing component may belong to one such set or
to more than one such set. For example, if a casing comprises 3
casing components--components I, II and III--and component II is in
conjunction with components I and III, whereas components I and III
are not in conjunction with one another, the casing can be
considered as having two sets of casing components, one set
consisting of components I and II, and the other set consisting of
components II and III.
[0397] Optionally, a retainer (optionally each retainer in a
casing) maintains one set of casing components in conjunction
(wherein each of the casing components is in conjunction with each
of the other casing components in the set).
[0398] Alternatively, any one retainer may optionally maintain two
or more sets of casing components (as described herein) in
conjunction.
[0399] Optionally, any one set of casing components in conjunction
is maintained in conjunction by a single retainer.
[0400] Alternatively, two or more retainers may optionally act
together to maintain the same set of casing components in
conjunction.
[0401] In some embodiments wherein two or more retainers maintain
the same set of casing components in conjunction, the casing is
configured such that the casing is breached upon removal of any one
of the aforementioned retainers.
[0402] In some embodiments wherein two or more retainers maintain
the same set of casing components in conjunction, the casing is
configured such that the casing is not breached upon removal of one
retainer, but rather, breached only upon removal of two or more of
the aforementioned retainers, and optionally only upon removal of
each of the aforementioned retainers.
[0403] In some embodiments of any one of the embodiments described
herein, the drug delivery system is configured such that an
internal force induces separation of the casing components upon
removal of the retainer.
[0404] Herein, the term "internal force" refers to a force applied
by one or more components of the drug delivery system, including
the casing and/or a substance within the casing. For example, a
component under tension and/or compression may apply a force upon
neighboring components or substances, and the drug delivery system
may optionally be configured such that such forces induce
separation of the casing components.
[0405] Herein, to "induce" separation of casing components means
that the force will tend to cause separation of casing components
upon removal of the retainer. Optionally, the retainer is
configured so as to oppose the force inducing separation (until it
is removed or otherwise ceases to oppose the force).
[0406] An internal force may optionally be present in the drug
delivery system at any time (e.g., any time from the manufacturing
of the drug delivery system onwards) or alternatively, the internal
force is present only under certain conditions (e.g., exposure to
an aqueous liquid, such as in the gastrointestinal tract). An
internal force may optionally be applied by at least a part of the
casing and/or a substance contained within the casing.
[0407] In some embodiments of any one of the embodiments described
herein, the drug delivery system is not configured such that an
internal force induces separation of the casing components upon
removal of the retainer. Rather, separation of the casing
components is induced, for example, by random movement, fluid flow
in the intestines, peristalsis, and/or other external forces.
[0408] In some embodiments of any one of the embodiments described
herein, the retainer forms a portion of an external surface of the
casing, such that at least a portion of the retainer is exposed to
the environment surrounding the casing.
[0409] In some embodiments of any one of the embodiments described
herein, the retainer is adhered to an external surface of at least
two casing components, and optionally forming a portion of an
external surface of the casing, thereby maintaining conjunction of
the casing components.
[0410] In some embodiments, a presence of the retainer at the
external surface allows the retainer to be sensitive to the
environment, for example, such that in a certain environment, the
retainer ceases to maintain conjunction of casing components (e.g.,
due to dissolution of at least a portion of the retainer, as
described herein).
[0411] In some embodiments of any one of the embodiments described
herein, the retainer comprises an enteric polymer (as defined
herein).
[0412] The pH dependency of solubility of an enteric polymer allows
the enteric polymer to serve as a solid substance in the stomach,
as well as under dry conditions (e.g., prior to oral
administration), while dissolving in at least a portion of the
intestines. Thus, the structure of a retainer comprising an enteric
polymer is affected by the location of the casing in the
gastrointestinal tract.
[0413] In some embodiments of any one of the embodiments described
herein, the enteric polymer is soluble in an aqueous solution at pH
5.5. In some such embodiments, dissolution of the enteric polymer
is effected soon after the drug delivery system reaches the
intestines, for example, in the duodenum.
[0414] In some embodiments of any one of the embodiments described
herein, the enteric polymer is not soluble in an aqueous solution
at pH 5.5, and is soluble in an aqueous solution at pH 6.0. In some
such embodiments, dissolution of the enteric polymer is effected
relatively soon after the drug delivery system reaches the
intestines, for example, in the duodenum.
[0415] In some embodiments of any one of the embodiments described
herein, the enteric polymer is not soluble in an aqueous solution
at pH 5.5 or 6.0, and is soluble in an aqueous solution at pH 6.5.
In some such embodiments, dissolution of the enteric polymer is
effected in the small intestines (e.g., in the jejunum), although
optionally not in the duodenum.
[0416] In some embodiments of any one of the embodiments described
herein, the enteric polymer is not soluble in an aqueous solution
at either pH 5.5, 6.0 or 6.5, and is soluble in an aqueous solution
at pH 7.0 and/or at pH 7.5. In some such embodiments, dissolution
of the enteric polymer is effected in the ileum or colon, and
optionally not in the duodenum or jejunum.
[0417] In some embodiments of any one of the embodiments described
herein, the retainer consists essentially of an enteric polymer. In
such embodiments, the whole retainer is potentially soluble under
intestinal conditions. However, such a retainer may cease to be
functional (e.g., cease to be capable of maintaining a conjunction
of casing components) upon partial dissolution of the retainer,
e.g., well before the whole retainer has dissolved.
[0418] In some embodiments of any one of the embodiments described
herein, the retainer comprises an enteric polymer as well as at
least one substance other than enteric polymer (e.g., a substance
which is water-insoluble at any pH in the gastro-intestinal tract).
In some such embodiments, the enteric polymer and other
substance(s) in the retainer are configured such that dissolution
of the enteric polymer in the retainer results in the retainer
ceasing to be functional (e.g., ceasing to be capable of
maintaining a conjunction of casing components).
[0419] In some embodiments of any one of the embodiments described
herein, a retainer may cease to be functional (e.g., cease to be
capable of maintaining a conjunction of casing components) by
separating (e.g., due to degradation) into two or more disconnected
portions, for example, wherein a portion of a retainer attached to
one casing component ceases to be connected to a portion of the
retainer attached to another casing component.
[0420] In some embodiments of any one of the embodiments described
herein, a retainer may cease to be functional (e.g., cease to be
capable of maintaining a conjunction of casing components) by being
degraded so as to be breached (without necessarily being degraded
into two or more disconnected portions), for example, wherein a
retainer forms an integral part of the casing, such that a breach
formed in the retainer per se forms a breach in the casing.
[0421] In some embodiments of any one of the embodiments described
herein, a retainer may cease to be functional (e.g., cease to be
capable of maintaining a conjunction of casing components) by
becoming disconnected (e.g., due to degradation) from one or more
casing components, for example, wherein a retainer is adhered to
the casing component (prior to degradation).
[0422] In some embodiments of any one of the embodiments described
herein, a retainer may cease to be functional (e.g., cease to be
capable of maintaining a conjunction of casing components) by being
deformed (e.g., due to degradation), for example, losing a shape
necessary for maintaining a conjunction of casing components (e.g.,
a shape suitable for clamping casing components).
[0423] In some embodiments of any one of the embodiments described
herein, the casing comprises a tubular structure.
[0424] Herein, the phrase "tubular structure" refers to a structure
(e.g., an open cylinder or topological equivalent thereof) having
an outer surface, an inner surface which surrounds an inner volume,
and two openings on substantially opposite sides of the tubular
structure which connect the inner volume to the surroundings of the
tubular structure. Optionally, the tubular structure has a
substantially circular and/or substantially oval cross-section in a
plane perpendicular to an axis between the two openings. However,
alternative shapes are also encompassed by the phrase "tubular
structure".
[0425] Optionally, the two openings of the tubular structure are
capped so as to form the casing.
[0426] Herein, the term "capped" refers to a presence of a
structure (also referred to herein as a "cap") which covers an
opening in another structure (e.g., a tubular structure), thereby
closing the opening. A cap may optionally be a retainer and/or
casing component described herein. Optionally, a cap has a concave
surface into which surrounds the opening, for example, wherein the
end of a tubular structure fits within a concave surface of a
cap.
[0427] In some embodiments of any one of the embodiments described
herein, at least one opening of a tubular structure described
herein is capped by a retainer. In some such embodiments, removal
of a retainer breaches the casing by exposing an opening of the
tubular structure. In some embodiments, the two openings of the
tubular structure are each capped by a retainer (e.g., two separate
retainers).
[0428] In some embodiments of any one of the embodiments described
herein, the casing comprises a flexible component (e.g., as
described herein) which comprises a flexible sheet folded into a
tubular structure.
[0429] Herein, the phrase "flexible sheet" refers to a
3-dimensional structure which is sufficiently thin in one dimension
to allow the sheet to be folded into a tubular structure.
[0430] In embodiments relating to a flexible sheet folded into a
tubular structure, different sides of the sheet which become in
conjunction upon folding into a tubular structure are considered
herein to be different casing components in conjunction.
[0431] Optionally, separation of casing components is effected by
unfolding of the flexible sheet (e.g., thereby destroying the
tubular structure).
[0432] Additionally or alternatively, separation of casing
components is effected by a mechanism other than unfolding the
flexible sheet, for example, by exposing an opening of the tubular
structure (e.g., by at least partial displacement of one or two
caps capping the tubular structure).
[0433] In embodiments relating to a flexible sheet folded into a
tubular structure, each end of the tubular structure is capped by a
retainer (e.g., as described herein). Optionally, separation of
casing components is effected by unfolding of the flexible sheet
upon removal or one the retainers and/or both of the retainers
capping the tubular structure.
[0434] In some embodiments of any one of the embodiments described
herein, the drug delivery system further comprises a substance
which swells upon contact with water, the substance being contained
within the casing, and the casing being configured such that upon
contact of the casing with an aqueous liquid (e.g., fluid in the
stomach and/or intestines), the substance swells. Swelling of the
substance may optionally be utilized to generate an internal force
described herein. By swelling in contact with water, the substance
may optionally provides control over release of the composition
comprising PTH and SNAC by, inter alia, facilitating release in a
time-dependent manner, for example, wherein a degree of swelling
(and optionally an internal force) is correlated with the time of
exposure to an aqueous liquid (e.g., time from oral
administration).
[0435] In some embodiments of any one of the embodiments described
herein, the casing is water-permeable in at least a portion
thereof, such that upon contact with an aqueous liquid, water
permeates the casing and causes the substance which swells upon
contact with water to swell. In some embodiments, the casing is
water-permeable in a portion of the casing which is adjacent to the
substance which swells upon contact with water. In some
embodiments, the casing is water-permeable only in a portion of the
casing which is adjacent to the substance which swells upon contact
with water, other portions of the casing being
water-impermeable.
[0436] In some embodiments of any one of the embodiments described
herein, a water-permeable portion of a casing contains at least one
perforation, the perforation allowing permeation of water. In some
embodiments the portion comprises a plurality of perforations. The
perforations are preferably of a size which allows water to
permeate but which is sufficiently small to prevent escape of
substances (e.g., the substance which swells upon contact with
water, the PTH, the SNAC) from within the casing. Techniques for
forming small perforations in a drug delivery system are known in
the art, and include, for example, laser perforation.
[0437] In some embodiments of any one of the embodiments described
herein, the casing contains a first compartment comprising the
substance which swells upon contact with water, and a second
compartment comprising the composition comprising PTH and SNAC. In
some embodiments, breaching of the casing upon removal of the
retainer is effected by separation of casing components, and the
casing is configured such that separation of the casing components
breaches the casing in a region containing the second compartment,
that is, the breach is effected in the vicinity of the composition
comprising PTH and SNAC.
[0438] In some embodiments, the first compartment and second
compartment are separated by a barrier which limits or prevents
contact between contents of the two compartments (e.g., between the
substance which swells upon contact with water and the composition
comprising PTH and SNAC). In some embodiments, the barrier is
movable upon swelling of the substance which swells upon contact
with water. In some embodiments, upon swelling of the substance,
the barrier moves such that the first compartment expands, and the
second compartment shrinks, thereby compressing the composition
comprising PTH and SNAC.
[0439] In some embodiments, the casing is configured such that the
composition comprising PTH and SNAC in the second compartment does
not come into contact, prior to breaching of the casing, with the
substance which swells upon contact with water, the water-permeable
portion of the casing, or a retainer (which is optionally on an
external surface of the casing). Without being bound by any
particular theory, it is believed that such embodiments are
particularly suitable for avoiding potential incompatibility
between the PTH and/or SNAC and the substances which provide
specific chemical and/or physical properties utilized for
controlled release (e.g., a substance which swells upon contact
with water, a water-permeable portion of the casing, and/or a
retainer which is sensitive to location in the gastrointestinal
tract).
[0440] In some embodiments, compression of the composition
comprising PTH and SNAC results in an internal force on at least a
portion of the casing which encloses the second compartment.
Optionally, such an internal force facilitates a sudden formation
of a relatively large breach (e.g., a breach of a size described
herein), thereby allowing for rapid release of the PTH and
SNAC.
[0441] In some embodiments, compression of the composition
comprising PTH and SNAC results in movement of the composition
comprising PTH and SNAC towards a region where a breach is formed
in the casing upon removal of a retainer, for example, in towards a
region adjacent to the retainer. Optionally, such movement of the
composition comprising PTH and SNAC facilitates rapid release of
the PTH and SNAC once the breach is formed.
[0442] A variety of substances which swell upon contact with water,
and which are suitable for use in a drug delivery system, are known
in the art, and may optionally be used in embodiments of the
invention. Such substances are commonly referred to in the art as
"disintegrants". Any substance known in the art as a "disintegrant"
(including the term "superdisintegrant") suitable for use in a drug
delivery system is encompassed herein by the phrase "substance
which swells upon contact with water". Examples of such substances
include, without limitation, povidone, crospovidone, croscarmellose
(e.g., croscarmellose sodium), carboxymethylcellulose (e.g.,
calcium carboxymethylcellulose, sodium carboxymethylcellulose),
hydroxypropyl methylcellulose, starch (e.g., corn starch, potato
starch, wheat starch, tapioca starch, rice starch), modified starch
(e.g., sodium starch glycolate) and silicon dioxide (e.g.,
colloidal silicon dioxide).
[0443] In some embodiments of any one of the embodiments described
herein, the substance which swells upon contact with water is
water-insoluble at 37.degree. C. Examples of water insoluble
substances which swell upon contact with water include, without
limitation, cross-linked hydrophilic polymers such as crospovidone
and croscarmellose, as well as starch and derivatives thereof.
Water-insolubility may optionally be beneficial in reducing escape
of the substance from the casing (e.g., via a perforation described
herein), which could reduce the degree of swelling of the substance
within the casing.
[0444] As discussed herein, except for at least a portion of a
retainer, the various portions of the casing, for example, casing
components and barriers according to respective embodiments
described herein, as well as portions of a retainer (e.g., a
retainer which comprises an enteric polymer described herein but
does not consist of an enteric polymer), may optionally be prepared
from any of a wide variety of substances, including relatively
inert substances.
[0445] In some embodiments of any one of the embodiments described
herein, such portions of the casing comprise a polymeric substance,
and optionally consist of a polymeric substance. In some
embodiments, the polymeric substance is a hydrophobic polymeric
substance. Examples of hydrophobic polymeric substances include,
without limitation, ethyl cellulose and other hydrophobic cellulose
ethers, polyvinyl acetate, polyethylene, poly(methyl methacrylate),
poly(ethyl methacrylate), poly(methyl acrylate), poly(ethyl
acrylate) and copolymers thereof (e.g., poly(ethylene-co-vinyl
acetate), poly(ethyl acrylate-co-methyl methacrylate)).
[0446] In some embodiments of any one of the embodiments described
herein, the hydrophobic polymeric substance is characterized in
that at a pH of 7.0, the polymeric substance is both
water-insoluble and does not absorb more than 20 weight percents of
water (weight of absorbed water relative to weight of substance).
In some embodiments, the hydrophobic polymeric substance is
characterized in that it does not absorb more than 10 weight
percents of water at pH 7.0. In some embodiments, the hydrophobic
polymeric substance is characterized in that it does not absorb
more than 5 weight percents of water at pH 7.0. In some
embodiments, the hydrophobic polymeric substance is characterized
in that it does not absorb more than 2 weight percents of water at
pH 7.0. In some embodiments, the hydrophobic polymeric substance is
characterized in that it does not absorb more than 1 weight
percents of water at pH 7.0.
[0447] Without being bound by any particular theory, it is believed
that hydrophobic polymeric substances tend to be relatively inert
due, for example, to a deficiency in capability to form
non-covalent bonds such as hydrogen bonds and ionic bonds (this
deficiency typically being associated with hydrophobicity).
[0448] In some embodiments of any one of the embodiments described
herein, the casing is formed from at least one substance (e.g.,
polymeric substance) which is water-insoluble at a pH of 7.0, with
the optional exception of any enteric polymer described herein
which is water-soluble at pH 7.0. It is to be appreciated that the
aforementioned substance which is water-insoluble at a pH of 7.0
may optionally be enteric polymers which are soluble only at a pH
above 7.0. In such embodiments, such portions of the casing
comprise a polymeric substance, and optionally consist of a
polymeric substance.
[0449] Optionally, the substance comprises a mixture of
water-insoluble and water-soluble polymers, such that the mixture
dissolves only slowly in aqueous solution (e.g., when the
percentage of water-soluble polymer in the mixture is small). Such
substances are considered herein to be water-insoluble if less than
1 gram dissolves in 1 liter of aqueous solution within 24 hours at
37.degree. C. (with gentle stirring).
[0450] Drug delivery systems described herein may optionally be
formulated to provide desired pharmacokinetics, for example, by
selecting an appropriate configuration of the casing, shape and/or
thickness of a retainer, pH dependence of an enteric polymer in a
retainer, an amount and/or type of substance which swells upon
contact with water, and/or a water-permeability of a
water-permeable portion of the casing described herein.
[0451] In some embodiments of any one of the embodiments described
herein, the drug delivery system is formulated such that absorption
of the PTH occurs rapidly once the casing is breached. It is to be
appreciated that rapid release of the PTH and SNAC allows for
control over the location of release in the gastrointestinal tract,
because gradual release from a formulation will generally result in
PTH and SNAC being released over a long portion of the intestinal
tract, due to movement of the formulation through the
gastrointestinal tract.
[0452] Without being bound by any particular theory, it is believed
that drug delivery systems according to some embodiments described
herein are particularly suitable for obtaining rapid release of PTH
and SNAC and absorption of PTH (following a controlled delay prior
to breaching of the casing), because the breach may optionally be
large enough to allow for rapid release (and subsequent absorption)
of the entire amount of PTH and SNAC in the drug delivery system,
whereas alternative methodologies (e.g., for releasing agents in
the intestines rather than in the stomach), such as use of
gradually disintegrating and/or dissolving coatings and/or
compositions, may result in a relatively gradual release of PTH and
SNAC through a small opening in a gradually
disintegrating/dissolving coating and/or gradual
disintegration/dissolution of a composition comprising PTH and
SNAC.
[0453] In some embodiments of any one of the embodiments described
herein, the rapidity of release from the drug delivery system is
such that absorption of the PTH following oral administration of
the drug delivery system is characterized by a ratio of AUC to Cmax
which is 3 hours or lower, according to any of the respective
embodiments described herein.
[0454] In some embodiments of any one of the embodiments described
herein, the drug delivery system enhances the efficacy of delivery
(e.g., as reflected by bioavailability) of the PTH, as compared to
administration of the contents of the composition comprising PTH
and SNAC without the casing described herein. Enhancement of the
efficacy may be, for example, due to protection of the PTH, SNAC
and/or protease inhibitor from gastric conditions.
[0455] In some embodiments of any one of the embodiments described
herein, the drug delivery system is formulated such that absorption
of the PTH following oral administration of the drug delivery
system is characterized by a bioavailability of the PTH which is at
least 20% higher than (120% of the level of) a bioavailability of
the PTH following oral administration of the composition comprising
PTH and SNAC (according to any of the respective embodiments
described herein) without the casing of the drug delivery system,
that is, the same composition as that within the casing of the drug
delivery system. In some embodiments, the bioavailability is at
least 50% higher than (150% of the level of) the bioavailability
upon oral administration without the casing. In some embodiments,
the bioavailability is at least twice (200% of the level of) the
bioavailability upon oral administration without the casing. In
some embodiments, the bioavailability is at least four-fold (400%
of the level of) the bioavailability upon oral administration
without the casing. In some embodiments, the bioavailability is at
least ten-fold (1000% of the level of) the bioavailability upon
oral administration without the casing. In some embodiments, the
bioavailability is at least twenty-fold (2000% of the level of) the
bioavailability upon oral administration without the casing.
[0456] Coated Particles:
[0457] In some embodiments of any one of the embodiments described
herein, the composition comprising PTH and SNAC (according to any
of the respective embodiments described herein) forms a part of a
drug delivery system comprising a plurality of solid particles,
which comprise a core comprising the composition comprising PTH and
SNAC; and an enteric coating (e.g., an enteric coating according to
any of the respective embodiments described herein). In some
embodiments, the coating covers the entire surface of the core.
[0458] In some embodiments, the enteric coating comprises an
enteric polymer (as defined herein), for example, according to any
of the respective embodiments described herein relating to an
enteric polymer.
[0459] The location in the gastrointestinal tract at which
dissolution of the enteric coating commences can be controlled
according to the pH dependence of the enteric coating and/or
enteric polymer, as described herein according to any of the
respective embodiments.
[0460] When dissolution of an enteric polymer and/or enteric
coating commences at any given pH and/or location in the
gastrointestinal tract (e.g., as described herein), a significant
amount of time may pass until the core is exposed and/or the
coating is disintegrated and/or completely dissolved, as the
dissolution of enteric polymer and/or enteric coating is not
necessarily a very rapid process. The time until the core is
exposed and/or the coating is disintegrated and/or completely
dissolved may optionally be controlled, for example, in accordance
with the thickness of the enteric coating, wherein thicker enteric
coatings are associated with longer dissolution times.
[0461] In some embodiments of any one of the embodiments described
herein, complete dissolution of the enteric coating is effected at
least 10 minutes after being subjected to an aqueous solution at a
pH in which the enteric coating is soluble (e.g., pH 5.5, 6.0, 6.5
or 7.0, as described herein). In some embodiments, complete
dissolution of the enteric coating is effected at least 30 minutes
after being subjected to such an aqueous solution. In some
embodiments, complete dissolution of the enteric coating is
effected at least 60 minutes after being subjected to such an
aqueous solution. In some embodiments, complete dissolution of the
enteric coating is effected at least 1200 minutes after being
subjected to such an aqueous solution.
[0462] In some embodiments of any one of the embodiments described
herein, the drug delivery system comprises a plurality of particles
which are held together, for example, enclosed within a capsule
and/or attached by a binding material. In some such embodiments,
the capsule (e.g., gelatin capsule) and/or binding material is
selected so as to degrade under conditions in the stomach (e.g.,
due to the low pH and/or susceptibility to enzymatic proteolysis in
the stomach), thereby releasing the particles, and allowing the
particles to travel individually through the gastrointestinal
tract.
[0463] The particles may optionally be in any of various forms,
including tablets, granules and microspheres. Coated tablets are
generally a suitable form of solid coated particle in embodiments
of a drug delivery system comprising a small number (e.g., 1-4) of
solid particles, whereas coated microspheres are generally a
suitable form of solid coated particle in embodiments of a drug
delivery system comprising a large number (e.g., at least 10, 100,
1,000) of solid particles.
[0464] Tablets, microspheres and additional particle types can be
prepared using known methodologies, for example, spheronization for
preparing microspheres, and pressing to prepare tablets. In
addition, numerous coating techniques will be known to the skilled
person, including, without limitation, spray coating, dip
coating.
[0465] In some embodiments of any of the embodiments described
herein, the drug delivery system comprises a plurality of
populations of a solid particle (a solid particle as described
herein according to any of the respective embodiments), wherein
each of the populations is characterized by a different release
profile of the PTH (and SNAC) within the cores thereof.
[0466] Without being bound by any particular theory, it is believed
that oral administration, in a single drug delivery system, of
populations with different release profiles can mimic the effect
administration of different doses of PTH (with SNAC).
[0467] Herein, the term "population" encompasses an individual
solid particle as well as a plurality of solid particles, for
example, at least 2 solid particles, at least 5 solid particles, at
least 10 solid particles, at least 20 solid particles, at least 50
solid particles, at least 100 solid particles, at least 200 solid
particles, at least 500 solid particles, at least 1,000 solid
particles, or at least 10,000 solid particles. Thus, for example, a
plurality of populations of a solid particle may optionally consist
of two different solid particles, each solid particle representing
a population. Alternatively, some or all of the populations may
comprise a plurality of particles.
[0468] In some embodiments of any of the embodiments described
herein relating to a population comprising more than one solid
particle, the solid particles of an individual population are
substantially similar, for example, being prepared by the same
technique.
[0469] In some embodiments of any of the embodiments described
herein, the drug delivery system comprises 2 populations of a solid
particle.
[0470] In some embodiments of any of the embodiments described
herein, the drug delivery system comprises at least 3 populations
of a solid particle. In some embodiments, the drug delivery system
comprises exactly 3 populations of a solid particle.
[0471] In some embodiments of any of the embodiments described
herein, the drug delivery system comprises at least 4 populations
of a solid particle. In some embodiments, the drug delivery system
comprises exactly 4 populations of a solid particle.
[0472] In some embodiments of any of the embodiments described
herein, at least one population of a solid particle comprises from
1 to 3 solid particles. In some embodiments, at least one
population of a solid particle comprises 1 or 2 solid particles. In
some embodiments, at least one population of a solid particle
comprises 1 solid particle.
[0473] In some embodiments of any of the embodiments described
herein, each population of a solid particle consists of from 1 to 3
solid particles. In some embodiments, each population of a solid
particle consists of 1 or 2 solid particles. In some embodiments,
each population of a solid particle consists of 1 solid
particle.
[0474] In some embodiments of any of the embodiments described
herein, at least one population of a solid particle comprises at
least 4 solid particles. In some embodiments, at least one
population of a solid particle comprises at least 10 solid
particles. In some embodiments, at least one population of a solid
particle comprises at least 30 solid particles. In some
embodiments, at least one population of a solid particle comprises
at least 100 solid particles.
[0475] In some embodiments of any of the embodiments described
herein, each population of a solid particle comprises at least 4
solid particles. In some embodiments, each population of a solid
particle comprises at least 10 solid particles. In some
embodiments, each population of a solid particle comprises at least
30 solid particles. In some embodiments, each population of a solid
particle comprises at least 100 solid particles.
[0476] In some embodiments of any of the embodiments described
herein, each of the populations of a solid particle is
characterized by a different structure of solid particle.
[0477] It is important to appreciate that the solid particles in a
population do not necessarily have identical structures, but
rather, variables defining the structure (e.g., coating thickness,
particle diameter and/or concentration of a component in the
coating and/or core) may optionally fit a statistical distribution
(including, without limitation, a normal distribution and/or a
Poisson distribution), wherein a "structure" of solid particle
which characterizes a population refers to a structure having the
highest probability, that is, the mode (e.g., as defined by the
mode of the variable(s)). Thus, for example, in the case of a first
population in which the coating thickness of the particles is
represented by a distribution with a mode of 0.1 mm and a standard
deviation of 0.05 mm, and a second population in which the coating
thickness is represented by a distribution with a mode of 0.5 mm
and a standard deviation of 0.2 mm, the populations are
characterized by different structures (a structure having a coating
thickness of 0.1 mm and a structure having a coating thickness of
0.5 mm), even though the distributions of the populations may
optionally overlap.
[0478] In some embodiments of any of the embodiments described
herein, the structure of the solid particles in the drug delivery
system (including the particles in all populations) is multimodal
(i.e., having two or more peaks), and each mode is associated with
a different population of solid particle.
[0479] In some embodiments of any of the embodiments described
herein, the populations are characterized by a different coating.
In some such embodiments, the populations are characterized by a
different enteric coating. The coatings (e.g., enteric coatings)
may optionally be different in any aspect, for example, composition
of the coating (e.g., concentration and/or species of enteric
polymer) and/or dimensions (e.g., thickness) of the coating.
[0480] In some embodiments, the populations are characterized by a
different thickness of enteric coating. In some embodiments, the
enteric coating in each population characterized by a different
coating thickness is composed of the same ingredients (e.g., such
that the enteric coatings of different populations differ only in
their thickness).
[0481] Without being bound by any particular theory, it is believed
that the properties of the coating in general, and the coating
thickness in particular, are especially suitable for controlling
the release profile of PTH (and SNAC) from particles, for example,
by using relatively thin coatings in one population to obtain
relatively rapid release from said population, and also by using
relatively thick coatings in another population to obtain
relatively slow release from said population.
[0482] In some embodiments of any of the embodiments described
herein, the drug delivery system is formulated such that a rate of
release of the PTH (i.e., an amount of PTH released per unit time)
as a function of time at pH 6 is characterized by at least two
peaks (i.e., rate of release as a function of time is a multimodal
function). In such embodiments, each peak may optionally be
considered as effectively representing a separate dose of PTH (with
SNAC), the drug delivery system releasing at least two doses at
different times.
[0483] In some embodiments of any of the embodiments described
herein, the drug delivery system is formulated such that a rate of
release of PTH (i.e., an amount of PTH released per unit time) as a
function of time at pH 7 is characterized by at least two peaks
(i.e., rate of release as a function of time is a multimodal
function).
[0484] The rate of release at pH 6 and/or pH 7 is optionally
determined by placing a drug delivery system in an aqueous solution
(optionally 1 liter) at 37.degree. C. with citrate (optionally 0.1
M) as buffer, and with gentle stirring (optionally according to the
USP paddle method II (USP 23), at 50 rotations per minute).
[0485] In some embodiments, a multimodal rate of release under any
given conditions (e.g., at pH 6 and/or pH 7) is obtained using
populations characterized by different enteric coating thicknesses
(e.g., according to any of the respective embodiments described
herein), wherein the enteric coatings (e.g., according to any of
the respective embodiments described herein) are soluble under such
conditions (e.g., at pH 6 and/or pH 7). In such embodiments, the
particles with the thicker coatings optionally take more time to
dissolve than particles with thinner coatings, such that a
population characterized by a relatively thin coating is associated
with a relatively early peak in the rate of release, whereas a
population characterized by a relatively thick coating is
associated with a later peak in the rate of release.
[0486] Without being bound by any particular theory, it is believed
that oral administration of a drug delivery system in which the
release rate from the solid particles is multimodal is particularly
suitable for mimicking the effect of release from solid particles
in a drug delivery system mimics the effect of multiple oral
administrations of PTH (and SNAC) at different times, while
avoiding the inconveniences associated with multiple
administration. For example, a bimodal release can mimic the effect
of two oral administrations, wherein the first peak corresponds to
a first oral administration, and a second (later) peak mimics the
effect of a second (later) oral administration. Similarly, a
trimodal (3 peak) release can mimic the effect of 3 oral
administrations, and so forth.
[0487] It is further believed that the lower the level of release
in a trough separating two peaks, relative to the level of release
at the peaks, the more effectively oral administration of the drug
delivery system mimics the effect of multiple oral administrations
of PTH (with SNAC) at different times.
[0488] It is further believed that such a drug delivery system
enhances the bone-growth promoting effect of PTH suitable for
treating osteoporosis by providing separate, transient doses of
PTH; rather than enhancing bone resorption (which is generally
undesirable when treating osteoporosis), as is expected to result
from continuous, gradual release of PTH.
[0489] In some embodiments of any of the embodiments described
herein relating to a rate of release as a function of time
characterized by at least two peaks, at least two of the peaks are
separated by a trough which is less than 75% of a level of the two
peaks separated by the trough. In some embodiments, at least two of
the peaks are separated by a trough which is less than 50% of a
level of the two peaks separated by the trough. In some
embodiments, at least two of the peaks are separated by a trough
which is less than 25% of a level of the two peaks separated by the
trough. In some embodiments, at least two of the peaks are
separated by a trough which is less than 10% of a level of the two
peaks separated by the trough.
[0490] In some embodiments of any of the embodiments described
herein relating to a rate of release as a function of time
characterized by at least two peaks, at least two of the peaks are
separated by at least 30 minutes. In some embodiments, the two
peaks are separated by at least 60 minutes. In some embodiments,
the two peaks are separated by at least 2 hours. In some
embodiments, the two peaks are separated by at least 4 hours. In
some embodiments, the two peaks are separated by at least 6
hours.
[0491] In some embodiments of any of the embodiments described
herein relating to populations characterized by different enteric
coatings, at least a portion of the different enteric coatings are
characterized by different pH-dependent solubility profiles. In
some embodiments, each of the populations in the drug delivery
system is characterized by a different pH-dependent solubility
profile than the other populations.
[0492] Herein, a "pH-dependent solubility profile" refers to the pH
values at which a substance (e.g., an enteric coating) is
water-soluble, as defined herein.
[0493] In some embodiments of any of the embodiments described
herein relating to enteric coatings characterized by different
pH-dependent solubility profiles, the enteric coatings are
characterized by differences in the lowest pH value (in a range of
from 5 to 8) at which each enteric coating is water-soluble (as
defined herein). In some embodiments, the differences in the lowest
pH value (in a range of from 5 to 8) at which each enteric coating
is water-soluble is at least 0.2 pH unit (e.g., wherein an enteric
coating is water-soluble at pH 6.0, and another enteric coating is
water-insoluble at a pH of up to at least 6.2). In some
embodiments, the differences in the lowest pH value at which each
enteric coating is water-soluble is at least 0.5 pH unit (e.g.,
wherein an enteric coating is water-soluble at pH 6.0, and another
enteric coating is water-insoluble at a pH of up to at least 6.5).
In some embodiments, the differences in the lowest pH value at
which each enteric coating is water-soluble is at least 1 pH unit
(e.g., wherein an enteric coating is water-soluble at pH 5.5, and
another enteric coating is water-insoluble at a pH of up to at
least 6.5). In some embodiments, the differences in the lowest pH
value at which each enteric coating is water-soluble is at least
1.5 pH unit (e.g., wherein an enteric coating is water-soluble at
pH 5.5, and another enteric coating is water-insoluble at a pH of
up to at least 7.0).
[0494] Without being bound by any particular theory, it is believed
that populations which are characterized by dissolution profile
differences in the lowest pH value (in a range of from 5 to 8) at
which each enteric coating is water-soluble will release core
contents (e.g., PTH and SNAC) at different times following oral
administration, as an orally administered object is typically
subjected, over the course of hours, to a gradually increasing the
pH in the gastrointestinal tract, beginning with a highly acidic pH
in the stomach, followed by a slightly acidic pH in the proximal
portion of the intestines, and later by an approximately neutral pH
in the distal portion of the intestines. It is further believed
that for each population, release of the core contents will be
effected primarily at the time and location the gradually
increasing pH reaches the lowest pH value (in a range of from 5 to
8) at which each enteric coating is water-soluble.
[0495] In some embodiments of any of the embodiments described
herein relating to populations characterized by different
pH-dependent solubility profiles, the drug delivery system further
comprises populations characterized by enteric coatings with
different enteric coating thicknesses (e.g., according to any of
the respective embodiments described herein).
[0496] In some embodiments of any of the embodiments described
herein relating to populations characterized by different
pH-dependent solubility profiles, the populations are characterized
by enteric coatings with substantially the same enteric coating
thicknesses (e.g., according to any of the respective embodiments
described herein).
[0497] In some embodiments of any one of the embodiments described
herein, the drug delivery system is formulated such that absorption
of the PTH as a function of time (e.g., the pharmacokinetic
profile) following oral administration is characterized by at least
two peaks in a level of PTH in the blood.
[0498] In such embodiments, the time until each of the first two
peaks may be defined as the first Tmax and second Tmax
respectively.
[0499] As used herein the term "Tmax" refers to the duration of
time between administration and when maximal concentration of an
agent (e.g., PTH) in the blood (e.g., plasma levels) occurs.
[0500] In some embodiments of any one of the embodiments described
herein, the first Tmax is no more than 30 minutes and the second
Tmax is at least 60 minutes. In some embodiments, the second Tmax
is at least 2 hours. In some embodiments, the second Tmax is at
least 4 hours. In some embodiments, the second Tmax is at least 6
hours. In some embodiments, the second Tmax is at least 8
hours.
[0501] In some embodiments of any one of the embodiments described
herein, the first Tmax is no more than 60 minutes and the second
Tmax is at least 2 hours (120 minutes). In some embodiments, the
second Tmax is at least 4 hours. In some embodiments, the second
Tmax is at least 6 hours. In some embodiments, the second Tmax is
at least 8 hours.
[0502] In some embodiments of any one of the embodiments described
herein, the first Tmax is no more than 2 hours, and the second Tmax
is at least 4 hours. In some embodiments, the second Tmax is at
least 6 hours. In some embodiments, the second Tmax is at least 8
hours.
[0503] In some embodiments of any of the embodiments described
herein relating to a pharmacokinetic profile characterized by at
least two peaks, at least two of the peaks are separated by a
trough which is less than 75% of a level of the two peaks separated
by the trough. In some embodiments, at least two of the peaks are
separated by a trough which is less than 50% of a level of the two
peaks separated by the trough. In some embodiments, at least two of
the peaks are separated by a trough which is less than 25% of a
level of the two peaks separated by the trough. In some
embodiments, at least two of the peaks are separated by a trough
which is less than 10% of a level of the two peaks separated by the
trough.
[0504] In some embodiments of any of the embodiments described
herein relating to a pharmacokinetic profile characterized by at
least two peaks, at least two of the peaks are separated by at
least 30 minutes. In some embodiments, the two peaks are separated
by at least 60 minutes. In some embodiments, the two peaks are
separated by at least 2 hours. In some embodiments, the two peaks
are separated by at least 4 hours. In some embodiments, the two
peaks are separated by at least 6 hours.
[0505] Miscellaneous Definitions:
[0506] The term "osteoporosis" as used herein refers to a medical
condition characterized by a reduction in bone mass and density,
and encompasses, for example, primary type 1 osteoporosis
(generally associated with menopause), primary type 2 osteoporosis
(generally associated with advanced age, e.g., an age of at least
75 years) and secondary osteoporosis (generally associated with a
chronic disease or disorder, and/or with prolonged use of
medications such as glucocorticoids). A presence of osteoporosis
may be determined according to any criteria used in the medical
arts. Optionally, osteoporosis is defined according to World Health
Organization criteria, e.g., a condition characterized by a bone
mineral density of 2.5 standard deviations or more below the mean
peak bone mass (average in young, healthy adults) as measured by
dual-energy x-ray absorptiometry.
[0507] The term "polypeptide" as used herein encompasses native
polypeptides (e.g., degradation products, synthetically synthesized
polypeptides and/or recombinant polypeptides), including, without
limitation, native proteins, fragments of native proteins and
homologs of native proteins and/or fragments thereof; as well as
peptidomimetics (typically, synthetically synthesized polypeptides)
and peptoids and semipeptoids which are polypeptide analogs, which
may have, for example, modifications rendering the polypeptides
(e.g., PTH and/or protease inhibitor) more stable while in a body
or more capable of penetrating into cells. Such modifications
include, but are not limited to N terminus modification, C terminus
modification, peptide bond modification, backbone modifications,
and residue modification. Methods for preparing peptidomimetic
compounds are well known in the art and are specified, for example,
in Quantitative Drug Design, C. A. Ramsden Gd., Chapter 17.2, F.
Choplin Pergamon Press (1992), which is incorporated by reference
as if fully set forth herein. Further details in this respect are
provided herein below.
[0508] Peptide bonds (--CO--NH--) within the polypeptide (e.g., PTH
and/or protease inhibitor) may be substituted, for example, by
N-methylated amide bonds (--N(CH.sub.3)--CO--), ester bonds
(--C(.dbd.O)--O--), ketomethylene bonds (--CO--CH.sub.2--),
sulfinylmethylene bonds (--S(.dbd.O)--CH.sub.2--), .alpha.-aza
bonds (--NH--N(R)--CO--), wherein R is any alkyl (e.g., methyl),
amine bonds (--CH.sub.2--NH--), sulfide bonds (--CH.sub.2--S--),
ethylene bonds (--CH.sub.2--CH.sub.2--), hydroxyethylene bonds
(--CH(OH)--CH.sub.2--), thioamide bonds (--CS--NH--), olefinic
double bonds (--CH.dbd.CH--), fluorinated olefinic double bonds
(--CF.dbd.CH--), retro amide bonds (--NH--CO--), peptide
derivatives (--N(R)--CH.sub.2--CO--), wherein R is the "normal"
side chain, naturally present on the carbon atom.
[0509] These modifications can occur at any of the bonds along the
polypeptide chain and even at several (2-3) bonds at the same
time.
[0510] Natural aromatic amino acids, Trp, Tyr and Phe, may be
substituted by non-natural aromatic amino acids such as
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic),
naphthylalanine, ring-methylated derivatives of Phe, halogenated
derivatives of Phe or O-methyl-Tyr.
[0511] The polypeptides of some embodiments of the invention (e.g.,
PTH and/or a protease inhibitor described herein) may also include
one or more modified amino acids or one or more non-amino acid
monomers (e.g. fatty acids, complex carbohydrates etc).
[0512] The term "amino acid" or "amino acids" is understood to
include the 20 naturally occurring amino acids; those amino acids
often modified post-translationally in vivo, including, for
example, hydroxyproline, phosphoserine and phosphothreonine; and
other unusual amino acids including, but not limited to,
2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine,
nor-leucine and ornithine. Furthermore, the term "amino acid"
includes both D- and L-amino acids.
[0513] Tables 1 and 2 below list naturally occurring amino acids
(Table 1), and non-conventional or modified amino acids (e.g.,
synthetic, Table 2) which can be used with some embodiments of the
invention.
TABLE-US-00001 TABLE 1 Amino Acid Three-Letter Abbreviation
One-letter Symbol Alanine Ala A Arginine Arg R Asparagine Asn N
Aspartic acid Asp D Cysteine Cys C Glutamine Gln Q Glutamic Acid
Glu E Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu L
Lysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P
Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine
Val V Any amino acid as above Xaa X
TABLE-US-00002 TABLE 2 Non-conventional amino acid Code
Non-conventional amino acid Code ornithine Orn hydroxyproline Hyp
.alpha.-aminobutyric acid Abu aminonorbornyl-carboxylate Norb
D-alanine Dala aminocyclopropane-carboxylate Cpro D-arginine Darg
N-(3-guanidinopropyl)glycine Narg D-asparagine Dasn
N-(carbamylmethyl)glycine Nasn D-aspartic acid Dasp
N-(carboxymethyl)glycine Nasp D-cysteine Dcys N-(thiomethyl)glycine
Ncys D-glutamine Dgln N-(2-carbamylethyl)glycine Ngln D-glutamic
acid Dglu N-(2-carboxyethyl)glycine Nglu D-histidine Dhis
N-(imidazolylethyl)glycine Nhis D-isoleucine Dile
N-(1-methylpropyl)glycine Nile D-leucine Dleu
N-(2-methylpropyl)glycine Nleu D-lysine Dlys
N-(4-aminobutyl)glycine Nlys D-methionine Dmet
N-(2-methylthioethyl)glycine Nmet D-ornithine Dorn
N-(3-aminopropyl)glycine Norn D-phenylalanine Dphe N-benzylglycine
Nphe D-proline Dpro N-(hydroxymethyl)glycine Nser D-serine Dser
N-(1-hydroxyethyl)glycine Nthr D-threonine Dthr N-(3-indolylethyl)
glycine Nhtrp D-tryptophan Dtrp N-(p-hydroxyphenyl)glycine Ntyr
D-tyrosine Dtyr N-(1-methylethyl)glycine Nval D-valine Dval
N-methylglycine Nmgly D-N-methylalanine Dnmala L-N-methylalanine
Nmala D-N-methylarginine Dnmarg L-N-methylarginine Nmarg
D-N-methylasparagine Dnmasn L-N-methylasparagine Nmasn
D-N-methylasparatate Dnmasp L-N-methylaspartic acid Nmasp
D-N-methylcysteine Dnmcys L-N-methylcysteine Nmcys
D-N-methylglutamine Dnmgln L-N-methylglutamine Nmgln
D-N-methylglutamate Dnmglu L-N-methylglutamic acid Nmglu
D-N-methylhistidine Dnmhis L-N-methylhistidine Nmhis
D-N-methylisoleucine Dnmile L-N-methylisolleucine Nmile
D-N-methylleucine Dnmleu L-N-methylleucine Nmleu D-N-methyllysine
Dnmlys L-N-methyllysine Nmlys D-N-methylmethionine Dnmmet
L-N-methylmethionine Nmmet D-N-methylornithine Dnmorn
L-N-methylornithine Nmorn D-N-methylphenylalanine Dnmphe
L-N-methylphenylalanine Nmphe D-N-methylproline Dnmpro
L-N-methylproline Nmpro D-N-methylserine Dnmser L-N-methylserine
Nmser D-N-methylthreonine Dnmthr L-N-methylthreonine Nmthr
D-N-methyltryptophan Dnmtrp L-N-methyltryptophan Nmtrp
D-N-methyltyrosine Dnmtyr L-N-methyltyrosine Nmtyr D-N-methylvaline
Dnmval L-N-methylvaline Nmval L-norleucine Nle L-N-methylnorleucine
Nmnle L-norvaline Nva L-N-methylnorvaline Nmnva L-ethylglycine Etg
L-N-methyl-ethylglycine Nmetg L-t-butylglycine Tbug
L-N-methyl-t-butylglycine Nmtbug L-homophenylalanine Hphe
L-N-methyl-homophenylalanine Nmhphe .alpha.-naphthylalanine Anap
N-methyl-.alpha.-naphthylalanine Nmanap penicillamine Pen
N-methylpenicillamine Nmpen .gamma.-aminobutyric acid Gabu
N-methyl-.gamma.-aminobutyrate Nmgabu cyclohexylalanine Chexa
N-methyl-cyclohexylalanine Nmchexa cyclopentylalanine Cpen
N-methyl-cyclopentylalanine Nmcpen
.alpha.-amino-.alpha.-methylbutyrate Aabu
N-methyl-.alpha.-amino-.alpha.-methylbutyrate Nmaabu
.alpha.-aminoisobutyric acid Aib N-methyl-.alpha.-aminoisobutyrate
Nmaib D-.alpha.-methylarginine Dmarg L-.alpha.-methylarginine Marg
D-.alpha.-methylasparagine Dmasn L-.alpha.-methylasparagine Masn
D-.alpha.-methylaspartate Dmasp L-.alpha.-methylaspartate Masp
D-.alpha.-methylcysteine Dmcys L-.alpha.-methylcysteine Mcys
D-.alpha.-methylglutamine Dmgln L-.alpha.-methylglutamine Mgln
D-.alpha.-methylglutamic acid Dmglu L-.alpha.-methylglutamate Mglu
D-.alpha.-methylhistidine Dmhis L-.alpha.-methylhistidine Mhis
D-.alpha.-methylisoleucine Dmile L-.alpha.-methylisoleucine Mile
D-.alpha.-methylleucine Dmleu L-.alpha.-methylleucine Mleu
D-.alpha.-methyllysine Dmlys L-.alpha.-methyllysine Mlys
D-.alpha.-methylmethionine Dmmet L-.alpha.-methylmethionine Mmet
D-.alpha.-methylornithine Dmorn L-.alpha.-methylornithine Morn
D-.alpha.-methylphenylalanine Dmphe L-.alpha.-methylphenylalanine
Mphe D-.alpha.-methylproline Dmpro L-.alpha.-methylproline Mpro
D-.alpha.-methylserine Dmser L-.alpha.-methylserine Mser
D-.alpha.-methylthreonine Dmthr L-.alpha.-methylthreonine Mthr
D-.alpha.-methyltryptophan Dmtrp L-.alpha.-methyltryptophan Mtrp
D-.alpha.-methyltyrosine Dmtyr L-.alpha.-methyltyrosine Mtyr
D-.alpha.-methylvaline Dmval L-.alpha.-methylvaline Mval
N-cyclobutylglycine Ncbut L-.alpha.-methylnorvaline Mnva
N-cycloheptylglycine Nchep L-.alpha.-methylethylglycine Metg
N-cyclohexylglycine Nchex L-.alpha.-methyl-t-butylglycine Mtbug
N-cyclodecylglycine Ncdec L-.alpha.-methyl-homophenylalanine Mhphe
N-cyclododecylglycine Ncdod .alpha.-methyl-.alpha.-naphthylalanine
Manap N-cyclooctylglycine Ncoct .alpha.-methylpenicillamine Mpen
N-cyclopropylglycine Ncpro .alpha.-methyl-.gamma.-aminobutyrate
Mgabu N-cycloundecylglycine Ncund .alpha.-methyl-cyclohexylalanine
Mchexa N-(2-aminoethyl)glycine Naeg
.alpha.-methyl-cyclopentylalanine Mcpen
N-(2,2-diphenylethyl)glycine Nbhm
N-(N-(2,2-diphenylethyl)carbamylmethyl-glycine Nnbhm
N-(3,3-diphenylpropyl)glycine Nbhe
N-(N-(3,3-diphenylpropyl)carbamylmethyl-glycine Nnbhe
1-carboxy-1-(2,2-diphenyl Nmbc 1,2,3,4-tetrahydroisoquinoline-3-
Tic ethylamino)cyclopropane carboxylic acid phosphoserine pSer
phosphothreonine pThr phosphotyrosine pTyr O-methyl-tyrosine
2-aminoadipic acid hydroxylysine
[0514] The polypeptides of some embodiments of the invention (e.g.,
PTH and/or a protease inhibitor described herein) are preferably
utilized in a linear form, although it will be appreciated that in
cases where cyclicization does not severely interfere with
polypeptide characteristics, cyclic forms of the polypeptide can
also be utilized.
[0515] In some embodiments of any one of the embodiments described
herein, the polypeptide (e.g., PTH and/or protease inhibitor) is
water-soluble.
[0516] Herein throughout, the term "soluble" refers to a compound
having a solubility of at least 1 gram per liter in an indicated
solvent at 37.degree. C.
[0517] For example, the term "water-soluble" refers to a compound
having a solubility of at least 1 gram per liter in an aqueous
solution at pH 7, unless another pH is explicitly indicated.
[0518] Water-soluble polypeptides preferably include one or more
(non-natural or natural) polar amino acids, including but not
limited to serine and threonine which are capable of increasing
polypeptide water-solubility due to their hydroxyl-containing side
chain. Optionally, a homolog of a polypeptide is selected so as to
be more water-soluble than the parent polypeptide, for example, by
replacing one or more amino acids in the polypeptide with polar
amino acids.
[0519] The polypeptides of some embodiments of the invention (e.g.,
PTH and/or a protease inhibitor described herein) may be
synthesized by any techniques that are known to those skilled in
the art of peptide synthesis. For solid phase peptide synthesis, a
summary of the many techniques may be found in J. M. Stewart and J.
D. Young, Solid Phase Peptide Synthesis, W. H. Freeman Co. (San
Francisco), 1963 and J. Meienhofer, Hormonal Proteins and Peptides,
vol. 2, p. 46, Academic Press (New York), 1973. For classical
solution synthesis see G. Schroder and K. Lupke, The Peptides, vol.
1, Academic Press (New York), 1965.
[0520] In general, these methods comprise the sequential addition
of one or more amino acids or suitably protected amino acids to a
growing polypeptide chain. Normally, either the amino or carboxyl
group of the first amino acid is protected by a suitable protecting
group. The protected or derivatized amino acid can then either be
attached to an inert solid support or utilized in solution by
adding the next amino acid in the sequence having the complimentary
(amino or carboxyl) group suitably protected, under conditions
suitable for forming the amide linkage. The protecting group is
then removed from this newly added amino acid residue and the next
amino acid (suitably protected) is then added, and so forth. After
all the desired amino acids have been linked in the proper
sequence, any remaining protecting groups (and any solid support)
are removed sequentially or concurrently, to afford the final
polypeptide compound. By simple modification of this general
procedure, it is possible to add more than one amino acid at a time
to a growing chain, for example, by coupling (under conditions
which do not racemize chiral centers) a protected tripeptide with a
properly protected dipeptide to form, after deprotection, a
pentapeptide and so forth. Further description of peptide synthesis
is disclosed in U.S. Pat. No. 6,472,505.
[0521] A preferred method of preparing the polypeptide compounds of
some embodiments of the invention (e.g., PTH and/or a protease
inhibitor described herein) involves solid phase peptide
synthesis.
[0522] Large scale polypeptide synthesis is described by Andersson
et al. [Biopolymers 2000; 55:227-250].
[0523] Herein, a "homolog" of a given polypeptide (e.g., PTH(1-84)
or a fragment thereof) refers to a polypeptide that exhibits at
least 80% homology, preferably at least 90% homology, and more
preferably at least 95% homology, and more preferably at least 98%
homology to the given polypeptide. In some embodiments, a homolog
of a given polypeptide further shares a therapeutic activity with
the given polypeptide. The percentage of homology refers to the
percentage of amino acid residues in a first polypeptide sequence
which match a corresponding residue of a second polypeptide
sequence to which the first polypeptide is being compared.
Generally, the polypeptides are aligned to give maximum homology. A
variety of strategies are known in the art for performing
comparisons of amino acid or nucleotide sequences in order to
assess degrees of identity, including, for example, manual
alignment, computer assisted sequence alignment and combinations
thereof. A number of algorithms (which are generally computer
implemented) for performing sequence alignment are widely
available, or can be produced by one of skill in the art.
Representative algorithms include, e.g., the local homology
algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2: 482);
the homology alignment algorithm of Needleman and Wunsch (J. Mol.
Biol., 1970, 48: 443); the search for similarity method of Pearson
and Lipman (Proc. Natl. Acad. Sci. (USA), 1988, 85: 2444); and/or
by computerized implementations of these algorithms (e.g., GAP,
BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software
Package Release 7.0, Genetics Computer Group, 575 Science Dr.,
Madison, Wis.). Readily available computer programs incorporating
such algorithms include, for example, BLASTN, BLASTP, Gapped BLAST,
PILEUP, CLUSTALW etc. When utilizing BLAST and Gapped BLAST
programs, default parameters of the respective programs may be
used. Alternatively, the practitioner may use non-default
parameters depending on his or her experimental and/or other
requirements (see for example, the Web site having URL
www(dot)ncbi(dot)nlm(dot)nihgov).
[0524] As used herein the term "about" refers to .+-.10%.
[0525] The terms "comprises", "comprising", "includes",
"including", "having" and their conjugates mean "including but not
limited to".
[0526] The term "consisting of" means "including and limited
to".
[0527] The term "consisting essentially of" means that the
composition, method or structure may include additional
ingredients, steps and/or parts, but only if the additional
ingredients, steps and/or parts do not materially alter the basic
and novel characteristics of the claimed composition, method or
structure.
[0528] The word "exemplary" is used herein to mean "serving as an
example, instance or illustration". Any embodiment described as
"exemplary" is not necessarily to be construed as preferred or
advantageous over other embodiments and/or to exclude the
incorporation of features from other embodiments.
[0529] The word "optionally" is used herein to mean "is provided in
some embodiments and not provided in other embodiments". Any
particular embodiment of the invention may include a plurality of
"optional" features unless such features conflict.
[0530] As used herein, the singular form "a", "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a protease inhibitor" and/or
"antacid compound" may include a plurality of compounds, including
mixtures thereof.
[0531] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0532] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
[0533] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0534] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0535] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable subcombination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
[0536] Various embodiments and aspects of the present invention as
delineated hereinabove and as claimed in the claims section below
find experimental support in the following examples.
EXAMPLES
[0537] Reference is now made to the following examples, which
together with the above descriptions illustrate some embodiments of
the invention in a non-limiting fashion.
Materials
[0538] 8-Aminocaprylic acid was obtained from Alfa-Aesar.
[0539] Magnesium stearate was obtained from Sigma-Aldrich.
[0540] O-acetylsalicyloyl chloride was obtained from
Sigma-Aldrich.
[0541] Soybean trypsin inhibitor (SBTI) was obtained from
Sigma-Aldrich.
[0542] Teriparatide was purchased from Bachem.
[0543] Sodium bicarbonate was obtained from Merck.
[0544] SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) was
prepared by reacting O-acetylsalicyloyl chloride with
8-aminocaprylic acid.
Example 1
Pharmacokinetic Profile of Orally Administered Parathyroid Hormone
(PTH)
[0545] Pharmacokinetic Study Design:
[0546] An open label comparative pharmacokinetic study was
performed in healthy volunteers over the course of 3 months. Each
volunteer received--in each of two visits--the same oral tablet
containing 0.75 mg of teriparatide, a recombinant form of
parathyroid hormone (1-34).
[0547] The formulation was composed of teriparatide (0.75 mg), SNAC
(sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), soybean trypsin
inhibitor (SBTI) and a small amount of magnesium stearate.
[0548] Tablets were administered in the morning after an 8-hour
overnight fast and immediately followed by 150 ml of water. At each
visit a standard meal was provided 3 hours after drug
administration. Patients did not eat or drink alcoholic or
caffeinated beverages. There was a two weeks period between the
visits.
[0549] To determine parathyroid hormone(1-34) (PTH(1-34))
concentrations, blood samples (4 ml each) were drawn via an
indwelling catheter from the forearm vein at predetermined time
points during each visit. The cannula was flushed with 1.5 ml
normal saline after each sampling. In addition, to avoid sample
dilution, 1 ml of blood was drawn and discarded before the next
sample. The blood samples were taken at following times: baseline
(predose), 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45
minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, 2 hours,
3 hours, 4 hours and 5 hours post-administration. Each blood sample
was collected into a single tube containing EDTA
(ethylenediaminetetraacetic acid) and placed on ice. Within 15
minutes of blood collection, samples were centrifuged for 10
minutes at 4.degree. C. (2500 rotations per minute) and the plasma
was separated and divided into two or three aliquots. Each aliquot
was transferred into appropriately labeled polypropylene tubes and
stored at approximately -20.degree. C. pending analysis. PTH(1-34)
levels were measured using an IDS-iSYS automated assay for the
measurement of intact PTH(1-34) in human plasma or serum. The
results of the assay do not include levels of PTH(1-84) such as
endogenous PTH.
[0550] Results:
[0551] As shown in Table 3 below and in FIGS. 1A-1C, the
pharmacokinetic profile of the administered parathyroid hormone
(1-34) was characterized by a sharp increase in plasma levels,
followed by a rapid decrease, such that a peak concentration (Cmax)
of parathyroid hormone(1-34) occurred within 20 minutes of
administration. As further shown therein, the Cmax was relatively
constant between different administrations in a given subject. As
further shown in FIGS. 1A-1C, parathyroid hormone(1-34) levels
returned to baseline levels within 60 minutes of tablet
administration.
TABLE-US-00003 TABLE 3 Pharmacokinetic data for three subjects
following two oral administrations of teriparatide Tmax Tmax Cmax
Cmax after 1st after 2nd after 1st after 2nd administration
administration administration administration Subject (minutes)
(minutes) (picogram/ml) (picogram/ml) A 15 20 195 283 B 10 20 124
116 C 10 20 35 36
[0552] As further shown in FIGS. 1A-1C, particularly in FIGS. 1B
and 1C, even slight variations in Tmax (e.g., from 10 to 20
minutes) result in different pharmacokinetic curves having little
overlap, because the peaks in PTH plasma levels are so narrow.
[0553] This result indicates the importance of data from individual
measurements, as opposed to averaged data from different
measurements. Averaging values from different measurements, even
different measurements in a single subject, would result in a
broader and lower curve which does not accurately represent the
rapidity of increase and decrease in plasma levels.
Example 2
Phase I Clinical Trial of Orally Administered Parathyroid Hormone
(PTH)
[0554] A Phase I clinical study of exemplary oral formulations
comprising teriparatide (parathyroid hormone (1-34)) was conducted
at the Hadassah Clinical Research Center. 42 healthy volunteers
were included throughout the study.
[0555] The formulation was composed of teriparatide (200, 400, 680,
1400 or 1800 .mu.g), SNAC (sodium 8-N-(2-hydroxybenzoyl)
aminocaprylate), soybean trypsin inhibitor and magnesium
stearate.
[0556] Tablets were administered in the morning after an 8-hour
overnight fast and immediately followed by 150 ml of water. At each
visit a standard meal was provided 3 hours after drug
administration. Patients did not eat or drink alcoholic or
caffeinated beverages.
[0557] To determine parathyroid hormone concentrations, blood
samples (4 ml each) were drawn via an indwelling catheter from the
forearm vein at predetermined time points. The cannula was flushed
with 1.5 ml normal saline after each sampling. In addition, to
avoid sample dilution, 1 ml of blood was drawn and discarded before
the next sample. The blood samples were taken at following times:
baseline (predose), 15 minutes, 30 minutes, 45 minutes, 60 minutes,
75 minutes, 90 minutes, 105 minutes, 2 hours, 3 hours, 4 hours and
5 hours post-administration. Each blood sample was collected into a
single tube containing EDTA (ethylenediaminetetraacetic acid) and
placed on ice. Within 15 minutes of blood collection, samples were
centrifuged for 10 minutes at 4.degree. C. (2500 rotations per
minute) and the plasma was separated and divided into two or three
aliquots. Each aliquot was transferred into appropriately labeled
polypropylene tubes and stored at approximately -20.degree. C.
pending analysis. PTH(1-34) levels were measured using an IDS-iSYS
automated assay for the measurement of intact PTH(1-34) in human
plasma or serum.
[0558] Oral administration of teriparatide was performed as
described hereinabove at doses of 200, 400, 680, 1400 or 1800
.mu.g. The Cmax of PTH(1-34) for each orally administered dose was
compared with the Cmax of PTH(1-34) for subcutaneous injection of
20 .mu.g teriparatide.
[0559] As shown in FIG. 2, the Cmax of PTH(1-34) following oral
administration was proportional to the dose, with oral
administration of roughly 750 .mu.g teriparatide providing a Cmax
equivalent to that of subcutaneous administration of 20 .mu.g
teriparatide.
[0560] As shown in FIG. 3, oral administration of 1800 .mu.g
teriparatide and subcutaneous administration of 20 .mu.g
teriparatide were characterized by similar Cmax values, the primary
difference in pharmacokinetic profile being that PTH levels
declined considerably more rapidly following oral administration
than after subcutaneous administration. It is to be appreciated
that a pharmacokinetic profile for an individual administration is
characterized by a narrower and higher curve than the curve shown
in FIG. 3, because averaging data from different measurements
results in a broader and lower curve, due to slight variations in
Tmax (as discussed in Example 1).
[0561] In addition, plasma levels of cAMP, a known marker of PTH
activity, were determined in order to confirm biological activity
of administered PTH. cAMP plasma levels were measured following
oral administration of 680 .mu.g teriparatide or subcutaneous
injection of 20 .mu.g teriparatide, as described hereinabove.
[0562] As shown in FIG. 4, oral administration of 680 .mu.g
teriparatide and subcutaneous administration of 20 .mu.g
teriparatide increased plasma cAMP levels to a similar degree. This
result confirms that the orally administered PTH exhibits
biological activity.
[0563] These results indicate that oral administration of PTH
results in biologically active increases in PTH levels, and for a
briefer period of time than obtained by subcutaneous
administration.
[0564] The brief period of increased PTH levels in the blood may be
advantageous for enhancing bone growth, as chronic exposure to PTH
has the opposite effect (enhancement of bone resorption) than
intermittent exposure to PTH.
Example 3
Casing Containing Parathyroid Hormone and Swellable Substance
[0565] A drug delivery system comprising a casing encapsulating
active ingredients, parathyroid hormone and SNAC (sodium
8-N-(2-hydroxybenzoyl)aminocaprylate) (per se, or formulated as a
pharmaceutical composition according to any of the respective
embodiments described herein) according to some embodiments of the
invention is optionally assembled as depicted in FIG. 12.
[0566] A first casing component (A) is filled with substance which
swells upon contact with water (B), followed by a barrier (C), and
active ingredients (parathyroid hormone and SNAC) (D), optionally
in granular form. A second casing component (E) is then placed in
contact with first casing component (A), thereby encapsulating (B),
(C) and (D). A layer of enteric polymer (not shown) as described
herein in any of the respective embodiments, is then formed over at
least a portion of an external surface of casing components (A) and
(E). Adhesion of the layer to at least a portion of each of
components (A) and (E) prevents separation of components (A) and
(B). Assembly may be performed such that active ingredients (D) do
not come into contact with any substance of the drug delivery
system other than casing component(s) (A) and/or (E) and barrier
(C).
[0567] FIGS. 13A-13C shows a mechanism of release of active
ingredients (parathyroid hormone and SNAC) from a drug delivery
system (optionally assembled as described hereinabove and in FIG.
12) according to some embodiments of the invention.
[0568] FIG. 13A depicts a drug delivery system according to some
embodiments of the invention, prior to administration. The drug
delivery system comprises a first casing component 1320 which is
water-permeable in at least a portion thereof (optionally a
perforated portion), as well as second casing component 1310 which
is in contact with first casing component 1320. Second casing
component 1310 is preferably water-impermeable. The region where
components 1310 and 1320 are in contact is coated by a layer 1330
of enteric polymer (as described herein in any of the respective
embodiments), which is adhered to an external surface of both
components 1310 and 1320, thereby preventing separation of
components 1310 and 1320 from one another. Encapsulated by casing
components 1310 and 1320 are substance 1340 which swells upon
contact with water, barrier 1350, and active ingredients
(parathyroid hormone and SNAC) 1360, optionally in granular
form.
[0569] FIG. 13B depicts a drug delivery system shown in FIG. 13A,
following contact with stomach contents subsequent to oral
administration. The drug delivery system comprises the same
components as described hereinabove, but differs in that substance
1340 is expanded due to permeation of aqueous liquid in the stomach
through casing component 1320 (optionally via one or more
perforations in component 1320). As a result of expansion of
substance 1340, barrier 1350 is displaced towards active
ingredients 1360, which are optionally displaced towards casing
component 1310 and/or compressed (e.g., reduction of volume of
voids in a vicinity of active ingredients 1360) by displacement of
barrier 1350. Expansion of substance 1340 optionally results in a
force being applied to casing component 1310, the force being
transmitted by displacement of barrier 1350 and by active
ingredients 1360 (e.g., by resistance of active ingredients 1360 to
compression). Layer 1330 of enteric polymer remains substantially
intact, as the enteric polymer does not dissolve in the acidic
environment of the stomach, thereby continuing to prevent
separation of components 1310 and 1320 from one another, even in
the abovementioned optional presence of a force applied to casing
component 1310.
[0570] FIG. 13C depicts a drug delivery system shown in FIGS. 13A
and 13B, following contact with intestinal contents subsequent to
oral administration. The layer of enteric polymer is ruptured as a
result of dissolution of enteric polymer in the mildly acidic or
non-acidic intestinal environment (e.g., pH of at least 5.5), and
optionally further facilitated by the abovementioned force applied
to casing component 1310. Upon rupture, the layer no longer
prevents separation of the casing components from one another. The
casing components separate, and the active ingredients, parathyroid
hormone and SNAC, are released rapidly from the casing.
[0571] Prior to separation of the casing components and release of
the parathyroid hormone and SNAC, the parathyroid hormone and SNAC
optionally do not contact any substance in the drug delivery system
other than any substance of the drug delivery system other than
casing component(s) 1310 and/or 1320 and barrier 1350.
[0572] Casing components 1310, 1320, (A) and/or (E) are optionally
composed of a polymeric substance which is water-insoluble at a pH
of 7.0, optionally a hydrophobic polymeric substance, such as ethyl
cellulose. Additionally or alternatively, casing components 1310,
1320, (A) and/or (E) are composed of a polymer which is
water-insoluble at a pH of 7.0, optionally a hydrophobic polymer,
mixed with a small amount of hydrophilic polymer, the mixture
dissolving only slowly in aqueous solution.
[0573] Substance 1340 and/or substance (B) are optionally a
substance recognized in the art as a disintegrant suitable for
pharmaceutical use.
[0574] Barrier 1350 and/or barrier (C) are optionally composed of a
polymeric substance which is water-insoluble at a pH of 7.0,
optionally a hydrophobic polymeric substance, such as ethyl
cellulose. Additionally or alternatively, barrier 1350 and/or
barrier (C) are composed of a polymer which is water-insoluble at a
pH of 7.0, optionally a hydrophobic polymer, mixed with a small
amount of hydrophilic polymer, the mixture dissolving only slowly
in aqueous solution.
[0575] The abovementioned enteric polymer (e.g., of layer 1330) is
optionally poly(methacrylic acid-co-ethyl acrylate) (optionally
with about a 1:1 ratio of methacrylic acid to ethyl acrylate), for
example, Eudragit.RTM. L100-55.
[0576] The abovementioned polymeric substance or polymer which is
water-insoluble at a pH of 7.0 is optionally composed of an enteric
polymer which dissolves at a pH of above 7.0 (e.g., in a
colon).
[0577] The active ingredients optionally comprise SNAC in an amount
according to any of the respective embodiments described herein,
and a therapeutically effective amount of parathyroid hormone,
optionally parathyroid hormone (1-34) (e.g., teriparatide),
optionally in an amount according to any of the respective
embodiments described herein.
Example 4
Casing Containing Parathyroid Hormone Formed from Sheet Folded into
Tubular Structure
[0578] FIG. 14 shows the structure of a casing according to some
embodiments of the invention.
[0579] A polymeric sheet (A) is folded into a tubular structure.
Caps (B) comprising an enteric polymer (as described herein in any
of the respective embodiments), optionally consisting essentially
of an enteric polymer, are attached at both ends of the tubular
structure, thereby forming a closed casing and preventing unfolding
of sheet (A) of the tubular structure. Attachment of the caps is
optionally effected by an adhesive. Alternatively or additionally,
attachment is effected by friction associated with pressure applied
to an inner surface of a cap by sheet (A), optionally pressure
associated with resistance of the sheet to folding.
[0580] The active ingredients parathyroid hormone and SNAC (sodium
8-N-(2-hydroxybenzoyl)aminocaprylate) (not shown) are placed in the
casing, optionally prior to prior to attachment of both caps, and
optionally subsequent to attachment of one cap and prior to
attachment of the second cap.
[0581] Upon partial and/or complete dissolution of enteric polymer
in one or both caps (B) in an intestinal environment, sheet (A)
unfolds, and the parathyroid hormone and SNAC are thereby released
rapidly from the casing.
[0582] Sheet (A) is optionally composed of a polymeric substance
which is water-insoluble at a pH of 7.0, optionally a hydrophobic
polymeric substance, such as ethyl cellulose. Additionally or
alternatively, sheet (A) is composed of a polymer which is
water-insoluble at a pH of 7.0, optionally a hydrophobic polymer,
mixed with a small amount of hydrophilic polymer, the mixture
dissolving only slowly in aqueous solution.
[0583] The abovementioned enteric polymer is optionally
poly(methacrylic acid-co-ethyl acrylate) (optionally with about a
1:1 ratio of methacrylic acid to ethyl acrylate), for example,
Eudragit.RTM. L100-55.
[0584] The abovementioned polymeric substance or polymer which is
water-insoluble at a pH of 7.0 is optionally composed of an enteric
polymer which dissolves at a pH of above 7.0 (e.g., in a
colon).
[0585] The active ingredients optionally comprise SNAC in an amount
according to any of the respective embodiments described herein,
and a therapeutically effective amount of parathyroid hormone,
optionally parathyroid hormone (1-34) (e.g., teriparatide),
optionally in an amount according to any of the respective
embodiments described herein.
Example 5
Effect of Antacid on Release Profile of Composition Comprising
Parathyroid Hormone and SNAG
[0586] Two tablet formulations were prepared, having the same
amounts of SNAC, trypsin inhibitor and teriparatide (parathyroid
hormone (1-34)), wherein one formulation further contained 100 mg
sodium bicarbonate and the other formulation did not contain sodium
bicarbonate. The tablets were in a form of a homogeneous
mixture.
[0587] Each tablet formulation was subjected to a dissolution test
in 100 ml of simulated gastric buffer (without pepsin), pH 2.0, at
37.degree. C., according to USP 23 Apparatus 2 (paddle) with 50
rotations per minute. The amount of released SNAC in each sample
was determined chromatographically, using an HPLC apparatus with
Cosmosil.TM. 5 C18-MS-II (4.6 ID.times.250 mm) column. Mobile phase
consisted of 50% acetonitrile and 50% phosphoric acid solution
(0.1%). Flow rate was 1 ml/minute and injection volume was 25
.mu.l. Amount of released SNAC was calculated as a percentage of
the amount of SNAC in the formulation.
[0588] As shown in FIG. 15, sodium bicarbonate considerably
enhanced the dissolution of SNAC in tablets, and preserved the
soluble fraction of SNAC.
[0589] These results indicate that formulation with an antacid such
as sodium bicarbonate can considerably enhance the effect of the
absorption enhancer SNAC when treating osteoporosis by oral
administration PTH.
Example 6
Effect of Antacid on Pharmacokinetic Profile of Orally Administered
Parathyroid Hormone (PTH)
[0590] An open label comparative pharmacokinetic study was
performed on ten healthy volunteers. On different visits, each
volunteer received the same oral tablet containing 0.75 mg of
teriparatide, a recombinant form of parathyroid hormone (1-34)
(PTH(1-34)). In the first visit, the tablet was administered with
150 ml water, whereas in the second visit the tablet was
administered with 150 ml of 3 mg/ml sodium bicarbonate aqueous
solution.
[0591] The formulation was composed of teriparatide (0.75 mg), SNAC
(sodium 8-N-(2-hydroxybenzoyl) aminocaprylate), soybean trypsin
inhibitor (SBTI) and a small amount of magnesium stearate.
[0592] Tablets were administered in the morning after an 8-hour
overnight fast. At each visit a standard meal was provided 3 hours
after drug administration. Patients did not eat nor drink alcoholic
or caffeinated beverages. There was a two week period between the
two visits.
[0593] To determine PTH(1-34) concentrations, blood samples were
drawn and PTH(1-34) levels were measured using an IDS-iSYS
automated assay, using procedures described in Example 1
hereinabove. Relative absorption was determined based on the AUC
(area under curve) parameter.
[0594] As shown in FIG. 16, co-administration with sodium
bicarbonate solution increased absorption of PTH(1-34) from an
orally administered formulation by about 35%, in comparison with
co-administration of the formulation with water.
[0595] These results indicate that co-administration with an
antacid enhances the ability of SNAC to promote absorption of
orally administered PTH for treatment of osteoporosis.
[0596] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
[0597] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention. To the extent that section headings are used,
they should not be construed as necessarily limiting.
* * * * *