U.S. patent application number 16/044125 was filed with the patent office on 2018-11-15 for vasopressin formulations for use in treatment of hypotension.
The applicant listed for this patent is Par Pharmaceutical, Inc.. Invention is credited to Vinayagam Kannan, Matthew Kenney.
Application Number | 20180325991 16/044125 |
Document ID | / |
Family ID | 59999884 |
Filed Date | 2018-11-15 |
United States Patent
Application |
20180325991 |
Kind Code |
A1 |
Kenney; Matthew ; et
al. |
November 15, 2018 |
VASOPRESSIN FORMULATIONS FOR USE IN TREATMENT OF HYPOTENSION
Abstract
Provided herein are peptide formulations comprising polymers as
stabilizing agents. The peptide formulations can be more stable for
prolonged periods of time at temperatures higher than room
temperature when formulated with the polymers. The polymers used in
the present invention can decrease the degradation of the
constituent peptides of the peptide formulations.
Inventors: |
Kenney; Matthew; (New Haven,
MI) ; Kannan; Vinayagam; (Rochester, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Par Pharmaceutical, Inc. |
Chestnut Ridge |
NY |
US |
|
|
Family ID: |
59999884 |
Appl. No.: |
16/044125 |
Filed: |
July 24, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15688341 |
Aug 28, 2017 |
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16044125 |
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15612649 |
Jun 2, 2017 |
9925233 |
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15688341 |
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15426693 |
Feb 7, 2017 |
9744209 |
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15612649 |
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15289640 |
Oct 10, 2016 |
9687526 |
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15426693 |
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14717877 |
May 20, 2015 |
9744239 |
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15289640 |
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14610499 |
Jan 30, 2015 |
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14717877 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 9/08 20130101; A61K 38/095 20190101; A61K 47/02 20130101; A61K
31/045 20130101; A61K 47/12 20130101; G01N 2030/027 20130101; A61K
45/06 20130101; A61K 47/10 20130101; A61K 47/26 20130101; G01N
30/74 20130101 |
International
Class: |
A61K 38/11 20060101
A61K038/11; A61K 47/10 20170101 A61K047/10; G01N 30/74 20060101
G01N030/74; A61K 47/26 20060101 A61K047/26; A61K 47/12 20060101
A61K047/12; A61K 9/00 20060101 A61K009/00; A61K 47/02 20060101
A61K047/02; A61K 45/06 20060101 A61K045/06; A61K 31/045 20060101
A61K031/045; A61K 9/08 20060101 A61K009/08 |
Claims
1-15. (canceled)
16. A method for increasing blood pressure in a subject in need
thereof, the method comprising a) providing a pharmaceutical
composition comprising: 20 units/mL vasopressin, or a
pharmaceutically acceptable salt thereof; a peptide of SEQ. ID.
NO.: 3 at an amount of no more than about 0.2% by mass of
vasopressin; a pharmaceutically acceptable excipient which is
acetic acid, acetate, or a combination thereof; optionally
chlorobutanol; and water, wherein the pharmaceutical composition is
at a pH of about 3.5 to about 4.1. b) diluting the pharmaceutical
composition with a diluent to provide a concentration from 0.1
units/mL to 1 unit/mL vasopressin, or a pharmaceutically acceptable
salt thereof, wherein the diluent is about 0.9% sodium chloride or
about 5% dextrose; c) intravenously administering the diluted
pharmaceutical composition to the subject.
17. The method of claim 16, wherein the peptide of SEQ. ID. NO.: 3
in the pharmaceutical composition is less than about 0.1% by mass
of vasopressin.
18. The method of claim 16, wherein the peptide of SEQ. ID. NO.: 3
in the pharmaceutical composition is about 0.1% by mass of
vasopressin.
19. The method of claim 16, wherein the peptide of SEQ. ID. NO.: 3
in the pharmaceutical composition is about 0.2% by mass of
vasopressin.
20. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.1% by mass of vasopressin.
21. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.2% by mass of vasopressin.
22. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.5% by mass of vasopressin.
23. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.6% by mass of vasopressin.
24. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.7% by mass of vasopressin.
25. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 2 at an amount of
about 0.8% by mass of vasopressin.
26. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.1% by mass of vasopressin.
27. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.5% by mass of vasopressin.
28. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.6% by mass of vasopressin.
29. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.7% by mass of vasopressin.
30. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.8% by mass of vasopressin.
31. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 4 at an amount of
about 0.9% by mass of vasopressin.
32. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 7 at an amount of
about 0.2% to about 0.3% by mass of vasopressin.
33. The method of claim 16, wherein the pharmaceutical composition
further comprises a peptide of SEQ. ID. NO.: 10 at an amount of
about 0.3% to about 0.4% by mass of vasopressin.
34. The method of claim 16, wherein the purity of vasopressin in
the pharmaceutical composition is at least 97% by HPLC.
35. The method of claim 16, wherein the purity of vasopressin in
the pharmaceutical composition is at least 98% by HPLC.
36. The method of claim 16, wherein the pharmaceutical composition
is at a pH of about 3.5.
37. The method of claim 16, wherein the pharmaceutical composition
is at a pH of about 3.6.
38. The method of claim 16, wherein the pharmaceutically acceptable
excipient in the pharmaceutical composition is acetic acid.
39. The method of claim 16, wherein the pharmaceutically acceptable
excipient in the pharmaceutical composition is acetate.
40. The method of claim 16, wherein the pharmaceutically acceptable
excipient in the pharmaceutical composition is a combination of
acetic acid and acetate.
41. The method of claim 16, wherein the subject has a hypotension
associated with vasodilatory shock.
42. The method of claim 41, wherein the vasodilatory shock is
post-cardiotomy shock or septic shock.
43. The method of claim 16, wherein the intravenous administration
provides to the subject from about 0.01 units/minute to about 0.1
units/minute vasopressin, or a pharmaceutically acceptable salt
thereof.
44. The method of claim 43, wherein the intravenous administration
further comprises titrating up by 0.005 units/minute vasopressin,
or a pharmaceutically acceptable salt thereof, at 10- to 15-minute
intervals before achieving a target blood pressure response.
45. The method of claim 43, wherein the intravenous administration
further comprises attaining a target blood pressure in the subject
and continuing the administration for a period of about 8 hours.
Description
SEQUENCE LISTING
[0001] The instant application contains a Sequence Listing which
has been submitted electronically in ASCII format and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Jan. 28, 2015, is named 47956-701.202_SL.txt and is 5,055 bytes
in size.
BACKGROUND
[0002] Vasopressin is a potent endogenous hormone, responsible for
maintaining plasma osmolality and volume in most mammals.
Vasopressin can be used clinically in the treatment of sepsis and
cardiac conditions, and in the elevation of patient's suffering
from low blood pressure. Current formulations of vasopressin
require refrigeration for maintenance or reconstitution of
lyophilized powders due to vasopressin's poor long-term
stability.
SUMMARY OF THE INVENTION
[0003] In some embodiments, the invention provides a pharmaceutical
composition comprising, in a unit dosage form: a) from about 0.01
mg/mL to about 0.07 mg/mL of vasopressin, or a
pharmaceutically-acceptable salt thereof; and b) a polymeric
pharmaceutically-acceptable excipient in an amount that is from
about 1% to about 10% by mass of the unit dosage form or the
pharmaceutically-acceptable salt thereof, wherein the unit dosage
form exhibits from about 5% to about 10% less degradation of the
vasopressin or the pharmaceutically-acceptable salt thereof after
storage for about 1 week at about 60.degree. C. than does a
corresponding unit dosage form, wherein the corresponding unit
dosage form consists essentially of: A) vasopressin, or a
pharmaceutically-acceptable salt thereof; and B) a buffer having
acidic pH.
BRIEF DESCRIPTION OF THE FIGURES
[0004] FIG. 1 is a chromatogram of a diluent used in vasopressin
assay.
[0005] FIG. 2 is a chromatogram of a sensitivity solution used in a
vasopressin assay.
[0006] FIG. 3 is a chromatogram of an impurity marker solution used
in a vasopressin assay.
[0007] FIG. 4 is a zoomed-in depiction of the chromatogram in FIG.
3.
[0008] FIG. 5 is a chromatogram of a vasopressin standard
solution.
[0009] FIG. 6 is a chromatogram of a sample vasopressin
preparation.
[0010] FIG. 7 is a UV spectrum of a vasopressin sample.
[0011] FIG. 8 is a UV spectrum of a vasopressin standard.
[0012] FIG. 9 plots vasopressin stability across a range of pH as
determined experimentally.
[0013] FIG. 10 illustrates the effects of various stabilizers on
vasopressin stability.
DETAILED DESCRIPTION
Vasopressin and Peptides of the Invention.
[0014] Vasopressin, a peptide hormone, acts to regulate water
retention in the body and is a neurotransmitter that controls
circadian rhythm, thermoregulation, and adrenocorticotrophic
hormone (ACTH) release. Vasopressin is synthesized as a pro-hormone
in neurosecretory cells of the hypothalamus, and is subsequently
transported to the pituitary gland for storage. Vasopressin is
released upon detection of hyperosmolality in the plasma, which can
be due to dehydration of the body. Upon release, vasopressin
increases the permeability of collecting ducts in the kidney to
reduce renal excretion of water. The decrease in renal excretion of
water leads to an increase in water retention of the body and an
increase in blood volume. At higher concentrations, vasopressin
raises blood pressure by inducing vasoconstriction.
[0015] Vasopressin acts through various receptors in the body
including, for example, the V1, V2, V3, and oxytocin-type (OTR)
receptors. The V1 receptors occur on vascular smooth muscle cells,
and the major effect of vasopressin action on the V1 receptor is
the induction of vasoconstriction via an increase of intracellular
calcium. V2 receptors occur on the collecting ducts and the distal
tubule of the kidney. V2 receptors play a role in detection of
plasma volume and osmolality. V3 receptors occur in the pituitary
gland and can cause ACTH release upon vasopressin binding. OTRs can
be found on the myometrium and vascular smooth muscle. Engagement
of OTRs via vasopressin leads to an increase of intracellular
calcium and vasoconstriction.
[0016] Vasopressin is a nonapeptide, illustrated below (SEQ ID NO.
1):
##STR00001##
[0017] At neutral to acidic pH, the two basic groups of
vasopressin, the N-terminal cysteine, and the arginine at position
eight, are protonated, and can each carry an acetate counterion.
The amide groups of the N-terminal glycine, the glutamine at
position four, and the asparagine at position five, are susceptible
to modification when stored as clinical formulations, such as unit
dosage forms. The glycine, glutamine, and asparagine residues can
undergo deamidation to yield the parent carboxylic acid and several
degradation products as detailed in EXAMPLE 1 and TABLE 1
below.
[0018] Deamidation is a peptide modification during which an amide
group is removed from an amino acid, and can be associated with
protein degradation, apoptosis, and other regulatory functions
within the cell. Deamidation of asparagine and glutamine residues
can occur in vitro and in vivo, and can lead to perturbation of the
structure and function of the affected proteins. The susceptibility
to deamidation can depend on primary sequence of the protein,
three-dimensional structure of the protein, and solution properties
including, for example, pH, temperature, ionic strength, and buffer
ions. Deamidation can be catalyzed by acidic conditions. Under
physiological conditions, deamidation of asparagine occurs via the
formation of a five-membered succinimide ring intermediate by a
nucleophilic attack of the nitrogen atom in the following peptide
bond on the carbonyl group of the asparagine side chain.
Acetylation is a peptide modification whereby an acetyl group is
introduced into an amino acid, such as on the N-terminus of the
peptide.
[0019] Vasopressin can also form dimers in solution and in vivo.
The vasopressin dimers can occur through the formation of disulfide
bridges that bind a pair of vasopressin monomers together. The
dimers can form between two parallel or anti-parallel chains of
vasopressin.
[0020] Vasopressin and associated degradation products or peptides
are listed in TABLE 1 below.
[0021] All amino acids are L-stereoisomers unless otherwise
denoted.
TABLE-US-00001 TABLE 1 SEQ ID Name Sequence NO. Vasopressin (AVP;
CYFQNCPRG-NH.sub.2 1 arginine vasopressin) Gly9-vasopressin
CYFQNCPRG 2 (Gly9-AVP) Asp5-vasopressin CYFQDCPRG-NH.sub.2 3
(Asp5-AVP) Glu4-vasopressin CYFENCPRG-NH.sub.2 4 (Glu4-AVP)
Glu4Gly9-vasopressin CYFENCPRG 5 (Glu4Gly9-AVP)
AcetylAsp5-vasopressin Ac-CYFQDCPRG-NH.sub.2 6 (AcetylAsp5-AVP)
Acetyl-vasopressin Ac-CYFQNCPRG-NH.sub.2 7 (Acetyl-AVP)
His2-vasopressin CHFQNCPRG-NH.sub.2 8 (His2-AVP) Leu7-vasopressin
CYFQNCLRG-NH.sub.2 9 (Leu7-AVP) D-Asn-vasopressin
CYFQ(D-Asn)CPRG-NH.sub.2 10 (DAsn-AVP) D-Cys1-vasopressin
(D-Cys)YFQNCPRG-NH.sub.2 11 D-Tyr-vasopressin
C(D-Tyr)FQNCPRG-NH.sub.2 12 D-Phe-vasopressin
CY(D-Phe)QNCPRG-NH.sub.2 13 D-Gln-vasopressin
CYF(D-Gln)NCPRG-NH.sub.2 14 D-Cys6-vasopressin
CYFQN(D-cys)PRG-NH.sub.2 15 D-Pro-vasopressin
CYFQNC(D-pro)RG-NH.sub.2 16 D-Arg-vasopressin
CYFQNCP(D-Arg)G-NH.sub.2 17
Therapeutic Uses.
[0022] A formulation of vasopressin can be used to regulate plasma
osmolality and volume and conditions related to the same in a
subject. Vasopressin can be used to modulate blood pressure in a
subject, and can be indicated in a subject who is hypotensive
despite treatment with fluid and catecholamines.
[0023] Vasopressin can be used in the treatment of, for example,
vasodilatory shock, post-cardiotomy shock, sepsis, septic shock,
cranial diabetes insipidus, polyuria, nocturia, polydypsia,
bleeding disorders, Von Willebrand disease, haemophilia, platelet
disorders, cardiac arrest, liver disease, liver failure,
hypovolemia, hemorrhage, oesophageal variceal haemorrhage,
hypertension, pulmonary hypertension, renal disease, polycystic
kidney disease, blood loss, injury, hypotension, meniere disease,
uterine myomas, brain injury, mood disorder. Formulations of
vasopressin can be administered to a subject undergoing, for
example, surgery or hysterectomy.
[0024] Plasma osmolality is a measure of the plasma's
electrolyte-water balance and can be indicative of blood volume and
hydration of a subject. Normal plasma osmolality in a healthy human
subject range from about 275 milliosmoles/kg to about 295
milliosmoles/kg. High plasma osmolality levels can be due to, for
example, diabetes insipidus, hyperglycemia, uremia, hypernatremia,
stroke, and dehydration. Low plasma osmolality can be due to, for
example, vasopressin oversecretion, improper functioning of the
adrenal gland, lung cancer, hyponatremia, hypothyroidism, and
over-consumption of water or other fluids.
[0025] Septic shock can develop due to an extensive immune response
following infection and can result in low blood pressure. Causes of
sepsis can include, for example, gastrointestinal infections,
pneumonia, bronchitis, lower respiratory tract infections, kidney
infection, urinary tract infections, reproductive system
infections, fungal infections, and viral infections. Risk factors
for sepsis include, for example, age, prior illness, major surgery,
long-term hospitalization, diabetes, intravenous drug use, cancer,
use of steroidal medications, and long-term use of antibiotics. The
symptoms of sepsis can include, for example, cool arms and legs,
pale arms and legs, extreme body temperatures, chills,
light-headedness, decreased urination, rapid breathing, edema,
confusion, elevated heart rate, high blood sugar, metabolic
acidosis, respiratory alkalosis, and low blood pressure.
[0026] Vasopressin can also be administered to regulate blood
pressure in a subject. Blood pressure is the measure of force of
blood pushing against blood vessel walls. Blood pressure is
regulated by the nervous and endocrine systems and can be used as
an indicator of a subject's health. Chronic high blood pressure is
referred to as hypertension, and chronic low blood pressure is
referred to as hypotension. Both hypertension and hypotension can
be harmful if left untreated.
[0027] Blood pressure can vary from minute to minute and can follow
the circadian rhythm with a predictable pattern over a 24-hour
period. Blood pressure is recorded as a ratio of two numbers:
systolic pressure (mm Hg), the numerator, is the pressure in the
arteries when the heart contracts, and diastolic pressure (mm Hg),
the denominator, is the pressure in the arteries between
contractions of the heart. Blood pressure can be affected by, for
example, age, weight, height, sex, exercise, emotional state,
sleep, digestion, time of day, smoking, alcohol consumption, salt
consumption, stress, genetics, use of oral contraceptives, and
kidney disease.
[0028] Blood pressure for a healthy human adult between the ages of
18-65 can range from about 90/60 to about 120/80. Hypertension can
be a blood pressure reading above about 120/80 and can be
classified as hypertensive crisis when there is a spike in blood
pressure and blood pressure readings reach about 180/110 or higher.
Hypertensive crisis can be precipitated by, for example, stroke,
myocardial infarction, heart failure, kidney failure, aortic
rupture, drug-drug interactions, and eclampsia. Symptoms of
hypertensive crisis can include, for example, shortness of breath,
angina, back pain, numbness, weakness, dizziness, confusion, change
in vision, nausea, and difficulty speaking.
[0029] Vasodilatory shock can be characterized by low arterial
blood pressure due to decreased systemic vascular resistance.
Vasodilatory shock can lead to dangerously low blood pressure
levels and can be corrected via administration of catecholamines or
vasopressin formulations. Vasodilatory shock can be caused by, for
example, sepsis, nitrogen intoxication, carbon monoxide
intoxication, hemorrhagic shock, hypovolemia, heart failure,
cyanide poisoning, metformin intoxication, and mitochondrial
disease.
[0030] Post-cardiotomy shock can occur as a complication of cardiac
surgery and can be characterized by, for example, inability to wean
from cardiopulmonary bypass, poor hemodynamics in the operating
room, development of poor hemodynamics post-surgery, and
hypotension.
Pharmaceutical Formulations.
[0031] Methods for the preparation of compositions comprising the
compounds described herein can include formulating the compounds
with one or more inert, pharmaceutically-acceptable excipients.
Liquid compositions include, for example, solutions in which a
compound is dissolved, emulsions comprising a compound, or a
solution containing liposomes, micelles, or nanoparticles
comprising a compound as disclosed herein. These compositions can
also contain minor amounts of nontoxic, auxiliary substances, such
as wetting or emulsifying agents, pH buffering agents, and other
pharmaceutically-acceptable additives.
[0032] Non-limiting examples of dosage forms suitable for use in
the disclosure include liquid, elixir, nanosuspension, aqueous or
oily suspensions, drops, syrups, and any combination thereof.
Non-limiting examples of pharmaceutically-acceptable excipients
suitable for use in the disclosure include granulating agents,
binding agents, lubricating agents, disintegrating agents,
anti-adherents, anti-static agents, surfactants, anti-oxidants,
coloring agents, flavouring agents, plasticizers, preservatives,
suspending agents, emulsifying agents, plant cellulosic material
and spheronization agents, and any combination thereof.
[0033] Vasopressin can be formulated as an aqueous formulation or a
lyophilized powder, which can be diluted or reconstituted just
prior to use. Upon dilution or reconstitution, the vasopressin
solution can be refrigerated for long-term stability for about one
day. Room temperature incubation or prolonged refrigeration can
lead to the generation of degradation products of vasopressin.
[0034] In some embodiments, a pharmaceutical composition of the
invention can be formulated for long-term storage of vasopressin at
room temperature in the presence of a suitable
pharmaceutically-acceptable excipient. The
pharmaceutically-acceptable excipient can increase the half-life of
vasopressin when stored at any temperature, such as room
temperature. The presence of the pharmaceutical excipient can
decrease the rate of decomposition of vasopressin at any
temperature, such as room temperature.
[0035] In some embodiments, a vasopressin formulation of the
invention comprises a pharmaceutically-acceptable excipient, and
the vasopressin has a half-life that is at least about 1%, at least
about 5%, at least about 10%, at least about 15%, at least about
20%, at least about 25%, at least about 30%, at least about 35%, at
least about 40%, at least about 45%, at least about 50%, at least
about 55%, at least about 60%, at least about 65%, at least about
70%, at least about 75%, at least about 80%, at least about 85%, at
least about 90%, at least about 95%, at least about 100%, at least
about 150%, at least about 200%, at least about 250%, at least
about 300%, at least about 350%, at least about 400%, at least
about 450%, at least about 500%, at least about 600%, at least
about 700%, at least about 800%, at least about 900%, or at least
about 1000% greater than the half-life of vasopressin in a
corresponding formulation that lacks the
pharmaceutically-acceptable excipient.
[0036] In some embodiments, a vasopressin formulation of the
invention has a half-life at about 0.degree. C. that is no more
than about 1%, no more than about 5%, no more than about 10%, no
more than about 15%, no more than about 20%, no more than about
25%, no more than about 30%, no more than about 35%, no more than
about 40%, no more than about 45%, no more than about 50%, no more
than about 55%, no more than about 60%, no more than about 65%, no
more than about 70%, no more than about 75%, no more than about
80%, no more than about 85%, no more than about 90%, no more than
about 95%, no more than about 100%, no more than about 150%, no
more than about 200%, no more than about 250%, no more than about
300%, no more than about 350%, no more than about 400%, no more
than about 450%, no more than about 500%, no more than about 600%,
no more than about 700%, no more than about 800%, no more than
about 900%, or no more than about 1000% greater than the half-life
of the formulation at another temperature, such as room
temperature.
[0037] The half-life of the compounds of the invention in a
formulation described herein at a specified temperature can be, for
example, about 1 hour, about 2 hours, about 3 hours, about 4 hours,
about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9
hours, about 10 hours, about 11 hours, about 12 hours, about 13
hours, about 14 hours, about 15 hours, about 16 hours, about 17
hours, about 18 hours, about 19 hours, about 20 hours, about 21
hours, about 22 hours, about 23 hours, about 24 hours, about 30
hours, about 36 hours, about 42 hours, about 48 hours, about 60
hours, about 3 days, about 4 days, about 5 days, about 6 days, or
about one week.
[0038] In some embodiments, a vasopressin formulation of the
invention comprises an excipient and the vasopressin has a level of
decomposition at a specified temperature that is about 1%, about
5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35%, about 40%, about 45%, about 50%, about 55%, about 60%, about
65%, about 70%, about 75%, about 80%, about 85%, about 90%, about
95%, about 100%, about 150%, about 200%, about 250%, about 300%,
about 350%, about 400%, about 450%, about 500%, about 600%, about
700%, about 800%, about 900%, or about 1000% less than the level of
decomposition of a formulation of the invention in the absence of
the excipient.
[0039] Pharmaceutical compositions of the invention can be used,
stored, tested, analyzed or assayed at any suitable temperature.
Non-limiting examples of temperatures include about 0.degree. C.,
about 1.degree. C., about 2.degree. C., about 3.degree. C., about
4.degree. C., about 5.degree. C., about 6.degree. C., about
7.degree. C., about 8.degree. C., about 9.degree. C., about
10.degree. C., about 11.degree. C., about 12.degree. C., about
13.degree. C., about 14.degree. C., about 15.degree. C., about
16.degree. C., about 17.degree. C., about 18.degree. C., about
19.degree. C., about 20.degree. C., about 21.degree. C., about
22.degree. C., about 23.degree. C., about 24.degree. C., about
25.degree. C., about 26.degree. C., about 27.degree. C., about
28.degree. C., about 29.degree. C., about 30.degree. C., about
31.degree. C., about 32.degree. C., about 33.degree. C., about
34.degree. C., about 35.degree. C., about 36.degree. C., about
37.degree. C., about 38.degree. C., about 39.degree. C., about
40.degree. C., about 41.degree. C., about 42.degree. C., about
43.degree. C., about 44.degree. C., about 45.degree. C., about
46.degree. C., about 47.degree. C., about 48.degree. C., about
49.degree. C., about 50.degree. C., about 51.degree. C., about
52.degree. C., about 53.degree. C., about 54.degree. C., about
55.degree. C., about 56.degree. C., about 57.degree. C., about
58.degree. C., about 59.degree. C., about 60.degree. C., about
61.degree. C., about 62.degree. C., about 63.degree. C., about
64.degree. C., about 65.degree. C., about 66.degree. C., about
67.degree. C., about 68.degree. C., about 69.degree. C., about
70.degree. C., about 71.degree. C., about 72.degree. C., about
73.degree. C., about 74.degree. C., or about 75.degree. C.
[0040] Pharmaceutical compositions of the invention can be used,
stored, tested, analyzed or assayed at room temperature. The room
temperature can be, for example, about 20.0.degree. C., about
20.1.degree. C., about 20.2.degree. C., about 20.3.degree. C.,
about 20.4.degree. C., about 20.5.degree. C., about 20.6.degree.
C., about 20.7.degree. C., about 20.8.degree. C., about
20.9.degree. C., about 21.0.degree. C., about 21.1.degree. C.,
about 21.2.degree. C., about 21.3.degree. C., about 21.4.degree.
C., about 21.5.degree. C., about 21.6.degree. C., about
21.7.degree. C., about 21.8.degree. C., about 21.9.degree. C.,
about 22.0.degree. C., about 22.1.degree. C., about 22.2.degree.
C., about 22.3.degree. C., about 22.4.degree. C., about
22.5.degree. C., about 22.6.degree. C., about 22.7.degree. C.,
about 22.8.degree. C., about 22.9.degree. C., about 23.0.degree.
C., about 23.1.degree. C., about 23.2.degree. C., about
23.3.degree. C., about 23.4.degree. C., about 23.5.degree. C.,
about 23.6.degree. C., about 23.7.degree. C., about 23.8.degree.
C., about 23.9.degree. C., about 24.0.degree. C., about
24.1.degree. C., about 24.2.degree. C., about 24.3.degree. C.,
about 24.4.degree. C., about 24.5.degree. C., about 24.6.degree.
C., about 24.7.degree. C., about 24.8.degree. C., about
24.9.degree. C., or about 25.0.degree. C.
[0041] A pharmaceutical composition of the disclosure can be a
combination of any pharmaceutical compounds described herein with
other chemical components, such as carriers, stabilizers, diluents,
dispersing agents, suspending agents, thickening agents, and/or
excipients. The pharmaceutical composition facilitates
administration of the compound to an organism. Pharmaceutical
compositions can be administered in therapeutically-effective
amounts, for example, intravenous, subcutaneous, intramuscular,
transdermal, or parenteral administration.
[0042] Pharmaceutical preparations can be formulated for
intravenous administration. The pharmaceutical compositions can be
in a form suitable for parenteral injection as a sterile
suspension, solution, or emulsion in oily or aqueous vehicles, and
can contain formulation agents such as suspending, stabilizing,
and/or dispersing agents. Pharmaceutical formulations for
parenteral administration include aqueous solutions of the active
compounds in water-soluble form. Suspensions of the active
compounds can be prepared as oily injection suspensions. Suitable
lipophilic solvents or vehicles include fatty oils such as sesame
oil, or synthetic fatty acid esters, such as ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions can
contain substances which increase the viscosity of the suspension,
such as sodium carboxymethyl cellulose, sorbitol, or dextran. The
suspension can also contain suitable stabilizers or agents which
increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions. Alternatively, the
active ingredient can be in powder form for constitution with a
suitable vehicle, for example, sterile pyrogen-free water, before
use.
Comparison Formulations.
[0043] A pharmaceutical composition described herein can be
analyzed by comparison to a reference formulation. A reference
formulation can be generated from any combination of compounds,
peptides, excipients, diluents, carriers, and solvents disclosed
herein. Any compound, peptide, excipient, diluent, carrier, or
solvent used to generate the reference formulation can be present
in any percentage, ratio, or amount, for example, those disclosed
herein. The reference formulation can comprise, consist essentially
of, or consist of any combination of any of the foregoing.
[0044] A non-limiting example of a comparison formulation
comprises, consists essentially of, or consists of: an amount, such
as about 20 Units or about 0.04 mg, of vasopressin or a
pharmaceutically-acceptable salt thereof, an amount, such as about
5 mg, of chlorobutanol (for example, hydrous), an amount, such as
about 0.22 mg, of acetic acid or a pharmaceutically-acceptable salt
thereof or a quantity sufficient to bring pH to about 3.4 to about
3.6, and water as needed. Another non-limiting example of a
comparison formulation comprises, consists essentially of, or
consists of: vasopressin or a pharmaceutically-acceptable salt
thereof, chlorobutanol, acetic acid, and a solvent such as water.
Another non-limiting example of a comparison formulation comprises,
consists essentially of, or consists of: vasopressin or a
pharmaceutically-acceptable salt thereof, chlorobutanol, and a
solvent such as water. Another non-limiting example of a comparison
formulation comprises, consists essentially of, or consists of:
vasopressin or a pharmaceutically-acceptable salt thereof, acetic
acid, and a solvent such as water. Another non-limiting example of
a comparison formulation comprises, consists essentially of, or
consists of: vasopressin or a pharmaceutically-acceptable salt
thereof and a solvent such as water. Another non-limiting example
of a comparison formulation comprises, consists essentially of, or
consists of: vasopressin or a pharmaceutically-acceptable salt
thereof and a buffer having acidic pH, such as pH 3.5 or any buffer
or pH described herein.
Dosage Amounts.
[0045] In practicing the methods of treatment or use provided
herein, therapeutically-effective amounts of the compounds
described herein are administered in pharmaceutical compositions to
a subject having a disease or condition to be treated. A
therapeutically-effective amount can vary widely depending on the
severity of the disease, the age and relative health of the
subject, the potency of the compounds used, and other factors.
Subjects can be, for example, humans, elderly adults, adults,
adolescents, pre-adolescents, children, toddlers, infants, or
neonates. A subject can be a patient.
[0046] Pharmaceutical compositions of the invention can be
formulated in any suitable volume. The formulation volume can be,
for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4
mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about
0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about
1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL,
about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL,
about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8
mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3
mL, about 3.4 mL, about 3.5 mL, about 3.6 mL, about 3.7 mL, about
3.8 mL, about 3.9 mL, about 4 mL, about 4.1 mL, about 4.2 mL, about
4.3 mL, about 4.4 mL, about 4.5 mL, about 4.6 mL, about 4.7 mL,
about 4.8 mL, about 4.9 mL, about 5 mL, about 5.1 mL, about 5.2 mL,
about 5.3 mL, about 5.4 mL, about 5.5 mL, about 5.6 mL, about 5.7
mL, about 5.8 mL, about 5.9 mL, about 6 mL, about 6.1 mL, about 6.2
mL, about 6.3 mL, about 6.4 mL, about 6.5 mL, about 6.6 mL, about
6.7 mL, about 6.8 mL, about 6.9 mL, about 7 mL, about 7.1 mL, about
7.2 mL, about 7.3 mL, about 7.4 mL, about 7.5 mL, about 7.6 mL,
about 7.7 mL, about 7.8 mL, about 7.9 mL, about 8 mL, about 8.1 mL,
about 8.2 mL, about 8.3 mL, about 8.4 mL, about 8.5 mL, about 8.6
mL, about 8.7 mL, about 8.8 mL, about 8.9 mL, about 9 mL, about 9.1
mL, about 9.2 mL, about 9.3 mL, about 9.4 mL, about 9.5 mL, about
9.6 mL, about 9.7 mL, about 9.8 mL, about 9.9 mL, or about 10
mL.
[0047] A therapeutically-effective amount of a compound described
herein can be present in a composition at a concentration of, for
example, about 0.1 units/mL, about 0.2 units/mL, about 0.3
units/mL, about 0.4 units/mL, about 0.5 units/mL, about 0.6
units/mL, about 0.7 units/mL, about 0.8 units/mL, about 0.9
units/mL, about 1 unit/mL, about 2 units/mL, about 3 units/mL,
about 4 units/mL, about 5 units/mL, about 6 units/mL, about 7
units/mL, about 8 units/mL, about 9 units/mL, about 10 units/mL,
about 11 units/mL, about 12 units/mL, about 13 units/mL, about 14
units/mL, about 15 units/mL, about 16 units/mL, about 17 units/mL,
about 18 units/mL, about 19 units/mL, about 20 units/mL, about 21
units/mL, about 22 units/mL, about 23 units/mL, about 24 units/mL
about 25 units/mL, about 30 units/mL, about 35 units/mL, about 40
units/mL, about 45 units/mL, or about 50 units/mL.
[0048] A therapeutically-effective amount of a compound described
herein can be present in a composition of the invention at a mass
of about, for example, about 0.01 .mu.g, about 0.05 .mu.g, about
0.1 .mu.g, about 0.15 .mu.g, about 0.2 .mu.g about 0.25 .mu.g,
about 0.3 .mu.g, about 0.35 .mu.g, about 0.4 .mu.g, about 0.5
.mu.g, about 0.6 .mu.g, about 0.7 .mu.g, about 0.8 .mu.g, about 0.9
.mu.g, about 1 .mu.g, about 2 .mu.g, about 3 .mu.g, about 4 .mu.g,
about 5 .mu.g, about 10 .mu.g, about 15 .mu.g, about 20 .mu.g,
about 25 .mu.g, about 30 .mu.g, about 35 .mu.g, about 40 .mu.g,
about 45 .mu.g, about 50 .mu.g, about 60 .mu.g, about 70 .mu.g,
about 80 .mu.g, about 90 .mu.g, about 100 .mu.g, about 125 .mu.g,
about 150 .mu.g, about 175 .mu.g, about 200 .mu.g, about 250 .mu.g,
about 300 .mu.g, about 350 .mu.g, about 400 .mu.g, about 450 .mu.g,
about 500 .mu.g, about 600 .mu.g, about 700 .mu.g, about 800 .mu.g,
about 900 .mu.g, about 1 mg, about 2 mg, about 3 mg, about 4 mg,
about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or
about 10 mg.
[0049] A therapeutically-effective amount of a compound described
herein can be present in a composition of the invention at a
concentration of, for example, about 0.001 mg/mL, about 0.002
mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL,
about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about
0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL,
about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07
mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about
0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about
0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about
1 mg/mL, about 1.5 mg/mL, about 2 mg/mL, about 2.5 mg/mL, about 3
mg/mL, about 3.5 mg/mL, about 4 mg/mL, about 4.5 mg/mL, about 5
mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL,
or about 10 mg/mL.
[0050] A therapeutically-effective amount of a compound described
herein can be present in a composition of the invention at a unit
of active agent/unit of active time. Non-limiting examples of
therapeutically-effective amounts can be, for example, about 0.01
units/minute, about 0.02 units/minute, about 0.03 units/minute,
about 0.04 units/minute, about 0.05 units/minute, about 0.06
units/minute, about 0.07 units/minute, about 0.08 units/minute,
about 0.09 units/minute or about 0.1 units/minute.
[0051] Pharmaceutical compositions of the invention can be
formulated at any suitable pH. The pH can be, for example, about 2,
about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about
2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55,
about 2.6, about 2.65, about 2.7, about 2.75, about 2.8, about
2.85, about 2.9, about 2.95, about 3, about 3.05, about 3.1, about
3.15, about 3.2, about 3.25, about 3.3, about 3.35, about 3.4,
about 3.45, about 3.5, about 3.55, about 3.6, about 3.65, about
3.7, about 3.75, about 3.8, about 3.85, about 3.9, about 3.95,
about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25,
about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about
4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8,
about 4.85, about 4.9, about 4.95, or about 5 pH units.
[0052] In some embodiments, the addition of an excipient can change
the viscosity of a pharmaceutical composition of the invention. In
some embodiments the use of an excipient can increase or decrease
the viscosity of a fluid by at least 0.001 Pascal-second (Pas), at
least 0.001 Pas, at least 0.0009 Pas, at least 0.0008 Pas, at least
0.0007 Pas, at least 0.0006 Pas, at least 0.0005 Pas, at least
0.0004 Pas, at least 0.0003 Pas, at least 0.0002 Pas, at least
0.0001 Pas, at least 0.00005 Pas, or at least 0.00001 Pas.
[0053] In some embodiments, the addition of an excipient to a
pharmaceutical composition of the invention can increase or
decrease the viscosity of the composition by at least 5%, at least
10%, at least 15%, at least 20%, at least 25%, at least 30%, at
least 35%, at least 40%, at least 45%, at least 50%, at least 55%,
at least 60%, at least 65%, at least 70%, at least 75%, at least
80%, at least 85%, at least 90%, at least 95%, or at least 99%. In
some embodiments, the addition of an excipient to a pharmaceutical
composition of the invention can increase or decrease the viscosity
of the composition by no greater than 5%, no greater than 10%, no
greater than 15%, no greater than 20%, no greater than 25%, no
greater than 30%, no greater than 35%, no greater than 40%, no
greater than 45%, no greater than 50%, no greater than 55%, no
greater than 60%, no greater than 65%, no greater than 70%, no
greater than 75%, no greater than 80%, no greater than 85%, no
greater than 90%, no greater than 95%, or no greater than 99%.
[0054] Any compound herein can be purified. A compound can be at
least 1% pure, at least 2% pure, at least 3% pure, at least 4%
pure, at least 5% pure, at least 6% pure, at least 7% pure, at
least 8% pure, at least 9% pure, at least 10% pure, at least 11%
pure, at least 12% pure, at least 13% pure, at least 14% pure, at
least 15% pure, at least 16% pure, at least 17% pure, at least 18%
pure, at least 19% pure, at least 20% pure, at least 21% pure, at
least 22% pure, at least 23% pure, at least 24% pure, at least 25%
pure, at least 26% pure, at least 27% pure, at least 28% pure, at
least 29% pure, at least 30% pure, at least 31% pure, at least 32%
pure, at least 33% pure, at least 34% pure, at least 35% pure, at
least 36% pure, at least 37% pure, at least 38% pure, at least 39%
pure, at least 40% pure, at least 41% pure, at least 42% pure, at
least 43% pure, at least 44% pure, at least 45% pure, at least 46%
pure, at least 47% pure, at least 48% pure, at least 49% pure, at
least 50% pure, at least 51% pure, at least 52% pure, at least 53%
pure, at least 54% pure, at least 55% pure, at least 56% pure, at
least 57% pure, at least 58% pure, at least 59% pure, at least 60%
pure, at least 61% pure, at least 62% pure, at least 63% pure, at
least 64% pure, at least 65% pure, at least 66% pure, at least 67%
pure, at least 68% pure, at least 69% pure, at least 70% pure, at
least 71% pure, at least 72% pure, at least 73% pure, at least 74%
pure, at least 75% pure, at least 76% pure, at least 77% pure, at
least 78% pure, at least 79% pure, at least 80% pure, at least 81%
pure, at least 82% pure, at least 83% pure, at least 84% pure, at
least 85% pure, at least 86% pure, at least 87% pure, at least 88%
pure, at least 89% pure, at least 90% pure, at least 91% pure, at
least 92% pure, at least 93% pure, at least 94% pure, at least 95%
pure, at least 96% pure, at least 97% pure, at least 98% pure, at
least 99% pure, at least 99.1% pure, at least 99.2% pure, at least
99.3% pure, at least 99.4% pure, at least 99.5% pure, at least
99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least
99.9% pure.
[0055] Compositions of the invention can be packaged as a kit. In
some embodiments, a kit includes written instructions on the
administration or use of the composition. The written material can
be, for example, a label. The written material can suggest
conditions methods of administration. The instructions provide the
subject and the supervising physician with the best guidance for
achieving the optimal clinical outcome from the administration of
the therapy. In some embodiments, the label can be approved by a
regulatory agency, for example the U.S. Food and Drug
Administration (FDA), the European Medicines Agency (EMA), or other
regulatory agencies.
Pharmaceutically-Acceptable Excipients.
[0056] Non-limiting examples of pharmaceutically-acceptable
excipients can be found, for example, in Remington: The Science and
Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing
Company, 1995); Hoover, John E., Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A.
and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker,
New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug
Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins
1999), each of which is incorporated by reference in its
entirety.
[0057] In some embodiments, the pharmaceutical composition provided
herein comprises a sugar as an excipient. Non-limiting examples of
sugars include trehalose, sucrose, glucose, lactose, galactose,
glyceraldehyde, fructose, dextrose, maltose, xylose, mannose,
maltodextrin, starch, cellulose, lactulose, cellobiose, mannobiose,
and combinations thereof.
[0058] In some embodiments, the pharmaceutical composition provided
herein comprises a buffer as an excipient. Non-limiting examples of
buffers include potassium phosphate, sodium phosphate, saline
sodium citrate buffer (SSC), acetate, saline, physiological saline,
phosphate buffer saline (PBS),
4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES),
3-(N-morpholino)propanesulfonic acid buffer (MOPS), and
piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), or
combinations thereof.
[0059] In some embodiments, a pharmaceutical composition of the
invention comprises a source of divalent metal ions as an
excipient. A metal can be in elemental form, a metal atom, or a
metal ion. Non-limiting examples of metals include transition
metals, main group metals, and metals of Group 1, Group 2, Group 3,
Group 4, Group 5, Group 6, Group 7, Group 8, Group 9, Group 10,
Group 11, Group 12, Group 13, Group 14, and Group 15 of the
Periodic Table. Non-limiting examples of metals include lithium,
sodium, potassium, cesium, magnesium, calcium, strontium, scandium,
titanium, vanadium, chromium, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, niobium, molybdenum, palladium,
silver, cadmium, tungsten, rhenium, osmium, iridium, platinum,
gold, mercury, cerium, and samarium.
[0060] In some embodiments, the pharmaceutical composition provided
herein comprises an alcohol as an excipient. Non-limiting examples
of alcohols include ethanol, propylene glycol, glycerol,
polyethylene glycol, chrlorobutanol, isopropanol, xylitol,
sorbitol, maltitol, erythritol, threitol, arabitol, ribitol,
mannitol, galactilol, fucitol, lactitol, and combinations
thereof.
[0061] Pharmaceutical preparations can be formulated with
polyethylene glycol (PEG). PEGs with molecular weights ranging from
about 300 g/mol to about 10,000,000 g/mol can be used. Non-limiting
examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG
550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG
3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG
20,000.
[0062] Further excipients that can be used in a composition of the
invention include, for example, benzalkonium chloride, benzethonium
chloride, benzyl alcohol, butylated hydroxyanisole, butylated
hydroxytoluene, dehydroacetic acid, ethylenediamine, ethyl
vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl
alcohol, phenylmercuric nitrate, potassium benzoate, potassium
metabisulfite, potassium sorbate, sodium bisulfite, sodium
metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum
monostearate, boric acid, calcium hydroxide, calcium stearate,
calcium sulfate, calcium tetrachloride, cellulose acetate pthalate,
microcrystalline cellulose, chloroform, citric acid, edetic acid,
and ethylcellulose.
[0063] In some embodiments, the pharmaceutical composition provided
herein comprises an aprotic solvent as an excipient. Non-limiting
examples of aprotic solvents include perfluorohexane,
.alpha.,.alpha.,.alpha.-trifluorotoluene, pentane, hexane,
cyclohexane, methylcyclohexane, decalin, dioxane, carbon
tetrachloride, freon-11, benzene, toluene, carbon disulfide,
diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl
acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether,
tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone,
N-methylpyrrolidinone, nitromethane, dimethylformamide,
acetonitrile, sulfolane, dimethyl sulfoxide, and propylene
carbonate.
[0064] The amount of the excipient in a pharmaceutical composition
of the invention can be about 0.01%, about 0.02%, about 0.03%,
about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%,
about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%,
about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%,
about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 60%, about 70%, about 80%, about
90%, about 100%, about 200%, about 300%, about 400%, about 500%,
about 600%, about 700%, about 800%, about 900%, or about 1000% by
mass of the vasopressin in the pharmaceutical composition.
[0065] The amount of the excipient in a pharmaceutical composition
of the invention can be about 0.01%, about 0.02%, about 0.03%,
about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%,
about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about
0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%,
about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%,
about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55% about 60%, about 65%, about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, about
99%, or about 100%, mass or by volume of the unit dosage form.
[0066] The ratio of vasopressin to an excipient in a pharmaceutical
composition of the invention can be about 100:about 1, about
95:about 1, about 90:about 1, about 85:about 1, about 80:about 1,
about 75:about 1, about 70:about 1, about 65:about 1, about
60:about 1, about 55:about 1, about 50:about 1, about 45:about 1,
about 40:about 1, about 35:about 1 about 30:about 1, about 25:about
1, about 20:about 1, about 15:about 1, about 10:about 1, about
9:about 1, about 8:about 1, about 7:about 1, about 6:about 1, about
5:about 1, about 4:about 1, about 3:about 1, about 2:about 1, about
1:about 1, about 1:about 2, about 1:about 3, about 1:about 4, about
1:about 5, about 1:about 6, about 1:about 7, about 1:about 8, about
1:about 9, or about 1:about 10.
Pharmaceutically-Acceptable Salts.
[0067] The invention provides the use of
pharmaceutically-acceptable salts of any therapeutic compound
described herein. Pharmaceutically-acceptable salts include, for
example, acid-addition salts and base-addition salts. The acid that
is added to the compound to form an acid-addition salt can be an
organic acid or an inorganic acid. A base that is added to the
compound to form a base-addition salt can be an organic base or an
inorganic base. In some embodiments, a pharmaceutically-acceptable
salt is a metal salt. In some embodiments, a
pharmaceutically-acceptable salt is an ammonium salt.
[0068] Metal salts can arise from the addition of an inorganic base
to a compound of the invention. The inorganic base consists of a
metal cation paired with a basic counterion, such as, for example,
hydroxide, carbonate, bicarbonate, or phosphate. The metal can be
an alkali metal, alkaline earth metal, transition metal, or main
group metal. In some embodiments, the metal is lithium, sodium,
potassium, cesium, cerium, magnesium, manganese, iron, calcium,
strontium, cobalt, titanium, aluminum, copper, cadmium, or
zinc.
[0069] In some embodiments, a metal salt is a lithium salt, a
sodium salt, a potassium salt, a cesium salt, a cerium salt, a
magnesium salt, a manganese salt, an iron salt, a calcium salt, a
strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a
copper salt, a cadmium salt, or a zinc salt.
[0070] Ammonium salts can arise from the addition of ammonia or an
organic amine to a compound of the invention. In some embodiments,
the organic amine is triethyl amine, diisopropyl amine, ethanol
amine, diethanol amine, triethanol amine, morpholine,
N-methylmorpholine, piperidine, N-methylpiperidine,
N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole,
pipyrrazole, imidazole, pyrazine, or pipyrazine.
[0071] In some embodiments, an ammonium salt is a triethyl amine
salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol
amine salt, a triethanol amine salt, a morpholine salt, an
N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine
salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine
salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an
imidazole salt, a pyrazine salt, or a pipyrazine salt.
[0072] Acid addition salts can arise from the addition of an acid
to a compound of the invention. In some embodiments, the acid is
organic. In some embodiments, the acid is inorganic. In some
embodiments, the acid is hydrochloric acid, hydrobromic acid,
hydroiodic acid, nitric acid, nitrous acid, sulfuric acid,
sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid,
salicylic acid, tartaric acid, ascorbic acid, gentisinic acid,
gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic
acid, glutamic acid, pantothenic acid, acetic acid, propionic acid,
butyric acid, fumaric acid, succinic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
citric acid, oxalic acid, or maleic acid.
[0073] In some embodiments, the salt is a hydrochloride salt, a
hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite
salt, a sulfate salt, a sulfite salt, a phosphate salt,
isonicotinate salt, a lactate salt, a salicylate salt, a tartrate
salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a
glucaronate salt, a saccarate salt, a formate salt, a benzoate
salt, a glutamate salt, a pantothenate salt, an acetate salt, a
propionate salt, a butyrate salt, a fumarate salt, a succinate
salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt,
a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt,
an oxalate salt , or a maleate salt.
Peptide Sequence.
[0074] As used herein, the abbreviations for the L-enantiomeric and
D-enantiomeric amino acids are as follows: alanine (A,Ala);
arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp);
cysteine (C, Cys); glutamic acid (E, Glu); glutamine (Q, Gln);
glycine (G, Gly); histidine (H, His); isoleucine (I, Ile); leucine
(L, Leu); lysine (K, Lys); methionine (M, Met); phenylalanine (F,
Phe); proline (P, Pro); serine (S, Ser); threonine (T, Thr);
tryptophan (W, Trp); tyrosine (Y, Tyr); valine (V, Val). In some
embodiments, the amino acid is a L-enantiomer. In some embodiments,
the amino acid is a D-enantiomer.
[0075] A peptide of the disclosure can have about 5%, about 10%,
about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,
about 75%, about 80%, about 81%, about 82%, about 83%, about 84%,
about 85%, about 86%, about 8'7%, about 88%, about 89%, about 90%,
about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,
about 9'7%, about 98%, about 99%, or about 100% amino acid sequence
homology to SEQ ID NO. 1.
[0076] In some embodiments, a pharmaceutical composition of the
invention comprises one or a plurality of peptides having about 80%
to about 90% sequence homology to SEQ ID NO. 1, about 88% to about
90% sequence homology to SEQ ID NO. 1 or 88% to 90% sequence
homology to SEQ ID NO. 1. In some embodiments, a pharmaceutical
composition of the invention comprises vasopression and one or more
of a second, third, fourth, fifth, sixth, seventh, eighth, ninth,
and tenth, peptide.
[0077] The ratio of vasopressin to another peptide in a
pharmaceutical composition of the invention can be, for example,
about 1000:about 1, about 990:about 1, about 980:about 1, about
970:about 1, about 960:about 1, about 950:about 1, about 800:about
1, about 700:about 1, about 600:1, about 500:about 1, about 400:
about 1, about 300:about 1, about 200:about 1, about 100:about 1,
about 95:about 1, about 90:about 1, about 85:about 1, about
80:about 1, about 75:about 1, about 70:about 1, about 65:about 1,
about 60:about 1, about 55:about 1, about 50:about 1, about
45:about 1, about 40:about 1, about 35:about 1, about 30:about 1,
about 25:about 1, about 20:about 1, about 19:about 1, about
18:about 1, about 17:about 1, about 16:about 1, about 15:about 1,
about 14:about 1, about 13:about 1, about 12:about 1, about
11:about 1, or about 10:about 1.
[0078] The amount of another peptide in a composition of the
invention can be, for example, about 0.01%, about 0.02%, about
0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about
0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%,
about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about
1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about
4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about
7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, about
10%, about 11%, about 12%, about 13%, about 14%, about 15%, about
16%, about 17%, about 18%, about 19%, about 20%, about 25%, about
30%, about 35%, about 40%, about 45%, about 50%, about 55%, about
60%, about 65%, about 70%, about 75%, about 80%, about 85%, about
90%, about 95%, or about 100% by mass of vasopressin.
[0079] Non-limiting examples of methods that can be used to
identify peptides of the invention include high-performance liquid
chromatography (HPLC), mass spectrometry (MS), Matrix Assisted
Laser Desorption Ionization Time-of-Flight (MALDI-TOF),
electrospray ionization Time-of-flight (ESI-TOF), gas
chromatography-mass spectrometry (GC-MS), liquid
chromatography-mass spectrometry (LC-MS), and two-dimensional gel
electrophoresis.
[0080] HPLC can be used to identify peptides using high pressure to
separate components of a mixture through a packed column of solid
adsorbent material, denoted the stationary phase. The sample
components can interact differently with the column based upon the
pressure applied to the column, material used in stationary phase,
size of particles used in the stationary phase, the composition of
the solvent used in the column, and the temperature of the column.
The interaction between the sample components and the stationary
phase can affect the time required for a component of the sample to
move through the column. The time required for component to travel
through the column from injection point to elution is known as the
retention time.
[0081] Upon elution from the column, the eluted component can be
detected using a UV detector attached to the column. The wavelength
of light at which the component is detected, in combination with
the component's retention time, can be used to identify the
component. Further, the peak displayed by the detector can be used
to determine the quantity of the component present in the initial
sample. Wavelengths of light that can be used to detect sample
components include, for example, about 200 nM, about 225 nm, about
250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm,
about 375 nm, and about 400 nm.
[0082] Mass spectrometry (MS) can also be used to identify peptides
of the invention. To prepare samples for MS analysis, the samples,
containing the proteins of interest, are digested by proteolytic
enzymes into smaller peptides. The enzymes used for cleavage can
be, for example, trypsin, chymotrypsin, glutamyl endopeptidase,
Lys-C, and pepsin. The samples can be injected into a mass
spectrometer. Upon injection, all or most of the peptides can be
ionized and detected as ions on a spectrum according to the mass to
charge ratio created upon ionization. The mass to charge ratio can
then be used to determine the amino acid residues present in the
sample.
[0083] The present disclosure provides several embodiments of
pharmaceutical formulations that provide advantages in stability,
administration, efficacy, and modulation of formulation viscosity.
Any embodiments disclosed herein can be used in conjunction or
individually. For example, any pharmaceutically-acceptable
excipient, method, technique, solvent, compound, or peptide
disclosed herein can be used together with any other
pharmaceutically-acceptable excipient, method, technique, solvent,
compound, or peptide disclosed herein to achieve any therapeutic
result. Compounds, excipients, and other formulation components can
be present at any amount, ratio, or percentage disclosed herein in
any such formulation, and any such combination can be used
therapeutically for any purpose described herein and to provide any
viscosity described herein.
EXAMPLES
Example 1
Impurities of Vasopressin as Detected by HPLC
[0084] To analyze degradation products of vasopressin that can be
present in an illustrative formulation of vasopressin, gradient
HPLC was performed to separate vasopressin from related peptides
and formulation components. TABLE 2 below depicts the results of
the experiment detailing the chemical formula, relative retention
time (RRT), molar mass, and structure of vasopressin and detected
impurities.
[0085] Vasopressin was detected in the eluent using UV absorbance.
The concentration of vasopressin in the sample was determined by
the external standard method, where the peak area of vasopressin in
sample injections was compared to the peak area of vasopressin
reference standards in a solution of known concentration. The
concentrations of related peptide impurities in the sample were
also determined using the external standard method, using the
vasopressin reference standard peak area and a unit relative
response factor. An impurities marker solution was used to
determine the relative retention times of identified related
peptides at the time of analysis.
[0086] Experimental conditions are summarized in TABLE 2 below.
TABLE-US-00002 TABLE 2 Column YMC-Pack ODS-AM, 3 .mu.m, 120 .ANG.
pore, 4.6 .times. 100 mm Column 25.degree. C. Temperature Flow Rate
1.0 mL/min Detector 215 nm Note: For Identification a Diode Array
Detector (DAD) was used with the range of 200-400 nm. Injection
Volume 100 .mu.L Run time 55 minutes Autosampler Vials
Polypropylene vials Time (min) % A % B Flow Pump (gradient) 0 90 10
1.0 40 50 50 1.0 45 50 50 1.0 46 90 10 1.0 55 90 10 1.0
[0087] The diluent used for the present experiment was 0.25% v/v
Acetic Acid, which was prepared by transferring 2.5 mL of glacial
acetic acid into a 1-L volumetric flask containing 500 mL of water.
The solution was diluted to the desired volume with water.
[0088] Phosphate buffer at pH 3.0 was used for mobile phase A. The
buffer was prepared by weighing approximately 15.6 g of sodium
phosphate monobasic monohydrate into a beaker. 1000 mL of water was
added, and mixed well. The pH was adjusted to 3.0 with phosphoric
acid. The buffer was filtered through a 0.45 .mu.m membrane filter
under vacuum, and the volume was adjusted as necessary.
[0089] An acetonitrile:water (50:50) solution was used for mobile
phase B. To prepare mobile phase B, 500 mL of acetonitrile was
mixed with 500 mL of water.
[0090] The working standard solution contained approximately 20
units/mL of vasopressin. The standard solution was prepared by
quantitatively transferring the entire contents of 1 vial of USP
Vasopressin RS with diluent to a 50-mL volumetric flask.
[0091] The intermediate standard solution was prepared by pipetting
0.5 mL of the working standard solution into a 50-mL volumetric
flask.
[0092] The sensitivity solution was prepared by pipetting 5.0 mL of
the intermediate standard solution into a 50-mL volumetric flask.
The solution was diluted to the volume with Diluent and mixed
well.
[0093] A second working standard solution was prepared as directed
under the standard preparation.
[0094] A portion of the vasopressin control sample was transferred
to an HPLC vial and injected. The control was stable for 120 hours
when stored in autosampler vials at ambient laboratory
conditions.
[0095] To prepare the impurities marker solution, a 0.05% v/v
acetic acid solution was prepared by pipetting 200.0 mL of a 0.25%
v/v acetic acid solution into a 1-L volumetric flask. The solution
was diluted to the desired volume with water and mixed well.
[0096] To prepare the vasopressin impurity stock solutions, the a
solution of each impurity was prepared in a 25 mL volumetric flask
and diluted with 0.05% v/v acetic acid to a concentration suitable
for HPLC injection.
[0097] To prepare the MAA/H-IBA (Methacrylic
Acid/.alpha.-Hydroxy-isobutyric acid) stock solution, a stock
solution containing approximately 0.3 mg/mL H-IBA and 0.01 mg/mL in
0.05% v/v acetic acid was made in a 50 mL volumetric flask.
[0098] To prepare the chlorobutanol diluent, about one gram of
hydrous chlorobutanol was added to 500 mL of water. Subsequently,
0.25 mL of acetic acid was added and the solution was stirred to
dissolve the chlorobutanol.
[0099] To prepare the impurity marker solution, vasopressin powder
was mixed with the impurity stock solutions prepared above.
[0100] The solutions were diluted to volume with the chlorobutanol
diluent. The solutions were aliquoted into individual crimp top
vials and stored at 2-8.degree. C. At time of use, the solutions
were removed from refrigeration (2-8.degree. C.) and allowed to
reach room temperature.
[0101] The vasopressin impurity marker solution was stable for at
least 120 hours when stored in auto-sampler vials at ambient
laboratory conditions. The solution was suitable for use as long as
the chromatographic peaks could be identified based on comparison
to the reference chromatogram.
[0102] To begin the analysis, the HPLC system was allowed to
equilibrate for at least 30 minutes using mobile phase B, followed
by time 0 min gradient conditions until a stable baseline was
achieved.
[0103] The diluent was injected at the beginning of the run, and
had no peaks that interfered with Vasopressin at around 18 minutes
as shown in FIG. 1.
[0104] A single injection of the sensitivity solution was
performed, wherein the signal-to-noise ratio of the Vasopressin was
greater than or equal to ten as shown in FIG. 2.
[0105] A single injection of the impurities marker solution was
then made. The labeled impurities in the reference chromatogram
were identified in the chromatogram of the marker solution based on
their elution order and approximate retention times shown in FIG. 3
and FIG. 4. FIG. 4 is a zoomed in chromatograph of FIG. 3 showing
the peaks that eluted between 15 and 30 minutes. The nomenclature,
structure, and approximate retention times for individual
identified impurities are detailed in TABLE 3.
[0106] A single injection of the working standard solution was made
to ensure that the tailing factor of the vasopressin peak was less
than or equal to about 2.0 as shown in FIG. 5.
[0107] A total of five replicate injections of the working standard
solution were made to ensure that the relative standard deviation
(% RSD) of the five replicate vasopressin peak areas was not more
than 2.0%.
[0108] Two replicate injections of the check standard preparation
were to confirm that the check standard conformity was
99.0%-101.0%. One injection of the control sample was made to
confirm that the assay of the control sample met the control limits
established for the sample.
[0109] Then, one injection of the working standard solution was
made.
[0110] Following the steps above done to confirm system
suitability, a single injection of each sample preparation was
made. The chromatograms were analyzed to determine the vasopressin
and impurity peak areas. The chromatogram is depicted in FIG.
6.
[0111] The working standard solution was injected after 1 to 4
sample injections, and the bracketing standard peak areas were
averaged for use in the calculations to determine peak areas of
vasopressin and associated impurities.
[0112] The relative standard deviation (% RSD) of vasopressin peak
areas for the six injections of working standard solution was
calculated by including the initial five injections from the system
suitability steps above and each of the subsequent interspersed
working standard solution injections. The calculations were done to
ensure that each of the % RSD were not more than 2.0%.
[0113] The retention time of the major peak in the chromatogram of
the sample preparation corresponded to that of the vasopressin peak
in the working standard solution injection that preceded the sample
preparation injection.
[0114] The UV spectrum (200-400 nm) of the main peak in the
chromatogram of the sample preparation compared to the UV spectrum
of vasopressin in the working standard preparation. FIG. 7 depicts
a UV spectrum of a vasopressin sample and FIG. 8 depicts a UV
spectrum of vasopressin standard.
[0115] To calculate the vasopressin units/mL, the following formula
was used:
Vasopressin units / mL = R U R S .times. Conc STD ##EQU00001##
[0116] where:
[0117] R.sub.U=Vasopressin peak area response of Sample
preparation.
[0118] R.sub.S=average vasopressin peak area response of bracketing
standards.
[0119] Conc STD =concentration of the vasopressin standard in
units/mL
[0120] To identify the impurities, the % Impurity and identity for
identified impurities (TABLE 3) that are were greater than or equal
to 0.10% were reported. Impurities were truncated to 3 decimal
places and then rounded to 2 decimal places, unless otherwise
specified.
[0121] The impurities were calculated using the formula below:
% impurity = R I R S .times. Conc STD 20 U / mL .times. 100 %
##EQU00002##
[0122] where:
[0123] R.sub.I=Peak area response for the impurity
[0124] 20 U/mL=Label content of vasopressin
[0125] TABLE 3 below details the chemical formula, relative
retention time (RRT in minutes), molar mass, and structure of
vasopressin and detected impurities.
TABLE-US-00003 TABLE 3 Name Formula Appr. RRT Molar Mass (g)
Vasopressin C.sub.46H.sub.65N.sub.15O.sub.12S.sub.2 1.00 1084.23
(Arginine Vasopressin, AVP) CYFQNCPRG-NH.sub.2 SEQ ID NO.: 1
(disulfide bridge between cys residues) Gly9-vasopressin
C.sub.46H.sub.64N.sub.14O.sub.13S.sub.2 1.07 1085.22 (Gly9-AVP)
CYFQNCPRG SEQ ID NO.: 2 (disulfide bridge between cys residues)
Asp5-vasopressin C.sub.46H.sub.64N.sub.14O.sub.13S.sub.2 1.09
1085.22 (Asp5-AVP) CYFQDCPRG-NH.sub.2 SEQ ID NO.: 3 (disulfide
bridge between cys residues) Glu4-vasopressin
C.sub.46H.sub.64N.sub.14O.sub.13S.sub.2 1.12 1085.22 (G1u4-AVP)
CYFENCPRG-NH.sub.2 SEQ ID NO.: 4 (disulfide bridge between cys
residues) Acetyl-vasopressin
C.sub.48H.sub.67N.sub.15O.sub.13S.sub.2 1.45 1126.27 (Acetyl-AVP)
Ac-CYFQNCPRG-NH.sub.2 SEQ ID NO.: 7 (disulfide bridge between cys
residues) D-Asn-vasopressin C.sub.46H.sub.65N.sub.15O.sub.12S.sub.2
0.97 1084.23 (DAsn-AVP) CYFQ(D-Asn)CPRG-NH.sub.2 SEQ ID NO.: 10
(disulfide bridge between cys residues) Dimeric-vasopressin
C.sub.92H.sub.130N.sub.30O.sub.24S.sub.4 1.22 2168.46 (Dimer-AVP)
(monomers cross linked by disulfide bridges)
Example 2
Investigation of pH.
[0126] To determine a possible pH for a vasopressin formulation
with good shelf life, vasopressin formulations were prepared in 10
mM citrate buffer diluted in isotonic saline across a range of pH.
Stability was assessed via HPLC as in EXAMPLE 1 after incubation of
the formulations at 60.degree. C. for one week. FIG. 9 illustrates
the results of the experiment. The greatest level of stability was
observed at pH 3.5. At pH 3.5, the percent label claim (% LC) of
vasopressin was highest, and the proportion of total impurities was
lowest.
Example 3
Effect of Peptide Stabilizers on Vasopressin Formulation
[0127] To observe the effect of stabilizers on the degradation of
vasopressin, a series of peptide stabilizers were added to a
vasopressin formulation as detailed in TABLE 4. Stability of
vasopressin was assessed via HPLC after incubation of the
formulations at 60.degree. C. for one week.
TABLE-US-00004 TABLE 4 PEG Poloxamer n-Methylpyrrolidone Ethanol
400 Glycerol 188 HPbCD.sup.a (NMP) 1% 1% 1% 1% 1% 1% 10% 10% 10%
10% 10% 10% .sup.aHydroxypropyl beta-Cyclodextrin
[0128] FIG. 10 illustrates the stability of vasopressin in terms of
% label claim at varying concentrations of stabilizer. The results
indicate that the tested stabilizers provided a greater stabilizing
effect at 1% concentration than at 10%. Also, in several cases the
stabilization effect was about 5% to about 10% greater than that
observed in the experiments of EXAMPLE 2.
Example 4
Effect of Buffer and Divalent Metals on Vasopressin Formulation
[0129] To determine whether different combinations of buffers and
use of divalent metals affect vasopressin stability, vasopressin
formulations with varying concentrations of citrate and acetate
buffers and variable concentrations of calcium, magnesium, and zinc
ions were prepared. Solutions of 0 mM, 10 mM, 20 mM, and 80 mM
calcium, magnesium, and zinc were prepared and each was combined
with 1 mM or 10 mM of citrate or acetate buffers to test
vasopressin stability.
[0130] The tested combinations provided vasopressin stability
comparable to that of a vasopressin formulation lacking buffers and
divalent metals. However, that the addition of divalent metal ions
was able to counteract the degradation of vasopressin caused by the
use of a citrate buffer.
Example 5
Effect of Non-Aqueous Solvent Formulations on Vasopressin
Stability
[0131] Several solvents were used to prepare vasopressin
formulations to assess vasopressin stability. The formulations were
prepared at 400 .mu.g/mL and stability was tested via HPLC after
incubation at 60.degree. C. for one week, 40.degree. C. for four
weeks, and 25.degree. C. for four weeks. The examined solvents
included water, DMSO, propylene glycol, PEG300, NMP, glycerol, and
ethanol. None of the tested solvents were able to increase the
stability of vasopressin in solution in comparison to an aqueous
formulation lacking a cosolvent.
Example 6
Illustrative Formulations for Assessment of Vasopressin
Stability
[0132] An aqueous formulation of vasopressin is prepared using 10%
trehalose, 1% sucrose, or 5% NaCl and incubated at 60.degree. C.
for one week, at which point stability of vasopressin is assessed
using HPLC.
[0133] A formulation containing 50 units of vasopressin is
lyophilized. The lyophilate is reconstituted with water and either
100 mg of sucrose or 100 mg of lactose, and the stability of
vasopressin is tested via HPLC after incubation at 60.degree. C.
for one week.
[0134] Co-solvents are added to a vasopressin solution to assess
vasopressin stability. 95% solvent/5% 20 mM acetate buffer
solutions are prepared using propylene glycol, DMSO, PEG300, NMP,
glycerol, and glycerol:NMP (1:1), and used to create formulations
of vasopressin. The stability of vasopressin is tested after
incubation at 60.degree. C. for one week.
[0135] Amino acid and phosphate buffers are tested with vasopressin
to assess vasopressin stability. Buffers of 10 mM glycine,
aspartate, phosphate are prepared at pH 3.5 and 3.8 and used to
create formulations of vasopressin. The stability of vasopressin is
tested after incubation at 60.degree. C. for one week.
[0136] A vasopressin formulation in 10% polyvinylpyrrolidone is
prepared to assess vasopressin stability. The stability of
vasopressin will be tested after incubation at 60.degree. C. for
one week.
[0137] A vasopressin formulation that contains 0.9% saline, 10 mM
acetate buffer, 0.2 unit/mL API/mL in 100 mL of total volume is
prepared. The pH of the solution is varied from pH 3.5-3.8 to test
the stability of vasopressin.
[0138] A vasopressin formulation in about 50% to about 80% DMSO
(for example, about 80%), about 20% to about 50% ethyl acetate (for
example, about 20%), and about 5% to about 30% polyvinylpyrrolidone
(PVP) (for example, about 10% by mass of the formulation) is
prepared to assess vasopressin stability. PVP K12 and PVP K17 are
each independently tested in the formulation. The stability of
vasopressin is tested after incubation at 60.degree. C. for one
week.
[0139] A vasopressin formulation in about 70% to about 95% ethyl
acetate, and about 5% to about 30% PVP is prepared to assess
vasopressin stability. PVP K12 and PVP K17 are each independently
tested in the formulation. The stability of vasopressin is tested
after incubation at 60.degree. C. for one week.
[0140] A vasopressin formulation in 90% DMSO and 10% PVP is
prepared to test vasopressin stability. PVP K12 and PVP K17 are
each independently tested in the formulation. The stability of
vasopressin is tested after incubation at 60.degree. C. for one
week.
Example 7
Illustrative Vasopressin Formulation for Clinical Use
[0141] A formulation for vasopressin that can be used in the clinic
is detailed in TABLE 5 below:
TABLE-US-00005 TABLE 5 Ingredient Function Amount (per mL)
Vasopressin, USP Active Ingredient 20 Units (~0.04 mg)
Chlorobutanol, Hydrous Preservative 5.0 mg NF Acetic Acid, NF pH
Adjustment To pH 3.4-3.6 (~0.22 mg) Water for injection, Diluent QS
USP/EP
Example 8
Illustrative Regimen for Therapeutic Use of a Vasopressin
Formulation
[0142] Vasopressin is indicated to increase blood pressure in
adults with vasodilatory shock (for example, adults who are
post-cardiotomy or septic) who remain hypotensive despite fluids
and catecholamines.
Preparation and Use of Vasopressin.
[0143] Vasopressin is supplied in a carton of 25 multi-dose vials
each containing 1 mL vasopressin at 20 units/mL.
[0144] Vasopressin is stored between 15.degree. C. and 25.degree.
C. (59.degree. F. and 77.degree. F.), and is not frozen.
[0145] Vials of vasopressin are to be discarded 48 hours after
first puncture.
[0146] Vasopressin is prepared according to TABLE 6 below:
TABLE-US-00006 TABLE 6 Mix Fluid Restriction? Final Concentration
Vasopressin Diluent No 0.1 units/mL 2.5 mL (50 units) 500 mL Yes 1
unit/mL 5 mL (100 units) 100 mL
[0147] Vasopressin is diluted in normal saline (0.9% sodium
chloride) or 5% dextrose in water (D5W) prior to use to either 0.1
units/mL or 1 unit/mL for intravenous administration. Unused
diluted solution is discarded after 18 hours at room temperature or
after 24 hours under refrigeration.
[0148] Diluted vasopressin should be inspected for particulate
matter and discoloration prior to use whenever solution and
container permit.
[0149] The goal of treatment with vasopressin is optimization of
perfusion to critical organs, but aggressive treatment can
compromise perfusion of organs, like the gastrointestinal tract,
for which function is difficult to monitor. Titration of
vasopressin to the lowest dose compatible with a
clinically-acceptable response is recommended.
[0150] For post-cardiotomy shock, a dose of 0.03 units/minute is
used as a starting point. For septic shock, a dose of 0.01
units/minute is recommended. If the target blood pressure response
is not achieved, titrate up by 0.005 units/minute at 10- to
15-minute intervals. The maximum dose for post-cardiotomy shock is
0.1 units/minute and for septic shock 0.07 units/minute. After
target blood pressure has been maintained for 8 hours without the
use of catecholamines, taper vasopressin by 0.005 units/minute
every hour as tolerated to maintain target blood pressure.
Vasopressin is provided at 20 units per mL of diluent, which is
packaged as 1 mL of vasopressin per vial, and is diluted prior to
administration.
Contraindications, Adverse Reactions, and Drug-Drug
Interactions.
[0151] Vasopressin is contraindicated in patients with known
allergy or hypersensitivity to 8-L-arginine vasopressin or
chlorobutanol. Additionally, use of vasopressin in patients with
impaired cardiac response can worsen cardiac output.
[0152] Adverse reactions have been observed with the use of
vasopressin, which adverse reactions include bleeding/lymphatic
system disorders, specifically, hemorrhagic shock, decreased
platelets, intractable bleeding; cardiac disorders, specifically,
right heart failure, atrial fibrillation, bradycardia, myocardial
ischemia; gastrointestinal disorders, specifically, mesenteric
ischemia; hepatobiliary disorders, specifically, increased
bilirubin levels; renal/urinary disorders, specifically, acute
renal insufficiency; vascular disorders, specifically, distal limb
ischemia; metabolic disorders, specifically, hyponatremia; and skin
disorders, specifically, and ischemic lesions.
[0153] These reactions are reported voluntarily from a population
of uncertain size. Thus, reliable estimation of frequency or
establishment of a causal relationship to drug exposure is
unlikely.
[0154] Vasopressin has been observed to interact with other drugs.
For example, use of vasopressin with catecholamines is expected to
result in an additive effect on mean arterial blood pressure and
other hemodynamic parameters. Use of vasopressin with indomethacin
can prolong the effect of vasopressin on cardiac index and systemic
vascular resistance. Indomethacin more than doubles the time to
offset for vasopressin's effect on peripheral vascular resistance
and cardiac output in healthy subjects.
[0155] Further, use of vasopressin with ganglionic blocking agents
can increase the effect of vasopressin on mean arterial blood
pressure. The ganglionic blocking agent tetra-ethylammonium
increases the pressor effect of vasopressin by 20% in healthy
subjects.
[0156] Use of vasopressin with furosemide increases the effect of
vasopressin on osmolar clearance and urine flow. Furosemide
increases osmolar clearance 4-fold and urine flow 9-fold when
co-administered with exogenous vasopressin in healthy subjects.
[0157] Use of vasopressin with drugs suspected of causing SIADH
(Syndrome of inappropriate antidiuretic hormone secretion), for
example, SSRIs, tricyclic antidepressants, haloperidol,
chlorpropamide, enalapril, methyldopa, pentamidine, vincristine,
cyclophosphamide, ifosfamide, and felbamate can increase the
pressor effect in addition to the antidiuretic effect of
vasopressin. Additionally, use of vasopressin with drugs suspected
of causing diabetes insipidus for example, demeclocycline, lithium,
foscarnet, and clozapine can decrease the pressor effect in
addition to the antidiuretic effect of vasopressin.
[0158] Halothane, morphine, fentanyl, alfentanyl and sufentanyl do
not impact exposure to endogenous vasopressin.
Use of Vasopressin in Specific Populations.
[0159] Vasopressin is a Category C drug for pregnancy.
[0160] Due to a spillover into the blood of placental
vasopressinase, the clearance of exogenous and endogenous
vasopressin increases gradually over the course of a pregnancy.
During the first trimester of pregnancy the clearance is only
slightly increased. However, by the third trimester the clearance
of vasopressin is increased about 4-fold and at term up to 5-fold.
Due to the increased clearance of vasopressin in the second and
third trimester, the dose of vasopressin can be up-titrated to
doses exceeding 0.1 units/minute in post-cardiotomy shock and 0.07
units/minute in septic shock. Vasopressin can produce tonic uterine
contractions that could threaten the continuation of pregnancy.
After delivery, the clearance of vasopressin returns to
preconception levels.
Overdosage.
[0161] Overdosage with vasopressin can be expected to manifest as a
consequence of vasoconstriction of various vascular beds, for
example, the peripheral, mesenteric, and coronary vascular beds,
and as hyponatremia. In addition, overdosage of vasopressin can
lead less commonly to ventricular tachyarrhythmias, including
Torsade de Pointes, rhabdomyolysis, and non-specific
gastrointestinal symptoms. Direct effects of vasopressin overdose
can resolve within minutes of withdrawal of treatment.
Pharmacology of Vasopressin.
[0162] Vasopressin is a polypeptide hormone that causes contraction
of vascular and other smooth muscles and antidiuresis, which can be
formulated as a sterile, aqueous solution of synthetic arginine
vasopressin for intravenous administration. The 1 mL solution
contains vasopressin 20 units/mL, chlorobutanol, NF 0.5% as a
preservative, and water for injection, USP adjusted with acetic
acid to pH 3.4-3.6.
[0163] The chemical name of vasopressin is Cyclo (1-6)
L-Cysteinyl-L-Tyrosyl-L-Phenylalanyl-L-Glutaminyl-L-Asparaginyl-L-Cystein-
yl-L-Prolyl-L-Arginyl-L-Glycinamide. Vasopressin is a white to
off-white amorphous powder, freely soluble in water. The structural
formula of vasopressin is:
##STR00002##
[0164] One mg of vasopressin is equivalent to 530 units.
[0165] The vasoconstrictive effects of vasopressin are mediated by
vascular V1 receptors. Vascular V1 receptors are directly coupled
to phopholipase C, resulting in release of calcium, leading to
vasoconstriction. In addition, vasopressin stimulates antidiuresis
via stimulation of V2 receptors which are coupled to adenyl
cyclase.
[0166] At therapeutic doses, exogenous vasopressin elicits a
vasoconstrictive effect in most vascular beds including the
splanchnic, renal, and cutaneous circulation. In addition,
vasopressin at pressor doses triggers contractions of smooth
muscles in the gastrointestinal tract mediated by muscular
V1-receptors and release of prolactin and ACTH via V3 receptors. At
lower concentrations typical for the antidiuretic hormone,
vasopressin inhibits water diuresis via renal V2 receptors. In
patients with vasodilatory shock, vasopressin in therapeutic doses
increases systemic vascular resistance and mean arterial blood
pressure and reduces the dose requirements for norepinephrine.
[0167] Vasopressin tends to decrease heart rate and cardiac output.
The pressor effect is proportional to the infusion rate of
exogenous vasopressin. Onset of the pressor effect of vasopressin
is rapid, and the peak effect occurs within 15 minutes. After
stopping the infusion, the pressor effect fades within 20 minutes.
There is no evidence for tachyphylaxis or tolerance to the pressor
effect of vasopressin in patients.
[0168] At infusion rates used in vasodilatory shock (0.01-0.1
units/minute), the clearance of vasopressin is 9 to 25 mL/min/kg in
patients with vasodilatory shock. The apparent half-life of
vasopressin at these levels is .ltoreq.10 minutes. Vasopressin is
predominantly metabolized and only about 6% of the dose is excreted
unchanged in urine. Animal experiments suggest that the metabolism
of vasopressin is primarily by liver and kidney. Serine protease,
carboxipeptidase and disulfide oxido-reductase cleave vasopressin
at sites relevant for the pharmacological activity of the hormone.
Thus, the generated metabolites are not expected to retain
important pharmacological activity.
Carcinogenesis, Mutagenesis, Impairment of Fertility.
[0169] Vasopressin was found to be negative in the in vitro
bacterial mutagenicity (Ames) test and the in vitro Chinese hamster
ovary (CHO) cell chromosome aberration test. In mice, vasopressin
can have an effect on function and fertilizing ability of
spermatozoa.
Clinical studies.
[0170] Increases in systolic and mean blood pressure following
administration of vasopressin were observed in seven studies in
septic shock and eight studies in post-cardiotomy vasodilatory
shock.
EMBODIMENTS
[0171] The following non-limiting embodiments provide illustrative
examples of the invention, but do not limit the scope of the
invention.
[0172] In some embodiments, the invention provides a pharmaceutical
composition comprising, in a unit dosage form: a) from about 0.01
mg/mL to about 0.07 mg/mL of vasopressin, or a
pharmaceutically-acceptable salt thereof; and b) a polymeric
pharmaceutically-acceptable excipient in an amount that is from
about 1% to about 10% by mass of the unit dosage form or the
pharmaceutically-acceptable salt thereof, wherein the unit dosage
form exhibits from about 5% to about 10% less degradation of the
vasopressin or the pharmaceutically-acceptable salt thereof after
storage for about 1 week at about 60.degree. C. than does a
corresponding unit dosage form, wherein the corresponding unit
dosage form consists essentially of: A) vasopressin, or a
pharmaceutically-acceptable salt thereof; and B) a buffer having
acidic pH. In some embodiments, the polymeric
pharmaceutically-acceptable excipient comprises a polyalkylene
oxide moiety. In some embodiments, the polymeric
pharmaceutically-acceptable excipient is a polyethylene oxide. In
some embodiments, the polymeric pharmaceutically-acceptable
excipient is a poloxamer. In some embodiments, the unit dosage form
has an amount of the polymeric pharmaceutically-acceptable
excipient that is about 1% the amount of the vasopressin or the
pharmaceutically-acceptable salt thereof. In some embodiments, the
first unit dosage form exhibits about 10% less degradation of the
vasopressin or the pharmaceutically-acceptable salt thereof after
storage for about 1 week at about 60.degree. C. than does the
corresponding unit dosage form. In some embodiments, the unit
dosage form further comprises SEQ ID NO. 2. In some embodiments,
the composition further comprises SEQ ID NO. 3. In some
embodiments, the composition further comprises SEQ ID NO. 4. In
some embodiments, the unit dosage form is an injectable of about 1
mL volume. In some embodiments, the unit dosage form consists
essentially of: a) about 0.04 mg/mL of vasopressin, or the
pharmaceutically-acceptable salt thereof; b) the polymeric
pharmaceutically-acceptable excipient in an amount that is from
about 1% to about 10% by mass of the vasopressin or the
pharmaceutically-acceptable salt thereof; and c) a plurality of
peptides, wherein each of the peptides has from 88% to 90% sequence
homology to the vasopressin or the pharmaceutically-acceptable salt
thereof. In some embodiments, one of the plurality of peptides is
SEQ ID NO.: 2. In some embodiments, one of the plurality of
peptides is SEQ ID NO.:3. In some embodiments, wherein one of the
plurality of peptides is SEQ ID NO.: 4. In some embodiments, the
buffer has a pH of about 3.5.
Sequence CWU 1
1
1719PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideC-term NH2 1Cys Tyr Phe Gln Asn Cys Pro Arg Gly 1
5 29PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 2Cys Tyr Phe Gln Asn Cys Pro Arg Gly 1 5
39PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideC-term NH2 3Cys Tyr Phe Gln Asp Cys Pro Arg Gly 1
5 49PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideC-term NH2 4Cys Tyr Phe Glu Asn Cys Pro Arg Gly 1
5 59PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptide 5Cys Tyr Phe Glu Asn Cys Pro Arg Gly 1 5
69PRTArtificial SequenceDescription of Artificial Sequence
Synthetic peptideN-term AcC-term NH2 6Cys Tyr Phe Gln Asp Cys Pro
Arg Gly 1 5 79PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptideN-term AcC-term NH2 7Cys Tyr Phe Gln Asn
Cys Pro Arg Gly 1 5 89PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideC-term NH2 8Cys His Phe Gln
Asn Cys Pro Arg Gly 1 5 99PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideC-term NH2 9Cys Tyr Phe Gln
Asn Cys Leu Arg Gly 1 5 109PRTArtificial SequenceDescription of
Artificial Sequence Synthetic peptideMOD_RES(5)..(5)D-AsnC-term NH2
10Cys Tyr Phe Gln Asn Cys Pro Arg Gly 1 5 119PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(1)..(1)D-CysC-term NH2 11Cys Tyr Phe Gln Asn Cys Pro
Arg Gly 1 5 129PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptideMOD_RES(2)..(2)D-TyrC-term NH2 12Cys Tyr
Phe Gln Asn Cys Pro Arg Gly 1 5 139PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(3)..(3)D-PheC-term NH2 13Cys Tyr Phe Gln Asn Cys Pro
Arg Gly 1 5 149PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptideMOD_RES(4)..(4)D-GlnC-term NH2 14Cys Tyr
Phe Gln Asn Cys Pro Arg Gly 1 5 159PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(6)..(6)D-CysC-term NH2 15Cys Tyr Phe Gln Asn Cys Pro
Arg Gly 1 5 169PRTArtificial SequenceDescription of Artificial
Sequence Synthetic peptideMOD_RES(7)..(7)D-ProC-term NH2 16Cys Tyr
Phe Gln Asn Cys Pro Arg Gly 1 5 179PRTArtificial
SequenceDescription of Artificial Sequence Synthetic
peptideMOD_RES(8)..(8)D-ArgC-term NH2 17Cys Tyr Phe Gln Asn Cys Pro
Arg Gly 1 5
* * * * *