NZ617195B2 - Short-acting dihydropyridines (clevidipine) for use in reducing stroke damage - Google Patents
Short-acting dihydropyridines (clevidipine) for use in reducing stroke damage Download PDFInfo
- Publication number
- NZ617195B2 NZ617195B2 NZ617195A NZ61719512A NZ617195B2 NZ 617195 B2 NZ617195 B2 NZ 617195B2 NZ 617195 A NZ617195 A NZ 617195A NZ 61719512 A NZ61719512 A NZ 61719512A NZ 617195 B2 NZ617195 B2 NZ 617195B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- stroke
- clevidipine
- medicament
- minutes
- pharmaceutically acceptable
- Prior art date
Links
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- 229960003597 clevidipine Drugs 0.000 title claims abstract description 36
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 title 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The disclosure relates to the use of clevidipine or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for reducing stroke damage in a subject with a stroke. The medicament may further comprise a lipid, an emulsifier, an antimicrobial agent, a tonicity modifier, an antioxidant, and a co-emulsifier. an antioxidant, and a co-emulsifier.
Description
SHORT-ACTING DIHYDROPYRIDINES (CLEVIDIPINE) FOR USE IN
REDUCING STROKE DAMAGE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 61/470,780,
filed on April 1, 2011, the contents of which are incorporated by reference herein, in their
entireties and for all purposes.
BACKGROUND OF THE INVENTION
A stroke is an interruption of blood supply to the brain because a blood vessel is
blocked or bursts open. When blood flow is stopped, the brain cannot get oxygen and
nutrients, and brain cells can die causing permanent damage. The effects of a stroke depend
on which part of the brain is injured and how severely it is affected. A very severe stroke
can cause sudden death.
After stroke, blood pressure is often elevated within hours. For every 10-mm Hg
increase over 180 mm Hg, the risk of neurological deterioration increases by 40% and the
risk of poor outcome increases by 23%. Adams et al., Stroke 38:1655-1711, 1670 (2007).
Lowering blood pressure can reduce damage caused by the stroke, for example, formation
of brain edema, hemorrhagic transformation of the infarction, vascular damage, and early
recurrent stroke. Aggressively lowering blood pressure among stroke patients however may
lead to neurological worsening by reducing perfusion pressure to ischemic areas of the brain.
Adams et al., Stroke 38:1655-1711, 1670 (2007). Thus, blood pressure management in
stroke patients poses a dilemma since severe elevations of blood pressure may place
inordinate strain on the heart and other vital organs yet lowering this elevated blood
pressure may reduce the blood flow to areas of the brain that are already receiving lesser
amounts of blood. Accordingly, the American Heart Association recommends treating
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arterial hypertension in acute ischemic stroke patients with anti-hypertensive agents having
“the potential for a rapid reversal if the drop in blood pressure leads to neurological
worsening” with the goal to avoid overtreating patients with a stroke. Adams et al., Stroke
38:1655-1711, 1670-1671 (2007).
Therefore, there remains a need for an anti-hypertensive drug that provides an
optimal balance of efficacy, precision (titratability), and safety in stroke patients, especially
acutely unstable patients. It is an object of the present invention to go some way towards
meeting this need and/or to provide the public with a useful choice.
SUMMARY OF THE INVENTION
The present invention provides a use of clevidipine, or a pharmaceutically
acceptable salt or ester thereof, in the manufacture of a medicament for reducing stroke
damage in a subject with a stroke, wherein the clevidipine, or a pharmaceutically acceptable
salt or ester thereof, has a half life in plasma of less than 30 minutes.
Also described is the use of a short active dihydropyridine compound for reducing
stroke damage and/or lowering blood pressure in a subject with a stroke, and
pharmaceutical compositions or medicaments comprising the short active dihydropyridine
compound.
A method for reducing stroke damage in a subject with a stroke in need thereof is
also described. Also described is a method for lowering blood pressure and reducing stroke
damage in a subject with a stroke in need thereof. These methods comprise administering
to the subject an effective amount of a pharmaceutical composition comprising a short
acting dihydropyridine compound. Discontinuation of administering the short acting
dihydropyridine compound may allow return of the blood pressure to a pre-treatment level
in the subject within 30 minutes. The short acting dihydropyridine compound may have a
short half life in plasma of less than 30 minutes, and is preferably clevidipine or a
pharmaceutically acceptable salt or ester thereof.
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The method may further comprise titrating the dose of the pharmaceutical
composition from an initial dose to a maintenance dose by multiple dosage adjustments,
whereby a desired blood pressure is achieved in the subject. The time interval between
dosage adjustments may be 5-10 minutes. Each dosage adjustment is preferably less than
doubling.
The subject is a mammal, preferably a human. The subject may have severe
hypertension.
The stroke may be an ischemic stroke or a hemorrhragic stroke. The ischemic stroke
may be a transient ischemic attack. The hemorrhagic stroke may be due to intracranial
hemorrhage. In particular, the intracranial hemorrhage may be intracerebral hemorrhage
(ICH).
The stroke damage may be neurological worsening, brain injury or death. It may be
permanent.
In a method according to the present disclosure, the pharmaceutical composition
may comprise 0.001-20 mg/ml, preferably 0.5 mg/ml, clevidipine or a pharmaceutically
acceptable salt or ester thereof. The pharmaceutical composition may further comprise a
pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition
has a pH of 6.0-8.8.
The pharmaceutical composition may be an emulsion. The emulsion may comprise
a lipid at 2-30% mg/ml and an emulsifier at 0.2-2 mg/ml. The pharmaceutical composition
may further comprise one or more agents selected from the group consisting of an
antimicrobial agent, a tonicity modifier, an antioxidant, and a co-emulsifier.
For each of the methods described herein, a medicament comprising an effective
amount of a short acting dihydropyridine compound is provided. The medicament is useful
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for reducing stroke damage and/or lowering blood pressure in a subject. The short acting
dihydropyridine compound preferably has a half life in plasma of less than 30 minutes.
More preferably, the short acting dihydropyridine compound is clevidipine or a
pharmaceutically acceptable salt or ester thereof.
A medicament described herein may comprise about 0.001-20 mg/ml, preferably 0.5
mg/ml, clevidipine or a pharmaceutically acceptable salt or ester thereof (e.g., clevidipine
butyrate). The medicament may further comprise a pharmaceutically acceptable carrier or
diluent. The medicament may be an emulsion, comprising a lipid at 2-30% mg/ml and an
emulsifier at 0.2-2 mg/ml. The medicament may further comprise an antimicrobial agent, a
tonicity modifier, an antioxidant, and/or a co-emulsifier. The pH of the medicament is in
the range of 6.0-8.8.
A method for preparing a medicament useful for reducing stroke damage and/or
lowering blood pressure in a subject with a stroke is described. The method may comprise
admixing a short acting dihydropyridine compound with a pharmaceutically acceptable
carrier or diluent. The method may also comprise admixing a short acting dihydropyridine
compound with a lipid, an emulsifier, and water. The method may further comprise adding
an antimicrobial agent, a tonicity modifier, an antioxidant, and/or a co-emulsifier. The
method may also further comprise adjusting the pH of the admixture to 6.0-8.8; and/or
placing the medicament in a sterile pre-filled syringe.
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure is based on the discovery that clevidipine, a short acting
dihydropyridine compound, is effective in reducing stroke damage and/or lowering blood
pressure in a patient with a stroke. In particular, clevidipine has “the potential for a rapid
reversal if the drop in blood pressure leads to neurological worsening” as recommended by
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the American Stroke Association for an anti-hypertensive agent for patients with a stroke.
Clevidipine provides the optimal balance of efficacy, precision (titratability), and safety.
Clevidipine is a dihydropyridine L-type calcium channel blocker. Having a
very short half-life (about 1 minute), clevidipine exhibits rapid onset of activity (2 to 4
minutes) and rapid offset of activity (full offset of activity in 5 to 15 minutes). The chemical
structure of clevidipine is shown in Formula I.
Formula I
The term “clevidipine” as used herein encompasses the compound of Formula I, as
well as tautomeric, enantiomeric and diastereomeric forms thereof, and racemic mixtures
thereof, other chemically active forms thereof, and pharmaceutically acceptable salts, esters,
isomers, stereo isomers, crystalline and amorphous forms of these compounds. One
particular example is clevidipine butyrate. These alternative forms and salts, processes for
their production, and pharmaceutical compositions comprising them, are well known in the
art and set forth in U.S. Patent Nos. 5,856,346, 5,739,152, and 6,350,877, as well as
International Patent Application Nos. PCT/US09/004399 and PCT/US09/52127.
Described herein are various methods, including a method for reducing stroke
damage in a subject with a stroke in need thereof, and a method for lowering blood pressure
and reducing stroke damage in a subject with a stroke in need thereof. These methods
comprise administering to the subject an effective amount of a pharmaceutical composition
comprising a short acting dihydropyridine compound. An example of the short acting
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dihydropyridine compound is clevidipine. Other short acting dihydropyridine compounds
may include compounds corresponding to formula I as set forth in U.S. Patent No.
,739,152, and formula I as set forth in U.S. Patent No. 5,856,346, and pharmaceutical
acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms thereof.
The short acting dihydropyridine compound may have a half life in plasma of less
than about 30, 15, 10, 5, or 2 minutes, preferably less than about 10 minutes, more
preferably less than about 5 minutes, most preferably less than about 2 minutes. The short
acting dihydropyridine compound has a rapid onset of activity as well as a rapid offset of
activity. A short acting drug reaches steady plasma drug concentration quickly (e.g., within
less than about one hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, or 5 minutes after
starting drug administration), and gets cleared quickly (e.g., within about five hours, three
hours, one hour, 30 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes, 2 minutes, 1
minute, or 30 seconds after ending drug administration). The full offset of activity may be
achieved within about one hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes,
3 minutes, 2 minutes, or 1 minute, preferably within 5-15 minutes. The short acting
dihydropyridine compound is preferably clevidipine or a pharmaceutically acceptable salt or
ester thereof.
A method described herein may comprise titrating the dose of the pharmaceutical
composition from an initial dose to a maintenance dose by multiple dosage adjustments
such that a desired blood pressure is achieved in the subject. The initial dose may be about
0.1-20 mg/hour, preferably about 1-2 mg/hour, of clevidipine or a pharmaceutically
acceptable salt or ester thereof. The maintenance dose may be about 0.1-50, 1-32, 1-16, or
4-6 mg/hour of clevidipine or a pharmaceutically acceptable salt or ester thereof. The time
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interval between dosage adjustments is about 1- 30 minutes, preferably 2-20 minutes, more
preferably about 5-10 minutes. Each dosage adjustment is preferably less than doubling.
The stroke may be ischemic or hemorrhagic. An ischemic stroke may be due to
thrombosis or embolism, which may be of cardiac origin. An ischemic stroke may be a
transient ischemic attack. It may also be total anterior circulation infarct (TACI), partial
anterior circulation infarct (PACI), lacunar infarct (LACI), or posterior circulation infarct
(POCI). A hemorrhagic stroke may be due to intracerebral hemorrhage, which may be
intra-axial or extra-axial. The intra-axial hemorrhage may be intraparentchymal or
intraventricular hemorrhage. The extra-axial hemorrhage may be epidural, subdural or
subarachnoid hemorrhage. In particular, the intracranial hemorrhage may be intracerebral
hemorrhage (ICH). Further, the stroke may be selected from the group consisting of right-
hemisphere stroke, left-hemisphere stroke, cerebella stroke, and brain stem stroke.
In a method described herein, the stroke damage may be neurological worsening (or
neurological deterioration), which may take place within about 3 months, 1 month, 1 week,
2 days or 1 day after the stroke. The stroke damage may be brain injury caused by, for
example, a hematoma. The hematoma may be subgaleal hematoma, cephalohematoma,
epidural hematoma, subdural hematoma, subarachnoid hematoma, or othematoma.
Reducing stroke damage may be, for example, reducing the expansion (or size) of a brain
hematoma. The stroke damage may also be brain edema, cerebral infarction, hemorrhagic
transformation of cerebral infarction, vascular damage, or a recurrent stroke. The recurrent
stroke may occur within about 6 months, 3 months, 1 month, 2 weeks or 1 week after the
stroke. Further, the stroke damage may be hypoxia, increased body temperature,
hypoglycemia, hyperglycemia or death, which may occur within about 3 months, 1 month, 1
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week, 2 days or 1 day after the stroke. In some embodiments, the stroke damage is
permanent.
Discontinuation of administering the short acting dihydropyridine compound may
allow return of the blood pressure to a pre-treatment level in the subject, for example, within
about 30, 20, 15, 10, 5 or 3 minutes, preferably about 15 minutes, more preferably about 10
minutes, most preferably about 5 minutes. The one minute half-life of clevidipine results in
a rapid offset of action with the return of blood pressure to pre-treatment levels within about
-15 minutes of the discontinuation of clevidipine.
The subject is a mammal, for example, a mouse, rat, dog, pig, or human, preferably
a human. The subject may be male or female. The subject may be at least 50, 55, 60 or 65
years old, preferably at least 55 years old. The subject may have severe hypertension,
and/or arterial hypertension. In the subject, the systolic blood pressure may be at least about
160, 180, 185, 220, or 230 mm Hg, and/or the diastolic blood pressure may be at least about
105, 110, 120, or 140 mm Hg.
The subject may have suffered from hypertensive encepthalopathy, aortic dissection,
acute renal failure, acute pulmonary edema, or acute myocardial infarction. The subject
may also have suffered from atrial fibrillation, diabetes, a family history of stroke, a
previous stroke, a previous transient ischemic attack, a heart disease, high cholesterol, or
sickle cell anemia.
The subject may have suffered from thrombosis. The thrombosis may be a large
vessel disease or a small vessel disease. The large vessel disease may be atherosclerosis,
vasoconstriction, aortic, carotid or vertebral artery dissection, an inflammatory disease of a
blood vessel wall, noninflammatory vasculopathy, Moyamoya disease, or fibromuscular
dysplasia. The inflammatory disease of a blood vessel wall may be selected from the group
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consisting of Takayasu arteritis, giant cell arteritis, and vasculitis. The small vessel disease
may be lipohyalinosis, fibrinoid degeneration, or microatheroma.
The subject may have received an anti-hypertensive drug or an anticoagulation drug.
The anti-hypertensive drug may be, for example, thiazide diuretics, angiotensin-converting
enzyme (ACE) inhibitors, calcium channel blockers, beta blockers, or angiotensin II
receptor antagonists. The anticoagulation drug may be warfarin, aspirin, or antiplatelet
drugs.
Clevidipine is an ideal parenteral anti-hypertensive medication as it provides an
optimal balance of efficacy (the ability to rapidly reduce blood pressure to target levels),
safety (the ability to avoid overshoot hypotension, and absence of toxicity and side-effects),
and precision (the ability to hit and maintain blood pressure target levels while avoiding
overshoot, and the speed with which titration can be accomplished). Additionally, in
patients with pre-existing or inter-current hepatic or renal dysfunction, agents that are
metabolized renally or hepatically are unsuitable.
Because of its rapid onset and offset, clevidipine can be titrated in a manner
allowing rapid upward and downward adjustments in dose as clinical circumstances dictate,
and substantially reducing the risk of overshoot hypotension, which is especially important
in hemodynamically unstable patients. Clevidipine is rapidly metabolized via blood and
tissue esterases, and does not accumulate in tissues. It can therefore be safely administered
to hepatically and renally compromised patients.
The term “an effective amount” refers to an amount of a pharmaceutical
composition comprising a short acting dihydropyridine compound (e.g., clevidipine)
required to achieve a stated goal (e.g., reducing stroke damage and/or lowering blood
pressure). The effective amount of the pharmaceutical compositions comprising a short
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acting dihydropyridine compound (e.g., clevidipine) may vary depending upon the stated
goals, the physical characteristics of the subject, the nature and severity of the stroke
damage and/or hypertension, existence of related or unrelated medical conditions, the nature
of the short acting dihydropyridine compound, the composition comprising the short acting
dihydropyridine compound (e.g., clevidipine), the means of administering the drug to the
subject, and the administration route. A specific dose for a given subject may generally be
set by the judgment of a physician. The pharmaceutical composition may be administered
to the subject in one or multiple doses.
The pharmaceutical composition may comprise about 0.001-20, 0.005-1, 0.01-1, or
0.05-0.5 mg/ml, preferably 0.5 mg/ml, clevidipine or a pharmaceutically acceptable salt or
ester thereof. The pharmaceutical composition may further comprise a pharmaceutically
acceptable carrier or diluent. Carriers, diluents and excipients suitable in the
pharmaceutical composition are well known in the art. Suitable pharmaceutical
compositions include the formulations (e.g., solutions and emulsions) described in U.S.
Patent Nos. 5,856,346, 5,739,152, and 6,350,877, as well as International Patent
Application Nos. PCT/US09/004399 and PCT/US09/52127.
The pharmaceutical composition may have a pH of about 5.6-10.0, preferably 6.0-
8.8, more preferably 6.5-8.0. For example, the pH may be about 6.2, 6.5, 6.75, 7.0, or 7.5.
The pharmaceutical composition may be an emulsion, freeze dried material from the
emulsion, or a concentrate for reconstitution (self-emulsifying system). Preferably, the
pharmaceutical composition is an emulsion. The emulsion may comprise a short acting
dihydropyridine compound, a lipid, an emulsifier, and water or a buffer. The lipid may be
present at about 2-30% mg/ml, and selected from the group consisting of soybean oil,
safflower seed oil, olive oil, cottonseed oil, sunflower oil, sesame oil, peanut oil, corn oil,
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medium chain triglycerides, triacetin, propylene glycol diesters, monoglycerides, and a
mixture of two or more thereof. The emulsifier may be present at about 0.2-2 mg/ml, and
be selected from the group consisting of egg yolk phospholipids, soybean phospholipids,
synthetic phosphatidyl cholines, purified phosphatidyl cholines and hydrogenated
phosphatidyl choline, and mixtures of two or more thereof.
The pharmaceutical composition may also comprise an antimicrobial agent, a
tonicity modifier, an antioxidant, and/or a co-emulsifier. The antimicrobial agent may be
present at about 0.01-1 mg/ml, and selected from the group consisting of benzyl alcohol,
EDTA, sodium ascorbate, citric acid, and mixtures, derivatives, and salts thereof. The
tonicity modifier may be present at about 2-3 mg/ml. The antioxidant may be present at
about 0.01-1 mg/ml, and selected from the group consisting of sodium ascorbate, sodium
citrate, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
propyl gallate, tocopherol, and a pharmaceutically acceptable salt thereof. The co-emulsifier
is present at about 0.01-2 mg/ml, and may be selected from the group consisting of glycerol
(or glycerin), poloxamers, Cremophor , poloxamines, polyoxyethylene stearates,
polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polysorbates, tocopherol
PEG succinate, cholic acid, deoxycholic acid, oleic acid, and pharmaceutically acceptable
salts thereof.
The pharmaceutical compositions described herein may be formulated, for example,
for oral, sublingual, intranasal, intraocular, rectal, transdermal, mucosal, topical or
parenteral administration. Parenteral administration may include intradermal, subcutaneous
(s.c., s.q., sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal (i.p.), intra-
arterial, intramedulary, intracardiac, intra-articular (joint), intrasynovial (joint fluid area),
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intracranial, intraspinal, and intrathecal (spinal fluids). Any device suitable for parenteral
injection or infusion of drug formulations may be used for such administration. For
example, the pharmaceutical composition may be contained in a sterile pre-filled syringe.
According to the present disclosure, the pharmaceutical compositions are preferably
administered to the subject in a parental dosage form, more preferably in an intravenous
dosage form. The intravenous dosage form may be a bolus intravenous dosage form or a
continuous intravenous infusion dosage form, preferably a continuous intravenous infusion
dosage form.
When administered as a continuous intravenous infusion dosage form, the
pharmaceutical composition may be administered to the subject at about 0.1-100, 0.1-50,
0.1-25, 0.1-10, 0.1-7.5, 0.1-5, 0.1-2.5, 0.1-2, 0.1-1, or 0.1-0.5 μg clevidipine, or a
pharmaceutically acceptable salt or ester thereof, per kg body weight per minute (e.g., about
0.1, 0.5, 1, 2, 5, 7.5, 10, 15, 20, 25, or 30 μg/kg/min), preferably about 1-10 μg/kg/min. The
pharmaceutical composition may be administered continuously for a period of at least about
0.1, 0.2, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 hours.
In some embodiments, medicaments comprising an effective amount of a short
acting dihydropyridine compound are described. The medicaments are useful for reducing
stroke damage and/or lowering blood pressure. The short acting dihydropyridine compound
preferably has a short half life in plasma (e.g., less than about 30, 15, 10, 5, or 2 minutes).
The short acting dihydropyridine compound is preferably clevidipine or a pharmaceutically
acceptable salt or ester thereof.
The medicament may comprise about 0.001-20, 0.005-1, 0.01-1, or 0.05-0.5 mg/ml,
preferably about 0.5 mg/ml, clevidipine or a pharmaceutically acceptable salt or ester
~ 13 ~
thereof. The medicament may further comprise a pharmaceutically acceptable carrier or
diluent.
The medicament may be an emulsion, comprising a lipid and an emulsifier. The
lipid may be present at about 2-30% mg/ml. The emulsifier may be present at about 0.2-2
mg/ml.
The medicament may further comprise one or more agents selected from the group
consisting of an antimicrobial agent, a tonicity modifier, an antioxidant, and a co-emulsifier,
which may be present at about 0.01-1 mg/ml, 2-3 mg/ml, 0.01-1 mg/ml, and 0.01-2 mg/ml,
respectively.
The medicament may have a pH of about 5.6-10.0, preferably about 6.0-8.8, more
preferably about 6.5-8.0. For example, the pH may be about 6.2, 6.5, 6.75, 7.0, or 7.5. The
medicament may be contained in a sterile pre-filled syringe.
In some other embodiments, methods for preparing the medicaments according to
the present disclosure are described. The preparation methods may comprise a short acting
dihydropyridine compound with a pharmaceutically acceptable carrier or diluent. The
preparation methods may also comprise combining a short acting dihydropyridine
compound with a lipid, an emulsifier, and water. The short acting dihydropyridine
compound may have a short half life in plasma (e.g., less than about 30, 15, 10, 5, or 2
minutes). Preferably, the short acting dihydropyridine compound is clevidipine or a
pharmaceutically acceptable salt or ester thereof. The methods may further comprise
adding one or more agents selected from the group consisting of an antimicrobial agent, a
tonicity modifier, an antioxidant, and a co-emulsifier; adjusting the pH of the admixture to
about 6.0-8.8; and/or placing the medicament in a sterile pre-filled syringe.
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The term “about” as used herein when referring to a measurable value such as an
amount, a percentage, and the like, is meant to encompass variations of ±20% or ±10%,
more preferably ±5%, even more preferably ±1%, and still more preferably ±0.1% from the
specified value, as such variations are appropriate.
The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification, and claims which
include the term “comprising”, it is to be understood that other features that are additional to
the features prefaced by this term in each statement or claim may also be present. Related
terms such as “comprise” and “comprised” are to be interpreted in similar manner.
All documents, books, manuals, papers, patents, published patent applications,
guides, abstracts, and other references cited herein are incorporated by reference in their
entirety. Other embodiments of the invention will be apparent to those skilled in the art
from consideration of the specification and practice of the invention disclosed herein. It is
intended that the specification and examples be considered as exemplary only, with the true
scope and spirit of the invention being indicated by the following claims.
In the description in this specification reference may be made to subject matter that
is not within the scope of the claims of the current application. That subject matter should
be readily identifiable by a person skilled in the art and may assist in putting into practice
the invention as defined in the claims of this application.
Claims (10)
1. Use of clevidipine, or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for reducing stroke damage in a subject with a stroke, wherein the clevidipine, or pharmaceutically acceptable salt thereof, has a 5 half life in plasma of less than 30 minutes.
2. The use of claim 1, wherein the medicament comprises 0.001-20 mg/ml clevidipine or a pharmaceutically acceptable salt or ester thereof. 10
3. The use of any one of claims 1 or claim 2, wherein the medicament is an emulsion.
4. The use of claim 3, wherein the emulsion comprises a lipid at 2-30% mg/ml. 15
5. The use of claim 3, wherein the emulsion comprises an emulsifier at 0.2-2 mg/ml.
6. The use of any one of claims 1-5, wherein the medicament comprises one or more agents selected from the group consisting of an antimicrobial agent, a tonicity 20 modifier, an antioxidant, and a co-emulsifier.
7. The use of any one of claims 1-6, wherein the medicament has a pH of 6.0-
8.8. 25 8. The use of any one of claims 1-7, wherein the medicament is contained in a sterile pre-filled syringe. ~ 16 ~
9. The use of any one of claims 1-8, wherein the medicament comprises a pharmaceutically acceptable carrier or diluent.
10. A use as claimed in claim 1, substantially as herein described or exemplified 5 with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161470780P | 2011-04-01 | 2011-04-01 | |
US61/470,780 | 2011-04-01 | ||
PCT/US2012/031449 WO2012135617A1 (en) | 2011-04-01 | 2012-03-30 | Short -acting dihydropyridines (clevidipine) for use in reducing stroke damage |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617195A NZ617195A (en) | 2015-09-25 |
NZ617195B2 true NZ617195B2 (en) | 2016-01-06 |
Family
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