U.S. patent application number 12/571039 was filed with the patent office on 2010-08-12 for novel parenteral carbamazepine formulation.
Invention is credited to Angela Birnbaum, James Cloyd, Stephen D. Collins, Ilo Leppik.
Application Number | 20100204178 12/571039 |
Document ID | / |
Family ID | 42540930 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204178 |
Kind Code |
A1 |
Cloyd; James ; et
al. |
August 12, 2010 |
NOVEL PARENTERAL CARBAMAZEPINE FORMULATION
Abstract
The present invention is directed to a
carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine. The
carbamazepine-cyclodextrin inclusion complex is prepared by the
admixture of a modified cyclodextrin and carbamazepine in a
physiologically acceptable fluid. Modified cyclodextrins include
2-hydroxypropyl-beta-cyclodextrin and sulfoalkyl cyclodextrins.
More particularly, the sulfoalkyl cyclodextrins are those described
and disclosed in U.S. Pat. Nos. 5,134,127 and 5,376,645. A
physiologically acceptable fluid includes sterile isotonic water,
Ringer's lactate, D5W (5% dextrose in water), physiological saline,
and similar fluids suitable for parenteral administration.
Inventors: |
Cloyd; James; (Edina,
MN) ; Birnbaum; Angela; (Minneapolis, MN) ;
Leppik; Ilo; (Minneapolis, MN) ; Collins; Stephen
D.; (Lake Forest, IL) |
Correspondence
Address: |
Edward P. Gamson;Suite 2200
120 S. Riverside Plaza
Chicago
IL
60606-3945
US
|
Family ID: |
42540930 |
Appl. No.: |
12/571039 |
Filed: |
September 30, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11542520 |
Oct 2, 2006 |
|
|
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12571039 |
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Current U.S.
Class: |
514/58 ;
536/123.1; 536/124 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 47/40 20130101; A61K 31/724 20130101; C08B 37/0012 20130101;
C08B 37/0015 20130101; A61P 25/08 20180101; A61K 9/0019
20130101 |
Class at
Publication: |
514/58 ;
536/123.1; 536/124 |
International
Class: |
A61K 31/724 20060101
A61K031/724; C08B 37/16 20060101 C08B037/16; A61P 25/08 20060101
A61P025/08 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 2, 2006 |
US |
PCT/US06/38508 |
Claims
1. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine comprising a
carbamazepine complexed with a modified cyclodextrin.
2. The complex of claim 1 wherein said modified cyclodextrin is a
sulfoalkyl-cyclodextrin.
3. The complex of claim 1 or 2 wherein said modified cyclodextrin
is sulfobutylether-7-beta-cyclodextrin.
4. The complex of claim 1 having a concentration of about 5 to
about 50 mg/ml carbamazepine.
5. The complex of claim 1 having a concentration of about 10 mg/ml
carbamazepine.
6. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine in which dosing is about
30% to about 100% of oral maintenance doses.
7. The complex of claim 6 wherein said dosing is about 65% to 75%
of oral maintenance doses.
8. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having a half-life of
about 8 to about 65 hours.
9. The complex of claim 8 having a half-life of about 24 hours.
10. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having an area under the
plasma concentration-time curve (AUC) of about 70% to about 130% of
the AUC for an oral carbamazepine dosage form.
11. The complex of claim 10 having an AUC of about 80% to about
125% of the AUC for an oral carbamazepine dosage form.
12. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having a minimum plasma
concentration (Cmin) of about. 70% to about 130% of the Cmin for an
oral carbamazepine dosage form.
13. The complex of claim 12 having a Cmin of about 80% to about
125% of the Cmin for an oral carbamazepine dosage form.
14. A carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having an intravenous
dosing interval of every four to twelve hours.
15. The complex of claim 14 having an intravenous dosing interval
of every six hours.
16. The complex of claim 14 having an intravenous dosing interval
of every eight hours.
17. A method of administering a carbamazepine-cyclodextrin
inclusion complex useful for the parenteral administration of
carbamazepine comprising: 1) providing a carbamazepine-cyclodextrin
inclusion complex; and 2) infusing said complex intravenously to a
patient in need thereof every four to twelve hours.
18. The method of claim 17 wherein the period of said infusing
occurs over about 5 to about 60 minutes.
19. The method of claim 17 wherein the period of said infusing
occurs over 30 minutes.
20. The method of claim 17 wherein the period of said infusing
occurs over 5 minutes.
21. The method of claim 17 wherein said infusing is done every six
hours.
22. The method of claim 17 wherein said infusing is done every
eight hours.
23. A method of preparing a carbamazepine-cyclodextrin inclusion
complex by admixing a modified cyclodextrin and carbamazepine in a
physiologically acceptable fluid to form a
carbamazepine-cyclodextrin inclusion complex.
24. The method of claim 23 further including the step of
sterilizing said carbamazepine-cyclodextrin inclusion complex.
25. The method of claim 23 wherein said physiologically acceptable
fluid is isotonic.
26. The method of claim 23 wherein said modified cyclodextrin is a
sulfoalkyl-cyclodextrin.
27. The method of claim 23 wherein said modified cyclodextrin is
sulfobutylether-7-betacyclodextrin.
Description
RELATED APPLICATIONS
[0001] This application claims priority from U.S. provisional
patent application 60/722,284 filed Sep. 30, 2005.
BACKGROUND OF THE INVENTION
[0002] Carbamazepine, or 5H-dibenz[b,f]azepine-5-carboxamide, is a
widely used antiepileptic agent. It is available in the U.S. as
Tegretol' brand chewable tablets of 100 mg, tablets of 200 mg and
suspension of 100 mg/5 mL, intended for oral administration as a
treatment for epilepsy or as a specific analgesic for trigeminal
neuralgia. Other brand names include Equetro, Carbatrol, Tegretol
XR and Epitol. Generic versions of these oral dosage forms are also
available. Dosage forms include Carbatrol available in 100, 200,
and 300 mg strengths; and Tegretol XR, available in 100, 200, and
400 mg strengths.
[0003] As shown in Table 1, recommended maintenance dosage levels
in adults and children over 12 years of age are 800-1200 mg daily,
although up to 2400 mg daily have been used in adults. In children
of 6 to 12 years of age, the maintenance dosage level is usually
20-30 mg/kg/d and in children less than 6 years old the maintenance
dosage level is usually 10-20 mg/kg/d.
TABLE-US-00001 TABLE 1 Labeled dosage for carbamazepine oral dosage
forms. Recommended Dosing Frequency Daily (for IR Age Maintenance
Dose formulations) <6 yrs 10-20 mg/kg 2-4 doses/day 6-12 yrs
20-30 mg/kg 2-4 doses/day max dose 1000 mg Children >12 yrs
400-1200 mg 2-4 doses/day 1600-2400 mg Adults-epilepsy 800-1200 mg
3-4 divided doses some pts require 1600-2400 mg Adults- 400-800 mg
2 doses/day trigeminal max dose 1200 mg neuralgia Adults-bipolar
Doses greater 2 doses/day disorder than 1600 mg have not been
studied Note: only Equetro, an extended release formulation is
approved for bipolar disorder.
[0004] For complex partial seizures (temporal lobe, psychomotor),
carbamazepine is a widely used anticonvulsant drug. It is also of
proven efficacy in the treatment of generalized tonic-clonic (grand
mal) seizures. Carbamazepine has also been used in treating simple
partial (focal or Jacksonian) seizures and in patients with mixed
seizure patterns which include the above, or other partial or
generalized seizures. It is not used in the treatment of absence
seizures (petit mal).
[0005] In addition to its proven effectiveness, carbamazepine has,
in many respects, a more favorable profile in terms of the
incidence and severity of side-effects than other anticonvulsants.
Thus, carbamazepine is less sedating and causes less intellectual
function impairment than other antiepileptic drugs such as
phenobarbital, primidone and phenyloin. Furthermore, carbamazepine
does not precipitate gingival hypertrophy, hirsutism, acne or other
undesired effects associated with phenyloin. These attributes have
helped to make carbamazepine the drug of choice in women and
children.
[0006] Use of carbamazepine is complicated by incomplete, slow and
variable absorption; extensive protein binding; and induction of
its own metabolism. From Spina E Chapter 21 in Antiepileptic Drugs
5th edition. Lippincott, Williams & Wilkins, Philadelphia, 2002
pp 236-246 and references cited therein. The absolute
bioavailability (the percentage of a dose that reaches the
bloodstream) for the immediate release and extended release tablets
has previously been estimated to range from 75-85 although the
absence of an intravenous formulation has precluded systematic
study of the extent and inter-patient variability in
absorption.
[0007] U.S. Pat. No. 5,231,089 to Bodor mentions the lack of an
injectable formulation for carbamazepine, noting that therefore
there has not been precise information relating to the drug's
absolute bioavailability. In addition, the lack of an injectable
formulation for carbamazepine means that there is no method for
providing emergent carbamazepine therapy to a patient in need
thereof, as occurs when patients are undergoing surgery, have
certain gastro-intestinal diseases, are unconscious or have
seizures that preclude oral drug administration, or that require
rapid re-establishment of steady state plasma levels.
[0008] The absence of an intravenous formulation places patients
treated with carbamazepine (sometimes referred to herein as CBZ) at
substantial medical risk. Sudden discontinuation of CBZ therapy for
whatever reason, can expose an individual to potentially life
threatening seizure emergencies. The only alternative is to give
the patient a different drug that is available as an intravenous
formulation. Exposure to a new medications exposes the patient to
adverse reactions and unknown efficacy.
[0009] Cyclodextrins, sometimes referred to as Schardinger's
dextrins, were first isolated by Villiers in 1891 as a digest of
Bacillus amylobacter on potato starch. The foundations of
cyclodextrin chemistry were laid down by Schardinger in the period
1903-1911. Until 1970, however, only small amounts of cyclodextrins
could be produced in the laboratory and the high. production cost
prevented the usage of cyclodextrins in industry. In recent years,
dramatic improvements in cyclodextrin production and purification
have been achieved and cyclodextrins have become much less
expensive, thereby making the industrial application of
cyclodextrins possible.
[0010] Cyclodextrins are cyclic oligosaccharides with hydroxyl
groups on the outer surface and a void cavity in the center. Their
outer surface is hydrophilic, and therefore they are usually
soluble in water, but the cavity has a lipophilic character. The
most common cyclodextrins are .alpha.-cyclodextrin,
.beta.-cyclodextrin and .gamma.-cyclodextrin, consisting of 6, 7
and 8 .alpha.-1,4-linked glucose units, respectively. The number of
these units determines the size of the cavity.
[0011] Cyclodextrins are capable of forming inclusion complexes
with a wide variety of hydrophobic molecules by taking up a whole
molecule (a "guest molecule"), or some part of it, into the void
cavity. The stability of the resulting complex depends on how well
the guest molecule fits into the cyclodextrin cavity. Common
cyclodextrin derivatives are formed by alkylation (e.g.,
methyl-and-ethyl.beta.-cyclodextrin) or hydroxyalkylation of the
hydroxyethyl-derivatives of .alpha.-, .beta.-, and
.gamma.-cyclodextrin) or by substituting the primary hydroxyl
groups with saccharides (e.g., glucosyl- and
maltosyl-.beta.-cyclodextrin). Hydroxypropyl-.beta.-cyclodextrin
and its preparation by propylene oxide addition to
.beta.-cyclodextrin, and hydroxyethyl-.beta.-cyclodextrin and its
preparation by ethylene oxide addition to .beta.-cyclodextrin, were
described in a patent of Gramera et al. (U.S. Pat. No. 3,459,731,
issued August 1969) over 35 years ago.
[0012] Although cyclodextrins have been used to increase the
solubility, dissolution rate and/or stability of a great many
compounds, it is also known there are many drugs for which
cyclodextrin complexation either is not possible or yields no
advantages. See J. Szejtli, Cyclodextrins in Drug Formulations:
Part II, Pharmaceutical Technology, 24-38, August, 1991. Despite
this potential pharmaceutical utility, certain cyclodextrins are
have limitations.
[0013] Cyclodextrins and their derivatives are mostly crystalline
solids. Concentration of some cyclodextrins in the renal tissue is
followed by crystal formation causing necrotic damage to the cells.
Despite forming water soluble clathrate complexes, the crystalline
cyclodextrin drug complexes have generally been limited in their
utility to sublingual or topical administration.
[0014] U.S. Pat. Nos. 5,134,127 and 5,376,645, whose disclosures
are incorporated herein by reference, are directed to novel
cyclodextrin derivatives, in particular sulfoalkyl cyclodextrin
derivatives, that overcome the limitations of other cyclodextrins.
In particular, the sulfoalkyl cyclodextrin derivatives disclosed
therein exhibit lower nephrotoxicity while exhibiting high aqueous
solubility.
[0015] The present invention is based, inter alia, on the
determination that carbamazepine stable inclusion complexes with
cyclodextrins are highly water soluble relative to the
non-complexed drug. Surprisingly and unexpectedly, the
carbamazepine-cyclodextrin inclusion complexes of the invention
result in an injectable formulation that provides significant
benefits and advantages over other carbamazepine formulations. For
example, the carbamazepine-cyclodextrin inclusion complexes of the
present invention are completely bioavailable, delivering 100% of
the dose to the bloodstream in a consistent and predictable manner
which is not the case with solid oral dosage forms. Also, unlike
solid oral dosage forms, the carbamazepine-cyclodextrin inclusion
complexes of the present invention can be administered to a patient
suffering from a generalized tonic-clonic or other acute seizure
via a peripheral rather than oral route. The
carbamazepine-cyclodextrin inclusion complexes of the present
invention satisfy a significant unmet medical need for a stable
injectable formulation of carbamazepine that overcomes the
limitations of poorly soluble and variably absorbed oral
formulations.
SUMMARY OF THE INVENTION
[0016] In one aspect, the present invention contemplates a
carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine comprising a
carbamazepine complexed with a modified cyclodextrin. Preferably,
the modified cyclodextrin is a sulfoalkyl-cyclodextrin. A preferred
modified cyclodextrin is sulfobutylether-7-beta-cyclodextrin. The
inclusion complex preferably has a concentration of about 5 to
about 50 mg/ml carbamazepine, and more preferably a concentration
of about 10 mg/ml carbamazepine.
[0017] In another aspect, the present invention, there is provided
a carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine in which dosing is about
30% to about 100% of oral maintenance doses, or preferably about
65% to 75% of oral maintenance doses.
[0018] In a further aspect, the present invention provides a
carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having a half-life of
about 8 to about 65 hours, and more preferably having a half-life
of about 24 hours. In another embodiment, the present invention
contemplates a carbamazepine-cyclodextrin inclusion complex useful
for the parenteral administration of carbamazepine having an area
under the plasma concentration-time curve (AUC) of about 70% to
about 130% of the AUC for an oral carbamazepine dosage form, and
more preferably having an AUC of about 80% to about 125% of the AUC
for an oral carbamazepine dosage form. In a further embodiment, the
present invention contemplates a carbamazepine-cyclodextrin
inclusion complex useful for the parenteral administration of
carbamazepine having a minimum plasma concentration (Cmin) of
about. 70% to about 130% of the Cmin for an oral carbamazepine
dosage form, and more preferably having a Cmin of about 80% to
about 125% of the Cmin for an oral carbamazepine dosage form.
[0019] In a still further aspect, the present invention provides a
carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine having an intravenous
dosing interval of every four to twelve hours, more preferably
having an intravenous dosing interval of every six hours, and still
more preferably having an intravenous dosing interval of every
eight hours.
[0020] In another embodiment the present invention provides a
method of administering a carbamazepine-cyclodextrin inclusion
complex useful for the parenteral administration of carbamazepine
comprising: 1) providing a carbamazepine-cyclodextrin inclusion
complex; and 2) infusing the complex intravenously to a patient in
need thereof every four to twelve hours.
[0021] Preferably, the period of infusing occurs over about 5 to
about 60 minutes, more preferably over 30 minutes and still more
preferably over 5 minutes. Preferably, the infusing is done every
six hours, or in another aspect every eight hours.
[0022] In a still further embodiment, the present invention
provides a method of preparing a carbamazepine-cyclodextrin
inclusion complex by admixing a modified cyclodextrin and
carbamazepine in a physiologically acceptable fluid to form a
carbamazepine-cyclodextrin inclusion complex. In another aspect,
the method further includes the step of sterilizing the
carbamazepine-cyclodextrin inclusion complex. Preferably, the
physiologically acceptable fluid is isotonic. Preferably, the
modified cyclodextrin is a sulfoalkyl-cyclodextrin. The modified
cyclodextrin is more preferably
sulfobutylether-7-beta-cyclodextrin.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows carbamazepine phase solubility as a function of
cyclodextrin concentration at ambient laboratory temperature. FIG.
1A represents the compiled solubility data. FIG. 1B represents the
averaged solubility data.
[0024] FIG. 2 shows the DSC/TGA overlay of Carbamazepine Orgamol
batch #899954.
[0025] FIG. 3 shows the DSC/TGA overlay of Carbamazepine Spectrum
batch #SA0491.
[0026] FIG. 4 shows the observed and predicted plasma
concentration-time profiles following intravenous administration of
100 mg of carbamazepine using a 3-compartment PK model.
[0027] FIG. 5 shows the simulated plasma concentration-time
profiles of carbamazepine following different infusion durations.
The mean IV dose=150 mg, the average adjusted IV dose assuming
F=0.7. Model parameters are the typical values parameters from the
three-compartment model.
[0028] FIG. 6 shows the effect of infusion duration on Cmax,ss
following IV administration of carbamazepine.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention is directed to a
carbamazepine-cyclodextrin inclusion complex useful for the
parenteral administration of carbamazepine.
[0030] As used herein, the term "parenteral" is given its ordinary
and customary meaning in the field of pharmaceutical drug routes of
administration. According to the Food and Drug Administration's
Center for Drug Evaluation and Research Data Standards Manual (CDER
Data Element Number C-DRG-00301; Data Element Name: Route of
Administration) "parenteral" refers to administration by injection,
infusion or implantation. Injection and infusion include
administration into a vein (intravenous), into an artery
(intraarterial), into a muscle (intramuscular), under the skin
(subcutaneous), and into the peritoneum (intraperitoneal).
Intrapulmonary (administration within the lungs or its bronchi) and
nasal (administration into the nose or by way of the nose) is also
contemplated. Any appropriate route of administration set forth in
the above-referenced Food and Drug Administration document is
specifically included within the scope of the instant invention,
and nothing herein shall be construed to limit in any way those
routes of administration that would be useful in connection with
the carbamazepine-cyclodextrin inclusion complex of the present
invention.
[0031] In one embodiment, the carbamazepine-cyclodextrin inclusion
complex is prepared by the admixture of a modified cyclodextrin and
carbamazepine in a physiologically acceptable fluid. Modified
cyclodextrins include 2-hydroxypropyl-beta-cyclodextrin and
sulfoalkyl cyclodextrins. More particularly, the sulfoalkyl
cyclodextrins are those described and disclosed in U.S. Pat. Nos.
5,134,127 and 5,376,645. A physiologically acceptable fluid
includes sterile isotonic water, Ringer's lactate, D5W (5% dextrose
in water), physiological saline, and similar fluids suitable for
parenteral administration.
[0032] After an admixture of the modified cyclodextrin and
carbamazepine is prepared, the admixture can be sterilized.
Sterilization can be by methods well known to those of ordinary
skill in the art, such as by autoclaving or by sterile filtration
such as passage through a 0.22 micron filter. After-sterilization,
the carbamazepine-cyclodextrin inclusion complex can be directly
packaged into sterile ampoules, containers for fluids suitable for
intravenous administration, or the complex can be lyophilized for
prolonged storage according to techniques well known in the
art.
[0033] The carbamazepine-cyclodextrin inclusion complex can be
prepared so that the concentration of carbamazepine ranges from 1
mg/ml to 50 mg/ml, more preferably from 1 mg/ml to 10 mg/ml, and
most preferably about 10 mg/ml. Variations in the carbamazepine
concentration in the carbamazepine-cyclodextrin inclusion complex
of the present invention is conventionally accomplished by varying
the amount of carbamazepine used in the preparation of that
inclusion complex, as described elsewhere herein.
[0034] The carbamazepine-cyclodextrin inclusion complex can be
administered parenterally in a single dose of up to 1600 mg, or
preferably up to 500 mg, more preferably divided doses from 20 to
500 mg, and most preferably divided doses from 75 to 400 mg. Dosing
is dependent upon the indication of the patient being treated, as
well as interactions with other drugs that the patient can be
taking, and other clinical considerations well within the skill of
the attending physician.
[0035] The carbamazepine-cyclodextrin inclusion complex of the
present invention has a bioavailability of 100% and a half-life of
about 24 hours. Resultant plasma concentrations after intravenous
administration are reasonably predictable with every 1 mg/kg dose
producing an increase in CBZ concentration of 0.75.+-.0.2 mg/L.
Given an average oral bioavailability of 65-75%, the initial IV
replacement dose will be 65-75% of a patient's maintenance dose
although some adjustment in subsequent IV doses may be necessary
depending on a patient's actual oral CBZ bioavailability. This
dosing regimen is selected in order to ensure that trough CBZ
concentrations remain within the therapeutic range, while
minimizing the risk of adverse events associated with elevated,
end-of-infusion of CBZ concentrations.
[0036] The carbamazepine-cyclodextrin inclusion complex of the
present invention preferably has certain pharmacokinetic parameters
statistically similar to those of oral CBZ dosage forms. For
example, the carbamazepine-cyclodextrin inclusion complex
preferably has a minimum plasma concentration (Cmin) of about 70%
to about 130% of the Cmin of an oral CBZ dosage form, and more
preferably from about 80% to about 125% of the Cmin of an oral CBZ
dosage form. Similarly, the carbamazepine-cyclodextrin inclusion
complex has an area under the plasma concentration-time curve (AUC)
of about 70% to about 130% of the AUC of an oral CBZ dosage form,
and more preferably from about 80% to about 125% of the AUC of an
oral CBZ dosage form. Workers of ordinary skill in the art of
pharmaceutical formulation are well acquainted with these concepts,
which are further explained in the Food and Drug Administrations'
Guidance for Industry entitled "Statistical Approaches to
Establishing Bioequivalence" of January 2001 (see the world wide
web fda.gov/cder/guidance/3616fnl.htm.)
[0037] The total daily intravenous (IV) dose can be administered as
four equal doses every six hours, infused over up to 60 minutes, or
preferably over 30 minutes, or more preferably over 15 minutes. As
is well known in the art, the infusion duration and dosing interval
can be adjusted depending upon clinical considerations within the
skill of the attending physician. For example, in a situation where
rapid return to steady-state levels of CBZ is desired, the infusion
duration can be as short as 2-5 minutes via IV push or IV bolus
administration to a patient in need thereof. In other embodiments,
the total daily IV dose can be administered as three equal doses
every eight hours, infused over up to 60 minutes, or preferably
over 30 minutes, or more preferably over 15 minutes. In further
embodiments, administration can be continuous, or can be
administered using a patient controlled device that permits
controlled dosing on an as needed basis. Other dosing schedules are
well known in the art, and can be readily determined by pharmacists
and physicians skilled in the art based upon considerations of, for
example, age of the patient, indication, divided dose and total
daily dosage.
[0038] In other embodiments, the carbamazepine-cyclodextrin
inclusion complexes of the present invention can be administered
via rectal, oral or nasal routes for those patients who either
cannot tolerate parenteral administration or who are so young that
parenteral administration is not practical. In addition, those
patients who can receive the formulation of the present invention
via an enteral route will obtain the benefits of substantially
complete bioavailability over present sold oral dosage forms.
Enteral administration does not require a change in the formulation
of the present invention, as those carbamazepine-cyclodextrin
inclusion complexes can be directly delivered enterally. Taste
masking formulations, well known in the art, can be used to modify
formulations designed to be administered orally to eliminate any
unpleasant taste. Taste masking is, however, related to patient
compliance rather than related to efficacy of the present invention
for enteral administration.
[0039] The carbamazepine-cyclodextrin inclusion complexes of the
present invention can be administered to a mammal in need of CBZ
treatment. The word "mammal" is given its ordinary and customary
meaning in the art, and includes human beings. Accordingly, the
carbamazepine-cyclodextrin inclusion complexes of the present
invention can be used in veterinary applications as well as the
treatment of human conditions. With respect to human treatment, the
carbamazepine-cyclodextrin inclusion complexes of the present
invention is particularly well suited for pediatric administration,
because the instant formulation does not require a peroral route of
administration.
[0040] The carbamazepine-cyclodextrin inclusion complexes of the
present invention can be used for any indication for which CBZ is
used. For example, CBZ is indicated for seizure disorders such as
partial seizures with complex symptoms (psychomotor, temporal lobe
epilepsy), generalized tonic-clonic (grand mal) seizures, mixed
seizure patterns or other partial or generalized seizures. CBZ is
also indicated for trigeminal neuralgia (tic douloureux) such as
treatment of pain associated with true trigeminal neuralgia and
bipolar disorders. CBZ is also beneficial in glossopharyngeal
neuralgia. Other uses include treatment of neurogenic diabetes
insipidus; certain psychiatric disorders, including schizoaffective
illness, depression, agitation, behavioral disturbances related to
dementia, resistant schizophrenia, and dyscontrol syndrome
associated with limbic system dysfunction; alcohol withdrawal;
fibromyalgia; neuropathy; status epilipticus; and refractory
seizure disorders.
[0041] While the carbamazepine-cyclodextrin inclusion complexes of
the present invention provide reduced toxicity and 100%
bioavailability compared to other parenteral carbamazepine
formulations such as a PEG400 formulation. Moreover, the complexes
of the present invention are less nephrotoxic while providing
similar solubilities and dissolution rates of
carbamazepine-cyclodextrin complexes.
[0042] Further details of the preferred embodiments of the present
invention are illustrated in the following examples, which are
understood to be non-limiting.
EXAMPLES
Example 1
Preparation of Carbamazepine-Cyclodextrin Inclusion Complex
[0043] 450 Grams of hydroxypropyl-beta-cyclodextrin (HPBCD) was
dissolved in 2.0 L of deionized water to generate a 22.50 w/v
solution. .sup.13C, .sup.15N-labeled carbamazepine (CBZ) [purchased
from Cambridge Isotope Laboratories (CIL), 50 Frontage Road,
Andover, Mass. 01810], 20 grams, was added to this solution. The
resulting admixture was stirred for 24 hours at room temperature
(20-25.degree. C.). After 24 hours, the solution was sterile
filtered through a sterile 0.22 micron Durapore filter into a
sterile receiver. Previously sterilized ampoules were then filled
and sealed under a nitrogen flush. The filled ampoules were stored
at 2-8.degree. C. The resulting inclusion complex had a CBZ
concentration of approximately 10 mg/ml.
Example 2
Stability Testing
[0044] Ampoules containing 10.1 mg/ml carbamazepine-cyclodextrin
inclusion complex were placed on room temperature stability studies
and sampled every six months. CBZ was detected by HPLC using UV
detection at 215 nm. Results are presented in Table 2.
TABLE-US-00002 TABLE 2 Stability of Intravenous, Stable-labeled
Carbamazepine Solution Initial Degradation Testing Concentration %
Product- CBZ: Date in Vial Recovery iminostilbine May 31, 2005 10.1
mg/ml 104.65% not detected Nov. 10, 2004 10.1 mg/ml 97.07% not
detected May 2, 2004 10.1 mg/ml 96.67% not detected
Example 3
Pharmacokinetics of Intravenous and Oral Carbamazepine in Patients
on Maintenance Therapy
[0045] Indwelling catheters were placed into the arms of test
subjects. A single 100 mg dose of stable-labeled (non-radioactive)
CBZ (SL-CBZ) was then infused over 10 minutes. At the end of the
infusion, the subject's usual morning dose of oral CBZ, less 100
mg, was administered. Blood pressure, heart rate and rhythm, and
infusion site discomfort were monitored during and for an hour
after the infusion. A single blood sample was collected prior to
the infusion and 12 samples were collected over the ensuing 96
hours. Plasma was separated from blood and analyzed, using a LC-MS
assay, for CBZ and CBZ-epoxide, an active metabolite, and
glucuronidated metabolite that is inactive Unbound CBZ was measured
following ultrafiltration. CBZ concentration-time data were
analyzed using a non-compartmental approach with the
pharmacokinetic software, WinNONLIN.
[0046] A validated LC-MS assay for SL-CBZ, CBZ and their respective
epoxide metabolites was used. Carbamazepine-d.sub.10 (CBZ-d.sub.10,
C/D/N Isotopes, Quebec, Canada) was used as the internal standard.
CBZ was assayed similar to that described by Osterloh and
Bertilsson. (Osterloh J, Bertilsson L. The absence of isotopic
effect during the elimination of deuterium labeled carbamazepine in
the rat. (Life Sci. 1978; 23:83-7.) To obtain a standard for
CBZ-glucuronide, it was isolated from the urine of patients on CBZ
monotherapy using a procedure similar to that previously published.
(Sinz M W, Remmel R P. Analysis of lamotrigine and lamotrigine
2-N-glucuronide in guinea pig blood and urine by reserved-phase
ion-pairing liquid chromatography. J Chromatogr. 1991; 571:217-30)
A 0.5 ml aliquot of patient plasma and 10 microliters of internal
standard was added to blank plasma and extracted with 3 volumes of
ethyl acetate. After shaking and centrifugation, the organic layer
was removed and evaporated under nitrogen gas to dryness. Each
sample was then redissolved with the addition of 25 microliters of
ethyl acetate. Plasma samples were measured for unbound and total
CBZ, CBZ glucuronide and CBZ-E by LCMS. Unbound drug was separated
from the bound fraction by ultrafiltration. The mobile phase
consists of 50% 0.05 M ammonium acetate buffer, pH 4.7, 50% MeOH at
a flow rate of 0.4 ml/min, on a reverse phase C-18 column. For
selected ion monitoring (SIM), signals at m/z 237 (CBZ), 239
(.sup.13C.sup.15N.sub.2-CBZ), 253 (CBZ-epoxide), 255
.sup.13C.sup.15N.sub.2--CBZ-epoxide) and 247 (CBZ-d.sub.10) were
measured with a PC-based Hewlett-Packard Chem-Station.RTM..
software. The lower limit of detection is 0.05 micrograms/ml for
CBZ. LC-MS method has been validated for the determination of
[.sup.13C,.sup.15N]-carbamazepine, carbamazepine, and their
10,11-epoxide metabolites in human plasma. Over a concentration
range of 1.5 to 12 micrograms/ml the percent coefficient of
variance was .ltoreq.5%.
[0047] Table 3 provides the pharmacokinetic parameters for 76
subjects. The range of oral CBZ daily dose ranged from 100 mg to
2400 mg for subjects in this study. As can be seen, the absolute
bioavailability of oral CBZ during maintenance therapy centers
around 70-75% with 30 of the 56 subjects having bioavailabilities
below 70%. The variability of bioavailability is also substantial
with a range of 0.35 to 1.65. The highly variable bioavailability
could be indicative of delayed release of drug from the various
immediate and extended release oral formulations of CBZ or from
continued absorption from an extended release dosage form into a
subsequent dosing interval. The distribution volume at steady state
(VSS) is 1.24.+-.0.439 L/kg. This is a previously unknown value
(due to the lack of an IV formulation) the now permits precise
dosing of an IV formulation to attain a targeted plasma CBZ
concentrations as might be required when initiating therapy in
patients whose oral therapy has been interrupted for 12 or more
hours.
[0048] Another clinically important observation is the prolonged
CBZ elimination half-life under steady-state conditions. The mean
value was determined to be 25.8 hours (range from 8.79 to 64.6
hours) in contrast with the reported range of 12 to 17 hours in the
package insert for Tegretol.degree. and Carbatrol.degree.. The most
likely explanation for this difference is the use of an SL-IV CBZ
solution in the present study that permitted rigorous
characterization of elimination for 2-3 half-lives while subjects
continued to take their oral CBZ doses as prescribed. The extended
half-lives observed in the adult subjects will limit the
fluctuation of CBZ concentrations following IV administration every
six hours, further reducing the risk of sub-therapeutic CBZ
concentrations.
TABLE-US-00003 TABLE 3 Carbamazepine Summary Pharmacokinetics AUCss
AUC Body (po) 0-.degree.o Age Weight T1/2 (.mu.g (.mu.g VSS CL
CLSS/F (yr) (kg) F (hr) hr/mL) hr/mL) (L/kg) (L/hr/kg) (L/hr/kg) N
76 76 70 76 70 76 76 76 70 Mean 46.9 81.7 0.742 25.8 89.5 38.2 1.24
0.040 0.045 (SD) (15.7) (17.7) (0.29) (11.2) (29.3) (15.3) (0.439)
(0.015) (0.024) Min 19.0 48.0 0.348 8.79 28.5 14.9 0.612 0.013
0.0087 Median 45.0 82.0 0.670 24.6 87.2 36.5 1.13 0.036 0.041 Max
87.0 151 1.65 64.6 168 94.5 3.17 0.089 0.122 Note: The values of F,
AUCss (po), and CLss/F included only 70 subjects due to 6 subjects
only receiving the morning IV dose of CBZ. The range of oral CBZ
daily dose ranged from 100 mg to 2400 mg.
[0049] The present study utilized the
2-hydroxypropyl-.beta.-cyclodextrin formulation for a drug
solubilizing agent of SL-CBZ. The pharmacokinetic data obtained
from this study, while not specifically designed to determine a
full replacement IV dosing regimen, can assist in establishing the
target dose for this study. The results from the present study
demonstrate a wide range of CBZ bioavailability values among
subjects, several of which had calculated bioavailability values
greater than 100%. As a result, a bioavailability value of 70% has
been chosen for use when dosing subjects in this sequential study.
This value is similar to the median F value (67%) determined from
subjects administered IV CBZ in the present study (n=76). The
justification for using the median bioavailability value for
correcting the dose for IV administration of CBZ in the current
study assumes that the true bioavailability in subjects should not
be greater than 100% especially at steady-state dosing levels. The
value of 70% is between the calculated mean F value of 75% and the
true rank order median value of 67%, and allows for an appropriate,
calculable IV dose adjustment. The typical subject should then
receive a daily IV dose that is 70% of that individual's daily oral
dose. This can produce CBZ plasma concentrations from the IV dose
that are comparable to those concentrations resulting from oral
administration in the majority of subjects. Thus, the results of
the present study provide initial safety and tolerability of a
carbamazepine-cyclodextrin combination in subjects along with
providing data that can be used to calculate the appropriate dose
and dosing interval for replacement IV therapy.
Example 4
Preparation of CBZ Standard Solution Equipment
[0050] Shimadzu HPLC systems with autosampler, pumps, degassers, UV
detector, column oven, system controllers, and Shimadzu Class VP
system Software
Cahn Microbalance
[0051] Shimadzu AY-120 Analytical balance pH meter, Orion pH/ISE
Model # 420 A
Labnet VX100 Vortex
Eppendorf Centrifuge 5415 D
Fisher Scientific FS30 Sonicator
LabQuake Shaker
Materials
TABLE-US-00004 [0052] Material Manufacturer Lot No. Carbamazepine
Spectrum SA0491 Carbamazepine Orgamol 899954 Cavitron Cargill
H3M134P 82004 Captisol Cydex CY03A020535 Acetonitrile Fisher 031168
Purified water
Preparation of CBZ Standard Solution (0.05 mg/L)
[0053] Weigh out 5 mg of CBZ and place in a 100 ml volumetric
flask. Fill to volume with 60% aqueous acetonitrile.
Preparation of Cyclodextrin Vehicles
[0054] The percent weight/volume cyclodextrin solutions were
prepared by adding the appropriate amount of cyclodextrin to a
flask and filling to the desired total volume (10 mL) with water,
as shown in the following Table 4.
TABLE-US-00005 TABLE 4 Amount of Cyclodextrin (g) 0.0 0.5 1.0 1.5
2.0 2.5 3.0 3.5 4.0 4.5 5.0 6.0 7.0 8.0 9.0 Cyclodextrin 0 5 10 15
20 25 30 35 40 45 50 60 70 80 90 in Water % (w/v)
In initial assays, the flasks were graduated cylinders. In
subsequent assays, the cyclodextrin was first dissolved in a small
volume of water, quantitatively transferred to a volumetric flask
which was then brought to volume with water.
Preparation of Samples for Phase Solubility
[0055] An excess of carbamazepine was added to each eppendorf tube.
Appropriate vehicles were added to each tube and the final volumes
were 1 mL.
Example 5
Phase Solubility
[0056] The solubility of CBZ was determined at ambient laboratory
temperatures in various concentrations of aqueous Captisol and
aqueous Cavitron (brand names of modified cyclodextrins useful in
the present invention). The drug substance was added to a
microcentrifuge tube and the appropriate vehicle was added.
Periodically, the samples were centrifuged and then an aliquot was
removed from the supernatant, diluted as necessary and assayed by
HPLC to determine the concentration. The phase solubility was
evaluated at least three times during each experiment to insure
that the mixture achieved equilibrium. In general, the early
concentration determination data (obtained approximately 2 hours
after mixing the CBZ and the vehicle) were omitted because CBZ
appeared to form supersaturated solutions initially before
equilibration. The solubilities reported in Table 5 are the average
of two or three concentration determinations obtained during the
respective time course.
TABLE-US-00006 TABLE 5 Phase solubility data for CBZ in the
presence of varying cyclodextrin concentrations Cyclodextrin
Captisol Cavitron CBZ source Spectrum Orgamol Orgamol Spectrum
Orgamol Orgamol Cyclodextrin Measured CBZ conc % Measured CBZ conc
% conc (% w/v) (mg/mL) Ave S.D. R.S.D. (mg/mL) Ave S.D. R.S.D. 0
0.2 0.2 0.2 0.2 0.0 0.0 0.3 0.2 0.2 0.2 0.0 13.3 5 2.4 2.2 2.4 2.3
0.1 4.9 3.8 2.7 3.0 3.2 0.6 18.0 10 6.2 4.1 4.6 5.0 1.1 22.1 4.1
5.4 5.6 5.0 0.8 16.2 15 6.9 6.4 7.7 7.0 0.7 9.4 12.3 8.2 8.4 9.6
2.3 24.0 20 9.4 9.2 10.3 9.6 0.6 6.1 16.4 10.9 11.1 12.8 3.1 24.4
25 11.8 11.4 12.3 11.8 0.5 3.8 14.8 14.0 14.3 14.4 0.4 2.8 30 14.6
13.5 15.2 14.4 0.9 6.0 17.9 15.9 16.2 16.7 1.1 6.5 35 16.3 15.9
18.4 16.9 1.3 8.0 20.7 18.1 19.9 19.6 1.3 6.8 40 19.3 18.3 20.8
19.5 1.3 6.5 23.2 22.5 22.0 22.6 0.6 2.7 45 21.8 20.6 22.5 21.6 1.0
4.4 27.3 25.5 25.7 26.2 1.0 3.8 50 26.6 22.5 24.8 24.6 2.1 8.3 31.5
27.8 28.0 29.1 2.1 7.3
FIG. 1A shows a graphical representation of the compiled solubility
data. From these data, it appears that the CBZ solubility at most
cyclodextrin concentrations is marginally improved in Cavitron, as
compared to Captisol. FIG. 1B shows the averaged solubility data
with the associated standard deviations. The latter Figure also
provides the trend lines for the averaged data.
Binding Constant
[0057] Assuming a 1:1 complex forms, the binding constant K.sub.1:1
can be calculated, according to the relationship:
K.sub.1:1=slope/[S.sub.0(1-slope)]
[0058] where S.sub.0 is the intrinsic solubility. The phase
solubility data were expressed in terms of molarity and the
equations of the lines were:
[0059] Captisol: y=0.4379x+0.0008r.sup.2=0.9989
[0060] Cavitron: y=0.3515x+0.0008r.sup.2=0.9954
[0061] From these equations, the binding constants of Captisol:CBZ
and Cavitron:CBZ were found to be 974 and 677 M.sup.-1,
respectively. These relatively weak associations are within the
range (100-20,000 M.sup.-1) of those commonly seen with drug:
cyclodextrin complexes (Crit. Rev. Ther. Drug Carrier Systems, 14
(1): 1-104, 1997). Stella et al. simulated drug release from
cyclodextrins upon dilution (Advanced Drug Del. Rev. 36, 3-16,
1999) and suggested that if complexes are diluted 100-fold in the
absence of any endogenous competing agent, approximately 30% of the
drug will remain complexed, and if they are diluted 1000-fold,
approximately 5% of the drug will remain complexed.
[0062] The minimal volume of distribution of a drug administered
intravenously is based on the plasma volume, which is approximately
5% of the body weight. Therefore, in a 70 kg subject, the plasma
volume is approximately 3.5 L. Alternatively, one could assume that
the volume of distribution is extracellular water, accounting for
approximately 30% of the total body weight, in which case the
volume of distribution is about 21 L.
[0063] Table 6 shows the theoretical dilutions that would result
from a 25 mg/mL formulation administered at different dose volumes.
These calculations do not assume that any endogenous compounds
might displace CBZ, and so they can be considered to be very
conservative estimations. If a 20 mL dose were administered, the
dilution ranges from 175-1,050-fold.
[0064] Based on the simulations of dilution effects, it appears
that 70-95% of the CBZ will immediately dissociate from the
inclusion complex in the blood if one assumes no interaction from
endogenous agents.
TABLE-US-00007 TABLE 6 Theoretical extent of dilution for a 25
mg/mL CBZ formulation CBZ dose, mg 200 500 800 Total dose 8 20 32
volume, mL Extent of Dilution Plasma volume, 438 175 109 3,500 ml.
Extracellular 2,625 1,050 656 volume, 21,000 mL
Method of Vehicle Preparation
[0065] The phase solubility data from the first set of assays
performed using the two cyclodextrins appear to be higher than all
of the subsequent phase solubility experiments (data not shown). In
this first assay, the cyclodextrin solutions were prepared by
weighing the appropriate amount of cyclodextrin and adding it to a
graduated cylinder and mixing to dissolve the solid. In all
subsequent assays, the appropriate amount of cyclodextrin was added
to a vial, dissolved, quantitatively transferred to a volumetric
flask, filled to volume with water and mixed. This second method of
vehicle preparation is more accurate and apparently significantly
influenced the resulting phase solubility data. However, it is very
difficult to prepare the cyclodextrin solutions volumetrically.
Effect of Cooling Saturated Solutions at 2-8.degree. C.
[0066] The saturated CBZ/cyclodextrin solutions were placed in a
2-8.degree. C. refrigerator and the appearances were recorded at
various times. At 24 hours, all of the solutions showed a
precipitate.
Example 6
Thermal Analysis
[0067] CBZ is known to exist in at least four different polymorphic
states (J. Pharm. Sci. 90, 1106-1114, 1990). At one point in this
study, it was suspected that the variability in the solubility data
might be due to polymorphic differences. Thermal analyses using
differential scanning calorimetry (DSC) and thermogravimetric
analysis (TGA) were performed on the Spectrum CBZ and the Orgamol
CBZ to determine if there were different polymorphs present in each
product. Table 7 summarizes the experimental conditions and the
thermal data.
TABLE-US-00008 TABLE 7 Thermal transitions obtained for CBZ from
two manufacturers. Thermogravimetric analysis Differential scanning
calorimetry Ramp 10.degree. C./min from Ramp 5.degree. C./min
25.degree. C. to 400.degree. C. From 25.degree. C. to 300.degree.
C. Vendor Initial % Sample Onset All Onset AH Lot-Batch weight
weight weight peak 1 Peak 1 Peak 1 peak 2 Peak 2 Peak 2 # (mg) loss
(mg) (.degree. C.) (.degree. C.) (l/g) (.degree. C.) (.degree. C.)
(l/g) Orgamol 9.687 87.25 3.246 161.92 165.25 14.03 183.22 185.70
117.2 899954 Spectrum 5.351 100.1 4.510 157.7 164.38 10.62 189.53
190.25 127.3 SA0491
Example 7
Appropriate Dosing Interval Determination
[0068] The most relevant factor in considering the dose adjustment
for intravenously administered CBZ is for treatment centers to
maintain plasma concentrations of CBZ above the therapeutic
threshold. Following administration of 100 mg of IV CBZ, observed
plasma concentrations followed a tri-exponential decay indicating a
very fast distribution to tissues followed by a slower elimination
of drug out of the body. Steady-state plasma concentrations of IV
CBZ were predicted using the method of superposition. Plasma
concentrations following a single dose of IV CBZ were scaled-up to
steady-state conditions, assuming linear pharmacokinetics, using an
accumulation ratio, a mean F of 0.7, and correcting for dose (see
Equations 1 and 2). As a result, this calculation allows for a
comparison of steady-state trough plasma concentrations following
oral (C.sub.0 and IV (C.sub.6hr) administration of CBZ respectively
assuming a dosing interval of once every six hours for the IV
formulation.
F = AUC r , SS ( Oral ) AUC 0 - .infin. ( I V ) .times. Dose ( I V
) Dose ( Oral ) Equation 1 C pSS ( I V ) = C pSD ( t ) ( I V ) +
Int exp - .lamda. T exp - .lamda. T 1 - exp - .lamda. T ( D po F )
D I V 4 Equation 2 ##EQU00001##
Where C.sub.pss(IV) is the plasma concentration (C) at steady state
for IV administration; C.sub.pSD is the plasma concentration after
a single dose; Int is the y-intercept resulting from linear
regression of the elimination phase; .lamda. is the terminal
elimination rate constant; D.sub.po is the total oral daily dose;
D.sub.IV is the single IV dose; F is the absolute bioavailability;
T is the dosing interval; and t is the time of each observed
concentration.
[0069] The observed mean, oral steady-state trough (C.sub.0) plasma
concentration of CBZ following twice daily dosing was 8.98 .mu.g/mL
(n=62 evaluable subjects) (see Table 8, "Statistical Comparison of
Trough Steady-State Carbamazepine Concentrations Following Oral BID
Dosing or Q6 IV Dosing Based on Mean F=0.70"). The mean
steady-state plasma concentration at the 6-hour time-point
following IV administration of CBZ was predicted to be 8.04
.mu.g/mL. Statistical comparison of these two trough values
following oral and IV administration of CBZ was found to be not
statistically different (.alpha.=0.10; p=0.1931). Thus, the dosing
frequency of every six hours following IV administration of CBZ
outlined is appropriate to maintain plasma concentrations above
this threshold and be comparable to trough levels following oral
administration. Analysis of the same parameters at the 12-hour
time-point, post-dose, indicated that the trough values were
significantly different suggesting that an IV dosing regimen of
every 12 hours would not be feasible to ensure the plasma
concentration of CBZ does not fall below the therapeutic range.
TABLE-US-00009 TABLE 8 Statistical Comparison of Trough
Steady-State Carbamazepine Concentrations Following Oral BID Dosing
or Q6 IV Dosing Based on Mean F = 0.70 Difference SE for the 90% CI
for the Carbamazepine Between Difference Difference in p-
Concentration N Mean the Means in the Means the Means value C.sub.0
62 8.98 0.09456 0.7158 (-0.254, 2.15) 0.1931 (oral only) C.sub.6 hr
(IV only) - 62 8.04 Mean F)
Example 8
Anticipated CBZ Maximum and Minimum Concentration Values During
Intravenous Administration: Subjects at the Extreme of
Carbamazepine Bioavailability
[0070] A subset analysis of the subject data (n=47), including only
those subjects taking extended release (ER) formulations of CBZ
twice daily (as indicated by the product label), was performed to
compare predicted maximum and minimum exposures of CBZ at
steady-state administered via IV infusion to those observed
following oral administration. CBZ concentration-time profiles
following IV administration will differ from oral administration to
the greatest extent for subjects on ER products, since these
products provide formulation dependent control of the
concentration-time profile. Subjects on extended release
formulations experience the least fluctuation in concentrations and
will maintain higher relative trough concentrations compared to any
non-extended release product. Thus, the analysis in this subset
gives a conservative assessment of potential differences in peak
and trough exposures following IV administration.
[0071] This analysis included calculations of predicted C.sub.max,
C.sub.min, and AUC.sub.ss values of CBZ for subjects predicted to
be at steady-state on IV therapy. In order to predict steady-state
plasma concentrations of IV CBZ, the same procedure for scaling
plasma concentrations of CBZ as stated previously was implemented
using Equations 1 and 2. Linear pharmacokinetics were assumed and
plasma concentrations following a single 100 mg dose of IV CBZ were
scaled-up to steady-state conditions using an accumulation ratio
(determined using each individual's terminal elimination rate
constant), and assuming a mean F of 0.7 for computation of the IV
dose administered.
[0072] Following scale-up of the plasma concentrations of CBZ to
steady-state, summary statistics of pharmacokinetic parameters were
reported to compare the range of CBZ C.sub.max, C.sub.min, and AUC
values between the oral (observed) and IV formulations of CBZ
assuming a bioavailability (F) of 0.7 (See Table 9, "Summary
Statistics of Predicted Steady-State Parameters Following
Administration of IV or Oral Carbamazepine"). The steady-state PK
parameters for the oral and IV formulations were obtained from data
within the 12 hour dosing interval following administration of the
ER products (Carbatrol..RTM.. and Tegretol XR..RTM..) or the 6 hour
interval after dosing of the IV product, respectively.
TABLE-US-00010 TABLE 9 Summary Statistics of Predicted Steady-State
Parameters Following Administration of IV or Oral Carbamazepine
Mean .+-. 5th 95th PK SD Minimum Percentile Median Percentile
Maximum Parameter N (.mu.g/mL) (.mu.g/mL) (.mu.g/mL) (.mu.g/mL)
(.mu.g/mL) (.mu.g/mL) IV C.sub.maxSS 47 11.75 .+-. 7.90 3.17 4.80
9.93 24.14 47.0 (mean F = 0.7) IV C.sub.minSS 47 8.63 .+-. 6.85
1.65 2.48 6.50 18.64 41.04 (mean F = 0.7) IV AUC.sub.ss 47 121.83
.+-. 90.93 26.88 43.10 93.69 257.16 551.11 (mean F = 0.7) Oral 47
9.92 .+-. 2.99 2.89 4.98 9.81 14.60 17.10 C.sub.maxss* Oral 47 9.32
.+-. 2.93 2.89 4.32 9.44 14.55 16.69 C.sub.minss Oral AUC.sub.ss 47
96.79 .+-. 28.08 28.48 50.11 96.01 145.51 167.58 *Oral Cmax, ss
estimate is based on highest observed concentration, and may not be
indicative of the subjects true Cmax, ss value due to sparse
sampling; this study was not designed to assess the Cmax, ss of
oral CBZ. *Oral Cmax, ss estimate is based on highest observed
concentration, and may not be indicative of the subjects true Cmax,
ss value due to sparse sampling; this study was not designed to
assess the Cmax, ss of oral CBZ.
[0073] The scaled-up steady-state CBZ concentrations were predicted
based upon a 100 mg single IV dose infused over 10 minutes. The
mean steady-state IV C.sub.max, value was 11.75 .mu.g/mL, a plasma
level that is higher compared to the mean oral C.sub.max at
steady-state (see Table 9). Given the wide range of individual
subject bioavailability values (F values) (see Table 3), subjects
taking high doses of oral CBZ and subjects at the extreme lower end
of bioavailability may experience maximum plasma concentrations of
CBZ that are in excess of the reported therapeutic range for this
compound (see Table 9). Subjects taking high doses of oral CBZ
compounded with an inherent low bioavailability could be at the
greatest risk for adverse effects due to elevated CBZ plasma
levels. The 70% dose adjustment would be the standard across all
subjects administered replacement IV CBZ therapy to ensure the
majority of subjects stay above the minimum (trough) therapeutic
threshold and thus preventing seizures. If a subject's true
bioavailability is less than the F value used for dosing, drug
accumulation will occur when the inclusion complex is administered
intravenously.
Example 9
Modeling and Simulation to Assess the Effect of Infusion Duration
on Cmax,ss Following Administration of Intravenous
Carbamazepine
[0074] CBZ bioavailability is extremely variable among subjects and
complicating factors such as formulations with different release
rates, doses, and dosing intervals add to an already complex
pharmacokinetic profile. Systemic exposures after IV administration
of CBZ will not vary amongst subjects to the extent that systemic
exposures vary after oral administration, since formulation
characteristics and bioavailability are excluded as sources of
variability following IV administration. Dose adjustments in
subjects for IV CBZ replacement therapy must protect against low
plasma concentration levels possibly leading to an increased risk
in break through seizures. Concurrently, the effects of increased
transient CBZ exposures can occur in some subjects at the extreme
low end of oral bioavailability or distribution volume.
[0075] The scaled IV CBZ concentration-time curves from the
pharmacokinetic data of subjects dosed over 10 minutes reveal that
the frequency distribution of C.sub.max values is unequal with a
skewed tail at the extreme high end of C.sub.max values. At a mean
bioavailability value for the population assigned to 70% (as is
appropriate for the dosing in the present invention), the mean
population C.sub.max value was 11.75 .mu.g/mL with a median value
of 9.93 .mu.g/mL. The 95th percentile C.sub.max value was 24.14
.mu.g/mL with a range of C.sub.max values from 3.17 .mu.g/mL to
47.00 .mu.g/mL (See Table 9, "Summary Statistics of Predicted
Steady-State Parameters Following Administration of IV or Oral
Carbamazepine").
[0076] To assess the effect of infusion duration on C.sub.max,ss
modeling and simulation was performed using the observed plasma
concentrations of CBZ following IV administration of the single 100
mg dose. Based on various diagnostic plots assessing
goodness-of-fit of the PK model, plasma concentrations of CBZ were
best described by a three-compartment model, displaying a very
rapid tissue distribution phase indicative of highly perfused
tissues such as the liver, lung and brain, a second distribution
phase indicative of deeper tissue penetration such as adipose
tissue, and a more prolonged elimination phase (FIG. 4). The
modeling results revealed that the mean t1/2 (.alpha.) and t1/2
(.beta.) were rapid (approximately 2 minutes and approximately 65
minutes, respectively), indicating that elevated plasma levels of
CBZ will be short-lived once an infusion is stopped. Population
mean terminal t1/2 (.gamma.) is approximately 28 hours, which is
comparable to the value based on noncompartmental analysis (Table
3). Assuming that the pharmacokinetics are linear and stationary,
using each subject's predicted parameters from the PK model,
simulations were performed at steady-state to determine the effect
of infusion duration on CBZ C.sub.max,ss (FIG. 5). The results
showed a decrease in the mean C.sub.max,ss as the infusion duration
increased (based upon a mean IV dose of 150 mg when dosed under
steady state conditions). The mean, modeled C.sub.max,ss value
after a 60 minute infusion was 10.68 .mu.g/mL compared to 10.04
.mu.g/mL after a 30 minute infusion compared to 11.69 .mu.g/mL
after a 15 minute infusion.
[0077] There was only an approximate 135 decrease in the mean
C.sub.max,ss value when the infusion duration was increased from 15
minutes to 1 hour.
[0078] Notably, the peak concentration from the typical value
simulation (150 mg IV dose) shown in FIG. 5 is comparable but
differed slightly to that of the scaled, observed IV C.sub.max,ss
reported in Table 9 (approximately 9.50 .mu.g/mL and 11.75 .mu.g/mL
respectively). The model dependent prediction (FIG. 6) more
accurately captures the time point of the true maximum
concentration, whereas the scaled, observed value (Table 9) is
dependent upon the time of collection. The median (maximum) elapsed
time between the end of infusion and the next time of collection
was 5.3 (38.0) minutes. With t1/2 (.alpha.) of 2.2 minutes,
considerable decay in concentration will occur during this time.
For the full population, the actual median (maximum) time to
observed C.sub.max,ss after the end of infusion was 5.8 (240)
minutes. Additionally, all modeled infusions were precisely of 15
minutes duration. If actual infusion durations were greater than 15
minutes, C.sub.max,ss would be lower than predicted by the model.
Finally, the typical value prediction modeled in FIG. 5 used each
individual's set of model parameters and a typical dose (150 mg,
the average adjusted IV dose assuming F=0.70), where the scaled
observed values are based on the range of individual doses along
with applying the superposition method at each observed
concentration. As shown in FIG. 6, the average C.sub.max,ss values
are similar with a 30 minute and 60 minute infusion
[0079] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The present embodiments are therefore to be considered in
all respects as illustrative and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description, and all the changes which come within the
meaning and range of equivalency of the claims are therefore
intended to be embraced therein.
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