U.S. patent application number 14/051021 was filed with the patent office on 2014-04-17 for formulations of low dose diclofenac and beta-cyclodextrin.
The applicant listed for this patent is Daniel B. Carr, Fred H. Mermelstein, Curtis Wright. Invention is credited to Daniel B. Carr, Fred H. Mermelstein, Curtis Wright.
Application Number | 20140107209 14/051021 |
Document ID | / |
Family ID | 38541808 |
Filed Date | 2014-04-17 |
United States Patent
Application |
20140107209 |
Kind Code |
A1 |
Wright; Curtis ; et
al. |
April 17, 2014 |
FORMULATIONS OF LOW DOSE DICLOFENAC AND BETA-CYCLODEXTRIN
Abstract
The present invention is directed to a pharmaceutical
composition containing a unit dose of a diclofenac compound
effective to induce analgesia; and a beta-cyclodextrin compound;
wherein the dose of the diclofenac compound is less than 10 mg. The
present invention is also directed to methods of treating a subject
in need of analgesia with the pharmaceutical compositions of the
invention.
Inventors: |
Wright; Curtis; (Rockport,
MA) ; Carr; Daniel B.; (Chestnut Hill, MA) ;
Mermelstein; Fred H.; (Newton, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wright; Curtis
Carr; Daniel B.
Mermelstein; Fred H. |
Rockport
Chestnut Hill
Newton |
MA
MA
MA |
US
US
US |
|
|
Family ID: |
38541808 |
Appl. No.: |
14/051021 |
Filed: |
October 10, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11689931 |
Mar 22, 2007 |
8580954 |
|
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14051021 |
|
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60786486 |
Mar 28, 2006 |
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Current U.S.
Class: |
514/567 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 47/40 20130101; C07H 3/06 20130101; A61P 25/04 20180101; A61K
31/196 20130101; A61K 31/195 20130101; C08B 37/0015 20130101; A61K
31/724 20130101; C07H 15/04 20130101; A61K 31/195 20130101; A61K
2300/00 20130101; A61K 31/724 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/567 |
International
Class: |
A61K 31/196 20060101
A61K031/196; A61K 47/40 20060101 A61K047/40 |
Claims
1. A pharmaceutical composition comprising: (a) an amount of a
diclofenac compound effective to induce an analgesic effect of at 1
38% on a Visual Analog Scale, wherein the amount does not exceed
about 37.5 mg; and (b) a beta-cyclodextrin compound, wherein the
pharmaceutical composition is an intravenous formulation.
2. The pharmaceutical composition of claim 1, wherein the
diclofenac compound is diclofenac sodium.
3. The pharmaceutical composition of claim 1, wherein the
cyclodextrin compound is 2-hydroxypropyl-beta-cyclodextrin.
4. The pharmaceutical composition of claim 1, wherein the dose
diclofenac compound is about 37.5 mg.
5. The pharmaceutical composition of claim 1, wherein the dose
diclofenac compound is about 18.75 mg.
6. The pharmaceutical composition of claim 1, wherein the dose
diclofenac compound is less than about 10 mg.
7. The pharmaceutical composition of claim 6, wherein the dose
diclofenac compound is about 9.4 mg.
8. The pharmaceutical composition of claim 6, wherein the dose
diclofenac compound is about 5 mg.
9. The pharmaceutical composition of claim 6, wherein the dose
diclofenac compound is about 3.75 mg.
10. The pharmaceutical composition of claim 1, further comprising a
stabilizer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.119,
based on U.S. Provisional Application Ser. No. 60/786,486, filed
Mar. 28, 2006, the disclosure of which is incorporated herein by
reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to pharmaceutical
compositions and methods of treating a subject in need of analgesia
with pharmaceutical compositions which contain diclofenac and
beta-cyclodextrin. Specifically, the compositions contain low doses
of diclofenac, namely less than 10 mg.
BACKGROUND OF THE INVENTION
[0003] Diclofenac is a well-known non-steroidal anti-inflammatory
drug ("NSAID") used in acute and chronic pain in both parenteral
and oral dosage forms. Oral dosages range from 100-200 mg/day,
while parenteral dosages range from 75-150 mg/day (1-2 mg/kg/day)
by either infusion or intermittent (divided) doses. Toxicity of
oral and parenteral forms are well known, with gastro-intestinal,
hemorrhagic, renal, hepatic, cardiovascular and allergic
(anaphylactic and severe dermal allergy) adverse events being most
significant.
[0004] Parenteral use of diclofenac has been limited due to limited
solubility, such that parenteral preparations have had to include
non-polar solvents in order to achieve concentrations (75 mg/3 ml)
which would allow intra-muscular (IM) administration of the desired
dose. This solubility has limited the parenteral use to IM use
and/or slow intravenous (IV) administration of diluted (100-500 ml
diluent) product.
[0005] U.S. Pat. No. 5,679,660 and co-pending application Ser. No.
10/999,155, filed Nov. 30, 2004, published as US 2005/0238674 A1 on
Oct. 27, 2005, both of which are incorporated by reference,
disclose novel formulations of diclofenac with
hydroxypropyl-beta-cyclodextrin, which allows a more concentrated
preparation and thus rapid intravenous administration. The data
show that the more concentrated the diclofenac/beta-cyclodextrin
formulation, the faster onset of action over current products.
[0006] Other than ease of administration and more rapid onset of
action, consequent on the improvements in the pharmaceutical
formulation, no other advantages were observed. The present
invention arises, in part, from the surprising discovery that
formulating a non-steroidal anti-inflammatory drug with
beta-cyclodextrin not only improves solubility and stability of the
drug, it also increases efficacy.
SUMMARY OF THE INVENTION
[0007] The present invention relates to a pharmaceutical
composition comprising a unit dose of a diclofenac compound
effective to induce analgesia; and a beta-cyclodextrin compound, in
which the dose of the diclofenac compound is less than 10 mg. This
dose is less than any effective dose previously reported or even
suggested for a formulation of a diclofenac and a beta-cyclodextrin
compound. The diclofenac compound can be a diclofenac salt, e.g.,
diclofenac sodium, as exemplified infra. The beta-cyclodextrin
compound can be 2-hydroxypropyl-beta-cyclodextrin, as exemplified
infra.
[0008] The pharmaceutical composition may further comprise a
stabilizer, such as monothioglycerol.
[0009] In specific embodiments, the pharmaceutical composition
provides a dose of diclofenac of about 9.4 mg, less than about 5
mg, and even about 3.75 mg.
[0010] The invention further provides a method for treating a
mammal in need of analgesia by administering a pharmaceutical
composition of the invention, as set forth above. In a specific
embodiment, the mammal is a human. In particular, the
pharmaceutical composition can be administered intravenously.
[0011] The advantageous methods of the invention pertain to other
formulations as well. Thus, the invention provides a method for
treating a mammal in need of analgesia by administering a
pharmaceutical composition comprising a dosage of a diclofenac
compound effective to induce analgesia; and a beta-cyclodextrin
compound, in which the dosage of the diclofenac compound is less
than about 1.3 mg/kg per day. In particular embodiments, the dosage
of diclofenac is less than 0.65 mg/kg per day, less than 0.33 mg/kg
per day, or less than 0.165 mg/kg per day.
[0012] In another embodiment of the methods of treatment, the
invention provides a method for treating a mammal in need of
analgesia by administering a pharmaceutical composition comprising
a dosage of a diclofenac compound effective to induce analgesia;
and a beta-cyclodextrin compound, wherein the dosage of the
diclofenac compound is less than a minimum approved dose for a
particular route of administration. The dose of the diclofenac
compound can have the same efficacy of pain relief as the minimum
approved dose, or it can have from about 70% to about 100% or from
about 40% to about 70% of the efficacy of pain relief as the
minimum approved dose. In addition, the dose of the diclofenac
compound can have the same duration of pain relief as the minimum
approved dose, or it can have from about two-thirds to the same
duration of pain relief, or from about one-third to about
two-thirds of the duration of pain relief, as the minimum approved
dose.
DESCRIPTION OF THE FIGURES
[0013] FIG. 1 contains a graphical representation of the 100 mm
visual analog pain relief (mm) afforded to patients over time
(hours) based on the formulation strengths administered. The tested
formulations include placebo, 3.75 mg Dyloject, 9.4 mg Dyloject,
18.75 mg Dyloject; 37.5 mg Dyloject, 75 mg Dyloject, and 30 mg
Ketorolac.
[0014] FIG. 2 illustrates the dose-response curve for peak
analgesia observed (mm VAS) over mg of formulation. Both diclofenac
and ketorolac formulations were tested.
[0015] FIG. 3 illustrates the dose-duration relationship examined
using the median time to re-medication (hours) in the single dose
phase. Two formulations of diclofenac were studied.
[0016] FIG. 4 illustrates the percentage of patients with NSAID
Adverse Events by dose of diclofenac (mg).
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention provides formulations of a diclofenac
compound with a beta-cyclodextrin compound. These formulations
unexpectedly provide for significant efficacy and duration of pain
relief at a lower dose than the current recommended doses of the
diclofenac. More particularly, at a reduced dose and dosage, the
formulation provides the same level of efficacy and the same
duration of analgesia as at the minimum approved dose and
dosage.
[0018] The invention is based, in part, on the results of a
comparison of the efficacy of diclofenac solubilized with
hydroxypropyl-beta-cyclodextrin to ketorolac and placebo for the
treatment of moderate-to-severe post-surgical pain. The efficacy of
diclofenac solubilized with hydroxypropyl-beta-cyclodextrin at
several dose levels suggests a faster onset of action. Most
notably, diclofenac formulated with hydroxypropyl-beta-cyclodextrin
provides single-dose efficacy at about 50%, about 25%, about 12.5%
and about 5% of the current recommended doses of diclofenac. This,
in combination with the known human pharmacokinetic results for the
formulation, supports reduced total daily doses of this NSAID with
anticipated lower risk of toxicity by reducing the extent and
duration of drug exposure. This is a novel finding and of clinical
importance.
[0019] The minimum effective dose of diclofenac solubilized with
hydroxypropyl-beta-cyclodextrin tested was 3.75 mg, demonstrating
that diclofenac, if solubilized with
hydroxypropyl-beta-cyclodextrin, may be administered at doses lower
than those previously considered necessary for postoperative
analgesia.
[0020] The term "diclofenac compound" refers to diclofenac or a
pharmaceutically acceptable diclofenac salt. A pharmaceutically
acceptable salt of diclofenac, can be an alkali metal salt, for
example the sodium or the potassium salt, or the salt formed with
an amine, e.g., a mono-, di- or tri-C.sub.1-C.sub.4 alkylamine, for
example diethyl- or triethyl-amine, hydroxy-C.sub.2-C.sub.4
alkylamine, for example ethanolamine, or hydroxy-C.sub.2-C.sub.4
alkyl-C.sub.1-C.sub.4 alkylamine, for example dimethylethanolamine,
or a quaternary ammonium salt, for example the tetramethylammonium
salt or the choline salt of diclofenac (see, e.g., U.S. Pat. No.
5,389,681). Preferably the diclofenac salt is diclofenac
sodium.
[0021] Suitable formulations of the present invention for
parenteral administration include cyclodextrin inclusion complexes.
One or more modified or unmodified cyclodextrins can be employed to
stabilize and increase the water solubility and efficacy of
compounds of the present invention. Useful cyclodextrins for this
purpose include beta-cyclodextrins.
[0022] The term "beta-cyclodextrin" as used herein refers to cyclic
alpha-1,4-linked oligosaccharides of a D-glucopyranose containing a
relatively hydrophobic central cavity and hydrophilic outer
surface. Particular efficacy has been observed in the present
invention utilizing hydroxypropyl-beta-cyclodextrin, however, other
substituted and unsubstituted beta-cyclodextrins can also be used
in the practice of the invention. Additional examples of
cyclodextrins that may be utilized are disclosed in U.S. Pat. Nos.
4,727,064, 4,764,604, 5,024,998, 6,407,079, 6,828,299, 6,869,939
and Jambhekar et al., 2004 Int. J. Pharm. 2004, 270(1-2) 149-66.
The formulations may be prepared as described in U.S. Pat. Nos.
5,679,660 and 5,674,854.
[0023] The "pharmaceutical compositions" for use in accordance with
the present invention can be formulated in any conventional manner
using one or more pharmaceutically acceptable carriers or
excipients. A "pharmaceutically acceptable" carrier or excipient,
as used herein, the term "pharmaceutically acceptable" means
approved by a regulatory agency of the Federal or a state
government or listed in the U.S. Pharmacopoeia or other generally
recognized pharmacopoeia for use in mammals, and more particularly
in humans.
[0024] Pharmaceutical compositions include solid dosage forms,
e.g., for perioral, transnasal (powder), or rectal (suppository)
administration; and liquid dosage forms, e.g., for parenteral
administration (injection), transnasal (spray), or perioral
administration. In a specific embodiment, the pharmaceutical
compositions of the present invention are liquid compositions
formulated for intravenous or intramuscular administration, and
particularly intravenous administration.
[0025] As used herein, the term "stabilizer" refers to a compound
optionally used in the pharmaceutical compositions of the present
invention in order to avoid the need for sulphite salts and
increase storage life. Optimal stabilizers include antioxidants,
specifically monothioglycerol and those described in U.S. Patent
Publication 2005/0238674.
[0026] The term "dosage" is intended to encompass a formulation
expressed in terms of mg/kg/day. The dosage is the amount of an
ingredient administered in accordance with a particular dosage
regimen. A "dose" is an amount of an agent administered to a
subject in a unit volume or mass, e.g., an absolute unit dose
expressed in mg of the agent. The dose depends on the concentration
of the agent in the formulation, e.g., in moles per liter (M), mass
per volume (m/v), or mass per mass (m/m). The two terms are closely
related, as a particular dosage results from the regimen of
administration of a dose or doses of the formulation. The
particular meaning in any case will be apparent from context.
[0027] The term "mammal" is intended to include, any warm-blooded
vertebrate having the skin more or less covered with hair. Most
preferably, the mammal is a human subject, but the mammal can also
be a non-human animal. Thus, the invention is useful in veterinary
medicine as well, e.g., for treating pain in a domestic pet, such
as a canine or feline, a faun animal, a work animal, or an animal
in a circus or zoological garden. The invention has particular
value in treating pain in a horse, particularly in sport, such as
thoroughbred and other race horses, rodeo horses, circus horses,
and dressage horses. A particular advantage of the invention is
that, by increasing the efficacy of a dosage of diclofenac, it is
possible to administer a therapeutic dosage that is below a maximum
allowed dose permitted by the particular regulatory authorities of
the sport.
[0028] The term "minimum approved dose" refers to the minimum
dosage that has received full regulatory approval by the
appropriate United States or foreign regulatory authority as safe
and effective for human or veterinary use.
[0029] The term "therapeutically effective" as applied to dose or
amount refers to that quantity of a compound or pharmaceutical
composition that is sufficient to result in a desired activity upon
administration to a mammal in need thereof. As used herein with
respect to the pharmaceutical compositions comprising an
antifungal, the term "therapeutically effective amount/dose" refers
to the amount/dose of a compound or pharmaceutical composition that
is sufficient to produce an effective response upon administration
to a mammal.
[0030] The term "amount" as used herein refers to quantity or to
concentration as appropriate to the context. In the present
invention, the effective amount of a compound refers to an amount
sufficient to treat a patient/subject in need of analgesia. The
effective amount of a drug that constitutes a therapeutically
effective amount varies according to factors such as the potency of
the particular drug, the route of administration of the
formulation, and the mechanical system used to administer the
formulation. A therapeutically effective amount of a particular
drug can be selected by those of ordinary skill in the art with due
consideration of such factors.
[0031] The term "about" or "approximately" means within an
acceptable error range for the particular value as determined by
one of ordinary skill in the art, which will depend in part on how
the value is measured or determined, i.e., the limitations of the
measurement system. For example, "about" can mean within 3 or more
than 3 standard deviations, per the practice in the art.
Alternatively, "about" can mean a range of up to 20%, preferably up
to 10%, more preferably up to 5%, and more preferably still up to
1% of a given value. Alternatively, particularly with respect to
biological systems or processes, the term can mean within an order
of magnitude, preferably within 5-fold, and more preferably within
2-fold, of a value.
[0032] As used herein, the term "treat" is used herein to mean to
relieve or alleviate at least one symptom of a disease in a
subject. Within the meaning of the present invention, the term
"treat" also denotes to arrest, delay the onset (i.e., the period
prior to clinical manifestation of a disease) and/or reduce the
risk of developing or worsening a disease.
Methods of Treatment
[0033] As noted above, the novel dosage formulations of the
invention are suitable for administering diclofenac to treat pain,
i.e., for analgesia. Various embodiments of the invention provide
for administration of unit doses to achieve a total dosage for the
desired effect. The examples demonstrate efficacy of a 3.75 mg dose
of diclofenac, which is about 5% of the minimum approved dose (and
about 5% or about 2.5% of the approved daily dosage). However, this
dose provides about 40% of the pain relief and one-third of the
duration as the minimum approved dose. Better results can be
achieved by selecting a dosage regimen with this dose of
diclofenac, e.g., increasing the frequency of administration, to
achieve a level and duration of pain relief acceptable for the
patient. Higher dose formulations likewise could provide such
relief. Such higher dose formulations are nevertheless lower than
any approved formulation, and the dosage regimen results in
administration of less diclofenac than the current approved minimum
dosage regimen.
[0034] A significant advantage of the invention results from the
ability to achieve efficacy with lower doses and overall daily
dosing of diclofenac. Consequently, it is possible to reduce the
dosage, and thus reduce toxicity.
[0035] In specific embodiments, the unit dose (i.e., the amount of
active drug administered at one time to a patient) is no more than
about 75%, no more than about 50%, no more than about 25%, no more
than about 12.5%, and no more than about 5%, of the approved
minimum dose. Doses that are about or greater than about 50% of the
approved minimum dose can show the same level and duration of pain
relieve as the minimum effective dose. Furthermore, by increasing
the frequency of administration of a lower dose formulation, the
patient can achieve the same levels of efficacy and duration of
pain relief as with the approved doses, with decreased
toxicity.
[0036] In another embodiment, then, the invention provides for
titrating the dose reduction of diclofenac and beta-cyclodextrin by
decreasing the unit dose to achieve an analgesic effect that is
sufficient, even at a reduced level, for the patient's needs, which
can be met by increasing the dosing frequency to achieve an
effective daily dosage that is still lower than the minimum
approved dose. The term "effect" means that there is a
statistically significant difference in a response in patients
taking the formulation containing the diclofenac relative to
patients taking a placebo.
[0037] The formulations of the invention can be administered via
any route, including parenteral, perioral, transnasal, and rectal.
Particular parenteral routes of administration include intravenous
and intramuscular injection.
[0038] The formulations of the invention are suitable for treating
pain by administration either or both prophylactically and after
onset of the pain. Thus, as used herein, the term "treat" (in any
of its grammatical forms) means to reduce pain through
administration of a formulation of the invention prior to or after
the onset of pain, or both. In particular, the formulations are
suitable in the treatment of acute painful conditions in humans and
animals such as headache, including migraine, trauma,
dysmenorrhoea, renal or biliary colic, post-operative pain, gout,
arthritis, cancer related pain, musculoskeletal pain, lower back
pain, fibromyalgia, and pain of infectious origin. Indeed, the low
dosage of diclofenac will have little or no anti-inflammatory
activity, so in the treatment of pain of infectious origin it will
have little effect on any immune response to the infectious
organism while achieving analgesia. In a specific embodiment,
exemplified below, the formulation is effective to treat
post-surgical dental pain resulting from surgical extraction of one
or more third molars. In addition, although not intending to be
bound by any particular mechanism of action, the formulation of the
invention may be used prophylactically to prevent the formation of
prostaglandins during and after surgery, with subsequent reduction
in immediate post-operative pain. Further, the formulation of the
invention may be used to modulate nuclear transcription factors,
such as NF-.kappa.B, or to modulate ion channel activity, for
example as described in Ocana, Maria et al., Potassium Channels and
Pain: Present Realities and Future Opportunities, 500 Eur. J.
Pharm. 203 (2004).
EXAMPLES
[0039] The present invention will be better understood by reference
to the following Examples, which are provided as exemplary of the
invention, and not by way of limitation.
Example 1
Analysis of Pain Relief Afforded to Patients Based on Administered
Dose
[0040] A 336-patient, seven treatment arm, randomized,
double-blind, single-dose, and placebo- and comparator-controlled,
parallel-group study was conducted. Patients were randomly assigned
to receive a single dose of either diclofenac sodium solubilized
with hydroxypropyl-beta-cyclodextrin (hereinafter "DIC"), ketorolac
tromethamine, or placebo.
[0041] Bolus IV injectable 2 ml solutions were prepared by
solubilizing diclofenac sodium with
hydroxypropyl-beta-cyclodextrin. The formulation strengths were as
follows:
[0042] Formulation: Diclofenac sodium solubilized with
hydroxypropyl-.beta.-cyclodextrin
[0043] Strengths: 75 mg, 37.5 mg, 18.75 mg, 9.4 mg and 3.75 mg
[0044] Dosage: Bolus IV injection (no less than 15 sec)
[0045] Batch Number: 063004 (PPS04010)
[0046] Manufacturer: Manufactured for Javelin by Precision
Pharma
[0047] Storage Conditions: Room temperature
[0048] Active Control/Comparator:
[0049] Formulation: Ketorolac Tromethamine
[0050] Strength: 30 mg
[0051] Dosage: Bolus IV injection (no less than 15 sec)
[0052] Batch Number: 21-430-DK
[0053] Manufacturer: Abbott Labs
[0054] Storage Conditions: Room temperature
[0055] Pain was assessed by each patient at Baseline (0 hour:
Visual Analog Scale (VAS) and categorical pain intensity only), at
5, 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10,
12 and 24 hours after administration of study medication and
immediately prior to the first dose of rescue medication. At each
post-dose time period, levels of pain intensity (categorical and
VAS) and pain relief (categorical and VAS) was assessed by each
patient. Patients were also provided with 2 stopwatches to measure
perceptible and meaningful pain relief.
[0056] The presence of a dose-response was tested with a step-down
testing procedure. Total pain relief (TOTPAR), peak pain relief,
pain intensity difference (SPID), summed peak reduction in pain
intensity difference (SPRID), and patient global evaluation was
analyzed with analysis of variance (ANOVA) with treatment, center,
and baseline categorical pain intensity as factors. The possibility
of interactions was investigated. Comparisons of the DIC groups
with the placebo and Ketorolac groups were performed with Dunnett's
test. The presence of a linear dose response for the ordered DIC
dose levels was tested with orthogonal contrasts for TOTPAR, SPID
and SPRID. Tests of individual DIC dose levels versus placebo for
TOTPAR, SPID, and SPRID were conducted with the Tukey, Ciminera,
and Heyse step-down testing procedure. The mean, standard
deviation, and sample size were presented for each treatment group.
Significant p-values (those less than or equal to 0.05) were
presented for each step of the procedure. Non-significant p-values
were represented with three dashes. Time to onset of perceptible
relief and time to onset of meaningful relief was analyzed with
survival analysis techniques. These variables were summarized with
number of observations, mean, standard deviation, median, and
range. Log-rank tests were used to compare treatments with respect
to survival distributions. The median time to event for each
treatment group was estimated with the Kaplan-Meier product limit
estimator. A 95% confidence interval for each estimated median time
to event was calculated.
[0057] The results of the study were strongly positive, novel and
could not have been anticipated from prior experience with
diclofenac. The doses had been chosen based on the currently
recommended minimally effective doses of 1 mg/kg (50 mg
immediate-release or 100 mg sustained-release orally or 75 mg
intramuscularly or intravenously). Based on these doses the test
conditions were a full dose (75 mg), half dose (37.5) mg, a
possibly effective dose (18.75 mg) and two placebo doses (9.75
& 3.4 mg). The findings were as follows:
TABLE-US-00001 TABLE 1 TOTPAR (Sum of Pain Relief VAS 0-100 mm
ratings 0-6 hours) Treatment Group Result % Maximum Effect Placebo
62.8 (SEM 9) 17% DIC 3.75 mg 134.1 (SEM 8) 38% DIC 9.4 mg 237.6
(SEM 15) 68% DIC 18.75 mg 284.4 (SEM 21) 82% DIC 37.5 mg 348.2 (SEM
30) 100% DIC 75 mg 346.3 (SEM 27) 100% ketorolac 400.3 (SEM 36)
100%
[0058] See FIG. 1 for the corresponding graphical representation of
the pain relief afforded to patients based on the formulation
strengths administered.
Example 2
Analysis of Efficacy & Duration of Pain Relief at Lower Doses
of Diclofenac
[0059] To explore this further, the dose-duration relationship in
the same study was examined using the median time to remedication
in the single-dose phase. Utilizing the results of study in Example
1, the efficacy and duration of pain relief were thoroughly
analyzed. The lowest IV dose of DIC (3.75 mg) had 38% of the effect
of the maximal dose, and the next lowest dose (9.4 mg) had 68% of
the maximal possible effect, despite being 5% and 12% respectively
of the current recommended minimally effective dose (1 mg/kg). FIG.
2 contains a graphical illustration of the dose-response for peak
analgesia observed in the study.
[0060] FIG. 3 depicts the dose-duration relationship examined using
the median time to remedication in the single dose phase. The peak
analgesic response was about 80% pain relief, with a 50% response
at a dose of 4-8 milligrams of Diclofenac in relation to dental
pain. Similar peak analgesic response was seen for 30 milligrams of
ketorolac. Given the shape of the dose response curve, it is clear
that lower doses of the DIC formulation achieved the same results
as the current established dose of diclofenac of 75 milligrams.
[0061] The findings show a 6 hour duration of effect for all doses
above about 20 milligrams (18 milligrams).
[0062] For most drugs the findings of significant activity at doses
far below the recommended doses would be of little significance due
to large therapeutic indices (wide ranges between the effective and
toxic doses). The opposite is true for parenteral NSAIDs; it has
been well established in the prior art that increasing the dose of
these drugs rapidly diminishes their utility due to increasing risk
of toxicity.
[0063] Thus the finding that with the new formulation of diclofenac
that 5%-12% of the usual dose can provide 38-68% of the desired
therapeutic effect is remarkable and unanticipated. This leads to
the possibility that the high early blood levels possible with the
new formulation allow lower total daily doses resulting in less
risk of toxicity.
[0064] This finding demonstrates efficacy with a lower daily dose
(25-75 mg/day) than current dosing of diclofenac (75-200 mg/day),
and anticipates better dosing paradigms (less than Q 12 hours)
offering the expectation of lesser toxicity. Proof of lesser
toxicity from available data from this study is suggestive, based
on the known relationship of dose and toxicity.
[0065] The novel diclofenac formulation allowed by
hydroxypropyl-.beta.-cyclodextrin has been shown to provide proof
of single-dose efficacy at 50%, 25%, 12.5% and 5% of the current
recommended doses of diclofenac. This in combination with the known
human pharmacokinetic results for the formulation supports reduced
total daily doses of this NSAID with anticipated lower risk of
toxicity by reducing the extent and duration of drug exposure.
[0066] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0067] Patents, patent applications publications product
descriptions, and protocols are cited throughout this application
the disclosures of which are incorporated herein by reference in
their entireties for all purposes.
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