U.S. patent number RE36,744 [Application Number 08/213,498] was granted by the patent office on 2000-06-20 for nasal administration of benzodiazepine hypnotics.
This patent grant is currently assigned to Ribogene, Inc.. Invention is credited to Arthur H. Goldberg.
United States Patent |
RE36,744 |
Goldberg |
June 20, 2000 |
Nasal administration of benzodiazepine hypnotics
Abstract
Nasal administration of benzodiazepines is described as
providing improved therapeutic effects as compared to conventional
delivery techniques. The compositions comprise a benzodiazepine
hypnotic in a pharmaceutically acceptable nasal carrier.
Inventors: |
Goldberg; Arthur H. (Montclair,
NJ) |
Assignee: |
Ribogene, Inc. (Hayward,
CA)
|
Family
ID: |
26936967 |
Appl.
No.: |
08/213,498 |
Filed: |
March 16, 1994 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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937045 |
Aug 20, 1992 |
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Reissue of: |
245031 |
Sep 16, 1988 |
04950664 |
Aug 21, 1990 |
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Current U.S.
Class: |
514/219; 424/45;
514/220 |
Current CPC
Class: |
A61K
9/0043 (20130101); A61K 31/55 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 31/55 (20060101); A01N
043/62 (); A61L 009/04 () |
Field of
Search: |
;424/45
;514/219,220 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 005 120 A1 |
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Sep 1987 |
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EP |
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0 183 527 B1 |
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Mar 1991 |
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EP |
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56-49313 |
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May 1981 |
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JP |
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58-500562 |
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Apr 1983 |
|
JP |
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61-47415 |
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Mar 1986 |
|
JP |
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62-500589 |
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Mar 1987 |
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JP |
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63-503303 |
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Dec 1988 |
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JP |
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82/03009 |
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Sep 1982 |
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WO |
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86/02553 |
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May 1986 |
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WO |
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87/03473 |
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Jun 1987 |
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WO |
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Other References
Wilton et al., "Intranasal Midazolam Premedication In Pre-School
Children", Anesthesia and Analgesia, 67:S260 (1988), published in
Feb. 1988. .
Morimoto et al., "Nasal Absorption Of Nifedipine From Gel
Preparations In Rats", Chem. Pharm. Bull, 35(7):3041 3044 (1987).
.
Danish Pharmaceutical Catalogue 1987 (Laegemiddelkataloget 1987);
pp. 277-278, 282, 527, 820, 853-854 and 910 (including translations
of relevant parts). .
The Merck Index (1983), p. 886:6056. .
Martindale 1982, pp. 1526, 1543-1544 and 1728. .
The Merck Index, 10th Edition, (1983), pp. 1308-1309. .
"Drug Delivery System" edited by Hitoshi Sezaki (Apr. 15, 1986),
published by Nankodo, pp. 126-128. .
"Revised Version of handbook of Pharmaceuticals" edited by
Osaka-Pref. Hospital-Pharmaceutist Association (Sho. 61-9-10),
published by Yakugyo-Jihosha, pp. 16-19, 40-41, 136-143..
|
Primary Examiner: Azpuru; Carlos A.
Attorney, Agent or Firm: Pennie & Edmonds LLP
Parent Case Text
.Iadd.This application is a continuation of application Ser. No.
07/937,045 filed Aug. 20, 1992, now abandoned, which is a reissue
of U.S. Pat. No. 4,950,664..Iaddend.
Claims
What is claimed is:
1. A composition for the administration of a hypnotic drug
comprising a systemically effective amount of a benzodiazepine in a
pharmaceutically acceptable .Iadd.aqueous .Iaddend.nasal
carrier.
2. The composition of claim 1, wherein the hypnotic drug comprises
the free base or pharmaceutically acceptable salt of a
benzodiazepine.
3. The composition of claim 1, wherein the benzodiazepine is
totally solubilized in the carrier.
4. The composition of claim 2, wherein a portion of the
benzodiazepine is dispersed in undissolved form in the carrier.
5. The composition of claim 2, wherein the benzodiazepine
comprises
triazolam.
6. The composition of claim 2, wherein the benzodiazepine comprises
midazolam.
7. The composition of claim 2, wherein the benzodiazepine comprises
temazepam.
8. The composition of claim 2, wherein the benzodiazepine .[.is.].
.Iadd.comprises .Iaddend.diazepam.
9. The composition of claim 2, wherein the benzodiazepine comprises
flurazepam.
10. A method for inducing an improved pharmacological response in a
mammal comprising the nasal administration of a composition
comprising a systemically effective amount of a benzodiazepine in a
pharmaceutically acceptable .Iadd.aqueous .Iaddend.nasal
carrier.
11. The method of claim 10, wherein the benzodiazepine is
essentially totally solubilized in the carrier to induce an
improved onset of pharmacological response.
12. The method of claim 10, wherein the composition is nasally
administered to a human subject in an amount effective for the
improvement of sleep.
13. The composition of claim 2, wherein the pharmaceutically
acceptable salt of a benzodiazepine is a carboxylic acid salt
having from about 10 to about 30 carbon atoms.
14. The method of claim 10, wherein the pharmaceutically acceptable
salt of a benzodiazepine is a carboxylic acid salt having from
about 10 to about 30 carbon atoms.
15. The composition of claim 2, wherein the benzodiazepine is in a
solution, suspension or gel .[.composed in major amount of.].
.Iadd.which includes .Iaddend.water.
16. The method of claim 10, wherein the benzodiazepine is in a
solution, suspension or gel .[.composed in major amount of.].
.Iadd.which includes .Iaddend.water. .Iadd.17. The composition of
claim 1, wherein the carrier is composed of
water..Iaddend..Iadd.18. The composition of claim 17, having the
physical form of a spray..Iaddend..Iadd.19. The composition of
claim 18, wherein the benzodiazepine is selected from the group
consisting of triazolam, midazolam, temazepam, diazepam and
flurazepam..Iaddend..Iadd.20. The composition of claim 1, wherein
the
carrier consists essentially of water..Iaddend..Iadd.21. The
composition
of claim 17 filled in an aerosol container..Iaddend..Iadd.22. The
composition of claim 1, wherein the benzodiazepine is in a
solution, suspension or gel composed in major amount of
water..Iaddend..Iadd.23. The composition of claim 22, having the
physical form of a spray..Iaddend..Iadd.24. The composition of
claim 22 filed in an aerosol
container..Iaddend..Iadd.25. A method for treating a mammal
suffering from anxiety comprising administering nasally a
systemically effective amount of midazolam in a pharmaceutically
acceptable nasal carrier during a period of anxiety..Iaddend.
Description
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a novel form of certain hypnotic
drugs and to their administration to mammals. They may be employed
for any of the conventional purposes for which hypnotics are known,
but especially for improving sleep.
Hypnotic drugs are a class of therapeutic agents which are commonly
employed to induce and/or to prolong sleep. They may also be
utilized to alleviate sleep disorders. Terms such as sedative,
anti-anxiety agent, minor tranquilizer and anxiolytic are sometimes
used somewhat interchangeably for such drugs because, in
appropriate dosages, these hypnotics can produce similar
effects.
There are a wide variety of hypnotic drugs. This term includes both
barbiturates and non-barbiturates. Typical barbiturate hypnotics
are aprobarbital and pentobarbital. Non-barbiturates recognized for
their hypnotic activity include benzodiazepines; antihistamines
having pronounced side effects such as diphenhydramine; serotonin
initiators such as L-tryptophane; and various other drugs including
ethinamate, chloral hydrate, ethchlorvynol, methyprylon and
glutethimide. Their hypnotic effect is commonly attributed to a
neurological mechanism involving depression of the central nervous
system. That effect is also frequently accompanied by a mild
reduction in such physiological functions as blood pressure and
respiration.
PRIOR ART
Numerous hypnotic drugs are already known. Many, for example, are
listed in the Physicians Desk Reference (PDR) published by Medical
Economics Company, Inc. They are widely used therapeutically to
improve sleep. Administration is generally performed either
parenterally or, more usually, orally by means of pills, tablets
and capsules. Their various uses are likewise well known.
Unfortunately, these drugs commonly exhibit a number of drawbacks
when conventionally administered. Some have undesirable side
effects. Many are inefficiently and variably absorbed from their
current dosage forms. Further, the onset of their pharmacological
activity is often delayed and/or the duration of that activity
limited pursuant to ordinary oral, subcutaneous and/or
intra-muscular administration.
Unlike the broad applicability of conventional routes of
administration, the nasal delivery of therapeutic agents is a
relatively recently discovered technique. It is also recognized
only for specific agents. Representative disclosures of nasal
administration of drugs include: U.S. Pat. No. 4,454,140 of
Goldberg et al; U.S. Pat. No's. 4,428,883; 4,284,648; and 4,394,390
of Hussain and U.S. Pat. No. 4,624,965 of Wenig.
While nasal administration has become an accepted route of
administration, the foregoing disclosures limit that mode of
delivery to the specific drugs described. Moreover, it has been
observed that many therapeutic agents cannot be usefully
administered by this unusual route. Consequently, nasal
administration remains a technique for which applicability is far
from universal and the results unpredictable.
SUMMARY OF INVENTION
It has been discovered that certain known hypnotic drugs can
normally be effectively administered to mammals, and especially to
humans, in novel compositions. More specifically, these
compositions are ones which contain a benzodiazepine hypnotic
adapted for nasal administration and comprise a solution,
suspension, ointment, gel or other useful nasal form. These nasal
compositions may be employed for any of the known therapeutic
purposes for which such hypnotics are known.
The utilization of a nasal form of these hypnotic drugs greatly
facilitates administration. As compared with parenteral
administration, for example, a simple aerosol container or a
dropper will suffice for delivery. From a therapeutic standpoint,
nasal administration often provides a hypnotic effect of improved
duration. It may also be more efficiently and precisely controlled
than through conventional means and permits a more rapid onset of
activity. These and additional advantages of the present invention
will become evident from the description and examples which
follow.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention and particularly the Examples and Tables, will be
more clearly understood when considered with the accompanying
drawings in which:
FIG. 1 is a graphic depiction of the comparative results of Example
1;
FIG. 2 is a graphic depiction of the comparative results of Example
2; and
FIG. 3 is a graphic depiction of the comparative results of Example
3.
DETAILED DESCRIPTION OF THE INVENTION
Any benzodiazepine drug capable of exhibiting a hypnotic activity
may be employed in accordance with the present invention. These
particularly include diazepam, triazolam, midazolam, temazepam and
flurazepam; although other, less common benzodiazepines may also be
utilized.
Any pharmaceutically acceptable form of these benzodiazepine drugs
may be utilized in accordance with the present invention. Generally
the selected therapeutic agent is provided in the chemical form
which has previously been found most efficacious for oral or
parenteral delivery. Most commonly, this comprises either the free
base or a pharmaceutically acceptable salt of the hypnotic
agent.
A peculiar facet of the present invention lies in the discovery of
the uniqueness of this class of hypnotics. Despite the recognized
equivalence of benzodiazepines with other subclasses of hypnotics,
they do not provide the many advantages enjoyed through the nasal
administration of benzodiazepines. In fact, it has been discovered
that many of these non-benzodiazepine hypnotics fail to exhibit
that therapeutic activity when they are administered nasally,
instead of by conventional method.
In the formulation of the present hypnotic compositions, a
relatively water soluble form of the benzodiazepine is usually
employed. Use of a fully dissolved form of the benzodiazepine
maximizes its immediate effect. Compositions containing the
therapeutic drug in a form having a limited solubility may be
employed where sustained release is desired. These compositions, in
which the therapeutic drug is not totally solubilized in its dosage
form provide a prolonged therapeutic activity. For this purpose, a
long chain carboxylic acid salt of the desired drug is often
preferred. The acid portion of the salt preferably contains from
about 10 to about 30 carbon atoms. Such salts, including stearates,
palmitates and the like, are readily synthesized by known
techniques.
The dosage forms of the present invention additionally comprise a
pharmaceutically acceptable nasal carrier. Any of the
benzodiazepines can be conveniently administered in such a carrier.
These compositions comprise a systemic, therapeutically effective
amount of the desired drug together with a pharmaceutically
acceptable nasal carrier therefore.
Nasal carriers suitable in accordance with the present invention
will be apparent to those skilled in the art of nasal
pharmaceutical formulations. Exemplary nasal carriers include
saline solutions; alcohols such as ethanol; glycols such as
propylene glycol; glycol ethers such as polyethylene glycol and
combinations of the foregoing with water and/or one another. For
still other examples, reference is made to the text entitled
"REMINGTON'S PHARMACEUTICAL SCIENCES", 14th edition, 1970.
The choice of a suitable carrier in accordance with the present
invention will depend on the exact nature of the particular nasal
dosage form required. A therapeutic agent may, for example, be
formulated into a nasal solution (for use as drops or as a spray),
a nasal suspension, a nasal ointment, a nasal gel or any other
nasal form. Preferred nasal dosage forms are solutions, suspensions
and gels. These normally contain a major amount of water
(preferably purified water) in addition to the active hypnotic
ingredient. Minor amounts of other ingredients such as tonicity
agents (e.g. NaCl) pH adjusters (e.g., a base such as NaOH),
emulsifiers or dispersing agents, buffering agents, preservatives,
wetting agents and jelling agents (e.g., methylcellulose) may also
be present. Particularly preferred compositions contain various of
the foregoing other ingredients so as to be isotonic and/or
buffered to the same pH as blood serum.
The present compositions may be administered to any of the subjects
recognized as being susceptible to benzodiazepine hypnotics. While
therefore generally useful in treatment of a broad spectrum of
mammals, the present invention is most desirably employed on human
subjects.
The efficacy of a hypnotic drug is most clearly revealed by its
concentration in the blood of the subject being treated. In
general, hypnotic activity is dependent upon the bioavailability of
therapeutic agent evidenced by that concentration. It is therefore
particularly significant that the present nasal administration of
benzodiazepines is characterized by a significantly faster onset
and more pronounced blood concentration of hypnotic than
conventional forms of administration. This insures an elevated and
more constant hypnotic effect.
Those skilled in the art will be aware that a systemic,
therapeutically effective amount of a particular benzodiazepine
hypnotic will vary with the particular drug as well as the type,
age, size, weight and general physical condition of the subject.
The amount will also vary dependent upon the particular therapeutic
effect desired. Typically the dosage level will be more similar to
the expected dosage level for intravenous administration than to
the dosage levels currently employed for other methods of
administration, for example, oral or rectal.
As a practical matter, the present therapeutic compositions will
normally be prepared in dosage unit forms to contain a systemic,
therapeutically effective amount of the selected hypnotic drug.
This can be similar to conventional dosage amounts of the drug. The
drug unit is normally less than 0.2 ml, optimally from 0.05 to 0.1
ml in volume. Desirably, nasal dosage units are prepared having a
lesser amount of drug, preferably from one-half to one-tenth of the
amount of therapeutic agent employed for conventional routes of
administration. This is made possible through the improved blood
concentration levels for benzodiazepines which have been observed
to result from nasal administration. These are the most preferred
types of compositions.
The present compositions are especially useful for improving sleep.
They may be utilized to more rapidly induce and/or to prolong
sleep. This use is not, however, exclusive. The present invention
may likewise be employed to enhance other known therapeutic
utilities of benzodiazepines.
The following examples are given by way of illustration only and
are not to be considered limitations of this invention. Many
apparent variations are possible without departing from the spirit
or scope thereof.
EXAMPLE 1
In two comparative studies separated in time by over one week; four
healthy male, 2-3 year old beagle dogs received oral and nasal
doses of triazolam. They were fasted overnight before each study
and food was withheld until the end of the experiment. They were
restrained in a dog sling during the studies while blood (3 ml) was
withdrawn from each dog through a cannula inserted into the
cephalic vein.
Oral Administration Studies: Two 0.5 mg triazolam tablets were
given to each dog with 50 ml of water. Blood samples were taken
from the cephalic vein at 0 min before administration and 15, 30,
45, 60, 120, 180, 240, 300, 360 and 420 min after administration.
The plasma samples were stored frozen until gas chromotographic
assay for triazolam.
Nasal Administration Studies: Thirty milligrams of triazolam powder
was dissolved in 5 ml of PEG 400 warmed at 55.degree.-60.degree. C.
After the solution was cooled to room temperature, an equal volume
of 1% methocel J5MS (Dow Chemical Company, Midland, Mich.) solution
was mixed with the triazolam solution. Air bubbles generated during
mixing were removed by centrifugation. The final concentration of
triazolam in the solvent mixture was assayed by an HPLC method. An
Altex C18, 4.6.times.150 mm column was used. The mobile phase
contained 60% of 0.05 M KH.sub.2 PO.sub.4 (pH=6.0, T. J. Baker) and
40% acetonitrile (Fisher Scientific). Flow rate of mobile phase was
1 ml/min. The wavelength used was 221 nm. The assayed
concentrations of triazolam solution range from 2.632 to 2.508
mg/ml.
Using a metered dose inhaler, triazolam solution was sprayed into
both nostrils of the dogs. The dose administered was determined by
weighting the bottle containing the triazolam solution before and
after spraying. The dose given to each dog was 0.9343, 1.040, 1.422
and 1.532 mg respectively. Blood sampling times were the same as in
the oral study. The plasma samples were frozen until GC assay for
triazolam.
GC Assay: To extract triazolam, 0.5 ml of plasma, 50 .mu.l of
internal standard (55 ng/ml clonazepam in methanol) and 3 ml of
hexane/methylene chloride (4:3) were vortexed together for 15
seconds and centrifuged for 4 minutes. The bottom aqueous layer was
frozen by dry ice/acetone and the upper organic layer was
transferred to another tube containing 1 ml of distilled water. The
mixture was vortexed for 15 seconds and centrifuged for 4 minutes.
Two ml of the upper organic layer was then pipetted into another
tube and evaporated to dryness in an vortex-evaporator. Fifty ml of
toluene was used for reconstitution.
The amount of triazolam in 3 ml of extract plasma was assayed by an
HP model 5830A GC-EC. The glass column used was a 6'.times.1/4" 2
mm on column w/o liner 6" coil (Anspec) with 3% OV-17 chromosorb
injcctor port and detector were 275.degree., 310.degree. and
350.degree. C., respectively. The flow rate for argon/methane
(95:5) gas 42 ml/min.
Results
The average dose-corrected plasma concentration of triazolam for
the dogs after oral and nasal administration of triazolam are shown
shown in FIG. 1. Plasma triazolam levels after nasal administration
were consistently higher than those for oral administration The
oral plasma concentration-time curve shows more variability than
with nasal administration. This is attributable to variability in
gastric emptying of the tablets. Table 1 shows the various relevant
pharmacokinetic parameters obtained from this study.
There was significant nasal absorption of triazolam. The mean AUC
after nasal administration was 2.4-fold larger than that of oral
route. Mean plasma triazolam concentration peaked at about 18.8
min. after nasal administration while that of oral route was about
48.8 min. The mean half-life was about the same in both routes of
administration. The mean, peak plasma concentration was 27.6 ng/ml
for nasal route and 7.0 ng/ml for oral administration. Thus nasal
administration provided triazolam both sooner and in a greater
amount than oral administration.
TABLE 1
__________________________________________________________________________
RELEVANT PHARMACOKINETIC PARAMETERS OF TRIAZOLAM AFTER ORAL AND
NASAL DELIVERY 1 AUC 2 AUC 3 AUC 4 CMAX 5 CMAX 6 TMAX 7 TMAX 8 T1/2
9 T1/2 0 NAME PO NASAL NASAL/PO PO NASAL PO NASAL PO NASAL
__________________________________________________________________________
1 DUNCAN 976.8 2148.6 2.20 7.60 27.20 45.0 15.0 103.7 62.7 2 GURNEY
911.4 2335.2 2.60 6.10 31.20 60.0 15.0 58.8 57.3 3 BUCKO 569.8
1598.8 2.80 5.50 25.20 60.0 15.0 58.1 65.3 4 EDRIK
670.4 1415.2 2.10 8.70 26.60 30.0 30.0 49.4 43.7 6 MEAN 782.1
1874.5 2.40 7.00 27.60 48.8 18.8 67.5 57.3 7 (SEM) 96.7 218.8 0.16
0.72 1.27 7.2 3.8 12.3 4.8
__________________________________________________________________________
EXAMPLE 2
The efficacy of oral versus nasal administration of midazolam was
examined using the methodology of Example 1, but modified to allow
at least three weeks between studies.
Oral Administration Studies: Five mg equivalent of midazolam free
base solution was given to each of four dogs with 50 ml of water.
Blood samples were taken from the cephalic vein at 0 min before
administration and 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min
after administration. The plasma samples were stored frozen until
GC assay for midazolam.
Nasal Administration Studies: 55.6 milligrams of midazolam HCl
powder was dissolved in 4 ml of distilled water. One ml of 7.5%
methocel J5MS (Dow Chemical Company, Midland, Mich.) solution was
mixed with the midazolam solution. Air bubbles generated during
mixing were removed by centrifugation. The pH of the solution was
3.62.
Midazolam solution was sprayed, using a meter dose inhaler into
both nostrils of the dogs. The dose given to each dog was 7.85,
7.89, 7.22, 5.61 mg free base. Blood sampling times were the same
as in the oral study. The plasma samples were frozen until GC assay
for midazolam.
GC Assay--for extraction, 0.5 ml of plasma, 100 .mu.l of internal
standard (100 ng/ml flurazepam in methanol) and 0.5 ml of 2N sodium
hydroxide were vortexed for 5 seconds. Five ml of hexane was then
added and the mixture was vortexed for one min. and centrifuges for
4 minutes. Four ml of the upper organic layer was then pipetted
into another tube and evaporated to dryness in an
vortex-evaporator. Fifty .mu.l of hexane/isoamyl alcohol (80:20)
was used for reconstitution.
Midazolam in plasma was assayed by a Hewlett Packard model 5830A
GC-EC. The glass column used was a 6'.times.1/4" 2 mm on column w/o
liner 6" coil (Anspec) with 3% OV-17 chromosorb W-HP 80/100 packing
(Anspec). The temperatures for column, injector port and detector
were 250.degree., 310.degree. and 310.degree. C., respectively. The
flow rate for argon/methane (95:5) gas was 33 ml/min.
Results and Discussion
The average dose-corrected plasma concentrations of midazolam for
the dogs after oral and nasal administration of midazolam is shown
in FIG. 2. Plasma midazolam levels after nasal administration were
consistently higher than after oral administration.
Table 2 shows various relevant pharmacokinetic parameters obtained
from this study. The AUCs listed under nasal and oral
administration were normalized with the dose administered. There
was a mean of 2.5-fold increase in AUC after nasal administration.
The Cmax after oral administration was 4 times lower than that of
nasal route. The Tmax after nasal administration was 2-fold earlier
than after oral administration. The mean half-life was about the
same in both routes of administration. There was significant
increase in bioavailability of midazolam after nasal versus oral
administration.
TABLE 2
__________________________________________________________________________
RELEVANT PHARMACOKINETIC PARAMETERS OF MIDAZOLAM AFTER ORAL AND
NASAL DELIVERY 1 AUC* 2 AUC* 3 AUC 4 CMAX* 5 CMAX# 6 TMAX@ 7 TMAX@
8 T1/2@ 9 T1/2@ 0 NAME PO NASAL NASAL/PO PO NASAL PO NASAL PO NASAL
__________________________________________________________________________
1 DUNCAN 235.6 842.9 3.58 22.2 159.0 15.0 15 43.5 36.1 2 GURNEY
242.0 520.8 2.15 15.0 111.2 45.0 15 50.6 26.8 3 BUCKO 157.8 338.5
2.15 17.8 47.1 30.0 15 19.4 36.5 4 EDRIK 333.2 650.8 1.95 42.8 87.9
30.0 15 19.3 33.8 6 MEAN 242.1 588.3 2.46 24.5 101.0 30.0 15 33.2
33.3 7 (SEM) 35.9 106.4 0.38 3.2 11.7 3.1 0 4.1 1.1
__________________________________________________________________________
9 *ngmin/ml-mg 10 #ng/ml 11 @min
EXAMPLE 3
The efficacy of oral versus nasal administration was examined using
the methodology of Example 2.
Oral Administration Studies: Fifteen mg of flurazepam HCl solution
was given to each dog with 50 ml of water. Blood samples were taken
from the cephalic vein at 0 min before administration and at 15,
30, 45, 60, 120, 180, 240, 300, 360 min after administration. The
plasma samples were stored frozen until GC assay for
flurazepam.
Nasal Administration Studies: One hundred and twenty milligrams of
flurazepam HCl powder was dissolved in 4 ml of distilled water. One
ml of 7.5% methocel J5MS (Dow Chemical Company, Midland, Mich.)
solution was mixed with the flurazepam solution. Air bubbles
generated during mixing were eliminated by centrifugation. The pH
of the solution was 1.82.
Flurazepam solution was sprayed into both nostrils of the dogs. The
dose given to the dogs was 14.5, 12.4, 12.1 and 12.5 mg as
flurazepam HCl. Blood sampling times were same as in the oral
study. The plasma samples were frozen until GC assay for
flurazepam.
GC Assay: For extraction, 0.5 ml of plasma, 50 .mu.l of internal
standard (100 ng/ml diazepam in methanol) and 0.5 ml of 2N sodium
hydroxide were vortexed for 5 seconds. Five ml of hexane was then
added and the mixture was vortexed together for one min. and
centrifuged for 4 minutes. Four ml of the upper organic layer was
then pipetted. Fifty .mu.l of hexane/isoamyl alcohol was used for
reconstitution.
Flurazepam in plasma was assayed by a Hewlett Packard model 5830A
GC-EC. The glass column used was a 6'.times.1/4" 2 mm on column w/o
liner 6" coil (Anspec) with 3% OV-17 chromosorb W-HP 80/100 packing
(Anspec). The temperatures for column, injector port and detector
were 250.degree., 310.degree. and 310.degree. C., respectively. The
flow rate for argon/methane (95:5) gas was 33 ml/min.
Results and Discussion
The average dose-corrected plasma concentrations of flurazepam for
each dog after oral and nasal administration of flurazepam are
shown in FIG. 3. Plasma flurazepam levels after nasal
administration were consistently higher than after oral
administration.
Table 3 shows relevant pharmacokinetic parameters obtained from
this study. The AUC for oral administration was estimated up to the
last data point because flurazepam was still in its distribution
phase As a result, half-life of the compound was not calculated.
The AUCs listed under nasal and oral administration were normalized
with the dose administered. There was a mean of 51-fold increase in
AUC after nasal administration. The Cmax after oral administration
was 15 times lower than that of nasal route. The Tmax after nasal
administration was half that of oral route.
TABLE 3
__________________________________________________________________________
RELEVANT PHARMACOKINETIC PARAMETERS OF FLURAZEPAM AFTER ORAL AND
NASAL DELIVERY 1 AUC* 2 AUC* 3 AUC 4 CMAX* 5 CMAX# 6 TMAX@ 7 TMAX@
8 T1/2@ 9 T1/2@ 0 NAME PO NASAL NASAL/PO PO NASAL PO NASAL PO NASAL
__________________________________________________________________________
1 DUNCAN 8.60 922.3 107.2 3.04 161.5 15.0 15 ***** 214.7 2 GURNEY
19.30 384.9 19.9 8.85 41.1 15.0 15 ***** 190.8 3 BUCKO 4.81 287.4
59.9 2.06 31.5 45.0 15 ***** 163.3 4 EDRIK 20.00 314.9 15.7 5.91
59.0 30.0 15 ***** 102.6 6 MEAN 13.20 477.4 50.7 4.97 73.3 26.3 15
***** 167.9 7 (SEM) 3.80 149.7 21.3 1.53 29.9 7.2 0 ***** 24.2
__________________________________________________________________________
9 *ngmin/ml-mg 10 #ng/ml 11 @min
EXAMPLE 4
A variety of hypnotics including chloral hydrate, sodium
pentobarbital and flurazepam were administered to Wistar rats to
compare the efficacy of oral and nasal administration. Because the
rats proved resistant to flurazepam by oral technique, no
comparison of that compound was possible.
Oral Administration Studies: The subjects were fasted for
approximately 18 hours; water was available ab libitum. Aqueous
solutions of chloral hydrate obtained from Sigma Chemical Co., Ltd.
and sodium pentobarbital were separately administered to groups of
the subject rats using a constant dose volume of 10mg/kg. Different
dosage levels were obtained by varying the aqueous concentrations
of therapeutic drug to identify an effective amount of
hypnotic.
The animals were then placed in a constant temperature environment
of 32.degree. C. The duration of sleeping time (measured by the
loss and reappearance of the righting reflex) was recorded for each
animal. The results within each group were then averaged.
Nasal Administration Studies: The methodology of the oral studies
was repeated with substitution of nasal administration of aqueous
solutions through a fine catheter inserted into the nostril. The
therapeutic drug was dosed at a constant volume of 50 .mu.l which
would deliver an amount of the hypnotic which would be orally
effective.
Results and Discussion
Wide variation of results between similarly treated subjects
occurred for nasal administration. That variation was attributed to
expulsion, as by sneezing, swallowing or inhalation. All of these
physiological responses interfered with administration. Despite
this interference, the data confirmed that these hypnotics, in
contrast to benzodizaepines, are significantly less effective where
administered nasally than by conventional technique.
The foregoing Examples are illustrative of the present invention.
The scope of this invention is indicated by the appended claims,
and all changes which come within the meaning and range of
equivalency of these claims are intended to be embraced
therein.
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