U.S. patent application number 10/815119 was filed with the patent office on 2005-01-13 for prostaglandin compositions and methods for the treatment of vasospasm.
This patent application is currently assigned to NexMed (Holdings) Inc.. Invention is credited to Bai, Jieshan, Liu, Liu, Lu, Mingqi, Mo, Y. Joseph, Wen, Tian.
Application Number | 20050009918 10/815119 |
Document ID | / |
Family ID | 33159705 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050009918 |
Kind Code |
A1 |
Wen, Tian ; et al. |
January 13, 2005 |
Prostaglandin compositions and methods for the treatment of
vasospasm
Abstract
Compositions and methods for the treatment of vasospasm are
provided comprising applying an amount of a semi-solid vasoactive
prostaglandin composition to the affected tissue. Also provided are
methods of improving microcirculation in a replanted body part.
Inventors: |
Wen, Tian; (Beijing, CN)
; Liu, Liu; (Beijing, CN) ; Lu, Mingqi;
(Lawrenceville, NJ) ; Bai, Jieshan; (Beijing,
CN) ; Mo, Y. Joseph; (Princeton, NJ) |
Correspondence
Address: |
BOWDITCH & DEWEY, LLP
161 WORCESTER ROAD
P.O. BOX 9320
FRAMINGHAM
MA
01701-9320
US
|
Assignee: |
NexMed (Holdings) Inc.
Robbinsville
NJ
|
Family ID: |
33159705 |
Appl. No.: |
10/815119 |
Filed: |
March 31, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60459896 |
Apr 2, 2003 |
|
|
|
Current U.S.
Class: |
514/573 ;
424/487; 514/54 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61P 9/00 20180101; A61K 47/18 20130101; A61K 47/14 20130101; A61P
9/14 20180101; A61P 43/00 20180101; A61P 7/02 20180101; A61P 9/10
20180101; A61K 47/26 20130101; A61K 47/36 20130101; A61K 47/10
20130101; A61K 31/5575 20130101 |
Class at
Publication: |
514/573 ;
514/054; 424/487 |
International
Class: |
A61K 031/557; A61K
031/715; A61K 009/14 |
Claims
We claim:
1. A semi-solid composition comprising: a vasoactive prostaglandin;
a penetration enhancer; a polymer thickener selected from the group
consisting of a polysaccharide gum and a polyacrylic acid polymer;
a lipophilic component that is selected from the group consisting
of an aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester, a liquid polyol and a mixture thereof; water and a
buffer system that provides a buffered pH value for said
composition in the range of about 3 to about 7.4.
2. The composition of claim 1 wherein the vasoactive prostaglandin
is selected from the group consisting of PGE.sub.1, PGA.sub.1,
PGB.sub.1, PGF.sub.1.alpha., 19-hydroxy-PGA.sub.1,
19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2, PGB.sub.2,
19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3, PGF.sub.3,
PGF.sub.3.alpha., a pharmaceutically acceptable salt thereof, a
lower alkyl ester thereof and a mixture.
3. The composition of claim 1 wherein the vasoactive prostaglandin
is selected from the group consisting of prostaglandin E.sub.1,
prostaglandin E.sub.2, a pharmaceutically acceptable salt thereof,
a lower alkyl ester thereof and a mixture thereof.
4. The composition of claim 1 wherein the composition has a
viscosity of about 5,000 centipoise (cps) to about 20,000 cps.
5. The composition of claim 1 wherein the composition has a
viscosity of about 7,000 cps to about 13,000 cps.
6. The composition of claim 1 wherein the polysaccharide gum is a
shear-thinning polysaccharide gum.
7. The composition of claim 6 wherein the shear-thinning
polysaccharide gum is a galactomannan gum.
8. The composition of claim 6 wherein the shear-thinning
polysaccharide gum is a modified galactomannan gum.
9. The composition of claim 8 wherein the modified galactomannan
gum is a modified guar gum.
10. The composition of claim 1 wherein the penetration enhancer is
selected from the group consisting of an alkyl-(N-substituted
amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate,
an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted
amino) alkanol alkanoate, a pharmaceutically acceptable salt
thereof and a mixture thereof.
11. The composition of claim 10 wherein the penetration enhancer is
dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically
acceptable salt thereof.
12. The composition of claim 1 wherein the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester.
13. The composition of claim 1 wherein the lipophilic component
comprises at least one glyceryl ester selected from the group
consisting of monoglycerides, diglycerides, triglycerides, and
mixtures thereof.
14. The composition of claim 1 wherein the lipophilic component
comprises at least one glyceryl ester selected from the group
consisting of glyceryl monooleate, triolein, trimyristin,
tristearin, and mixtures thereof.
15. The composition of claim 1 wherein the buffer system provides a
buffered pH value for said composition in the range of about 3 to
about 6.5.
16. The composition of claim 1 wherein the composition further
comprises an emulsifier selected from the group consisting of
sucrose esters, polyoxyethylene sorbitan esters, long chain
alcohols, and glyceryl esters.
17. The composition of claim 16 wherein the emulsifier comprises at
least one glyceryl ester selected from the group consisting of
glyceryl monooleate, triolein, trimyristin, tristearin, and
mixtures thereof.
18. The composition of claim 1 wherein the composition further
comprises a fragrance.
19. The composition of claim 1 wherein the composition further
comprises up to about 5 percent myrtenol, based on the total weight
of the composition.
20. The composition of claim 1 wherein the composition further
comprises a preservative.
21. The composition of claim 1 wherein the composition further
comprises a topical anesthetic.
22. A method of treating vasospasm in a subject needing such
treatment comprising the step of: applying to the region of the
subject's tissue requiring treatment an effective amount of a
semi-solid composition, the composition comprising: a vasoactive
prostaglandin; a penetration enhancer; a polymer thickener selected
from the group consisting of a shear-thinning polysaccharide gum
and a shear-thinning polyacrylic acid polymer; a lipophilic
component that is selected from the group consisting of an
aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester, a liquid polyol and a mixture thereof; water and a
buffer system that provides a buffered pH value for said
composition in the range of about 3 to about 7.4.
23. The method of claim 22 wherein the tissue is skin.
24. The method of claim 22 wherein the tissue is vascular
extima.
25. The method of claim 22 wherein the vasoactive prostaglandin is
selected from the group consisting of prostaglandin E.sub.1,
prostaglandin E.sub.2, a pharmaceutically acceptable salt thereof,
a lower alkyl ester thereof and a mixture thereof.
26. The method of claim 22 wherein the penetration enhancer is
selected from the group consisting of an alkyl-(N-substituted
amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate,
an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted
amino) alkanol alkanoate, a pharmaceutically acceptable salt
thereof and a mixture thereof.
27. The method of claim 22 wherein the penetration enhancer is
dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically
acceptable salt thereof.
28. The method of claim 22 wherein the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester.
29. A method of improving microcirculation in a replanted body part
in a subject needing such treatment comprising the step of:
applying to the vascular extima of the blood vessels an effective
amount of a semi-solid composition comprising a vasoactive
prostaglandin; a penetration enhancer; a polymer thickener selected
from the group consisting of a polysaccharide gum and a polyacrylic
acid polymer; a lipophilic component that is selected from the
group consisting of an aliphatic C.sub.1 to C.sub.8 alcohol, an
aliphatic C.sub.8 to C.sub.30 ester, a liquid polyol and a mixture
thereof; water and a buffer system that provides a buffered pH
value for said composition in the range of about 3 to about
7.4.
30. The method of claim 29 further comprising the step of applying
an effective amount of the semi-solid prostaglandin composition to
the skin of the replanted body part and adjacent skin of the
body.
31. The method of claim 29 wherein the vasoactive prostaglandin is
selected from the group consisting of prostaglandin E.sub.1,
prostaglandin E.sub.2, a pharmaceutically acceptable salt thereof,
a lower alkyl ester thereof and a mixture thereof.
32. The method of claim 29 wherein the composition has a viscosity
of about 5,000 centipoise (cps) to about 20,000 cps.
33. The method of claim 29 wherein the composition has a viscosity
of about 7,000 cps to about 13,000 cps.
34. The method of claim 29 wherein the polysaccharide gum is a
shear-thinning polysaccharide gum.
35. The method of claim 34 wherein the shear-thinning
polysaccharide gum is a galactomannan gum.
36. The method of claim 34 wherein the shear-thinning
polysaccharide gum is a modified galactomannan gum.
37. The method of claim 36 wherein the modified galactomannan gum
is a modified guar gum.
38. The method of claim 29 wherein the penetration enhancer is
selected from the group consisting of an alkyl-(N-substituted
amino) alkanoate, an alkyl-2-(N,N-disubstituted amino) alkanoate,
an (N-substituted amino) alkanol alkanoate, an (N,N-disubstituted
amino) alkanol alkanoate, a pharmaceutically acceptable salt
thereof and a mixture thereof.
39. The method of claim 29 wherein the penetration enhancer is
dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically
acceptable salt thereof.
40. The method of claim 29 wherein the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester.
41. The method of claim 29 wherein the polymer thickener is a
polyacrylic acid polymer.
42. The method of claim 29 wherein the lipophilic component
comprises at least one glyceryl ester selected from the group
consisting monoglycerides, diglycerides, triglycerides, and
mixtures thereof.
43. The method of claim 29 wherein the lipophilic component
comprises at least one glyceryl ester selected from the group
consisting of glyceryl monooleate, triolein, trimyristin,
tristearin, and mixtures thereof.
44. The method of claim 29 wherein the acidic buffer system
provides a buffered pH for the composition in the range of about 3
to about 6.5.
45. The method of claim 29 wherein the composition further
comprises an emulsifier selected from the group consisting of
sucrose esters, polyoxyethylene sorbitan esters, long chain
alcohols, and glyceryl esters.
46. The method of claim 29 wherein the emulsifier comprises at
least one glyceryl ester selected from the group consisting of
glyceryl monooleate, triolein, trimyristin, tristearin, and
mixtures thereof.
47. The method of claim 29 wherein the composition further
comprises a fragrance.
48. The method of claim 29 wherein the composition further
comprises up to about 5 percent myrtenol, based on the total weight
of the composition.
49. The method of claim 29 wherein the composition further
comprises a preservative.
50. The method of claim 29 wherein the composition further
comprises a topical anesthetic.
51. The method in accordance with claim 1 wherein the composition
further comprises a topical anesthetic.
52. A method of improving local microcirculation in a tissue
comprising: applying to the surface of the tissue an effective
amount of a semi-solid composition, the composition comprising a
vasoactive prostaglandin selected from the group consisting of
prostaglandin E.sub.1, prostaglandin E.sub.2, a pharmaceutically
acceptable salt thereof, a lower alkyl ester thereof and a mixture
thereof; a penetration enhancer selected from the group consisting
of an alkyl (N-substituted amino) ester elected from the group
consisting of an alkyl-(N-substituted amino) alkanoate, an
alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted
amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol
alkanoate, a pharmaceutically acceptable salt thereof and a mixture
thereof; a polymer thickener selected from the group consisting of
a polysaccharide gum and a polyacrylic acid polymer; a lipophilic
component that is selected from the group consisting of an
aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester, a liquid polyol and a mixture thereof; water and a
buffer system that provides a buffered pH value for said
composition in the range of about 3 to about 7.4.
53. The method of claim 52 further comprising the step of applying
the semi-solid composition to the vascular extima of the blood
vessels supplying the tissue.
54. The method of claim 52 wherein the surface to which the
composition is applied is the surface of the skin.
55. The method of claim 52 wherein the polysaccharide gum is a
shear-thinning polysaccharide gum.
56. The method of claim 55 wherein the shear-thinning
polysaccharide gum is a galactomannan gum.
57. The method of claim 55 wherein the shear-thinning
polysaccharide gum is a modified galactomannan gum.
58. The method of claim 57 wherein the modified galactomannan gum
is a modified guar gum.
59. The method of claim 52 wherein the polymer thickener is a
polyacrylic acid polymer.
60. The method of claim 52 wherein the penetration enhancer is
dodecyl 2-(N,N-dimethylamino)-propionate or a pharmaceutically
acceptable salt thereof.
61. The method of claim 52 wherein the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester.
62. A method of preventing reperfusion injury of an affected tissue
comprising the steps of: providing the composition of claim 1; and
applying the composition to the surface of the affected tissue.
63. The method of claim 62 further comprising the step of applying
the composition to the vascular extima of blood vessels supplying
the affected tissue.
64. The method of claim 62 wherein the normal blood perfusion
volume is restored in the affected tissue in no more than ten
minutes.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/459,896, filed Apr. 2, 2003. The
entire content of the above application is incorporated herein by
reference in entirety.
BACKGROUND OF THE INVENTION
[0002] Vasospasm is a constriction of blood vessels, resulting in
ischemia of the tissue supplied by the blood vessels. Prolonged
spasm in arteries, veins, and vein grafts has been described as a
physiologic complication in microsurgery for over 20 years (Buncke,
H. J, Microsurgery: Transplantation-Replantation, on-line edition,
Chapter 36, http://buncke.org/textbook.html, accessed Dec. 13,
2002). Vasospasm results from several processes including intrinsic
smooth muscle contraction, local noradrenaline metabolism,
neurogenic and hormonal processes, and prostaglandin metabolism.
Topical agents, such as magnesium sulfate, lidocaine, papaverine
and chlorpromazine have been reported to successfully relieve
vasospasm. Other described methods for relieving vasospasm include
nerve blocks, systemic adrenergic agents and systemic vasodilating
agents such as sodium nitroprusside (Buncke, on-line edition,
http://buncke.org/book/ch36/ch36.sub.--2.html). Experimental
attempts to find roles for modifiers of prostaglandin function,
sympatholytics, calcium channel blockers and numerous other drugs
have generally not succeeded in producing either clearly applicable
models or reproducibly positive results (Buncke, on-line edition,
http://buncke.org/book/ch36/ch36.sub.--5.html). Vasospasm may be
elicited by cold, mechanical trauma or chemical mediators,
including adrenalin.
[0003] If circulation is not re-established in time, tissue damage
may result due to reperfusion injury. Reperfusion injury refers to
the cellular changes and tissue damage seen after a period of total
ischemia followed by reperfusion. Extremity replantation, organ
transplantation, free flap tissue reconstruction and even
myocardial infarction and stroke are all clinical examples of
interval tissue ischemia which can lead to tissue loss due to
reperfusion injury after blood flow is re-established. Tissue
reperfusion injury, seen in its full clinical extent as the
no-reflow phenomenon, appears as inflammatory response to
reperfusion, resulting in the ultimate death of the tissue.
[0004] Prostaglandin E.sub.1 is a derivative of prostanoic acid, a
20-carbon atom lipid acid, represented by the formula: 1
[0005] and is commercially available, e.g., from Chinoin
Pharmaceutical and Chemical Works Ltd. (Budapest, Hungary) under
the designation "Alprostadil USP," from Pharmacia & Upjohn
under the designation "Caverject". Prostaglandin E.sub.1 complexed
with alpha-cyclodextrin is available as alprostatil alfadex from
Ono Pharmaceuticals (Japan) and in an injectable form under the
designation "Edex.RTM." or "Viradex.RTM." from Schwarz Pharma
(Germany).
[0006] Prostaglandin E.sub.1 is a vasodilator useful to maintain
open blood vessels and, therefore, to treat peripheral vascular
disease among other ailments. While the potential benefits from
transdermal delivery of prostaglandin E.sub.1 have long been
recognized, prior efforts at developing a topical composition for
prostaglandin delivery have not been fully successful. Working
alone, most drugs, prostaglandin formulations included, do not
sufficiently permeate the skin to provide drug concentration levels
comparable to those obtained from other drug delivery routes. To
overcome this problem, topical drug formulations typically include
a skin penetration enhancer. Skin penetration enhancers also may be
referred to as absorption enhancers, accelerants, adjuvants,
solubilizers, sorption promoters, etc. Whatever the name, such
agents serve to improve drug absorption across the skin. Ideal
penetration enhancers not only increase drug flux across the skin,
but do so without irritating, sensitizing, or damaging skin.
Furthermore, ideal penetration enhancers should not adversely
affect the physical qualities of the available dosage forms (e.g.,
cream or gel), or the cosmetic quality of the topical
composition.
[0007] A wide variety of compounds have been evaluated as to their
effectiveness in enhancing the rate of penetration of drugs through
the skin. See, for example, Percutaneous Penetration Enhancers,
Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton,
Fla. (1995), which surveys the use and testing of various skin
penetration enhancers, and Buyuktimkin et al., Chemical Means of
Transdermal Drug Permeation Enhancement in Transdermal and Topical
Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),
Interpharm Press Inc., Buffalo Grove, Ill. (1997).
SUMMARY OF THE INVENTION
[0008] We have found that administration of prostaglandin
compositions comprising a penetration enhancer relieves
constriction of a blood vessel in vasospasm and restores blood
flow. The method and compositions are useful for the relief of
vasospasm in several conditions, including vasospasm occurring
during and following replantation surgery. In other aspects, the
invention provides methods and compositions for improving
microcirculation in a replanted body part. In other embodiments,
the present invention provides methods of treating tissue ischemia.
In further preferred embodiments, the present invention provides
compositions and methods for preventing reperfusion injury.
[0009] In one embodiment, the invention provides a method of
treating vasospasm in a subject needing such treatment comprising
the steps of applying an effective amount of a semi-solid
prostaglandin composition to the region of the subject's tissue
requiring treatment, the composition comprising a vasoactive
prostaglandin; a polymeric thickener selected from the group
consisting of a polysaccharide gum and a polyacrylic acid polymer;
a lipophilic component that is selected from the group consisting
of an aliphatic C.sub.1 to C.sub.8 alcohol, an aliphatic C.sub.8 to
C.sub.30 ester and mixtures thereof; water and a buffer system that
provides a buffered pH value for the composition in the range of
about 3 to about 7.4. In particularly preferred embodiments, the
composition further comprises a penetration enhancer. In preferred
embodiments, the present invention provides a composition
comprising an effective amount of a vasoactive prostaglandin; a
penetration enhancer selected from the group consisting of an
alkyl-(N-substituted amino) alkanoate, an
alkyl-2-(N,N-disubstituted amino) alkanoate, an (N-substituted
amino) alkanol alkanoate, an (N,N-disubstituted amino) alkanol
alkanoate, a pharmaceutically acceptable salt thereof and a mixture
thereof; a polymer thickener selected from the group consisting of
a polyacrylic acid polymer, a polysaccharide gum, a modified
polysaccharide gum and mixtures thereof; a lipophilic component;
water and a buffer system, wherein the pH of the composition is 3
to 7.4. The composition may be applied topically to the skin,
parenterally (e.g., subcutaneously) or directly to exposed tissues
such as the vascular extima of blood vessels during surgery or
wound treatment.
[0010] The vasoactive prostaglandin is suitably selected from the
group consisting of PGE.sub.1, PGA.sub.1, PGB.sub.1,
PGF.sub.1.alpha., 19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1,
PGE.sub.2, PGA.sub.2, PGB.sub.2, 19-hydroxy-PGA.sub.2,
19-hydroxy-PGB.sub.2, PGE.sub.3, PGF.sub.3.alpha., a
pharmaceutically acceptable salt thereof, a lower alkyl ester
thereof and a mixture thereof. Preferably, the vasoactive
prostaglandin is selected from the group consisting of
prostaglandin E.sub.1, prostaglandin E.sub.2, a pharmaceutically
acceptable salt thereof, a lower alkyl ester thereof and a mixture
thereof. In preferred embodiments, the vasoactive prostaglandin is
PGE.sub.1. If the vasoactive prostaglandin is PGE.sub.1, the dose
per application is suitably at least about 0.08 mg PGE.sub.1,
preferably about 0.08 mg to about 0.64 mg PGE.sub.1.
[0011] In some preferred embodiments, the composition exhibits
non-Newtonian rheological properties, suitably comprising a
shear-thinning polysaccharide gum or a shear-thinning polyacrylic
acid polymer. In one embodiment, the composition is thixotropic. In
another embodiment, the composition is pseudoplastic. In preferred
embodiments, the composition has a viscosity of about 5,000
centipoise (cps) to about 20,000 cps, more preferably from about
7,000 cps to about 13,000 cps.
[0012] In preferred embodiments, the shear-thinning polysaccharide
gum is a galactomannan gum or a modified galactomannan gum. A
preferred modified galactomannan gum is a modified guar gum. In one
embodiment, the penetration enhancer is dodecyl
2-(N,N-dimethylamino)-propionate or a pharmaceutically acceptable
salt thereof. In another embodiment, the penetration enhancer
comprises a mixture of lauric acid, isopropyl myristate and
triethanolamine. In one embodiment, the lipophilic component
comprises at least one aliphatic C.sub.8 to C.sub.30 ester. In a
preferred embodiment, the lipophilic component comprises at least
one glyceryl ester selected from the group consisting of
monoglycerides, diglycerides, triglycerides, and mixtures thereof.
In another embodiment, the lipophilic component comprises at least
one glyceryl ester selected from the group consisting of glyceryl
monooleate, triolein, trimyristin, tristearin, and mixtures
thereof.
[0013] Typically, the acidic buffer system provides a buffered pH
value for said composition in the range of about 3 to about 7.4,
more preferably about 3.0 to about 6.5, most preferably from about
3.5 to about 6.0. In certain embodiments the composition further
comprises an emulsifier selected from the group consisting of
sucrose esters, polyoxyethylene sorbitan esters, long chain
alcohols, and glyceryl esters. Suitably, the emulsifier comprises
at least one glyceryl ester selected from the group consisting of
glyceryl monooleate, triolein, trimyristin, tristearin, and
mixtures thereof. Optionally, the composition further comprises a
fragrance. In some embodiments the composition further comprises up
to about 5 percent myrtenol, based on the total weight of the
composition. Suitably, the composition further comprises a
preservative. In other embodiments, the composition further
comprises a topical anesthetic.
[0014] In preferred embodiments, the present invention provides a
method of preventing reperfusion injury of ischemic tissue by
providing a composition of the present invention, applying the
composition to the surface of the affected tissue, and optionally,
applying the composition to the vascular extima of blood vessels
supplying the affected tissue. In preferred embodiments, the
vascular perfusion volume to the tissue returns to normal within 30
minutes, more preferably in 10 minutes, optimally less than 10
minutes after the application of the composition. In other aspects,
the present invention provides a composition useful in the
manufacture of a medicament for the treatment of vasospasm, for
improving local microcirculation, especially in a replanted body
part, or for preventing reperfusion injury.
[0015] Other and further aims, purposes, features, advantages,
embodiments and the like will be apparent to those skilled in the
art from the present specification and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows images of the transilluminated shaved dorsal
surfaces of the right (FIG. 1A) and left ears (FIG. 1B) of a
rabbit. The two arrows in each Fig. indicate the vasospasm that was
observed 5 minutes after injections of 2 ml of a 0.1% adrenaline
solution into the tissue next to the central arteries and veins
near the base of both ears.
[0017] FIG. 2 shows images of the transilluminated shaved dorsal
surfaces of the right (FIG. 2A) and left ears (FIG. 2B) of the
rabbit of FIG. 1 about five minutes after topical application of
125 mg of a topical composition comprising 0.4 weight percent (wt
%) PGE.sub.1 onto the skin adjacent to the central artery and vein
near the bottom of the right ear (FIG. 2A). At 15 minutes post
application, all blood vessels on the right ear were dilated,
including the site of the vasospasm (between the two arrows). All
blood vessels were dilated normally and showed good circulation
thirty-five minutes after the application. In comparison, the blood
vessels of the left ear that was treated with the blank control
remained in vasospasm (arrows, FIG. 2B).
[0018] FIG. 3 is a graphical representation of the averaged results
of a study of vasospasm in rabbit ears that is illustrated by FIG.
1 and FIG. 2. As noted above, a single administration of 80 mg
topical composition with various PGE.sub.1 concentrations was
applied onto the skin area, 0.5-2 cm above the ear base, 10 minutes
after the typical time a vasospasm appeared in the central ear
artery. Administration of the topical composition comprising 0.1,
0.2, 0.4 or 0.8 weight percent PGE.sub.1 provided respective doses
of 80 (filled circles), 160 (filled triangles), 320 ("X") and 640
("*") micrograms (.mu.g) of PGE, as well as cream without PGE.sub.1
(0 .mu.g PGE.sub.1, filled diamonds) and positive control (0.4%
PGE.sub.1 topical composition without penetration enhancer, filled
circles).
[0019] FIG. 4 is a graphical representation of the averaged results
of a study of vascular perfusion volume in vasospasm in rabbit ears
as measured by transcutaneous laser Doppler blood flowmetry. As
noted above, a single administration of 80 mg topical composition
with various PGE.sub.1 concentrations was applied onto the skin
area, 0.5-2 cm above the ear base, 10 minutes after the typical
time a vasospasm appeared in the central ear artery. Administration
of the topical composition comprising 0.1, 0.2, 0.4 or 0.8 weight
percent PGE.sub.1 provided respective doses of 80 (filled circles),
160 (filled triangles), 320 ("X") and 640 ("*") micrograms (.mu.g)
of PGE.sub.1 as well as cream without PGE.sub.1 (0 .mu.g PGE.sub.1,
filled diamonds) and positive control (0.4% PGE.sub.1 topical
composition without penetration enhancer, filled circles).
Measurements were taken of the normal condition of the blood
vessels after anesthesia, at 10 minutes after vasospasm was
induced, and at 10, 15, 30, 60, 90 and 120 minutes after the
administration of the various PGE.sub.1 compositions. Data are
presented as mean .+-.standard deviation. S* refers to the time of
the vasospasm; A** refers to the time of the administration of
topical composition.
[0020] FIG. 5A and FIG. 5B show ultrasonograms of blood flow in the
femoral artery of a rabbit.
[0021] FIG. 6 is a graphical representation of the averaged results
of a study of vascular perfusion volume in vasospasm in rabbit
femoral artery as measured by ultrasonography. As noted above, a
single administration of 40 mg of a topical composition with
various PGE.sub.1 concentrations was applied to the surface of a
surgically exposed portion of a femoral artery, 10 minutes after
the application of adrenaline hydrochloride. Administration of the
topical composition comprising 0.1, 0.2, 0.4 or 0.8 weight percent
PGE.sub.1 provided respective doses of 80 (filled circles), 80
(filled triangles), 160 ("X") and 320 ("*") micrograms (.mu.g) of
PGE.sub.1 as well as cream without PGE.sub.1 (0 .mu.g PGE.sub.1,
filled diamonds) and 160 .mu.g PGE.sub.1 topical composition
without DDAIP (filled circles). Measurements were taken of the
normal condition of the blood vessels after anesthesia, at 5 and 10
minutes after vasospasm was induced, and at 5, 10, 15, 30, 60, 90
and 120 minutes after the administration of the various PGE.sub.1
compositions. Data are presented as mean .+-.standard deviation. S*
refers to the time of the vasospasm; A** refers to the time of the
administration of topical composition.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Vasospasm is a recognized problem that limits the success of
replantation of body parts such as fingers, arms and legs. Even if
microsurgery is performed to reconnect severed blood vessels,
vasospasm can impair the surgeon's ability to suture during
surgery, and can block post-surgery blood flow to the reattached
limb. When the vasospasm occurs before the microsurgery, the blood
vessels can be so rigid that the surgeon is unable to perform the
anastomosis. If the vasospasm occurs after the microsurgery, the
blood vessel on one side of the anastomosis could get so rigid that
blood flow was blocked.
[0023] Current treatment with vasodilators has a success rate
around 20%, and effects are not seen for 30-60 minutes or longer.
If the treatment with current therapy is a failure, tissue damage
due to ischemia beyond the region of vasospasm causes the loss of
the reattached limb. In such cases, the surgeon must amputate the
limb, causing additional suffering to the subject, and involving
additional expense and hospitalization time.
[0024] In general, treatment with the methods and topical
prostaglandin compositions of the present invention produced an
increase in blood flow through the region of vasospasm within about
five minutes. The treatment has a high success rate in early
clinical studies, approaching 100% effectiveness. In these studies,
the subjects were 20 patients who were treated and studied at
Beijing Jishuitan Hospital. Arms, legs or fingers of the patients,
generally severed because of automobile or factory accidents, were
reattached (replantation) involving microsurgery for arterial
anastomosis.
[0025] Definitions
[0026] Unless otherwise stated, the following terms used in this
application, including the specification and claims, have the
definitions given below. It must be noted that, as used in the
specification and the appended claims, the singular forms "a," "an"
and "the" include plural referents unless the context clearly
dictates otherwise.
[0027] "Alkyl" means the monovalent linear or branched saturated
hydrocarbon radical, consisting solely of carbon and hydrogen
atoms, having from one to twenty carbon atoms inclusive, unless
otherwise indicated. Examples of an alkyl radical include, but are
not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, tetradecyl,
eicosyl, and the like.
[0028] "Lower alkyl" means the monovalent linear or branched
saturated hydrocarbon radical, consisting solely of carbon and
hydrogen atoms, having from one to six carbon atoms inclusive,
unless otherwise indicated. Examples of a lower alkyl radical
include, but are not limited to, methyl, ethyl, propyl, isopropyl,
tert-butyl, n-butyl, n-hexyl, and the like.
[0029] "Lower alkoxy" means the radical -O-R, wherein R is a lower
alkyl radical as defined above. Examples of a lower alkoxy radical
include, but are not limited to, methoxy, ethoxy, isopropoxy, and
the like.
[0030] "Halogen" means the radical fluoro, bromo, chloro, and/or
iodo.
[0031] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "optional
bond" means that the bond may or may not be present, and that the
description includes single, double, or triple bonds.
[0032] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic, and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary as well as human
pharmaceutical use.
[0033] A "pharmaceutically acceptable salt" of a compound means a
salt that is pharmaceutically acceptable, as defined above, and
that possesses the desired pharmacological activity of the parent
compound. Such salts include:
[0034] 1. acid addition salts formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic
acid, trifluoroacetic acid, sulfuric acid, nitric acid, phosphoric
acid, boric acid and the like; or formed with organic acids such as
acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic
acid, p-chlorobenzenesulfonic acid, cinnamic acid, citric acid,
cylcopentanepropionic acid, ethanesulfonic acid,
1,2-ethanedisulfonic acid, formic acid, fumaric acid, glucoheptonic
acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid,
heptanoic acid, o-(hydroxybenzoyl)benzoic acid, hydroxynaphtoic
acid, 2-hydroxyethanesulfonic acid, lactic acid, lauryl sulfuric
acid, maleic acid, malic acid, malonic acid, mandelic acid,
methanesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic
acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), muconic
acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic
acid, propionic acid, pyruvic acid, salicylic acid, stearic acid,
succinic acid, tartaric acid, tertiary butylacetic acid,
p-toluenesulfonic acid, trifluoromethanesulfonic acid,
trimethylacetic acid, and the like; or
[0035] 2. salts formed when an acidic proton present in the parent
compound either is replaced by a metal ion, e.g., an alkali metal
ion, an alkaline earth ion, or an aluminum ion; or coordinates with
an organic or inorganic base. Acceptable organic bases include
diethanolamine, ethanolamine, N-methylglucamine, triethanolamine,
tromethamine, methylamiine, ethylamine, hydroxyethylamine,
propylamine, dimethylamine, diethylamine, trimethylamine,
triethylamine, ethylenediamine, hydroethylamine, morpholine,
piperazine, and guanidine and the like. Acceptable inorganic bases
include aluminum hydroxide, ammonium hydroxide, calcium hydroxide,
potassium hydroxide, sodium carbonate, sodium hydroxide and
hydrazine. The preferred pharmaceutically acceptable salts are the
salts formed from hydrochloric acid, and trifluoroacetic acid.
[0036] "Subject" means mammals and non-mammals. "Mammals" means any
member of the class Mammalia including, but not limited to, humans,
non-human primates such as chimpanzees and other apes and monkey
species; farm animals such as cattle, horses, sheep, goats, and
swine; domestic animals such as rabbits, dogs, and cats; laboratory
animals including rodents, such as rats, mice, and guinea pigs; and
the like. Examples of non-mammals include, but are not limited to,
birds, and the like. The term "subject" does not denote a
particular age or sex.
[0037] A "therapeutically effective amount" means an amount of a
compound that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" will vary depending on the
compound, the disease state being treated, the severity or the
disease treated, the age and relative health of the subject, the
route and form of administration, the judgement of the attending
medical or veterinary practitioner, and other factors.
[0038] The term "pharmacological effect" as used herein encompasses
effects produced in the subject that achieve the intended purpose
of a therapy. In one preferred embodiment, a pharmacological effect
means that vasospasm symptoms of the subject being treated are
prevented, alleviated, or reduced. For example, a pharmacological
effect would be one that results in the prevention or reduction of
vasospasm in a treated subject.
[0039] "Disease state" means any disease, condition, symptom, or
indication.
[0040] "Treating" or "treatment" of a disease state includes:
[0041] 1. preventing the disease state, i.e. causing the clinical
symptoms of the disease state not to develop in a subject that may
be exposed to or predisposed to the disease state, but does not yet
experience or display symptoms of the disease state,
[0042] 2. inhibiting the disease state, i.e., arresting the
development of the disease state or its clinical symptoms, or
[0043] 3. relieving the disease state, i.e., causing temporary or
progressive regression of the disease state or its clinical
symptoms.
[0044] "Pro-drug" means a pharmacologically inactive form of a
compound which must be metabolized in vivo by a subject after
administration into a pharmacologically active form of the compound
in order to produce the desired pharmacological effect. After
administration to the subject, the pharmacologically inactive form
of the compound is converted in vivo under the influence of
biological fluids or enzymes into a pharmacologically active form
of the compound. Although metabolism occurs for many compounds
primarily in the liver, almost all other tissues and organs,
especially the lung, are able to carry out varying degrees of
metabolism. Pro-drug forms of compounds may be utilized, for
example, to improve bioavailability, mask unpleasant
characteristics such-as bitter taste, alter solubility for
intravenous use, or to provide site-specific delivery of the
compound. Reference to a compound herein includes pro-drug forms of
a compound.
[0045] In a preferred embodiment, the pharmaceutical composition
comprises at least one vasoactive prostaglandin, preferably
prostaglandin E.sub.1, a penetration enhancer, a polymeric
thickener, a lipophilic component, water and a buffer system that
provides a buffered pH value for said composition in the range of
about 3 to about 7.4. In one preferred embodiment, the penetration
enhancer is an alkyl (N-substituted amino) ester or a
pharmaceutically acceptable salt thereof.
[0046] Vasoactive prostaglandins are those that act as peripheral
vasodilators, including naturally occurring prostaglandins such as
PGE.sub.1, PGA.sub.1, PGB.sub.1, PGF.sub.1.alpha.,
19-hydroxy-PGA.sub.1, 19-hydroxy-PGB.sub.1, PGE.sub.2, PGA.sub.2,
PGB.sub.2, 19-hydroxy-PGA.sub.2, 19-hydroxy-PGB.sub.2, PGE.sub.3,
PGF.sub.3.alpha.; semisynthetic or synthetic derivatives of natural
prostaglandins, including carboprost tromethamine, dinoprost
tromethamine, dinoprostone, lipoprost, gemeprost, metenoprost,
sulprostone and tiaprost. Prostaglandin E.sub.1 and prostaglandin
E.sub.2 are particularly preferred vasoactive prostaglandins for
use in conjunction with the present method.
[0047] Additionally, simultaneous administration of one or more
non-ecosanoid vasodilators may be desirable and may in some cases
exhibit a synergistic effect. The combination of prazosin with
prostaglandin E.sub.1 has been found to be particularly
advantageous in this regard.
[0048] Suitable non-ecosanoid vasodilators include, but are not
limited to: nitrates such as nitroglycerin, isosorbide dinitrate,
erythrityl tetranitrate, amyl nitrate, sodium nitroprusside,
molsidomnine, linsidomine chlorhydrate ("SIN-1") and
S-nitroso-N-acetyl-d,1-penicillarn- ine ("SNAP"); amino acids such
as L-arginine; long and short acting .alpha.-adrenergic blockers
such as phenoxybenzamine, dibenamine, phentolamine, tamsulosin and
indoramin, especially quinazoline derivatives such as alfuzosin,
bunazosin, doxazosin, terazosin, prazosin, and trimazosin;
vasodilative natural herbal compositions and bioactive extracts
thereof, such as gosyajinki-gan, Satureja obovata, bai-hua qian-hu,
lipotab, saiboku-to, vinpocetine, Gingko biloba, bacopa, Gynostemma
pentaphyllum, gypenosides, Evodia rutaecarpa, rutaecarpine,
dehydroevodiamine, dan-shen, salviae miltiorrhizae radix,
shosaikoto, Zizyphi fructus, ginseng and mixtures thereof (U.S.
Pat. No. 6,007,824); ergot alkaloids such as ergotamine and
ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride,
cianergoline, delorgotrile, disulergine, ergonovine maleate,
ergotamine tartrate, etisulergine, lergotrile, lysergide,
mesulergine, metergoline, metergotamine, nicergoline, pergolide,
propisergide, proterguride and terguride; antihypertensive agents
such as diazoxide, hydralazine and minoxidil; vasodilators such as
nimodepine, pinacidil, cyclandelate, dipyridamole and isoxsuprine;
chlorpromazine; haloperidol; yohimbine; trazodone and vasoactive
intestinal peptides.
[0049] Prostaglandin E.sub.1 is well known to those skilled in the
art. Reference may be had to various literature references for its
pharmacological activities, side effects, and normal dosage ranges.
See for example, Physician's Desk Reference, 51st Ed. (1997), The
Merck Index, 12th Ed., Merck & Co., N.J. (1996), and Martindale
The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical Press
(1982). Prostaglandin E.sub.1 as well as other compounds referenced
herein are intended to encompass pharmaceutically acceptable
derivatives including physiologically compatible salts and ester
derivatives thereof.
[0050] The quantity of vasoactive prostaglandin, such as
prostaglandin E.sub.1, in the pharmaceutical composition is a
therapeutically effective amount and necessarily varies according
to the desired dose, the dosage form (e.g., suppository or
topical), and the particular form of vasoactive prostaglandin used.
The term "prostaglandin" as used generically herein refers to the
prostaglandin free acid and pharmaceutically acceptable derivatives
thereof, including, for example PGE.sub.1, pharmaceutically
acceptable salts and lower alkyl esters thereof (the term "lower
alkyl" as used herein means straight chain or branched chain alkyl
containing one to four carbon atoms). The composition generally
contains between 0.001 percent to 1 percent of vasoactive
prostaglandin, e.g., prostaglandin E.sub.1, typically contains
between 0.05 percent to 1 percent, preferably from 0.1 percent to
0.5 percent, based on the total weight of the composition.
[0051] When used in combination with a vasoactive prostaglandin, a
piperazinyl quinazoline antihypertensive, such as prazosin, is
present in the amount of about 0.1 mg to about 2.0 mg per unit
dose, depending on the potency of the particular piperazinyl
quinazoline antihypertensive and the type and dose of vasoactive
prostaglandin used. The dose and the proportion of vasoactive
prostaglandin and the piperazinyl quinazoline antihypertensive can
be routinely determined by one of ordinary skill without undo
experimentation.
[0052] Working alone, most drugs, prostaglandin formulations
included, do not sufficiently permeate the skin to provide drug
concentration levels comparable to those obtained from other drug
delivery routes. To overcome this problem, topical drug
formulations typically include a skin penetration enhancer. Skin
penetration enhancers also may be referred to as absorption
enhancers, accelerants, adjuvants, solubilizers, sorption
promoters, etc. Whatever the name, such agents serve to improve
drug absorption across the skin. Ideal penetration enhancers not
only increase drug flux across the skin, but do so without
irritating, sensitizing, or damaging skin. Furthermore, ideal
penetration enhancers should not adversely affect the physical
qualities of the available dosage forms (e.g. cream or gel), or the
cosmetic quality of the topical composition.
[0053] A wide variety of compounds have been evaluated as to their
effectiveness in enhancing the rate of penetration of drugs through
the skin. See, for example, Percutaneous Penetration Enhancers,
Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., Boca Raton,
Fla. (1995), which surveys the use and testing of various skin
penetration enhancers, and Buyuktimkin et al., Chemical Means of
Transdermal Drug Permeation Enhancement in Transdermal and Topical
Drug Delivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),
Interpharm Press Inc., Buffalo Grove, Ill. (1997). Suitable
penetration enhancers for use in prostaglandin topical compositions
are disclosed in U.S. Pat. Nos. 4,980,378, 5,082,866 and 6,118,020,
and published international patent application WO 95/09590. Topical
compositions employing such penetration enhancers for the delivery
of prostaglandins are disclosed in U.S. Pat. Nos. 6,046,244,
6,323,241, 6,414,028, and 6,489,207.
[0054] The topical composition of the present invention can contain
one or more penetration enhancers. Among the preferred penetration
enhancers for the present invention are ethanol, propylene glycol,
glycerol, ethyl laurate, triethanolamine, isopropyl palmitate,
isopropyl myristate, lauric acid, laurocapram (Azone.TM.),
dioxolanes (described in U.S. Pat. No. 4,861,764), macrocyclic
ketones, HP-101, oxazolidones and biodegradable penetration
enhancers (described in U.S. Pat. Nos. 4,980,378 and 5,082,866 to
Wong et al. such as alkyl-2-(N,N-disubstituted amino) alkanoates
(e.g., dodecyl N,N-dimethylamino isoproprionate (DDAIP)),
N,N-disubstituted amino alkanol alkanoates (WO 95/09590) and
mixtures thereof. When present, isopropyl myristate is present in
the amount of about 0.1 to about 10 weight percent, preferably
about 3 weight percent. When present, triethanolamine is present in
the amount of about 0.1 to about 5 weight percent, preferably about
0.5 weight percent. When present, lauric acid is present in the
amount of about 0.1 to about 5 weight percent, preferably about 1
weight percent.
[0055] The penetration enhancer is present in an amount sufficient
to enhance the penetration of the vasoactive prostaglandin, e.g.,
prostaglandin E.sub.1. The specific amount varies necessarily
according to the desired release rate and the specific form of
prostaglandin E.sub.1 used. Generally, the penetration enhancer is
present in an amount ranging from about 0.5 weight percent to about
20 weight percent, based on the total weight of the composition.
Preferably, the penetration enhancer is present in an amount
ranging from about 1 weight percent to about 10 weight percent of
the composition. More preferably, the penetration enhancer is
present in an amount ranging from about 1 weight percent to about 5
weight percent of the composition.
[0056] In general, suitable penetration enhancers can be chosen
from those listed above as well as sulfoxides, alcohols, fatty
acids, fatty acid esters, polyols, amides, surfactants, terpenes,
alkanones, organic acids and mixtures thereof. See generally
Chattaraj, S. C. and Walker, R. B., Penetration Enhancer
Classification, pp.5-20 in Maibach, H. I., and Smith, H. E.,
(eds.), Percutaneous Penetration Enhancers, CRC Press, Inc., Boca
Raton, Fla. (1995) and Buyuktimkin, N., et al., Chemical Means of
Transdermal Drug Permeation Enhancement, in Gosh, T. K., et al.,
(eds.) Transdermal and Topical Drug Delivery Systems, Interpharm
Press, Inc., Buffalo Grove, Ill. (1997). Suitable sulfoxides
include dimethylsulfoxide, decylmethylsulfoxide and mixtures
thereof. Suitable alcohols include ethanol, propanol, butanol,
pentanol, hexanol, octanol, nonanol, decanol, 2-butanol,
2-pentanol, benzyl alcohol, caprylic alcohol, decyl alcohol, lauryl
alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl
alcohol, olcyl alcohol, linolyl alcohol, linolenyl alcohol and
mixtures thereof. Suitable fatty acids include valeric, heptanoic,
pelargonic, caproic, capric, lauric, myristic, stearic, oleic,
linoleic, linolenic, caprylic, isovaleric, neopentanoic,
neoheptanoic, neononanoic, trimethyl hexanoic, neodecanoic and
isostearic acids and mixtures thereof.
[0057] Suitable fatty acid esters include isopropyl n-butyrate,
isopropyl n-hexanoate, isopropyl n-decanoate, isopropyl myristate,
isopropyl palmitate, octyldodecyl myristate, ethyl acetate, butyl
acetate, methyl acetate, methylvalerate, methylpropionate, diethyl
sebacate, ethyl oleate, ethyl laurate and mixtures thereof.
Suitable polyols include propylene glycol, polyethylene glycol,
ethylene glycol, diethylene glycol, triethylene glycol, dipropylene
glycol, glycerol, propanediol, sorbitol, dextrans, butanediol,
pentanediol, hexanetriol and mixtures thereof.
[0058] Suitable amides include urea, dimethylacetamide,
diethyltoluamide, dimethylformrnamide, dimethyloctamide,
dimethyldecamide, 1-alkyl-4-imidazolin-2-one, pyrrolidone
derivatives, cyclic amides, hexamethylenelauramide and its
derivatives, diethanolamine, triethanolamine and mixtures thereof.
Suitable pyrrolidone derivatives include 1-methyl-2-pyrrolidone,
2-pyrrolidone, 1-lauryl-2-pyrrolidone,
1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-pyrrolidone,
1-lauryl-4-carboxy-2-pyrrolidone, 1-decyl-thioethyl-2-pyrrolidone
(HP-101), 1-methyl-4-methoxycarbonyl-2-pyrrolidone,
1-hexyl-4-methoxycarbonyl-2-pyrrolidone,
1-lauryl-4-methoxycarbonyl-2-pyr- rolidone,
N-cyclohexylpyrrolidone, N-dimethylaminopropylpyrrolidone,
N-cocoalkypyrrolidone, N-tallowalkypyrrolidone, fatty acid esters
of N-(2-hydroxymethyl)-2-pyrrolidone and mixtures thereof. Suitable
cyclic amides include 1-dodecylazacycloheptane-2-one (laurocapram,
Azone.RTM.), 1-geranylazacycloheptan-2-one,
1-famesylazacycloheptan-2-one,
1-geranylgeranylazacycloheptan-2-one,
1-(3,7-dimethyloctyl)azacycloheptan- -2-one,
1-(3,7,11-trimethyloctyl)azacycloheptan-2-one,
1-geranylazacyclohexane-2-one, 1-geranylazacyclopentan-2,5-dione,
1-famesylazacyclopentan-2-one and mixtures thereof.
[0059] Suitable surfactants include anionic surfactants, cationic
surfactants, nonionic surfactants, bile salts and lecithin.
Suitable anionic surfactants include sodium laurate, sodium lauryl
sulfate and mixtures thereof. Suitable cationic surfactants include
cetyltrimethylammonium bromide, tetradecyltrimethylammonium
bromide, benzalkonium chloride, octadecyltrimethylammonium
chloride, cetylpyridinium chloride, dodecyltrimethylammonium
chloride, hexadecyltrimethylammonium chloride, and mixtures
thereof. Suitable nonionic surfactants include
.alpha.-hydro-.omega.-hydroxy-poly(oxyethyle- ne)-poly(oxypropyl)
poly(oxyethylene)block copolymers, polyoxyethylene ethers,
polyoxyethylene sorbitan esters, polyethylene glycol esters of
fatty alcohols and mixtures thereof. Suitable
.alpha.-hydro-.omega.-hydro- xy-poly(oxyethylene)-poly(oxypropyl)
poly(oxyethylene)block copolymers include Poloxamers 231, 182, and
184 and mixtures thereof. Suitable polyoxyethylene ethers include
4-lauryl ether (Brij 30), (Brij 93), (Brij 96), 20-oleyl ether
(Brij 99) and mixtures thereof. Suitable polypxyethylene sorbitan
esters include the monolaurate (Tween 20, Span 20) the
monopalmitate (Tween 40), the monostearate (Tween 60), and the
monooleate (Tween 80) and mixtures thereof. Suitable polyethylene
glycol esters of fatty acids include the 8-oxyethylene stearate
ester (Myrj 45), (Myrj 51), the 40-oxyethylene stearate ester (Myrj
52) and mixtures thereof. Suitable bile salts include sodium
cholate, sodium salts of laurocholic, glycolic and desoxycholic
acids and mixtures thereof.
[0060] Suitable terpenes include D-limonene, .alpha.-pinene,
.beta.-enrene, .alpha.-terpineol, terpinen-4-ol, carvol, carvone,
pulegone, piperitone, menthone, menthol, geraniol, cyclohexene
oxide, limonene oxide, .alpha.-pinene oxide, cyclopentene oxide,
1,8-cineole, ylang oil, anise oil, chenopodium oil, eucalyptus oil
and mixtures thereof. Suitable alkanones include N-heptane,
N-octane, N-nonane, N-decane, N-undecane, N-dodecane, N-tridecane,
N-tetradecane, N-hexadecane and mixtures thereof. Suitable organic
acids include citric acid, succinic acid, salicylic acid,
salicylates (including the methyl, ethyl and propyl glycol
derivatives), tartaric acid and mixtures thereof.
[0061] In a preferred embodiment, the penetration enhancer is an
alkyl-2-(N-substituted amino)-alkanoate, an (N-substituted
amino)-alkanol alkanoate, or a mixture of these. For convenient
reference, alkyl-2-(N-substituted amino)-alkanoates and
(N-substituted amino)-alkanol alkanoates can be grouped together
under the label alkyl (N-substituted amino) esters.
[0062] Alkyl-2-(N-substituted amino)-alkanoates suitable for the
present invention can be represented as follows: 2
[0063] wherein n is an integer having a value in the range of about
4 to about 18; R is a member of the group consisting of hydrogen,
C.sub.1 to C.sub.7 alkyl, benzyl and phenyl; R.sub.1 and R.sub.2
are members of the group consisting of hydrogen and C.sub.1 to
C.sub.7 alkyl; and R.sub.3 and R.sub.4 are members of the group
consisting of hydrogen, methyl and ethyl.
[0064] Preferred are alkyl (N,N-disubstituted amino)-alkanoates
such as C.sub.4 to C.sub.18 alkyl (N,N-disubstituted
amino)-acetates and C.sub.4 to C.sub.18 alkyl (N,N-disubstituted
amino)-propionates and pharmaceutically acceptable salts and
derivatives thereof. Exemplary specific alkyl-2-(N,N-disubstituted
amino)-alkanoates include dodecyl 2-(N,N dimethylamino)-propionate
(DDAIP); 3
[0065] and dodecyl 2-(N,N-dimethylamino)-acetate (DDAA); 4
[0066] Alkyl-2-(N-substituted amino)-alkanoates are known. For
example, dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) is
available from Steroids, Ltd. (Chicago, Ill.). In addition,
alkyl-2-(N,N-disubstituted amino)-alkanoates can be synthesized
from more readily available compounds as described in U.S. Pat. No.
4,980,378 to Wong et al., which is incorporated herein by reference
to the extent that it is not inconsistent. As described therein,
alkyl-2-(N,N-disubstituted amino)-alkanoates are readily prepared
via a two-step synthesis. In the first step, long chain alkyl
chloroacetates are prepared by reaction of the corresponding long
chain alkanols with chloromethyl chloroformate or the like in the
presence of an appropriate base such as triethylamine, typically in
a suitable solvent such as chloroform. The reaction can be depicted
as follows: 5
[0067] wherein R, R.sub.3, R.sub.4 and n are defined as above. The
reaction temperature may be selected from about 10 degrees Celsius
to about 200 degrees Celsius or reflux, with room temperature being
preferred. The use of a solvent is optional. If a solvent is used,
a wide variety of organic solvents may be selected. Choice of a
base is likewise not critical. Preferred bases include tertiary
amines such as triethylamine, pyridine and the like. Reaction time
generally extends from about one hour to three days.
[0068] In the second step, the long chain alkyl chloroacetate is
condensed with an appropriate amine according to the scheme: 6
[0069] wherein n, R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are
defined as before. Excess amine reactant is typically used as the
base and the reaction is conveniently conducted in a suitable
solvent such as ether. This second step is preferably run at room
temperature, although temperature may vary. Reaction time usually
varies from about one hour to several days. Conventional
purification techniques can be applied to ready the resulting ester
for use in a pharmaceutical compound.
[0070] Suitable (N-substituted amino)-alkanol alkanoates can be
represented by the formula: 7
[0071] wherein n is an integer having a value in the range of about
5 to about 18; y is an integer having a value in the range of 0 to
about 5; and R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
and R.sub.7 are members of the group consisting of hydrogen,
C.sub.1 to C.sub.8 alkyl, and C.sub.1 to C.sub.8 aryl; and R.sub.8
is a member of the group consisting of hydrogen, hydroxyl, C.sub.1
to C.sub.8 alkyl, and C.sub.1 to C.sub.8 aryl. The preparation of
suitable (N-substituted amino)-alkanol alkanoates and their
advantages over previously known penetration enhancers are
disclosed in published international patent application WO
95/09590.
[0072] Preferred are (N-substituted amino)-alkanol alkanoates such
as C.sub.5 to C.sub.18 carboxylic acid esters and pharmaceutically
acceptable salts thereof. Exemplary specific (N,N-disubstituted
amino)-alkanol alkanoates include
[0073] 1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD); 8
[0074] 1-(N,N-dimethylamino)-2-propanol myristate (DAIPM); 9
[0075] 1-(N,N-dimethylamino)-2-propanol oleate (DAIPO); 10
[0076] The (N,N-disubstituted amino)-alkanol alkanoates are readily
prepared by reacting the corresponding aminoalkinol with lauroyl
chloride in the presence of triethylamine. A solvent such as
chloroform is optional but preferred. For example,
1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl
chloride in chloroform and in the presence of triethylamine to form
1-(N,N-dimethyl-amino)-2-propanol dodecanoate (DAIPD). Among the
suitable penetration enhancers for the present invention DDAIP is
generally preferred.
[0077] The penetration enhancer is present in an amount sufficient
to enhance the penetration of the prostaglandin E.sub.1. The
specific amount varies necessarily according to the desired release
rate and the specific form of prostaglandin E.sub.1 used.
Generally, this amount ranges from about 0.5 percent to about 10
percent, based on the total weight of the composition. In one
embodiment, where the vasoactive prostaglandin is prostaglandin
E.sub.1, the penetration enhancer is DDAIP in the amount of about
0.01 to about 5 weight percent of the composition.
[0078] Additionally, other known transdermal penetration enhancers
can also be added, if desired. Illustrative are dimethyl sulfoxide
(DMSO), dimethyl acetamide (DMA), 2-pyrrolidone,
N,N-diethyl-m-toluamide (DEET), 1-dodecylazacycloheptane-2-one
(Azone.RTM., a registered trademark of Nelson Research),
N,N-dimethylformamide, N-methyl-2-pyrrolidone, calcium
thioglycolate, oxazolidinone, dioxolane derivatives, laurocapram
derivatives, and macrocyclic enhancers such as macrocyclic
ketones.
[0079] Natural and modified polysaccharide gums are also an
important ingredient of the composition. Suitable representative
gums are those in the natural and modified galactomannan gum
category. A galactomannan gum is a carbohydrate polymer containing
D-galactose and D-mannose units, or other derivatives of such a
polymer. There is a relatively large number of galactomannans,
which vary in composition depending on their origin. The
galactomannan gum is characterized by a linear structure of
.beta.-D-mannopyranosyl units linked (1.fwdarw.4). Single membered
.alpha.-D-manopyranosyl units, linked (1.fwdarw.6) with the main
chain, are present as side branches. Galactomannan gums include
guar gum, which is the pulverized endosperm of the seed of either
of two leguminous plants (Cyamposis tetragonalobus and psoraloids)
and locust bean gum, which is found in the endosperm of the seeds
of the carobtree (ceratonia siliqua). Suitable modified
polysaccharide gums include ethers of natural or substituted
polysaccharide gums, such as carboxymethyl ethers, ethylene glycol
ethers and propylene glycol ethers. An exemplary substituted
polysaccharide gum is methylcellulose.
[0080] Other suitable representative gums include agar gum,
carrageenan gum, ghatti gum, karaya gum, rhamsan gum and xanthan
gum. The composition of the present invention may contain a mixture
of various gums, or mixture of gums and acidic polymers.
[0081] Gums, and galactomannan gums in particular, are well-known
materials. See for instance, Industrial Gums: Polysaccharides &
Their Derivatives, Whistler R. L. and BeMiller J. N. (eds.), 3rd
Ed. Academic Press (1992) and Davidson R. L., Handbook of
Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980).
Most gums are commercially available in various forms, commonly a
powder, and ready for use in foods and topical compositions. For
example, locust bean gum in powdered form is available from Tic
Gums Inc. (Belcam, Md.).
[0082] When present, the polysaccharide gums are present in the
range from about 0.1 percent to about 5 percent, based on the total
weight of the composition, with the preferred range being from 0.5
percent to 3 percent. In one preferred embodiment, 2.5 percent by
weight of a polysaccharide gum is present. Illustrative
compositions are given in the examples, below.
[0083] An optional alternative to the polysaccharide gum is a
polyacrylic acid polymer. A common variety of polyacrylic acid
polymer is known generically as "carbomer." Carbomer is polyacrylic
acid polymers lightly cross-linked with polyalkenyl polyether. It
is commercially available from the B. F. Goodrich Company (Akron,
Ohio) under the designation "CARBOPOL.TM.." A particularly
preferred variety of carbomer is that designated as "CARBOPOL
940."
[0084] Other polyacrylic acid polymers suitable for use are those
commercially available under the designations "Pemulen.TM." (B. F.
Goodrich Company) and "POLYCARBOPHIL.TM." (A.H. Robbins, Richmond,
Va.). The Pemulen.TM. polymers are copolymers of C.sub.10 to
C.sub.30 alkyl acrylates and one or more monomers of acrylic acid,
methacrylic acid or one of their simple esters crosslinked with an
allyl ether of sucrose or an allyl ether of pentaerythritol. The
POLYCARBOPHIL.TM. enhancer is a polyacrylic acid cross-linked with
divinyl glycol.
[0085] Where polyacrylic acid polymers are present, they represent
about 0.5 percent to about 5 percent of the composition, based on
its total weight.
[0086] Semi-solid compositions and penetration enhancers suitable
for the practice of the present invention are described in detail
in U.S. Pat. Nos. 6,046,244, 6,118,020 and 6,323,241, the teachings
of which are incorporated herein by reference.
[0087] The semi-solid composition has a suitably chosen viscosity
such that the composition is naturally retained at the site of
administration. The semi-solid composition can exhibit Newtonian or
non-Newtonian rheological characteristics. In some preferred
embodiments, the semi-solid composition of the present invention
exhibits non-Newtonian rheological characteristics, i.e. in which
the apparent viscosity is dependent on the shear rate applied to
the composition. Preferably the composition has "shear-thinning"
rheological properties. As used herein, "shear-thinning" refers to
a reduction in apparent viscosity (the ratio of shear stress to the
shear rate) with increasing shear rate, whether the reduction in
apparent viscosity is time independent (pseudoplastic), time
dependent (thixotropic) or associated with a yield stress, defined
as a stress that must be exceeded before flow starts, (Bingham
plastics and generalized Bingham plastics). See, generally, Harris,
J., & Wilkinson, W. L., "Non-Newtonian Fluid," pp.856-858 in
Parker, S. P., ed., McGraw-Hill Encyclopedia of Physics, Second
Edition, McGraw-Hill, New York, 1993. A suitable viscosity range of
the composition is from about 5,000 centipoise (cps) to about
20,000 cps, preferably from about 7,000 cps to about 13,000
cps.
[0088] Another important component is a lipophilic component. As
used herein "lipophilic component" refers to an agent that is both
lipophilic and hydrophilic. One of ordinary skill in the
pharmaceutical arts will understand that the lipophilic nature, or
"lipophilicity" of a given compound is routinely quantified for
comparison to other compounds by using the partition coefficient.
The partition coefficient is defined by the International Union of
Pure and Applied Chemistry (IUPAC) as the ratio of the distribution
of a substance between two phases when the heterogeneous system (of
two phases) is in equilibrium; the ratio of concentrations (or,
strictly speaking, activities) of the same molecular species in the
two phases is constant at constant temperature.
[0089] The C.sub.1 to C.sub.8 aliphatic alcohols, the C.sub.2 to
C.sub.30 aliphatic esters, and their mixtures can serve as
lipophilic component. Illustrative suitable alcohols are ethanol,
n-propanol and isopropanol, while suitable esters are ethyl
acetate, butyl acetate, ethyl laurate, methyl propionate, isopropyl
myristate and isopropyl palmitate. As used herein, the term
"aliphatic alcohol" includes polyols such as glycerol, propylene
glycol and polyethylene glycols. In one embodiment, a mixture of
alcohol and ester is preferred, and in particular, a mixture of
ethanol and ethyl laurate is preferred. In another embodiment,
about 0.1 to about 10 percent by weight isopropyl myristate,
preferably about 3 percent by weight isopropyl myristate is
substituted for ethyl laurate. In some embodiments, the lipophilic
component includes at least one liquid polyol. In preferred
embodiments, the liquid polyol is a polyethylene glycol selected
from the group consisting of polyethylene glycol 200, polyethylene
glycol 400 and polyethylene glycol 600. When polyethylene glycol is
used, polyethylene glycol is present in the amount of about 1
weight percent to about 25 weight percent, based on the total
weight of the composition. A preferred polyethylene glycol is
polyethylene glycol 400 (PEG 400). When present, polyethylene
glycol 400 is about 1 weight percent to about 25 weight percent,
preferably about 3 weight percent to about 20 weight percent, based
on the total weight of the composition.
[0090] In one embodiment, the C.sub.2 to C.sub.30 aliphatic esters,
and their mixtures comprising the lipophilic component include
C.sub.8 to C.sub.30 aliphatic esters of glycerol selected from the
group consisting of monoglycerides, diglycerides, triglycerides,
and mixtures thereof. Suitable aliphatic esters include glyceryl
esters of saturated fatty acids, unsaturated fatty acids and
mixtures thereof. Suitable saturated fatty acids include caproic
acid, caprylic acid, capric acid, lauric acid, myristic acid,
palmitic acid, stearic acid, arachidic acid, behenic acid and
lignoceric acid. In a preferred embodiment, about 0.1 to about 5
percent, preferably about 1 weight percent lauric acid is present.
Suitable unsaturated fatty acids include oleic acid, linoleic acid
and linolenic acid. Suitable glyceryl esters include glyceryl
monooleate, triolein, trimyristin and tristearin, perferably
trimyristin.
[0091] The concentration of lipophilic component required
necessarily varies according to other factors such as the desired
semi-solid consistency and the desired skin penetration promoting
effects. Suitably the concentration of lipophilic component is in
the range of 0.5 percent to 40 percent by weight based on the total
weight of the composition. The preferred topical composition
contains lipophilic component in the range of 7 percent to 40
percent by weight based on the total weight of the composition.
[0092] Where a mixture of aliphatic alcohol and aliphatic ester are
employed, the suitable amount of alcohol is in the range of 0.5
percent to 10 percent. In one preferred embodiment, the amount of
alcohol is in the range of 5 percent to 15 percent, while that of
aliphatic ester is in the range from 2 percent to 15 percent (again
based on the total weight of the composition). In another preferred
embodiment, the amount of alcohol is in the range of 0.5 percent to
10 percent, while that of aliphatic ester is in the range from 0
percent to 10 percent (again based on the total weight of the
composition).
[0093] The concentration of lipophilic component required
necessarily varies according to other factors such as the desired
semi-solid consistency and the desired skin penetration promoting
effects. The preferred topical composition contains lipophilic
component in the range of 7 percent to 40 percent by weight based
on the total weight of the composition. Where a lipophilic
component that is a mixture of aliphatic alcohol and aliphatic
ester is used, the preferred amount of alcohol is in the range of 5
percent to 15 percent, while that of aliphatic ester is in the
range from 2 percent to 15 percent (again based on the total weight
of the composition).
[0094] An optional, but preferred, component is an emulsifier.
Although not a critical factor, a suitable emulsifier generally
will exhibit a hydrophilic-lipophilic balance number greater than
10. Sucrose esters, and specifically sucrose stearate, can serve as
emulsifiers for the composition. Sucrose stearate is a well-known
emulsifier available from various commercial sources. When an
emulsifier is used, sucrose stearate present up to about 2 percent,
based on the total weight of the composition, is preferred. The
preferred amount of sucrose stearate emulsifier can also be
expressed as a weight ratio of emulsifier to polysaccharide gum. A
ratio of 1 to 6 emulsifier to gum is preferred, and a ratio of 1 to
4 is most preferred to generate the desired semi-solid consistency
and separation resistance.
[0095] Other emulsifiers are also suitable including
polyoxyethylene sorbitan esters, long chain alcohols, preferably
cetostearyl alcohol, and fatty acid glycerides. Suitable
polyoxyethylene sorbitan esters include the monolaurate (Tween 20,
Span 20) the monopalmitate (Tween 40), the monostearate (Tween 60),
and the monooleate (Tween 80) and mixtures thereof. Preferred fatty
acid glycerides include glyceryl monooleate, triolein, trimyristin
and tristearin.
[0096] The composition includes an acid buffer system. Acid buffer
systems serve to maintain or buffer the pH of compositions within a
desired range. The term "buffer system" or "buffer" as used herein
has reference to a solute agent or agents which, when in a water
solution, stabilize such solution against a major change in pH (or
hydrogen ion concentration or activity) when acids or bases are
added thereto. Solute agent or agents which are thus responsible
for a resistance to change in pH from a starting buffered pH value
in the range indicated above are well known. While there are
countless suitable buffers, potassium phosphate monohydrate has
proven effective for compositions of the present invention.
[0097] The final pH value of the pharmaceutical composition may
vary within the physiologically compatible range. Necessarily, the
final pH value is not irritating to human skin. Without violating
this constraint, the pH may be selected to improve prostaglandin
E.sub.1 stability and to adjust consistency when required. In one
embodiment, the preferred pH value is about 3 to about 7.4, more
preferably about 3.0 to about 6.5, most preferably from about 3.5
to about 6.0.
[0098] The remaining component of the composition is water, which
is necessarily purified. The composition contains water in the
range of about 50 to about 90 percent, based on the total weight of
the composition. The specific amount of water present is not
critical, however, being adjustable to obtain the desired
consistency and/or concentration of the other components.
[0099] Prostaglandin E.sub.1 stabilizers, coloring agents,
rheological agents, and preservatives can be added to the extent
that they do not overly limit prostaglandin E.sub.1 skin
penetration or prevent the desired semi-solid consistency.
[0100] Contemplated dosage forms of the semi-solid pharmaceutical
composition are creams, gels, ointments, colloidal suspensions and
the like, also including but not limited to compositions suitable
for use with transdermal patches and like devices.
[0101] The ingredients listed above may be combined in any order
and manner that produces a stable composition comprising a
prostaglandin E.sub.1 evenly dispersed throughout a semi-solid
formulation. One available approach to preparing such compositions
involves evenly dispersing the polysaccharide gum (or polyacrylic
acid polymer) in a premixed water/buffer solution and then
thoroughly homogenizing (i.e. mixing) the resulting mixture, which
can be labeled "Part A." When present, the emulsifier is added to
the water/buffer solution before dispersing the polysaccharide gum.
Any suitable method of adjusting the pH value of Part A to the
desired level may be used, for example, by adding concentrated
phosphoric acid or sodium hydroxide.
[0102] Separately, the prostaglandin E.sub.1 is dissolved with
agitation in the lipophilic component, which itself may be a
mixture of alcohols, esters, or alcohol with ester. Next, the
penetration enhancer is added. Alternatively, when the lipophilic
component includes both an alcohol and an ester, the prostaglandin
E.sub.1 can be dissolved in the alcohol before adding the
penetration enhancer followed by the ester. In either case, the
resulting mixture can be labeled "Part B." The final step involves
slow addition (e.g. dropwise) of Part B into Part A under constant
mixing.
[0103] The resulting topical composition, when compared to exhibits
the advantageous properties described above, including improved
prostaglandin E.sub.1 permeation and bioavailability without drug
overloading, reduced skin damage and related inflammation, and
increased flexibility in design of dosage forms. These compositions
can be used for prolonged treatment of peripheral vascular disease,
male impotency and other disorders treated by prostaglandin
E.sub.1, while avoiding the low bioavailability and rapid chemical
decomposition associated with other delivery methods. Application
of prostaglandin E.sub.1 in a topical composition to the skin of a
subject allows a predetermined amount of prostaglandin E.sub.1 to
be administered continuously to the subject and avoids undesirable
effects present with a single or multiple administrations of larger
dosages by injection. By maintaining a sustained dosage rate, the
prostaglandin E.sub.1 level in the subject's target tissue can be
better maintained within the optimal therapeutic range.
[0104] In one embodiment, a composition comprises about 0.01
percent to about 5 percent modified polysaccharide gum; about 0.001
percent to about 1 percent of a prostaglandin selected from the
group consisting of PGE.sub.1, pharmaceutically acceptable salts
thereof, lower alkyl esters thereof and mixtures thereof; about 0.5
percent to about 10 percent DDAIP or salts thereof; about 0.5
percent to about 10 percent of a lower alcohol selected from the
group consisting of ethanol, propanol, isopropanol and mixtures
thereof; about 0.5 percent to about 10 percent on anrester selected
from the group consisting of ethyl laurate, isopropyl myristate,
isopropyl laurate and mixtures thereof; based on the weight of the
composition, and an acid buffer. Preferably the composition also
comprises up to about 2 percent sucrose stearate.
[0105] Optionally the composition also comprises up to about 5
percent emulsifier. Preferably, the composition also comprises up
to about 2 percent emulsifier. Suitable emulsifiers include
polysorbates such as Tweens, glyceryl monooleate, triolein,
trimyristin and tristearin. A preferred emulsifier is
trimyristin.
[0106] The practice of the present invention is demonstrated in the
following examples. These examples are meant to illustrate the
invention rather than to limit its scope. Variations in the
treating compositions which do not adversely affect the
effectiveness of prostaglandin E.sub.1 will be evident to one
skilled in the art, and are within the scope of this invention. For
example, additional ingredients such as coloring agents,
anti-microbial preservatives, emulsifiers, perfumes, prostaglandin
E.sub.1 stabilizers, and the like may be included in the
compositions as long as the resulting composition retains desirable
properties, as described above. When present, preservatives are
usually added in amounts of about 0.05 to about 0.30%. Suitable
preservatives include methylparabens (methyl PABA), propylparabens
(propyl PABA) and butylhydroxy toluene (BHT). Suitable perfumes and
fragrances are known in the art; a suitable fragrance is up to
about 5 percent myrtenol, preferably about 2 percent myrtenol,
based on the total weight of the composition. The compositions of
the present invention can also include a small amount, about 0.01
to about 4% by weight, of a topical anesthetic, if desired. Typical
topical anesthetics include lidocaine, dyclonine, dibucaine,
pharmaceutically acceptable salts and mixtures thereof. In one
preferred embodiment, the topical anesthetic is about 0.5 percent
dyclonine, based on the weight of the composition.
[0107] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form is a packaged preparation, where the package containing
the discrete quantities of the pharmaceutical preparation is, e.g.
a rigid plastic dispenser or flexible packet.
[0108] Another aspect of the invention is an article of manufacture
that comprises a composition for treating erectile dysfunction as
described above in a suitable container, preferably in a container
such as the dispenser disclosed in U.S. Pat. No. 6,224,573, in
combination with labeling instructions. Alternatively, the
container can be a tube with a suitable orifice size, such as an
extended tip tube, pouch, packet, or squeeze bottle and made of any
suitable material, for example rigid plastic or flexible
plastic.
[0109] The labeling instructions can come in the form of a
pamphlet, a label applied to or associated with the packaging of
the article of manufacture.
[0110] Unless otherwise indicated, each composition is prepared by
conventionally admixing the respective indicated components
together.
EXAMPLE 1
[0111] Exemplary Compositions
[0112] Exemplary Composition A was prepared as follows. Part A was
formed by dissolving 0.4 parts prostaglandin E.sub.1 (Alprostadil
USP) in 5 parts ethyl alcohol. Next, 5 parts dodecyl
2-(N,N-dimethylamino)-propiona- te were mixed into the
alcohol-prostaglandin E.sub.1 solution, followed by 5 parts ethyl
laurate.
[0113] Part B was prepared starting from a pH 5.5 water/buffer
solution. The water/buffer solution was prepared by adding
sufficient potassium phosphate monohydride to purified water to
create a 0.1 M solution. The pH of the water/buffer solution was
adjusted to 5.5 with a strong base solution (1 N sodium hydroxide)
and a strong acid (1 N phosphoric acid). The buffer solution
represented about 80 parts of the total composition. All parts
specified herein are parts by weight.
[0114] To the buffer solution was added 0.5 parts ethyl laurate.
Next, the locust bean gum (in powder form) was dispersed in the
buffer solution and homogenized using a homogenizer. Table 1,
below, contains a list of ingredients.
[0115] The resulting composition was a spreadable, semi-solid
suitable for application to the skin without the need for
supporting devices such as patches and adhesive strips. The
composition was both homogenous in appearance and resistant to
separation.
1TABLE 1 Topical Prostaglandin E.sub.1 Compositions Ingredient (wt
%) A B C D E F G H I prehydrated locust bean 3 3 3 3 3 3 3 -- --
gum prehydrated modified -- -- -- -- -- -- -- 3 -- guar gum Xanthan
gum -- -- -- -- -- -- -- -- 2 water/buffer (pH 5.5) 81 81 81 81 81
81 81 81 82.7 sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 -- --
prostaglandin E.sub.1 0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 0.4 DDAIP 5 5
5 5 5 5 5 2.5 1.8 ethanol 5 5 5 5 5 5 10 5 5 ethyl laurate 5 5 5 5
5 5 -- 3 -- Isopropyl myristate -- -- -- -- -- -- -- -- 3
triethanolamine -- -- -- -- -- -- -- -- 0.5 lauric acid -- -- -- --
-- -- -- -- 1
[0116] Additional exemplary compositions B-I are prepared in the
same manner using the components listed in Table 1. As noted above,
in other embodiments, such as Composition H, the composition may
include a modified polysaccharide gum, suitably a modified
galactomannan gum, such as a guar gum. Alternatively, a polyacrylic
acid polymer may be used instead of the polysaccharide gum.
EXAMPLE 2
[0117] Pharmacodynamic Study of a Topical PGE.sub.1 Composition as
an Antagonist for Vasospasm
[0118] The spasmolysis (reversal of vasospasm) and vasodilation
effects of a topical PGE.sub.1 composition (Composition H of
Example 1 modified as appropriate to contain the indicated amount
of PGE.sub.1) on vasospasm induced by adrenalin hydrochloride were
studied in vivo by monitoring vascular diameter changes in rabbit
ears.
2TABLE 2 Drugs Used Drug Name Size Function Batch No. Supplier
Sumianxin 1.5 ml/ General 20020425 Veterinary Ampule Anesthesia
Research Institute of Changchun Agricultural- Pastoral University
Adrenaline 1 mg/1 ml Vasospasm 20010625 Tianjing People's HCl
Induction Pharmaceuticals Blank Sterile 0.0% PGE.sub.1 Blank 020401
NexMed Cream Control Pharmaceuticals 0.4% PGE.sub.1 Positive 020401
(Zhongshan), Ltd. w/o Control penetration enhancers PGE.sub.1
Sterile 0.1% PGE.sub.1 Test 020401 Cream 0.2% PGE.sub.1 Composition
020401 0.4% PGE1 020401 0.8% PGE1 020401
[0119] Note: Positive control was 0.4% PGE.sub.1 sterile cream
without DDAIP penetration enhancer; all other PGE.sub.1 cream
preparations contained 2.5 wt % DDAIP penetration enhancer.
Sumianxin is a mixture of baodingning (5% dimethyl aniline thiazole
hydrochloride with 10% EDTA) and haloperidol.
[0120] New Zealand Rabbits, weight 2-3 kg, no gender preference,
used in the study were provided by the Breed Branch of Beijing
Yuancheng Miaomu Company, Ltd., license No. SCK2002-004. General
anesthesia was induced by intramuscular injection of SUMIANXIN (0.3
ml/kg). A total of 60 rabbits were randomly assigned into 6 groups
with 10 rabbits per group. Testing was preformed at a constant room
temperature of 20 degrees Celsius. Blood vessels were imaged and
recorded using a Sony DSC-S75 Digital Camera. Vessel diameters were
measured using Adobe Photoshop 6.0 Software.
[0121] After shaving and preparation of the rabbit ears, 0.05 ml of
adrenaline hydrochloride (1 mg/ml) was injected into the tissue
surrounding the central artery 1 cm above the base of the ear. The
vasospasm was typically observed about five minutes after the
adrenalin injection. A single administration of 80 mg topical
composition with various PGE.sub.1 concentrations was applied onto
the skin area, 0.5-2 cm above the ear base, 10 minutes after the
appearance of the typical vasospasm in the central ear artery.
Administration of PGE.sub.1 at a concentration of 0.1, 0.2, 0.4 and
0.8 weight percent provided respective doses of 80, 160, 320 and
640 micrograms (.mu.g) of PGE.sub.1. Digital photographs were taken
of the normal condition of the blood vessels after anesthesia, at
10 minutes after vasospasm was induced, and at 10, 15, 30, 60, 90
and 120 minutes after the administration of the various PGE.sub.1
topical compositions.
[0122] The digital images were uploaded into a computer and
analyzed using Adobe Photoshop 6.0 software. The diameter of the
central artery at a point 1.5 cm above the base of the ear was
measured with an accuracy of 0.1 mm. The data are reported in Table
3, below, as mean diameter .+-.standard deviation (SD); t-test was
used for statistical analysis.
3TABLE 3 Vessel Diameter Before And After Administration of Cream
Group Positive Blank 80 .mu.g 160 .mu.g 320 .mu.g 640 .mu.g Control
Control N 10 10 10 10 10 10 Normal 2.9 .+-. 0.13 2.5 .+-. 0.13 2.7
.+-. 0.12 2.8 .+-. 0.15 2.8 .+-. 0.17 2.8 .+-. 0.20 Condition after
Anesthesia 10 minutes after 0.7 .+-. 0.14 0.5 .+-. 0.12 0.6 .+-.
0.11 0.4 .+-. 0.08 0.4 .+-. 0.12 0.6 .+-. 0.12 Vasospasm 10 minutes
after 1.1 .+-. 0.18 1.6 .+-. 0.12 2.5 .+-. 0.16 2.6 .+-. 0.09 1.4
.+-. 0.13 1.2 .+-. 0.16 Application 15 minutes after 2.0 .+-. 0.16
2.3 .+-. 0.15 2.8 .+-. 0.14 2.8 .+-. 0.16 1.4 .+-. 0.18 1.4 .+-.
0.15 Application 30 minutes after 2.1 .+-. 0.14 2.5 .+-. 0.16 2.8
.+-. 0.17 2.8 .+-. 0.13 1.4 .+-. 0.16 1.4 .+-. 0.22 Application 60
minutes after 1.1 .+-. 0.18 2.1 .+-. 0.18 3.2 .+-. 0.18 3.2 .+-.
0.12 1.4 .+-. 0.16 1.5 .+-. 0.17 Application 90 minutes after 1.4
.+-. 0.16 2.1 .+-. 0.16 2.8 .+-. 0.19 3.2 .+-. 0.13 1.4 .+-. 0.14
1.5 .+-. 0.16 Application 120 minutes 1.7 .+-. 0.22 2.1 .+-. 0.17
2.8 .+-. 0.20 2.8 .+-. 0.19 1.8 .+-. 0.24 2.0 .+-. 0.18 after
Application
[0123] FIGS. 1A-1B shows images of the transilluminated shaved
dorsal surfaces of the right (FIG. 1A) and left ears (FIG. 1B) of a
rabbit. The two arrows in each Fig. indicate the vasospasm that was
observed 5 minutes after injections of 2 ml of a 0.1% adrenaline
solution into the tissue next to the central arteries and veins
near the base of both ears.
[0124] FIGS. 2A-2B show images of the transilluminated shaved
dorsal surfaces of the right (FIG. 2A) and left ears (FIG. 2B) of
the rabbit of FIG. 1 about five minutes after topical application
of 125 mg 0.4% topical PGE.sub.1 composition onto the skin next to
the central artery and vein near the bottom of the right ear (FIG.
2A). At 15 minutes post application, all blood vessels on the right
ear were dilated, including the site of the vasospasm (between the
two arrows. At 35 minutes after the application, all blood vessels
were dilated normally and showed good circulation. In comparison,
the blood vessels of the left ear that was treated with the blank
control remained in vasospasm (arrows, FIG. 2B).
[0125] The averaged data are reported in Table 3, above, as mean
diameter .+-.standard deviation (SD), N=10, and shown graphically
in FIG. 3. FIG. 3 is a graphical representation of the averaged
results of a study of vasospasm in rabbit ears that is illustrated
by FIG. 1 and FIG. 2. As noted above, a single administration of 80
mg topical composition with various PGE.sub.1 concentrations was
applied onto the skin area, 0.5-2 cm above the ear base, 10 minutes
after the typical time a vasospasm appeared in the central ear
artery. Administration of the topical composition comprising 0.1,
0.2, 0.4 or 0.8 weight percent PGE.sub.1 provided respective doses
of 80 (filled circles), 160 (filled triangles), 320 ("X") and 640
("*") micrograms (.mu.g) of PGE.sub.1 as well as cream without
PGE.sub.1 (0 .mu.g PGE.sub.1, filled diamonds) and positive control
(0.4% PGE.sub.1 topical composition without penetration enhancer,
filled circles). Digital photographs were taken of the normal
condition of the blood vessels after anesthesia, at 10 minutes
after vasospasm was induced, and at 10, 15, 30, 60, 90 and 120
minutes after the administration of the various PGE.sub.1
compositions. Data are presented as mean vessel diameter i standard
deviation. S* refers to the time of the vasospasm; A** refers to
the time of the administration of topical composition.
4TABLE 4 The Average Time (minutes) Required To Return To The
Initial Vessel Diameter. (N = 10 for each group) 320 .mu.g without
DDAIP 0 .mu.g (Positive (Blank Control in Control) This Study) 80
.mu.g 160 .mu.g 320 .mu.g 640 .mu.g 120 120 120 30 .+-. 16.37 15
.+-. 18.18 10 .+-. 11.11
[0126] The average time required to return to the initial vessel
diameter is provided in Table 4, above. The treatment with the
blank control composition ("0 .mu.g PGE.sub.1"), 0.4% PGE.sub.1
topical composition without DDAIP penetration enhancer and a
topical composition comprising 80 .mu.g PGE.sub.1 did not produce
recovery of vessel diameter within the 120 minute duration of the
test. Administration of topical compositions having higher amounts
of PGE.sub.1 produced recovery of vessel diameter and showed a
dose-dependent decrease in the time required for recovery. In this
study, there was a more than six-fold difference between
compositions with and without DDAIP at the 320 mg dose of
PGE.sub.1, a supra threshold effective dose.
5TABLE 5 The Duration (minutes) The Initial Vessel Diameter Was
Greater Than The Diameter Before Vasospasm. (N = 10 for each group)
320 .mu.g 0.4 wt % PGE.sub.1 0 .mu.g without 0 wt % DDAIP PGE.sub.1
(Positive 80 .mu.g 160 .mu.g 320 .mu.g 640 .mu.g (Blank Control in
0.1 wt % 0.2 wt % 0.4 wt % 0.8 wt % Control) This Study) PGE.sub.1
PGE.sub.1 PGE.sub.1 PGE.sub.1 0 30 0 5 105 120
[0127] The average time required to return to the initial vessel
diameter is provided in Table 5, above, showing additional
vasodilation beyond the baseline. The treatment with the blank
control composition, 0.4% PGE.sub.1 topical composition without
DDAIP penetration enhancer and a topical composition comprising 0.1
wt % PGE.sub.1 did not produce any time within the 120 minute
duration of the test when the vessel diameter was greater than the
pre-vasospasm value. Administration of topical compositions having
higher amounts of PGE.sub.1 resulted in dose-dependent dilation of
the vessels. "Positive" indicates the result obtained with the
composition that contained 320 .mu.g (0.4 wt %) PGE.sub.1 but
lacked DDAIP. Note that in this study there was more than a
three-fold difference seen in the effects of compositions with and
without DDAIP with the same effective doses, 320 .mu.m, of
PGE.sub.1.
[0128] At ten and fifteen minutes after administration of the drug:
Compared to blank control group, the changes in vessel diameter
produced by 80 .mu.g PGE.sub.1 cream and the positive control
composition were not significant (P>0.05), but the changes in
vessel diameter produced by the rest of the other PGE.sub.1
compositions were significant at the P<0.01 level. Significant
differences (P<0.01) were observed between all treatments except
between 320 .mu.g and 640 .mu.g PGE.sub.1 treatments
(P>0.05).
[0129] At 30 minutes after administration of the drug: Compared to
blank control treatment, significant differences (P<0.01) in
vascular diameter changes were observed for treatment with each of
the PGE.sub.1 concentrations except the positive control treatment
(P>0.05). Among experimental treatments, significant differences
(P<0.01) were observed between all treatments except between 320
.mu.g and 640 .mu.g PGE.sub.1 treatments (P>0.05).
[0130] At 60 minutes and at 90 minutes after administration of the
drug: Compared to blank control treatment, significant differences
(P<0.01) in the vascular diameter changes were observed for
treatment with each of the PGE.sub.1 concentrations except the 80
.mu.g treatment and the positive control treatment (P>0.05).
Among experimental treatments, significant differences (P<0.01)
were observed between all treatments except between 320 .mu.g and
640 .mu.g PGE.sub.1 treatments (P>0.05).
[0131] At 120 minutes after administration of the drug: Compared to
blank control group, significant differences (P<0.01) of the
vascular diameter changes were observed for treatment with each of
the PGE.sub.1 concentrations except the 80 .mu.g, 160 .mu.g
PGE.sub.1 and the positive control treatments (P>0.05). Among
experimental groups, significant differences (P<0.01) were
observed between all treatments except between 320 .mu.g and 640
.mu.g PGE.sub.1 treatments (P>0.05).
[0132] The results showed that, compared to the blank control
group, significant differences (P<0.01) were observed for 320
.mu.g and 640 .mu.g PGE.sub.1 treatments at every time point, while
no significant changes were found between these latter two groups
(P<0.05). While a dose-dependent effect was observed in the
range 0.2-0.8 weight percent PGE.sub.1 for topical compositions
having the DDAIP penetration enhancer, a topical composition having
0.4 weight percent PGE.sub.1 but lacking DDAIP had effects
comparable to those of the blank control that lacked PGE.sub.1.
EXAMPLE 3
[0133] Laser Doppler Study of Vascular Perfusion Volume Charges in
Treatment of Vasospasm Using a Topical PGE.sub.1 Composition
[0134] The spasmolysis (reversal of vasospasm) and vasodilation
effects of a topical PGE.sub.1 composition (Composition H of
Example 1 modified as appropriate to contain the indicated amount
of PGE.sub.1) on vasospasm induced by adrenalin hydrochloride were
studied by monitoring vascular perfusion volume changes of central
arteries of rabbit ears. Rabbits were obtained and anesthetized and
vasospasm induced as described in Example 2, above. A total of 60
rabbits were randomly assigned into 6 groups with 10 rabbits per
group.
[0135] Vascular perfusion volume and skin temperature were measured
using the PeriFlux 5000 laser Doppler blood flowmetry system
(Perimed AB, Stockholm, Sweden). As in Example 2, above, a single
administration of 80 mg topical composition with various PGE.sub.1
concentrations was applied onto the skin area, 0.5-2 cm above the
ear base, 10 minutes after the appearance of the typical vasospasm
in the central ear artery. The laser probe was fixed at the area of
central artery about 1.5 cm above the ear base. Measurements were
made at time points of normal condition after anesthesia, 10
minutes after vasospasm, 10 minutes, 15 minutes, 30 minutes, 60
minutes, 90 minutes, and 120 minutes after administration of the
drug.
6TABLE 6 The vascular perfusion volume changes before and after the
drug administration (ml/min) Group Positive Blank 80 .mu.g 160
.mu.g 320 .mu.g 640 .mu.g Control Control N 10 10 10 10 10 10
Normal 124 .+-. 4.90 128 .+-. 4.45 127 .+-. 3.33 123 .+-. 3.06 127
.+-. 5.84 126 .+-. 4.69 Condition after Anesthesia 10 minutes after
14 .+-. 1.49 17 .+-. 1.70 15 .+-. 1.94 13 .+-. 2.16 15 .+-. 3.16 12
.+-. 2.00 Vasospasm 10 minutes after 19 .+-. 1.16 40 .+-. 2.40 126
.+-. 6.15 139 .+-. 10.84 25 .+-. 2.94 16 .+-. 2.06 Application 15
minutes after 20 .+-. 1.94 90 .+-. 3.02 145 .+-. 6.70 170 .+-. 4.67
24 .+-. 1.70 20 .+-. 2.98 Application 30 minutes after 97 .+-. 6.15
130 .+-. 5.94 152 .+-. 6.29 196 .+-. 5.87 25 .+-. 2.54 30 .+-. 4.88
Application 60 minutes after 56 .+-. 7.69 85 .+-. 4.59 197 .+-.
3.97 205 .+-. 2.79 29 .+-. 1.83 35 .+-. 5.03 Application 90 minutes
after 63 .+-. 6.80 94 .+-. 4.11 152 .+-. 4.88 196 .+-. 5.44 50 .+-.
6.93 48 .+-. 5.93 Application 120 minutes 95 .+-. 10.33 92 .+-.
3.68 146 .+-. 3.33 167 .+-. 7.10 62 .+-. 5.89 70 .+-. 7.33 after
Application
[0136] The averaged data are reported in Table 6, above, as mean
vascular perfusion volume .+-.standard deviation (SD), N=10, and
shown graphically in FIG. 4. FIG. 4 is a graphical representation
of the averaged results of a study of vascular perfusion volume in
vasospasm in rabbit ears as measured by transcutaneous laser
Doppler blood flowmetry. As noted above, a single administration of
80 mg topical composition with various PGE.sub.1 concentrations was
applied onto the skin area, 0.5-2 cm above the ear base, 10 minutes
after the typical time a vasospasm appeared in the central ear
artery. Administration of the topical composition comprising 0.1,
0.2, 0.4 or 0.8 weight percent PGE.sub.1 provided respective doses
of 80 (filled circles), 160 (filled triangles), 320 ("X") and 640 (
micrograms (.mu.g) of PGE.sub.1 as well as cream without PGE.sub.1
(0 .mu.g PGE.sub.1, filled diamonds) and positive control (0.4%
PGE.sub.1 topical composition without penetration enhancer, filled
circles). Measurements were taken of the normal condition of the
blood vessels after anesthesia, at 10 minutes after vasospasm was
induced, and at 10, 15, 30, 60, 90 and 120 minutes after the
administration of the various PGE.sub.1 compositions. Data are
presented as mean .+-.administration of topical composition.
Positive control, 0 .mu.g and 80 .mu.g groups did not achieve
normal vascular perfusion by the study end point of 120 minutes
after administration of the drug.
7TABLE 7 The Accumulated Change In Vascular Perfusion Volume
Between 10 Minutes After The Vasospasm To 120 Minutes After The
Application Of the Topical Composition (ml/min, N = 10 for each
group) 0 .mu.g PGE.sub.1 80 .mu.g 160 .mu.g 320 .mu.g 640 .mu.g 320
.mu.g PGE.sub.1 (Blank Control) PGE.sub.1 PGE.sub.1 PGE.sub.1
PGE.sub.1 without DDAIP 4595 .+-. 564 7590 .+-. 657 10960 .+-. 361
18550 .+-. 278 21753 .+-. 335 4356 .+-. 213
[0137] The accumulated vascular perfusion volume that occurred
between 10 minutes after the vasospasm and 120 minutes after the
application of the topical composition is presented in Table 7,
above. The treatment with the blank control composition ("0 .mu.g
PGE.sub.1") and the positive control, 0.4% PGE.sub.1 topical
composition without penetration enhancer produced small, comparable
changes in vascular perfusion volume. Administration of topical
compositions having higher amounts of PGE.sub.1 produced a greater
accumulated change in vascular perfusion volume and showed a
dose-dependent increase.
8TABLE 8 The Average Time Required To Return To The Initial
Vascular Perfusion Volume (Minutes, N = 10 for each group) 0 .mu.g
PGE.sub.1 20 .mu.g PGE.sub.1 80 .mu.g 160 .mu.g 320 .mu.g 640 .mu.g
(Blank Control) without DDAIP PGE.sub.1 PGE.sub.1 PGE.sub.1
PGE.sub.1 120 120 120 30 10 7
[0138] The average time required after administration of the
topical composition to return to the initial vascular perfusion
volume are presented in Table 8, above. The treatment with the
blank control composition ("0 .mu.g PGE.sub.1"), 0.4% PGE.sub.1
topical composition without penetration enhancer and a topical
composition comprising 80 .mu.g PGE.sub.1 did not produce recovery
of vascular perfusion volume within the 120 minute duration of the
test. Administration of topical compositions having higher amounts
of PGE.sub.1 produced recovery of vascular perfusion volume and
showed a dose-dependent decrease in the time required for
recovery.
[0139] Ten to ninety minutes after administration of the drug:
Compared to blank control group, no significant differences
(P>0.05) of vascular perfusion changes of positive control group
was noticed, while significant differences (P<0.01) of vascular
perfusion changes of other PGE.sub.1 concentration groups were
observed.
[0140] One hundred and twenty minutes after administration of the
drug: Compared to blank control group, significantly different
(P<0.01) vascular perfusion changes were observed for all of the
PGE.sub.1 concentration groups. Compared to 160kg PGE.sub.1 group,
significantly different (P<0.01) vascular perfusion changes were
observed for all of the PGE.sub.1 concentration groups except
positive control and 80.mu.g PGE.sub.1 concentration groups
(P<0.01).
[0141] The experimental results indicated topical application of
PGE.sub.1 sterile cream is an effective antagonist for
adrenaline-induced vasospasm and vascular perfusion changes. A
dose-dependent relationship was observed for PGE.sub.1 in the
concentration range of 80 .mu.g to 640 .mu.g.
EXAMPLE 4
[0142] Pharmacodynamic Study of a Study of a Topical PGE.sub.1
Composition as an Antagonist for Vasospasm During Surgical
Operation in Rabbit
[0143] The spasmolysis (reversal of vasospasm) and vasodilation
effects of a topical PGE.sub.1 composition (Composition H of
Example 1 modified as appropriate to contain the indicated amount
of PGE.sub.1) on vasospasm induced by adrenaline hydrochloride were
studied by monitoring vascular diameter changes in rabbit ears.
[0144] Rabbits were obtained and anesthetized as described in
Example 2, above. A total of 70 rabbits were randomly assigned into
7 groups with 10 rabbits per group.
[0145] Blood flow velocity and vascular cross section area were
measured and analyzed using a Toshiba Multifunction Ultrasonography
6000 system.
[0146] A portion of femoral artery about 2 cm long was exposed
through a 3 cm incision. Four drops of adrenaline hydrochloride (1
mg/1 ml) were dropped by a 1 ml syringe onto the surface of center
of the exposed segment of femoral artery to induce vasospasm. The
entire test was performed under a constant room temperature of 20
degrees Celsius. About ten minutes after the application of
adrenaline hydrochloride, the operating field was irrigated with
sterile saline topically and dried with sterile pad. A single
administration of 40 mg topical composition with various PGE.sub.1
concentrations was applied onto the surface of the 2 cm portion of
the isolated femoral artery. A single administration of four drops
of papaverine (30 mg/ml) from a 1 ml syringe onto this field was
used as a positive control.
[0147] The incision was closed after the application of the topical
composition. The ultrasonic probe was put at a fixed location 1 cm
from the incision. The values of the blood flow velocity and
vascular cross sections were recorded by the Toshiba Multifunction
Ultrasonography at time points of normal condition after
anesthesia, 5 minutes and 10 minutes after vasospasm, 5 minutes, 10
minutes, 15 minutes, 30 minutes, 60 minutes, 90 minutes, and 120
minutes after administration of the drug. In general, blood flow
volume=blood flow velocity x vascular cross section The data were
expressed as average .+-.SD; t-test was used for statistical
analysis. The averaged data are reported in Table 9, below, as
instantaneous blood flow volume i standard deviation (SD), N=10,
and shown graphically in FIG. 6.
9TABLE 9 The instantaneous blood flow volume changes before and
after the drug administration (mm.sup.3/s) Group 160 .mu.g w/o
Blank 40 .mu.g 80 .mu.g 160 .mu.g 320 .mu.g DDAIP Papaverine
Control N 10 10 10 10 10 10 10 Normal 326 .+-. 14.40 318 .+-. 14.92
327 .+-. 13.22 321 .+-. 12.75 332 325 .+-. 9.80 330 .+-. 15.09
Condition 5 min after 104 .+-. 5.64 105 .+-. 5.48 109 .+-. 4.74 107
.+-. 5.56 105 107 .+-. 4.11 108 .+-. 6.70 Vasospasm 10 min after 87
.+-. 5.66 86 .+-. 5.10 82 .+-. 4.14 87 .+-. 4.32 84 86 .+-. 4.76 84
.+-. 5.94 Vasospasm 5 min after 206 .+-. 10.54 230 .+-. 11.16 816
.+-. 23.12 364 .+-. 14.92 142 319 .+-. 13.27 149 .+-. 8.68 Drug 10
min 251 .+-. 15.36 292 .+-. 13.14 769 .+-. 24.97 254 .+-. 25.30 182
358 .+-. 13.95 132 .+-. 10.04 after Drug 15 min 289 .+-. 18.55 292
.+-. 12.45 654 .+-. 22.50 582 .+-. 24.58 247 402 .+-. 18.44 146
.+-. 8.43 after Drug 30 min 183 .+-. 13.86 413 .+-. 14.28 490 .+-.
16.29 649 .+-. 25.97 290 435 .+-. 17.76 197 .+-. 12.53 after Drug
60 min 214 .+-. 12.57 307 .+-. 12.06 462 .+-. 17.68 809 .+-. 27.46
256 296 .+-. 12.58 210 .+-. 16.44 after Drug 90 min 262 .+-. 13.56
290 .+-. 12.06 455 .+-. 12.61 562 .+-. 25.70 274 287 .+-. 11.96 254
.+-. 16.73 after Drug 120 min 287 .+-. 14.16 271 .+-. 10.89 451
.+-. 11.42 541 .+-. 23.06 279 274 .+-. 10.88 266 .+-. 18.29 after
Drug
[0148] FIG. 6 is a graphical representation of the averaged results
of vascular perfusion volume in rabbit femoral artery as measured
by ultrasonography. As noted above, a single administration of 40
mg of topical composition with various PGE.sub.1 concentrations was
applied to the surface of a surgically exposed portion of a femoral
artery, 10 minutes after the application of adrenaline
hydrochloride. Administration of the topical composition comprising
0.1, 0.2, 0.4 or 0.8 weight percent PGE.sub.1 provided respective
doses of 80 (filled circles), 80 (filled triangles), 160 ("X") and
320 ("*") micrograms (.mu.g) of PGE.sub.1 as well as cream without
PGE.sub.1 (0 .mu.g PGE.sub.1, filled diamonds), (0.4% PGE.sub.1
topical composition without penetration enhancer, filled circles)
and a positive control of 4 drops of 30mg/ml papaverine.
Measurements were taken of the normal condition of the blood
vessels after anesthesia, at 5 and 10 minutes after vasospasm was
induced, and at 5, 10, 15, 30, 60, 90 and 120 minutes after the
administration of the various PGE.sub.1 compositions. Data are
presented as mean .+-.standard deviation. S* refers to the time of
the vasospasm; A** refers to the time of the administration of
topical composition. The composition lacking the penetration
enhancer DDAIP showed significantly lesser effect than the
composition having the same dose of PGE.sub.1 with DDAIP.
10TABLE 10 The accumulated blood flow volume (cm.sup.3) from 10
minutes after vasospasm to 120 minutes after drug administration (N
= 10 for each group) 0 .mu.g PGE.sub.1 (Blank 40 .mu.g 80 .mu.g 160
.mu.g 320 .mu.g Control) PGE.sub.1 PGE.sub.1 PGE.sub.1 PGE.sub.1
Papaverine 1525 .+-. 100.78 1686 .+-. 2243 .+-. 3598 .+-. 4466 .+-.
2341 .+-. 95.85 85.46 106.98 175.71 94.87
[0149] The accumulated blood flow volume that occurred between 10
minutes after the vasospasm and 120 minutes after the application
of the topical composition is presented in Table 10, above. The
treatment with the blank control composition ("0 .mu.g PGE.sub.1")
and a composition comprising 40 .mu.g PGE.sub.1 produced small,
comparable changes in vascular perfusion volume. Administration of
papaverine produced a slightly greater effect that was comparable
to that produced by composition comprising 80 .mu.g PGE.sub.1.
Administration of topical compositions having higher amounts of
PGE.sub.1 produced a greater accumulated change in blood flow
volume and showed a dose-dependent increase.
11TABLE 11 The Average Time Required To Return To The Initial Blood
Flow Volume (Minutes, N = 10 for each group) 0 .mu.g PGE.sub.1 40
.mu.g 160 .mu.g 320 .mu.g (Blank Control) PGE.sub.1 80 .mu.g
PGE.sub.1 PGE.sub.1 PGE.sub.1 Papaverine 120 120 15 5 5 5
[0150] The average times required after administration of the
topical composition to return to the initial blood flow volume are
presented in Table 11, above. The treatment with the blank control
composition ("0 .mu.g PGE.sub.1") and the 40 .mu.g PGE.sub.1
composition did not produce a recovery of blood flow volume within
the 120 minute duration of the test. Administration of topical
compositions having higher amounts of PGE.sub.1 produced recovery
of blood flow volume as did papaverine.
[0151] At 10 to 90 minutes after administration of the drug:
Compared to blank control group, significant differences
(P<0.01) of instantaneous blood flow volume (mm.sup.3/s) of all
PGE.sub.1 concentration groups were observed.
[0152] At 120 minutes after administration of the drug: Compared to
blank control group, significant differences (P<0.01) of
instantaneous blood flow volume (mm.sup.3/s) of all PGE.sub.1
concentration groups were observed except 40 .mu.g, 80 .mu.g, and
positive control groups (P>0.05).
[0153] The experimental results indicated application of PGE.sub.1
sterile cream directly to the exposed surface of a blood vessel
could effectively counteract the adrenaline induced instantaneous
blood flow volume changes and improve topical blood flow. The
vascular dilation effect of PGE.sub.1 sterile cream appears to be
better than papaverine. A dose-dependent relationship was observed
for PGE.sub.1 between the concentration range of 80 .mu.g to 320
.mu.g.
EXAMPLE 5
[0154] Result of Pilot Studies on Topical Applications of a
Specially Formulated 0.4% PGE.sub.1 Topical Composition
[0155] The objects of these pilot studies were designed to explore
the efficacy of a specially formulated 0.4 wt % PGE.sub.1 topical
composition for treating vasospasm and skin disorders that result
from insufficient local blood circulation. Twenty four adult New
Zealand rabbit, 3-4 kg, were divided into three groups: 12 rabbits
were assigned into a Test Study Group; 6 rabbits were assigned into
a PGE.sub.1 Control Group and 6 rabbits were assigned into an
Alcohol Control Group. One rabbit of each Group was selected to
enter the study at the same time for each of the first six
studies.
[0156] The rabbit's right ear was selected to be the test
application site, while its left ear was observed as a control. An
adrenaline solution (0.2 ml of a 0.1% (1:1000) solution) was
injected into the area adjacent to both the central artery and vein
near the bottom of both ears. Classic vasospasm appeared five
minutes later on both ears. One of three test substances, 125 mg of
a 0.4% PGE.sub.1 topical composition containing 1.8% DDAIP HCl was
applied to a 2 cm.times.2 cm area of skin adjacent to the central
artery and vein of the right ear.
[0157] Vasospasm was induced in the same way in both ears of the
rabbits of the PGE.sub.1 Control Group and the Alcohol Control
Group. Similarly, 1 mg of PGE.sub.1 dissolved in 75% aqueous
ethanol, or the 75% aqueous ethanol vehicle alone were applied to
the right ears of the rabbits of the PGE.sub.1 Control Group and
the Alcohol Control Group respectively. The time course of changes
in blood vessel diameter was observed.
[0158] In the Test Study Group, the vasospasm was alleviated five
minutes after the 0.4 wt % PGE.sub.1 topical composition was
applied to the skin of the right ear. The vessels of the right ear
were obviously dilated 15 minutes later. The vascular bed of the
right ear was also dilated and reaching a maximum at 30 minutes
after application. The blood flow of the right ear increased
obviously. The effect lasted two hours then disappeared gradually.
The vasospasm of the left ear alleviated spontaneously two hours
later.
[0159] In the PGE.sub.1 Control Group, the vasospasm was alleviated
slightly 20 minutes after the application of PGE.sub.1 onto the
skin of the right ear. The vessels of the right ear were dilated 30
minutes later. The dilation effect lasted 60 minutes then
disappeared. No significant remaining changes were observed of the
vascular bed of the right ear. The vasospasm of the left ear lasted
two hours then disappeared spontaneously. In the Alcohol Control
Group, the vasospasm was alleviated slightly 10 minutes after the
application of 75% Alcohol onto the skin of the right ear. The
vasospasm disappeared 90 minutes later. No significant remaining
changes were observed of the vascular bed of the right ear. The
vasospasm of the left ear lasted two hours then disappeared
automatically.
EXAMPLE 6
[0160] Topical Application to Improve and Prevent Local Vasospasm
during Surgery
[0161] The use of topical prostaglandin compositions during surgery
for the prevention and treatment of local vasospasm was
studied.
[0162] Approximately 125 mg of the topical prostaglandin
composition H of Example 2 containing 0.4% PGE.sub.1 (dose 0.5 mg
PGE.sub.1) was applied to the vascular extima at the anastomotic
site when local vasospasm appeared during vascular anastomosis. The
changes of local vascular and systemic hemodynamics before and
after vasospasm were observed and recorded. Eleven subjects were
assigned to three groups.
[0163] Group 1 consisted of six subjects who needed arteriovenous
fistula repair due to renal failure and for whom systemic
application of vasodilator was contraindicated due to several
concomitant diseases. Approximately 125 mg of the topical
prostaglandin composition was applied onto the vascular extima
after shaping the arteriovenous fistula during arteriovenous
anastomosis.
[0164] Group 2 contained two subjects who were emergency hand
trauma patients, who had classic vasospasm right after the injury.
Approximately 125 mg of the topical prostaglandin composition was
applied onto the vascular extima at the anastomotic site after
vascular anastomosis.
[0165] Group 3 consisted of three subjects who were vascular
surgical patients. Vasospasm appeared in two subjects of Group 3
after vascular anastomosis performed when removing a clot.
Vasospasm appeared in the other Group 3 subject after vascular
anastomosis performed when removing vascular obliteration.
Approximately 125 mg of the topical prostaglandin composition was
applied onto the vascular extima at the anastomotic site after
vascular anastomosis.
[0166] No other vasodilators were given to the patients after the
surgery. Changes of local vascular diameter were recorded by
macroscopy using a digital camera. Laser Doppler flowmetry was also
used to measure local hemodynamic changes.
[0167] The topical prostaglandin composition was applied after
classic vasospasm appeared after vascular anastomosis and lasting
for more than 15 minutes without spontaneous alleviation.
Typically, the vasospasm was alleviated 2-5 minutes after the
application of the topical prostaglandin composition, and the blood
vessel was obviously dilated after 10 minutes. The diameter of the
blood vessel generally increased to about twice that seen during
the vasospasm; while the arterial pulse appeared to be reinforced
as well. The dilation effect continued and was also observed at
twenty minutes following application. Local blood flow as measured
by laser Doppler blood flowmetry showed a five-fold increase in
maximum local blood flow compared to prior to application of the
topical prostaglandin composition. No significant changes of blood
pressure and pulse were noted. No secondary vasospasm was noted in
any patient during the two-week observation period following
surgery. The wound healing progressed satisfactorily.
[0168] While the foregoing is intended to be illustrative of the
present invention, the scope is defined by the appended claims.
Numerous variations and modifications may be effected without
departing from the true spirit and scope of the invention.
* * * * *
References