U.S. patent application number 10/944416 was filed with the patent office on 2005-05-05 for pharmaceutical delivery system.
Invention is credited to Cuca, Robert C., Levinson, R. Saul, Mariani, Elio, Riley, Thomas C..
Application Number | 20050095245 10/944416 |
Document ID | / |
Family ID | 34381092 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050095245 |
Kind Code |
A1 |
Riley, Thomas C. ; et
al. |
May 5, 2005 |
Pharmaceutical delivery system
Abstract
A pharmaceutical formulation to treat vaginal conditions in a
human patient comprises: at least one active agent; a modified
release dosage form which provides extended release of the
anti-infective agent upon vaginal administration to the patient;
and wherein the formulation, when containing a total dose of the
anti-infective agent of about 25 .mu.g to about 500 mg based on the
active agent will produce a plasma concentration versus time curve
(ng/mL versus hours) having an area under the curve (AUC) of less
than about 600 ng/mL.hr.
Inventors: |
Riley, Thomas C.;
(Manchester, MO) ; Levinson, R. Saul;
(Chesterfield, MO) ; Cuca, Robert C.; (Glen
Carbon, IL) ; Mariani, Elio; (Chesterfield,
MO) |
Correspondence
Address: |
NATH & ASSOCIATES, PLLC
Sixth Floor
1030 15th Street, N.W.
Washington
DC
20005
US
|
Family ID: |
34381092 |
Appl. No.: |
10/944416 |
Filed: |
September 20, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60504017 |
Sep 19, 2003 |
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60507138 |
Oct 1, 2003 |
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Current U.S.
Class: |
424/145.1 ;
514/10.2; 514/171; 514/2.4; 514/2.9; 514/20.1; 514/3.7; 514/4.4;
514/44R; 514/9.7; 514/9.8 |
Current CPC
Class: |
A61P 15/02 20180101;
A61P 31/04 20180101; A61P 31/10 20180101; A61K 9/0034 20130101;
A61P 15/00 20180101; A61K 9/0036 20130101 |
Class at
Publication: |
424/145.1 ;
514/171; 514/044; 514/002 |
International
Class: |
A61K 039/395; A61K
031/56; A61K 048/00 |
Claims
What is claimed is:
1. A pharmaceutical formulation to treat vaginal conditions in a
human patient comprising: an effective amount of at least one
active agent; a modified release dosage form which provides
modified release of said active agent or agents upon vaginal
administration to said patient; and wherein said formulation, when
containing a total dose of each active agent of about 25 .mu.g to
about 500 mg based on said active agent will produce a plasma
concentration versus time curve (ng/ml versus hours) having an area
under the curve (AUC) of less than about 600 ng./mL.hr; and wherein
the at least one active agent is selected from the group consisting
of antibacterial agents, antiviral agents, spermicides, hormone
agents, growth enhancing agents, cytokines, antitrichomonial
agents, antiprotozoan agents, antimycoplasm agents, antiretroviral
agents, nucleoside analogues, reverse transcriptase inhibitors,
protease inhibitors, contraceptive agents, sulfadrugs,
sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine
agents, antibody agents, peptide agents, protein agents,
polysaccharide agents, nucleic acids, plasmids, liposomes,
carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic
agents, steroid agents, growth enhancing agents, libido enhancers,
androgenic substances, chitin derivatives, environment modifying
agents such as pH modifiers, and mixtures and combinations
thereof.
2. The pharmaceutical formulation as recited in claim 1, wherein
said formulation when containing an antimicrobial agent as the
active agent, and when containing a total dose of said
antimicrobial agent of about 100 mg, will produce a plasma
concentration versus time curve (ng/ml versus hours) having an area
under the curve (AUC) between about 25 to about 350 ng/mL.hr.
3. The pharmaceutical formulation as recited in claim 1, wherein
said dosage form is comprised of: a. an emulsion comprising at
least two phases, one phase comprises an external lipoidal phase
and the other phase comprising an internal non-lipoidal phase
wherein said lipoidal phases is continuous and the said
non-lipoidal phase comprises at least 70% by volume of said
emulsion; b. one or more primary stabilizing surfactants selected
from the group consisting of phospholipid, non-ionic ester and
mixtures thereof; and c. when said stabilizing surfactants is a
phospholipid then one or more auxiliary stabilizing surfactants are
added and when said stabilizing surfactants is non-ionic ester then
optionally one or more auxiliary stabilizing surfactants are
added.
4. The pharmaceutical formulation as recited in claim 1, wherein
said active agent is an antimicrobial agent selected from the group
consisting of clindamycin, clindamycin phospate, clindamycin
hydrochloride, salts thereof, complexes of clindamycin base and
mixtures thereof.
5. The pharmaceutical formulation as recited in claim 4, wherein
said antimicrobial agent is clindamycin phosphate.
6. The pharmaceutical formulation as recited in claim 4, wherein
said antimicrobial agent is present in an amount of less than about
5% weight/weight based on said clindamycin.
7. The pharmaceutical formulation as recited in claim 4, wherein
said antimicrobial agent is present in an amount equal to or less
than about 2% weight/weight based on said clindamycin.
8. The pharmaceutical formulation as recited in claim 4, wherein
said antimicrobial agent is present in an amount equal to or less
than about 1% weight/weight based on said clindamycin.
9. The pharmaceutical formulation as recited in claims 1, 3 or 4,
wherein said active agent has properties of a surface active
agent.
10. The pharmaceutical formulation as recited in claim 9 wherein
said surface active agent is selected from the group consisting of
Erythromycin, Clarithromycin, Azithromycin, Penicillins,
Cephalosporins, Bacitracins, Polymyxins, Metronidazoles and
Streptomycins.
11. The pharmaceutical formulation as recited in claim 1 having at
least one anti-bacterial agent and further comprising and
antifungal agent.
12. The pharmaceutical formulation as recited in claim 1, 3, 4 or
10 further comprised of an acid buffered phase.
13. The pharmaceutical formulation as recited in claim 12 wherein
said acid buffer phase is isotonic, hypertonic or hypotonic.
14. The pharmaceutical formulation as recited in claim 12 wherein
said acid buffered phase is hypertonic.
15. The pharmaceutical formulation as recited in claim 12 wherein
said acid buffered phase comprises a member selected from the group
consisting of a weak acid and it's conjugate base, citric acid,
acetic acid, a salt of citric acid or acetic acid and mixtures
thereof.
16. The pharmaceutical formulation as recited in claim 12, wherein
said pharmaceutical formulation has a pH between about 3 and about
6.
17. The pharmaceutical formulation as recited in claim 16, wherein
said pharmaceutical formulation has a pH between about 4 and about
5.
18. The pharmaceutical formulation as recited in claims 16 or 17,
wherein said pharmaceutical formulation has a pH of about 4.5.
19. The pharmaceutical formulation as recited in claim 12 wherein
said pharmaceutical formulation has a pH of about 4.5.
20. The pharmaceutical formulation as recited in claim 1, wherein
said plasma concentration versus time curve has a maximum
concentration (Cmax) of about 0.4 to about 100 ng/mL.
21. The pharmaceutical formulation as recited in claim 20, wherein
the time to reach said Cmax is about 0.5 to about 90 hours.
22. The pharmaceutical formulation as recited in claim 21, wherein
said time is about 20 to about 30 hours.
23. The pharmaceutical formulation as recited in claim 22, wherein
said time is an average time of about 26 hours.
24. The pharmaceutical formulation as recited in claim 1, 2, or 21
wherein said active agent will produce plasma concentration versus
time curve of less than about 10 ng/mL.
25. The pharmaceutical formulation as recited in claim 3, wherein
said phospholipid is selected from the group consisting of
lecithin, refined lecithin and mixtures thereof.
26. The pharmaceutical formulation as recited in claims 3 or 25
wherein said primary stabilizing surfactant contains less than
about 95% phosphatidylcholine.
27. The pharmaceutical formulation as recited in claims 3 or 25
wherein said primary stabilizing surfactant contains about 90%
phosphatidylcholine.
28. The pharmaceutical formulation as recited in claim 3, wherein
said auxliary stabilizing surfactants are selected from the group
consisting of polyglycerol-3-oleate, glycerol monoisostearate and
mixtures thereof.
29. The pharmaceutical formulation as recited in claims 3 or 28,
wherein said auxiliary stabilizing surfactants are present in said
pharmaceutical formulation in amounts of about 2 to 15%
weight/weight.
30. The pharmaceutical formulation as recited in claims 1, 2, 4 or
10 wherein said formulation affects treatment of said vaginal
condition in a single dose.
31. The pharmaceutical formulation as recited in claims 1, 2, 4 or
10 wherein said formulation affects treatment of said vaginal
condition in multiple doses.
32. The pharmaceutical formulation as recited in claims 1, 2, 4 or
10 wherein said active agent is released from said pharmaceutical
formulation for extended periods of time.
33. A pharmaceutical formulation comprising: a. an active
pharmaceutical having surfactant properties; b. an emulsion
comprising at least two phases, one phase comprises an external
lipoidal phase and the other phase comprising an internal
non-lipoidal phase wherein said lipoidal phases is continuous and
the said non-lipoidal phase comprises at least 70% by volume of
said emulsion; c. one or more primary stabilizing surfactants
selected from the group consisting of phospholipid, non-ionic ester
and mixtures thereof; and d. when said stabilizing surfactants is a
phospholipid then one or more auxiliary stabilizing surfactants are
added and when said stabilizing surfactants is a non-ionic ester
then optionally one or more auxiliary stabilizing surfactants are
added.
34. The pharmaceutical formulation of claim 33 wherein said active
pharmaceutical is selected from the group consisting of antifungal
agents, antibacterial agents, antimicrobial agents, antiviral
agents, spermicides, hormone agents, growth enhancing agents,
cytokines, antitrichomonial agents, antiprotozoan agents,
antimycoplasm agents, antiretroviral agents, nucleoside analogues,
reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agents, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof.
35. The pharmaceutical formulation as recited in claim 34, wherein
said active agent is an antimicrobial agent.
36. The pharmaceutical formulation as recited in claim 35 wherein
said antimicrobial agent is selected from the group consisting of
clindamycin, clindamycin phospate, clindamycin hydrochloride, salts
thereof, complexes of clindamycin base and mixtures thereof.
37. The pharmaceutical formulation as recited in claim 36, wherein
said antimicrobial agent is clindamycin phosphate.
38. The pharmaceutical formulation as recited in claim 35, wherein
said antimicrobial agent is present in an amount of less than about
5% weight based on clindamycin.
39. The pharmaceutical formulation as recited in claim 38, wherein
said antimicrobial agent is present in an amount of less than about
2% weight based on clindamycin.
40. The pharmaceutical formulation as recited in claim 33 or 37
wherein the active agent will produce a plasma concentration versus
time curve of less than 50 ng/mL.
41. The pharmaceutical formulation as recited in claims 33, 35 or
37, wherein said active agent is a surface active agent.
42. The pharmaceutical formulation as recited in claims 33, wherein
said pharmaceutically acceptable carrier is further comprised of an
acid buffered phase, which is isotonic, hypertonic or
hypotonic.
43. The pharmaceutical formulation as recited in claim 42, wherein
said buffered phase comprises a member selected from the group
consisting of a salt of citric acid, an ester of citric acid,
acetic acid, a salt of citric acid or acetic acid, an ester of
acetic acid and mixtures thereof.
44. The pharmaceutical formulation as recited in claim 33 or 42,
wherein the active agent is metronidazole.
45. The pharmaceutical formulation as recited in claim 44, wherein
the pharmaceutical formulation has a pH of about 4.5.
46. The pharmaceutical formulation as recited in claim 42, wherein
the pharmaceutical formulation has a pH between about 3 and about
6.
47. The pharmaceutical formulation as recited in claim 46, wherein
the pharmaceutical formulation has a pH between about 4 and about
5.
48. The pharmaceutical formulation as recited in claims 42 or 47,
wherein the pharmaceutical formulation has a pH of about 4.5.
49. The pharmaceutical formulation as recited in claim 33, wherein
the plasma concentration versus time curve has a maximum
concentration (Cmax) of about 0.4 to about 100 ng/mL.
50. The pharmaceutical formulation as recited in claim 49, wherein
the time to reach said Cmax is about 0.5 to about 90 hours.
51. The pharmaceutical formulation as recited in claim 50, wherein
said time is about 20 to about 30 hours.
52. The pharmaceutical formulation as recited in claim 51, wherein
said time is about 26 hours.
53. The pharmaceutical formulation as recited in claims 49 or 50,
wherein the formulation has an AUC of about 25.00 to about 600.00
ng/mL.hr.
54. The pharmaceutical formulation as recited in claim 49 or 0.50,
wherein Cmax is about 75.00 ng/mL.
55. The pharmaceutical formulation as recited in claim 33, wherein
said phospholipid or said non-ionic ester is selected from the
group consisting of lecithin, refined lecithin and mixtures
thereof.
56. The pharmaceutical formulation as recited in claims 33 or 55,
wherein said primary stabilizing surfactants contain less than
about 95% phosphatidylcholine.
57. The pharmaceutical formulation as recited in claims 33 or 55,
wherein said primary stabilizing surfactants contain less than
about 90% phosphatidylcholine.
58. The pharmaceutical formulation as recited in claims 33 or 55,
wherein said primary stabilizing surfactants contain less than
about 75% phosphatidylcholine.
59. The pharmaceutical formulation as recited in claim 33, wherein
said auxiliary stabilizing surfactants are selected from the group
consisting of polyglycerol-3-oleate, glycerol monoisostearate and
mixtures thereof.
60. The pharmaceutical formulation as recited in claims 33 or 59,
wherein said auxiliary stabilizing surfactants are present in said
pharmaceutical formulation in amounts of about 2 to 15%
weight/weight.
61. The pharmaceutical formulation as recited in claims 33 or 37,
wherein said formulation affects treatment of said vaginal
condition in a single dose.
62. The pharmaceutical formulation as recited in claims 33 or 37,
wherein said formulation affects treatment of said vaginal
condition is multiple doses.
63. The pharmaceutical formulation as recited in claims 33 or 37,
wherein said active agent is released from said pharmaceutical
formulation for extended periods of time.
64. A composition for treating a vaginal infection, comprising: an
effective amount of at least one active agent; a modified release
dosage form which provides modified release of said active agent or
agents upon vaginal administration to said patient; and wherein
said formulation, when containing a total dose of each active agent
of about 25 .mu.g to about 500 mg based on said active agent will
produce a plasma concentration versus time curve (ng/ml versus
hours) having an area under the curve (AUC) of less than about 600
ng/mL.hr; and wherein the at least one active agent is selected
from the group consisting of antibacterial agents, antiviral
agents, spermicides, hormone agents, growth enhancing agents,
cytokines, antitrichomonial agents, antiprotozoan agents,
antimycoplasm agents, antiretroviral agents, nucleoside analogues,
reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agents, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof; and wherein said composition is
administered in a single administration and is statistically
equivalent to seven doses of a conventional clindamycin vaginal
cream, 2% in the treatment of bacterial vaginosis.
65. A pharmaceutical formulation to treat vaginal conditions in a
human patient comprising: an effective amount of at least one
active antibacterial agent; a modified release dosage form for
vaginal administration to said patient; wherein said active
antibacterial agent is not an antifungal agent; and wherein said
formulation, when containing a total dose of each active
antibacterial agent of about 25 .mu.g to about 500 mg based on said
active agent will produce a plasma concentration versus time curve
(ng/ml versus hours) having an area under the curve (AUC) of less
than about 600 ng/mL.hr.
66. A pharmaceutical formulation to treat vaginal conditions in a
human patient comprising: an effective amount of at least one
active antibacterial agent; a modified release dosage form for
vaginal administration to said patient; wherein said active
antibacterial agent is not an antifungal agent; wherein said
antifungal agent is not butaconazole; and wherein said formulation,
when containing a total dose of each active antibacterial agent of
about 25 .mu.g to about 500 mg based on said active agent will
produce a plasma concentration versus time curve (ng/ml versus
hours) having an area under the curve (AUC) of less than about 600
ng/mL.hr.
67. A method of treating a vaginal infection by administering a
therapeutically effective amount of a pharmaceutical formulation to
treat said vaginal condition comprising administering to said
patient the formulation accomplishes a biologic endpoint of claim
1.
68. The method of claim 67, wherein said formulation, when
containing a total dose of said antimicrobial agent of about 100 mg
based on said active agent will produce a plasma concentration
versus time curve (ng/ml versus hours) having an area under the
curve (AUC) between about 25 to about 350 ng/mL.hr.
69. The method of claim 67, wherein said dosage form comprises: a.
an emulsion comprising at least two phases, one phase comprises an
external lipoidal phase and the other phase comprising an internal
non-lipoidal phase wherein said lipoidal phases is continuous and
the said non-lipoidal phase comprises at least 70% by volume of
said emulsion; b. one or more primary stabilizing surfactants
selected from the group consisting Phospholipid or non-ionic ester;
and c. when said stabilizing surfactants is a Phospholipid then one
or more auxiliary stabilizing surfactants and when said stabilizing
surfactants is non-ionic ester then optionally one or more
auxiliary stabilizing surfactants.
70. The method of claim 69, wherein said active agent is selected
from the group consisting of antibacterial agents, antiviral
agents, spermicides, hormone agents, growth enhancing agents,
cytokines, antitrichomonial agents, antiprotozoan agents,
antimycoplasm agents, antiretroviral agents, nucleoside analogues,
reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agerts, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof.
71. The method claim 70, wherein said active agent is an
antibacterial agent selected from the group consisting of
clindamycin, clindamycin phospate, clindamycin hydrochloride, salts
thereof, complexes of clindamycin base and mixtures thereof.
72. The method of claim 71, wherein said antibacterial agent is
clindamycin phosphate.
73. A method of treating a vaginal infection comprising
administering to a patient in need thereof a single dose of a
therapeutically effective pharmaceutical formulation comprising an
active pharmaceutical formulation having surfactant properties,
wherein treatment of said vaginal infection is affected with said
single dose.
74. The method of claim 73, wherein said vaginal infection is
bacterial vaginitis.
75. A method of stabilizing a clindamycin formulation by adding one
or more primary stabilizing surfactants selected from the group
consisting of a phospholipid, a non-ionic ester, and mixtures
thereof; wherein when said stabilizing surfactant is a
phospholipid, then one or more auxiliary stabilizing surfactants
are added, and when said stabilizing surfactant is a non-ionic
ester, then optionally one or more auxiliary stabilizing
surfactants are added.
76. A method of treating or preventing a reoccurrence of a vaginal
infection in a patient comprising administering a single dose of a
pharmaceutical formulation comprising an active pharmaceutical
having surfactant properties to a patient in need thereof effective
to treat said vaginal condition.
77. A method of treating a vaginal infection by administering a
pharmaceutical formulation for vaginal administration comprising:
an effective amount of at least one active agent; a modified
release dosage form which provides modified release of said active
agent or agents upon vaginal administration to said patient; and
wherein said formulation, when containing a total dose of each
active agent of about 25 .mu.g to about 500 mg based on said active
agent will produce a plasma concentration versus time curve (ng/ml
versus hours) having an area under the curve (AUC) of less than
about 600 ng/mL.hr; and wherein the at least one active agent is
selected from the group consisting of antibacterial agents,
antiviral agents, spermicides, hormone agents, growth enhancing
agents, cytokines, antitrichomonial agents, antiprotozoan agents,
antimycoplasm agents, antiretroviral agents, nucleoside analogues,
reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agents, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof; and wherein said administration
is a single administration and is statistically equivalent to seven
doses of a conventional clindamycin vaginal cream, 2% in the
treatment of bacterial vaginosis.
78. A method for treating vaginal conditions, which comprises:
administering topically to a vaginal mucosal tissue site a modified
release pharmaceutical formulation comprising at least one active
agent, wherein the formulation maintains topical residence in a
vaginal cavity for up to 10 days; and wherein systemic absorption
of the at least one active agent is minimized.
79. A method for treating vaginal conditions, which comprises:
administering topically to a vaginal mucosal tissue site a modified
release pharmaceutical formulation comprising at least one active
agent, wherein the formulation maintains topical residence in a
vaginal cavity for up to 7 days; and wherein systemic absorption of
the at least one active agent is minimized.
80. The method of claim 79 wherein said formulation, when
containing a total dose of each active agent of about 25 .mu.g to
about 500 mg based on said active agent will produce a plasma
concentration versus time curve (ng/ml versus hours) having an
area-under the curve (AUC) of less than about 600 ng/mL.hr.
81. The method of claim 79, wherein said formulation when
containing an antimicrobial agent as the active agent, and when
containing a total dose of said antimicrobial agent of about 100
mg, will produce a plasma concentration versus time curve (ng/ml
versus hours) having an area under the curve (AUC) between about 25
to about 350 ng/mL.hr.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is directed to delivery systems, which
stabilize surface active therapeutic agents, or those therapeutic
agents which obtain surface active properties in a delivery system.
These systems are suitable for use in the vaginal cavity, as well
as other mucosal cavities of the body. The invention is
additionally concerned with preparations demonstrating a modified,
controlled, extended or sustained release of the active and/or
therapeutic agent and a minimal number of administrations to
produce efficacy upon administration of said delivery system.
[0003] 2. Description of the Related Art
[0004] One significant aspect of medicine is the treatment of the
female reproductive system for the prevention, treatment,
mitigation, diagnosis and cure of diseases and the prevention of
conception. Usually, this involves the delivery of active agents to
the vaginal cavity and its environs. Systems to affect the delivery
of such agents are usually in the form of gels, foams, creams,
suppositories and quick dissolving tablets. These delivery systems,
regardless of formulation or method of manufacture, have not
reliably demonstrated the ability to deliver active agents in a
controlled manner with lower systemic absorption within the vaginal
cavity for long periods of time, and particularly for 12 hours or
longer. This may be attributed to the vaginal cavity environment as
well as to the known formulations designed to administer drugs
thereto.
[0005] The vaginal cavity is subject to conditions rendering it a
target for disease and infection; however, as previously noted, it
is extremely difficult to deliver an active agent to this area for
an extended period of time. The vaginal cavity exhibits an aqueous
environment containing secreting glands whose fluids create an
acidic pH in the range of 4.5 to 5.5. The environment of the vagina
is conducive to the growth of various microbes, such as bacteria,
fungi, yeast and other microorganisms since it is warm, moist and
dark. It is also the vestibule for menstrual debris and the
residual seminal fluid from sexual intercourse. The crevices of the
vaginal cavity facilitate the retention of undesirable bacteria,
fungi, yeast and other microorganisms, as well as the debris from
menstruation and sexual intercourse. The vaginal cavity is also
subject to considerable physical deformation, such as during sexual
intercourse or during the insertion of tampons.
[0006] Active agents having pharmaceutical qualities have been
developed and approved for use in the treatment of conditions and
diseases of the vaginal cavity and the prevention of conception.
These include fungicides, antibiotics, spermicides, etc. Although
pharmaceutically active agents have been developed, it has been
difficult to achieve optimal potential effectiveness from these
agents due to the inadequacy of currently available drug delivery
systems. The majority of gels, foams, creams, suppositories and
tablets presently used as vaginal delivery systems can breakdown
almost immediately following insertion into the vaginal cavity and
have minimal bioadherence to the vaginal walls. Often, this is
believed to be due to their water miscibility and/or their lack of
physical stability at 37 degrees C. (body temperature). Further,
the nature of the active/therapeutic agent itself can cause the
delivery system to deteriorate. This may be due to the fact that
the active/therapeutic agent possesses surface active properties or
obtains surface active characteristics when placed into various
delivery systems known in the art. Examples of vaginal delivery
systems, can be found in U.S. Pat. Nos. 5,655,303 and 5,266,329,
both of which are incorporated herein by reference in their
entirety.
[0007] Many known systems exhibit limited effectiveness since they
rapidly release their active agents in an uncontrolled manner and
rapid manner. Further, conventional systems also result in a
relatively high systemic absorption of the active agent, which may
be due in part to the instability of the system. This level of
systemic absorption is such that in a plasma concentration versus
time curve will result in an area under the curve (AUC) of at least
about 200 ng/mL.hr. Typically, the AUC will be much higher, e.g.,
at least about 300 to as much as 4,500 ng/mL.hr. Further,
conventional dosage forms are frequently discharged as an offensive
leakage and drippage along with the minute vaginal secretions that
are a normal physiological function. One particular clindamycin
phosphate vaginal formulation currently known in the art is sold as
Cleocin.RTM. and manufactured by Pharmacia & Upjohn.
[0008] The pharmacology of clindamycin is known in the art. See for
example, Aroutcheva, A., et al., The inhibitory effect of
clindamycin on Lactobacillus in vitro., Infectious diseases in
Obstetrics and Gynecology, 9, 2001, (4), 239-44; and Muli, F., et
al., Use of continuous-culture biofilm system to study the
antimicrobial susceptibilities of Gardnerella vaginalis and
Lactobacillus acidophilus., Antimicrobial agents and chemotherapy,
42, June 1998, (6) 1428-32, both of which are incorporated herein
by reference in their entirety.
[0009] The toxicology of clindamycin is also well known in the art.
See for example, Gray, J. E., et al., The Oral Toxicity of
Clindamycin in Laboratory Animals., Toxicology and Applied
Pharmacology 21, 1972, 516-531; and Bollert, J. A., et al.,
Teratogenicity and Neonatal Toxicity of Clindamycin 2-Phosphate in
Laboratory Animals., Toxicology and Applied Pharmacology 27,
322-329, both of which are incorporated herein by reference in
their entirety.
[0010] A controlled release system delivers the active agent to the
site of action, activity, expected activity, absorption or use in a
predetermined manner. This contrasts with conventional immediate
release systems, which require frequent repetitive dosing in order
to achieve the desired level of active agent. An unexpected
advantage of a controlled release system is that the drug is
administered fewer times a day or fewer times during the therapy
period than conventional systems since the drug level in the
vaginal cavity is maintained at a constant or controlled level.
Unfortunately, the controlled release systems known in the art do
not affect the total number of days that are required to treat a
condition.
[0011] The present invention is advantageous because it provides a
system for the delivery of an active agent in a controlled manner
in the vaginal cavity for an extended period of at least several
days. The vaginal drug delivery system may take the form of a
multi-phase liquid or semi-solid, which is easily introduced into
the vaginal cavity. Additionally, due to the bioadhesive nature of
the delivery system, the material introduced into the vaginal
cavity does not seep or seepage is reduced from this body cavity in
an offensive manner. In comparison to conventional vaginal drug
delivery with conventional creams and ointments, the present
technology is further advantageous in 0.5 that it reduces the
number of administrations needed to obtain efficacy for active
agents such as, clindamycin phosphate. The conventional clindamycin
phosphate vaginal cream (Cleocin.TM. Vaginal Cream) needs to be
administered nightly for 7 consecutive nights in order to affect a
cure. The present technology needs to be administered only once to
affect the same cure.
[0012] Besides advantages regarding the convenience afforded by a
single dose administration, the present technology is also
characterized with providing a highly cost effective treatment for
vaginal infections in that only one applicator is needed to do the
treatment as contrasted to 7 applicators needed for the
conventional cream product. Additionally, since only 100 mg of
active drug (2% of a 5.0 gram application) is needed with the
present technology, as compared to 700 mg of active drug required
for a full dose of therapy with the conventional cream (2% of 5.0
gram times 7 applications) a significant savings in active drug and
excipients is also achieved.
SUMMARY OF THE INVENTION
[0013] The present inventive subject matter is directed to a
pharmaceutical formulation to treat vaginal conditions in a human
patient comprising: an effective amount of at least one active
agent; a modified release dosage form which provides modified
release of said active agent or agents upon vaginal administration
to said patient; and wherein said formulation, when containing a
total dose of each active agent of about 25 .mu.g to about 500 mg
based on said active agent will produce a plasma concentration
versus time curve (ng/ml versus hours) having an area under the
curve (AUC) of less than about 600 ng./mL.hr; and wherein the at
least one active agent is selected from the group consisting of
antibacterial agents, antiviral agents, spermicides, hormone
agents, growth enhancing agents, cytokines, antitrichomonial
agents, antiprotozoan agents, antimycoplasm agents, antiretroviral
agents, nucleoside analogues, reverse transcriptase inhibitors,
protease inhibitors, contraceptive agents, sulfadrugs,
sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine
agents, antibody agents, peptide agents, protein agents,
polysaccharide agents, nucleic acids, plasmids, liposomes,
carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic
agents, steroid agents, growth enhancing agents, libido enhancers,
androgenic substances, chitin derivatives, environment modifying
agents such as pH modifiers, and mixtures and combinations
thereof.
[0014] The present inventive subject matter is further drawn to a
pharmaceutical formulation comprising: an active pharmaceutical
having surfactant properties; an emulsion comprising at least two
phases, one phase comprises an external lipoidal phase and the
other phase comprising an internal non-lipoidal phase wherein said
lipoidal phases is continuous and the said non-lipoidal phase
comprises at least 70% by volume of said emulsion; one or more
primary stabilizing surfactants selected from the group consisting
of phospholipid, non-ionic ester and mixtures thereof; and when
said stabilizing surfactants is a phospholipid then one or more
auxiliary stabilizing surfactants are added and when said
stabilizing surfactants is a non-ionic ester then optionally one or
more auxiliary stabilizing surfactants are added.
[0015] Still further, the present inventive subject matter is
directed to A composition for treating a vaginal infection,
comprising: an effective amount of at least one active agent; a
modified release dosage form which provides modified release of
said active agent or agents upon vaginal administration to said
patient; and wherein said formulation, when containing a total dose
of each active agent of about 25 .mu.g to about 500 mg based on
said active agent will produce a plasma concentration versus time
curve (ng/ml versus hours) having an area under the curve (AUC) of
less than about 600 ng/mL.hr; and wherein the at least one active
agent is selected from the group consisting of antibacterial
agents, antiviral agents, spermicides, hormone agents, growth
enhancing agents, cytokines, antitrichomonial agents, antiprotozoan
agents, antimycoplasm agents, antiretroviral agents, nucleoside
analogues, reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agents, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof; and wherein said composition is
administered in a single administration and is statistically
equivalent to seven doses of a conventional clindamycin vaginal
cream, 2% in the treatment of bacterial vaginosis.
[0016] Yet further, the present inventive subject matter is drawn
to a pharmaceutical formulation to treat vaginal conditions in a
human patient comprising: an effective amount of at least one
active antibacterial agent; a modified release dosage form for
vaginal administration to said patient; wherein said active
antibacterial agent is not an antifungal agent; and wherein said
formulation, when containing a total dose of each active
antibacterial agent of about 25 .mu.g to about 500 mg based on said
active agent will produce a plasma concentration versus time curve
(ng/ml versus hours) having an area under the curve (AUC) of less
than about 600 ng/mL.hr.
[0017] Another embodiment of the present inventive subject matter
is drawn to a pharmaceutical formulation to treat vaginal
conditions in a human patient comprising: an effective amount of at
least one active antibacterial agent; a modified release dosage
form for vaginal administration to said patient; wherein said
active antibacterial agent is not an antifungal agent; wherein said
antifungal agent is not butaconazole; and wherein said formulation,
when containing a total dose of each active antibacterial agent of
about 25 .mu.g to about 500 mg based on said active agent will
produce a plasma concentration versus time curve (ng/ml versus
hours) having an area under the curve (AUC) of less than about 600
ng/mL.hr.
[0018] A further embodiment of the present inventive subject matter
is directed to a method of stabilizing a clindamycin formulation by
adding one or more primary stabilizing surfactants selected from
the group consisting of a phospholipid, a non-ionic ester, and
mixtures thereof; wherein when said stabilizing surfactant is a
phospholipid, then one or more auxiliary stabilizing surfactants
are added, and when said stabilizing surfactant is a non-ionic
ester, then optionally one or more auxiliary stabilizing
surfactants are added.
[0019] An even further embodiment of the present inventive subject
matter is drawn to a method of treating or preventing a
reoccurrence of a vaginal infection in a patient comprising
administering a single dose of a pharmaceutical formulation
comprising an active pharmaceutical having surfactant properties to
a patient in need thereof effective to treat said vaginal
condition.
[0020] An additional further embodiment of the present inventive
subject matter is drawn to a method of treating a vaginal infection
by administering a pharmaceutical formulation for vaginal
administration comprising: an effective amount of at least one
active agent; a modified release dosage form which provides
modified release of said active agent or agents upon vaginal
administration to said patient; and wherein said formulation, when
containing a total dose of each active agent of about 25 .mu.g to
about 500 mg based on said active agent will produce a plasma
concentration versus time curve (ng/ml versus hours) having an area
under the curve (AUC) of less than about 600 ng/mL.hr; and wherein
the at least one active agent is selected from the group consisting
of antibacterial agents, antiviral agents, spermicides, hormone
agents, growth enhancing agents, cytokines, antitrichomonial
agents, antiprotozoan agents, antimycoplasm agents, antiretroviral
agents, nucleoside analogues, reverse transcriptase inhibitors,
protease inhibitors, contraceptive agents, sulfadrugs,
sulfonamides, sulfones, hygiene agents, probiotic agents, vaccine
agents, antibody agents, peptide agents, protein agents,
polysaccharide agents, nucleic acids, plasmids, liposomes,
carbohydrate polymers, transgenic bacteria, yeast, chemotherapeutic
agents, steroid agents, growth enhancing agents, libido enhancers,
androgenic substances, chitin derivatives, environment modifying
agents such as pH modifiers, and mixtures and combinations thereof;
and wherein said administration is a single administration and is
statistically equivalent to seven doses of a conventional
clindamycin vaginal cream, 2% in the treatment of bacterial
vaginosis.
[0021] Further still an embodiment is drawn to method for treating
vaginal conditions, which comprises: administering topically to a
vaginal mucosal tissue site a modified release pharmaceutical
formulation comprising at least one active agent, wherein the
formulation maintains topical residence in a vaginal cavity for up
to 10 days; and wherein systemic absorption of the at least one
active agent is minimized.
[0022] Yet another embodiment is drawn to a method for treating
vaginal conditions, which comprises: administering topically to a
vaginal mucosal tissue site a modified release pharmaceutical
formulation comprising at least one active agent, wherein the
formulation maintains topical residence in a vaginal cavity for up
to 7 days; and wherein systemic absorption of the at least one
active agent is minimized.
[0023] Still a further embodiment is drawn to a method of reducing
adverse effects of an active pharmaceutical ingredient formulation
comprising administering to a patient in need thereof a
pharmaceutical formulation comprising an active pharmaceutical
having surfactant properties to a patient in need thereof.
[0024] In currently available products, containing clindamycin
phosphate for use intravaginally in the treatment of bacterial
vaginosis, the common system of delivery is a semi-solid cream. The
dosage form is conventional in that it consists of a continuous
aqueous phase and a disperse non-aqueous phase. The active drug
being solubilized, or dispersed in the aqueous phase which allows
immediate contact of active pharmaceutical ingredients with
surfaces which are in need of relief from microbial insult. It also
allows dilution, rinsing and leakage of the product from these
surfaces and does not allow the optimum contact time required to
effectively impact the life cycle of those organisms which are
infecting the surrounding tissues. Subsequent to this, multiple
applications of the product 3 to 7 times a week are needed to
provide relief and cure of the condition. The required repeated
application of the active pharmaceutical ingredients (API's) using
this system increases the potential for systemic uptake and also
increases the likelihood of tissue irritation.
[0025] In order to increase the contact time of the API to be more
effective against microorganisms and at the same time reduce the
systemic uptake and irritation potential, the reduction of multiple
doses is a desired strategy. In order to reduce the dosage
requirement one must overcome the physical loss of the delivery
system through dilution, rinsing or leakage caused by indigenous
fluids and temperature. A system that will adhere to the mucosal
surfaces and resist rinsing through aqueous fluids while at the
same time release levels of the active pharmaceutical ingredient at
a rate which will minimize systemic uptake but stay in contact with
infected surfaces long enough to interfere with the infecting
organisms life cycle would reduce the number of applications
needed.
[0026] A system of this nature has been developed which provides
vaginal delivery systems, which release an active agent to a site
of absorption or action in a controlled manner and is bioadherent
to the vaginal surfaces. This system which releases active agent to
a site in a controlled manner for at least three hours and is
bioadherent has a continuous phase that is lipoidal and a disperse
or internal phase that is nonlipoidal and is described in U.S. Pat.
No. 5,266,329. This system as described however, when used with a
compound which exhibits surfactant like behavior becomes physically
unstable and looses the advantage of it's bioadherent nature and
resistance to wash off.
[0027] In order to overcome this destabilization one strategy is to
add a surfactant which will counter-act or modify the influence of
the API's behavior. Possible mechnisms targeted can be molecular
structure, charge, orientation at the interface, effect on surface
energies, solubility in either phase, shift in equilibrium of
molecules absorbed at the interface, replacement of interfacial
molecular populations, change in concentration. These variables are
considered singly or in combination. The exact mechanisms are not
completely understood; however, it is the effect of stabilization
that the present formulations achieve. Our efforts unexpectedly
focused on non-ionic surfactants and phospholipids used either
alone or in combination with formulations that were stable before
the addition of the API.
[0028] It has been unexpectedly found that phospholipids in
combination with surfactants from a system previously destabilized
with Clindamycin phosphate became physically stable.
[0029] From physical observation of these initial formulations and
the purity of the phospholipids initially used it was determined
that the phospholipids composition needed refinement. It was found
that phosphotidyl choline purified to a level of 90% produced an
emulsion with optimum physical properties.
[0030] In addition to the surfactant combination containing
phospholipids, surfactants were found which either alone or in
combination produced the desired emulsion containing Clindamycin
phosphate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 represents the relative bioavailability of an
inventive formulation over time as compared to a known
formulation.
[0032] FIG. 2 represents the therapeutic cure rate of an inventive
formulation as compared to a known formulation.
[0033] FIG. 3 depicts the primary and secondary efficacy outcomes
per protocol population for an inventive formulation as compared to
a known formulation.
[0034] FIG. 4 depicts the linear plot of mean plasma clindamycin
concentrations versus time.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0035] The purpose of the present invention is to stabilize known
active agents that have surfactant-like properties in an emulsion
form. The present invention is primarily directed to vaginal
delivery systems and delivery systems which are effective upon
mucosal tissues, such as those of the mouth, throat, nasal cavity,
vulvovaginal and rectum. In the instance of vaginal delivery, the
systems are characterized by their ability to deliver agents to a
specific site in the vaginal cavity, in a controlled manner over a
prolonged period of time. The systems are bioadherent to the
epithelial tissue and are comprised of at least two phases. The
systems when in a vaginal environment retain their integrity and
display physical stability for an extended residence time within
the vaginal cavity.
[0036] As discussed above, the vaginal cavity produces an aqueous
environment conducive to the growth of bacteria, fungi, yeast and
microorganisms. The known systems are not optimally effective for
treating such conditions either due to their water miscability,
lack of bioadhesion, or lack of physical stability in the vaginal
environment of 37 degrees C. The vaginal cavity as defined herein
not only includes the vagina, but also associated surfaces of the
female urinary tract, such as, the ostium of the urethra. Delivery
systems are a combination of nonactive ingredients which serve to
solubilize, suspend, thicken, dilute, emulsify, stabilize,
preserve, protect, color, flavor and fashion an active agent into
an acceptable and efficacious preparation for the safe and
convenient delivery of an accurate dose of said active agent.
[0037] The term "active agent" as used herein refers to agents
selected from the group consisting of antifungal agents,
antibacterial agents, antimicrobial agents, anti-infective agents,
antiviral agents, spermicides, hormone agents, growth enhancing
agents, cytokines, antitrichomonial agents, antiprotozoan agents,
antimycoplasm agents, antiretroviral agents, nucleoside analogues,
reverse transcriptase inhibitors, protease inhibitors,
contraceptive agents, sulfadrugs, sulfonamides, sulfones, hygiene
agents, probiotic agents, vaccine agents, antibody agents, peptide
agents, protein agents, polysaccharide agents, nucleic acids,
plasmids, liposomes, carbohydrate polymers, transgenic bacteria,
yeast, chemotherapeutic agents, steroid agents, growth enhancing
agents, libido enhancers, androgenic substances, chitin
derivatives, environment modifying agents such as pH modifiers, and
mixtures and combinations thereof.
[0038] Antibacterial agents are those agents which when
administered have a therapeutically effective impact on bacterial
growth. This impact may be to slow or inhibit such growth.
Preferable antimicrobial agents are selected from the group
consisting of clindamycin, clindamycin phospate, clindamycin
hydrochloride, salts thereof, complexes of clindamycin base and
mixtures thereof. Antibacterial agents also include nitromidazoles,
such as metronidazole, timidazole, nimorazole, omidazole, and
benznidazole. Other compounds which have a mixed activity, which
includes antibacterial activity, and are also considered
antibacterials for use in the present invention. These include, but
are not limited to, fenticonazole, ciclopirox, econazole,
butenafine HCl, and nafimidone.
[0039] An additional aspect of the present invention involves the
use of combinations of active agents that have surfactant
properties and active agents that do not possess such properties. A
non-limiting example of such a formulation could include an
antibacterial active agent and an antifungal active agent, such as
clindamycin along with butoconazole.
[0040] It is essential to the present inventive formulations that
the delivery system not only release an active agent, but that it
releases the agent in a controlled manner to a site of optimal
absorption or action. That is, an agent is made available for
absorption, pharmacological or other effect at a site of absorption
or action, in an amount sufficient to cause a desired response
consistent with the intrinsic properties of the agent and which
provides for maintenance of this response at an appropriate level
for a desired period of time. Thus, the systems described herein
are characterized by the controlled release of an active substance
from a delivery system at a receptor site, site of action, site of
absorption, or site of use and the achievement of the desired
effect at that site. The systems of the invention are not miscible
in water and are not harmful for use in the vaginal cavity.
[0041] Of note in the present system is the fact that long term,
modified, controlled and/or sustained release can be affected over
a long period of time, at least about 24 hours to about 96 hours
and as long as 7 to 10 days, through the administration of a low
number of doses. In some cases as little as one dose can be
administered to cover a treatment period of a number of days. Doses
may be given once daily, multiple daily doses, every other day,
every two, three, four days, etc., are within the scope of this
invention. Alternatively, for treating recurring conditions,
administration on the first and fourth days are feasible.
[0042] Not only does the present system have the ability to deliver
an active pharmaceutical ingredient, i.e., an active agent, over an
extended period of time, but the active agent will retain a
relatively low plasma concentration (C max) throughout the
administration. For example, a plasma concentration achieved with a
single dose of 2% clindamycin may be about 1.000 to about 40.000
ng/mL. Further, in comparing the plasma concentration versus time
(ng/mL versus hours), the area under curve (AUC) may be determined
and will generally remain below about 1,341.76 ng/mL.hr. Typically,
the AUC is less than 600 ng/mL.hr, and for example can be between
about 25 and 350 ng/mL.hr. Both the plasma concentration and the
area under curve displayed by the present product are lowered as
opposed to the known formulations.
[0043] The systems are comprised of unit cells. These unit cells
are the basic, nondivisible, repeating units of the system. The
unit cells have internal and external phases, which represent the
internal and external phases of the systems. The systems may be
described in conventional classifications, such as emulsions,
emulsions/dispersion, double emulsions, suspensions within
emulsions, suppositories, foams, creams, ovules, inserts, and etc.
The systems are usually in the form of emulsions either of medium
or high internal phase ratio, preferably greater than 70% and more
preferably greater than 75% by volume. The delivery systems are
liquids or semi-solids with viscosities that range from 5,000 to
one million centipoise, preferably 100,000 to 800,000 centipoise.
The systems in order to adhere to the vaginal cavity must have
sufficient viscosity to retain their integrity.
[0044] The unit cells have an internal phase which may be
discontinuous and which is nonlipoidal. The nonlipoidal character
of the phase renders it miscible with water. Preferably the
internal phase comprises water, glycerine, sorbitol solutions or
combinations thereof. Generally, it is desirable that the internal
phase be of high osmotic pressure. The internal phase may be
multiphasic and may be a solution, suspension, emulsion or
combination thereof and it contains at least a portion of the
active agent. Also, the internal phase may contain suspended
solids, emulsions, osmotic enhancers, extenders and dilutants, as
well as fragrances, colors, flavors, and buffers.
[0045] The resistance of a solution to changes in hydrogen ion
concentration upon the addition of small amounts of acid or alkali
is termed buffer action. A solution which possesses such properties
is known as a buffer solution. It is said to possess reserve
acidity and reserve alkalinity. Buffer solutions usually consist of
solutions containing a mixture of a weak acid and it's sodium or
potassium salt or of a weak base and it's salt. A buffer then is
usually a mixture of an acid and it's conjugate base.
[0046] The solution containing equal concentrations of an acid and
it's salt, or a half-neutralized solution of the acid, has maximum
buffer capacity. Other mixtures also possess considerable buffer
capacity, but the pH will differ slightly from the half-neutralized
acid.
[0047] The preparation of a buffer solution of a definite pH is a
relatively simple process if the acid (or base) of appropriate
dissociation constant is found. Small variations in pH are obtained
by variations in the ratio of the acid to the salt concentration
according to the equation:
pH=pk.sub.a+log [salt]/[acid]
[0048] The vaginal cavity exhibits an aqueous environment
containing secreting glands whose fluids create an acidic pH in the
range of 4.5 to 5.5. Therefore, in order to generate a buffer
solution which has a pH of approximately 4.5, an acid with a
pk.sub.a of approximately this value would be needed. Monoprotic
acetic acid, for example, has a pk.sub.a value of 4.74 and the
first two ionizable protons from citric acid have values of 3.13
and 4.76 respectively. Lactic acid is another example with a
pk.sub.a of approximately 3.9.
[0049] While theoretical amounts of an acid and salt can be derived
from the equation above, in a formulation that is a complicated
mixture of many dissolved species it is more practical to titrate a
given amount of an acid, typically citric acid or acetic acid, with
a solution of known concentration of either sodium or potassium
hydroxide until the desired pH value is obtained in the actual
formulation.
[0050] The unit cells also have an external phase. This phase is
lipoidal and is the continuous phase of the systems. The term
lipoidal pertains to any of a group of organic compounds comprising
the neutral fats, fatty acids, waxes, phosphatides, petrolatum,
fatty acid esters of monoprotic alcohols and mineral oils having
the following common properties: insoluble in water, soluble in
alcohol, ether, chloroform or other fat solvents, and which exhibit
a greasy feel. Examples of oils suitable for use in these delivery
systems are mineral oils with viscosities of 5.6 to 68.7
centistokes, preferably 25 to 65 centistokes, and vegetable oils
illustrated by coconut, palm kernel, cocoa butter, cottonseed,
peanut, olive, palm, sunflower seed, sesame, corn, safflower, rape
seed, soybean and fractionated liquid triglycerides of short chain
(naturally derived) fatty acids. This external phase may also
contain fragrances, colors, flavors, and buffers. Of specific
interest in the external phase is the use of phospholipids or
non-ionic esters which stabilize the system, prevent phase
separation and may impart little to no color on the resultant
product. Refined forms of lecithin are particularly preferred in
this regard. While not being bound by any particular theory, it is
believed that refined lecithins may act to reside at the oil and
water interface point in order to impart stability, especially in
systems containing drugs having surfactant properties, which may
disrupt the oil and water interface. This stability may be due to
increased attraction between molecules within the interface, and a
physical barrier created thereby protecting the interface from the
surfactant drug. Refined lecithins may have a very high percentage
of phosphatidylcholine, wherein the charged end of the molecule is
large in comparison to other phosphatides. Due to
phosphatidylcholine's hydrophilic nature, it is also possible that
they become partially solubilized in the aqueous phase side of the
system interface while the lipid end of the molecule is anchored in
the oil phase. Thus, the large hydrophilic end of the molecule may
provide the barrier to the absorption of active ingredients having
surfactant qualities. Preferably, the refined lecithin will contain
not less than about 70% phosphatidylcholine and, more preferably,
not less than about 80%. The refined lecithin may contain as much
as about 96% phosphatidylcholine. Typically, food grade lecithin is
not acceptable, but may be used when the formulation is modified by
means known to one of ordinary skill in the art. Phospholipon 90,
manufactured by the American Lecithin Company, is a preferred
refined lecithin according to the present invention.
[0051] The active agent may be any of those which are approved for
or used for the treatment, prophylaxis, cure or mitigation of any
disease of the vagina, urinary tract, cervix or other female
reproductive organ or inducement of conception; for aesthetic or
cosmetic usage, for diagnostic purposes; for systemic drug therapy;
or for sex determination of offspring. The agent must have utility
when administered by delivery to all or a portion of the vaginal
surfaces. Potential agents are normally well-known due to their
need for governmental approval or common usage. At least a portion
of the active agent must usually be contained in the internal phase
in order to obtain the release characteristics of the systems.
[0052] It has been found that when active agents including
antibiotics, such as, clindamycin, are used as part of the active
agent, the conventional treatment period or quantity of agent used
is reduced by at least 25%. Normally a controlled release drug
system reduces the number of times a day that a drug must be
administered. However, it does not affect the overall length of
treatment. With respect to certain active agents it has been
discovered that the drug delivery system described herein reduces
the treatment period by at least 25%. Tests utilizing clindamycin
upon bacterial vaginitis, e.g., Gardnerella morphotype, have
demonstrated this unexpected result. It is believed that this
effect can be achieved with other antibacterial agents and
antifungal agents. Thus, the treatment of microbes can be achieved
in much shorter time or with substantially less drug with the
system of the invention.
[0053] Adjacent unit cells have common external phases. The
external phase of the unit cells provides the continuous phase of
the system. The unit cells may utilize emulsifiers. Preferably, the
emulsifiers are soluble in the lipoidal or external phase. Suitable
emulsifiers are those oil miscible, surface active compounds which
are acceptable for use in foods, pharmaceuticals, and/or cosmetics.
Examples of such emulsifiers are low molecular weight
polyglycerols, which have been esterified with fatty acids or fatty
acid esters, or mono and diglyceride mixtures alone or with the
addition of metallic soaps, such as, aluminum stearate. The
metallic soaps appear to improve the characteristics of some of the
emulsions.
[0054] The systems can be introduced into the vaginal cavity by the
use of conventional applicators or other coating or spraying means.
Although the systems are deformable at physiological temperatures,
approximately 37 degrees C., they do not lose integrity in the same
manner as the known systems. The present delivery systems, unlike
known systems, are not characterized by offensive leakage from the
vaginal cavity following the insertion of the system. Since the
present systems break down over an extended period, nonaqueous
components are either absorbed or released from the vaginal cavity
at an unnoticeable rate, which makes no significant increase in
normal secretions.
[0055] The characteristics of these systems are a result of their
inherent integrity under vaginal conditions. The systems release
the active agent in the vaginal cavity due to diffusion of the
active agent, rupture of the unit cells and/or a combination of
these two mechanisms. This release of active agent can be linear or
non-linear depending on the composition of the system. Factors
which effect the release rate are the percentage of active agent
contained in each of the phases; and the type of system, such as,
emulsion, double emulsion, suspension; thickness of the external
membrane; amount and nature of emulsifier in the external phase;
osmotic pressure of the internal phase; pH of the internal phase;
diffusibility of the active species through the external phase
membrane; etc. Within the physiological environment of the vaginal
cavity all of the chemical and physical forces present, including
fluids, enzymes, pH, chemical balance, temperature, and shear
forces from body movement, affect the rate of breakdown of the
system. These forces are not believed to destroy the integrity of
the systems at the same rate as other known systems.
[0056] The systems may be prepared by well-known continuous or
batch processes. When processing using conventional emulsions,
shear force is applied to the system components by use of
homogenizers, mills, impingement surfaces, ultrasound, shaking or
vibration. Unlike conventional emulsions, the mixing shear should
be at low levels in order to prevent destruction of the system
resulting from excess energy used in the process. Temperature is
not usually a critical factor in the preparation of the systems.
The temperatures utilized will be dependent upon the final end
product desired. Phase combination is usually performed at ambient
temperatures.
[0057] The systems may be prepared by mixing the internal with the
external phase in a planetary-type mixer with sweep blade with
counter-rotating mixer by pumping the aqueous phase into the oil
phase. Another manner of preparing the system is by use of a
continuous mixer, which comprises multiple impellers. The external
phase is first introduced into the continuous mixer until it
reaches the level of the lowest impeller in the mixing chamber. The
two phases are then simultaneously introduced through the bottom of
the mixer in proper proportion as its impeller or impellers rotate
to apply a shear to the components. The finished product emerges
through the top of the mixer. The actual speed of the impeller or
impellers will vary, depending upon the product produced as will
the rate of flow of the two phase streams. In some preparations,
both methods are used. The emulsion is prepared in the
planetary-type with sweep blade with the counter-rotating mixer.
The emulsion is the pumped through the continuous mixer to increase
emulsion viscosity.
[0058] Depending upon the characteristics, such as solubility,
etc., of the active pharmaceutically active ingredient, the active
ingredient may be added in either the aqueous or oil phase. In
either case, the active ingredient may be added into the
appropriate phase to preserve its therapeutic nature and activity.
Where the active is both water and oil soluble or minimally water
and/or soluble, the active may be dispersed in the phase resulting
in the most physically and chemically stable product or results in
the cost effective and/or simplified production process.
[0059] The following examples are illustrative of preferred
embodiments of the invention and are not to be construed as
limiting the inventive subject matter thereto. All polymer
molecular weights are mean average molecular weights. All
percentages are based on the percent by weight of the final
delivery system or formulation prepared unless otherwise indicated
and all totals equal 100% by weight:
EXAMPLE 1
[0060] This example demonstrates the preparation of a formulation
according to the present inventive subject matter.
1 Wt % Water, purified, USP 45.3 Sorbitol Solution 36.8 Edetate
Disodium, USP 0.05 Clindamycin Phosphate, USP 2.80 Mineral Oil, USP
7.00 Polyglyceryl-3-Oleate 2.70 Glycerol Monoisostearate 2.70
Lecithin, Phospholipon 90G 1.00 Silicon Dioxide, Hydrophobic 1.00
Microcrystalline Wax, NF 0.40 Methylparaben, NF 0.20 Propylparaben,
NF 0.05 Analysis: target Result Clindamycin 20 mg/g 104% of target
Methylparaben 2.0 mg/g 97.5% of target Propylparaben 0.5 mg/g 96.9%
of target Viscosity in process 860,000 cps
[0061] NB: The amount of active ingredient and water to be added is
calculated per batch based upon the assay and water content of the
raw materials.
[0062] General Method of Preparation (Scale-up/Submission
Batch)
[0063] Aqueous Phase Preparation
[0064] 1. The following items are loaded into a stainless steel
mixing tank equipped with a cover and variable speed mixer and
mixed at room temperature until all solids are dissolved: At this
time after water and sorbitol are mixed if buffers are used i.e.,
citrate salts or others, they are added to the solution and
dissolved
[0065] Water, Purified
[0066] Sorbitol Solution
[0067] Edetate Disodium
[0068] 2. Clindamycin Phosphate is added to this solution and mixed
until dissolved.
[0069] Oil Phase Preparation
[0070] 3. The following items are loaded into a stainless steel
jacketed kettle equipped with a sweep blade and variable speed
mixer and mixed at 70-75.degree. C. until all solids are
dissolved:
[0071] Mineral Oil
[0072] Polyglyceryl-3-Oleate
[0073] Glyceryl Monoisostearate
[0074] Microcrystalline Wax
[0075] 4. A portion of the material from Step 3 is drained from the
kettle and placed in a smaller stainless steel container. Then
Phospholipon 90G is added and the mixture is stirred at
80-85.degree. C. until the Phoshpolipon 90G is completely
dissolved.
[0076] 5. After the Phospolipon 90G has dissolved, the solution
from Step 4 is returned to the kettle of
[0077] Step 3 and Methylparaben and Propylparaben are added and
dissolved at 70-75.degree. C.
[0078] 6. While mixing Silicon Dioxide, Hydrophobic is added to the
kettle and mixed to create an initial dispersion.
[0079] 7. While mixing, the material from Step 6 is transferred
through a colloid mill into a stainless steel jacketed kettle
equipped with counter rotation blade and sweep blade.
[0080] Phase Combination
[0081] 8. While mixing the oil phase from Step 7 the aqueous phase
from Step 2 is added in a controlled fashion by means of a transfer
pump until phase addition is complete. Mixing is then continued for
a predetermined period of time to establish the preliminary
emulsion.
[0082] 9. The preliminary emulsion is then transferred by means of
a transfer pump through a secondary mixing chamber at
pre-established flow rates and mixing speeds in order to achieve
final viscosity.
[0083] 10. The material is then transferred into bulk containers
for packaging into individual applicators.
EXAMPLE 2
[0084]
2 Water, purified, USP 41.978 Sorbitol Solution 39.600 Edetate
Disodium, USP 0.0500 Clindamycin Phosphate, USP 2.6900 Mineral Oil,
USP 10.000 PEG-30 Dipolyhydroxystearate 5.0000 Microcrystalline
Wax, NF 0.4250 Methylpataben, NF 0.1800 Propylparaben, NF 0.0500
Analysis: target Result Clindamycin 20 mg/g 76.8% of target
Methylparaben 2.0 mg/g 98.5% of target Propylparaben 0.5 mg/g 96.5%
of target Viscosity initial 224,000 cps
[0085] NB: The amount of active ingredient and water to be added is
calculated per batch based upon the assay and water content of the
raw materials.
[0086] The formulation was prepared in accordance the general
methodology provided herein.
EXAMPLE 3
[0087]
3 Water, purified, USP 45.23 Sorbitol Solution 30.00 Edetate
Disodium, USP 0.250 Clindamycin Phosphate, USP 2.690 Mineral Oil,
USP 8.000 Sorbitan Monoisostearate 8.000 Sorbitan Monostearate
4.000 Silicon Dioxide, Hydrophobic 1.000 Microcrystalline Wax, NF
0.600 Methylparaben, NF 0.180 Propylparaben, NF 0.050 Analysis:
target Result Clindamycin 20 mg/g 101% of target Methylparaben 2.0
mg/g 99.9% of target Propylparaben 0.5 mg/g 100.7% of target
Viscosity initial 400,000 cps
[0088] NB: The amount of active ingredient and water to be added is
calculated per batch based upon the assay and water content of the
raw materials.
[0089] The formulation was prepared in accordance with the general
methodology provided herein.
EXAMPLE 4
[0090] The formulations of Example 4 cover a citrate buffered
clindamycin, a citrate buffered metronidazole and a non-buffered
metronidazole. These formulations can be prepared according to the
process as set forth in Example 1.
[0091] Such formulations would be expected to administer
therapeutic effective amounts to patients being treated.
4 Buffered Clindamycin Water, purified, USP 45.300 Sorbitol
Solution, USP 36.100 Edetate Disodium. USP 00.050 Citric Acid USP
anhydrous 00.490 Potassium Hydroxide 00.240 Clindamycin Phosphate,
USP 2.800 Mineral Oil, USP 7.000 Polyglyceryl-3-oleate 2.700
Glycerol Monoisostearate 2.700 Lecithin, Phospholipon 90G 1.000
Silicon Dioxide, Hydrophobic 1.000 Microcrystalline Wax, NF 0.400
Methylparaben, NF 0.200 Propylparaben, NF 0.050 Buffered
Metronidazole Water, purified, USP 42.810 Sorbitol Solution, USP
40.149 Edetate Disodium. USP 00.250 Citric Acid USP anhydrous
00.490 Potassium Hydroxide 00.230 Metronidazole, USP 0.750 Mineral
Oil, USP 8.032 Sorbitan Monoisostearate 4.000 Sorbitan Tristearate
1.426 Silicon Dioxide, Hydrophobic 1.013 Microcrystalline Wax, NF
0.600 Methylparaben, NF 0.200 Propylparaben, NF 0.050 Non-Buffered
Metronidazol Water, purified, USP 42.810 Sorbitol Solution, USP
40.869 Edetate Disodium. USP 00.250 Metronidazole, USP 0.750
Mineral Oil, USP 8.032 Sorbitan Monoisostearate 4.000 Sorbitan
Tristearate 1.460 Silicon Dioxide, Hydrophobic 1.013
Microcrystalline Wax, NF 0.600 Methylparaben, NF 0.200
Propylparaben, NF 0.050 Microcrystalline Wax, NF 0.400
EXAMPLE 5
[0092]
5 Water 41.310 Sorbitol 70% 40.869 EDTA, disodium, USP 00.250
Metronidazole 00.750 Gloria Mineral Oil, USP 8.032 Hydrogenated
Castor Oil 1.500 Sorbitan Monoisostearate 4.000 Sorbitan
Monostearate 1.426 Hydrophobic Silicone Dioxide 1.013
Microcrystalline Wax 0.600 Methylparaben, NF 0.200 Proplyparaben,
NF 0.050
[0093] The formulation was prepared in accordance with the general
methodology provided herein.
EXAMPLE 6
[0094]
6 Water 41.310 Sorbitol 70% 40.869 EDTA, disodium, USP 00.250
Metronidazole 00.750 Gloria Mineral Oil, USP 8.032 Beeswax, NF
1.500 Sorbitan Monoisostearate 4.000 Sorbitan Monostearate 1.426
Hydrophobic Silicone Dioxide 1.013 Microcrystalline Wax 0.600
Methylparaben, NF 0.200 Proplyparaben, NF 0.050
[0095] The formulation was prepared in accordance with the general
methodology, provided herein.
EXAMPLE 7
[0096]
7 Water 41.881 Sorbitol 70% 35.869 EDTA, disodium, USP 00.250
Metronidazole 00.750 Gloria Mineral Oil, USP 7.000 Petrolatum 6.000
Sorbitan Monoisostearate 5.000 Sorbitan Monostearate 1.400
Hydrophobic Silicone Dioxide 1.000 Microcrystalline Wax 0.600
Methylparaben, NF 0.200 Proplyparaben, NF 0.050
[0097] The formulation was prepared in accordance with the general
methodology provided herein.
[0098] Biological Data
[0099] The formulation of Example 1, as a clindamycin Vaginal Cream
2% was compared to Cleocin.RTM. Vaginal Cream 2%. Twenty healthy
women received single 5 gm doses of the Example 1 and reference
formulations according to a two-treatment, two-period, two-sequence
randomized crossover design with a two-week washout between
periods. Blood samples for measurement of plasma clindamycin
concentration were collected before and 1, 2, 3, 4, 5, 6, 7, 8, 10,
12, 14, 16, 20, 24, 30, 36, 48, 72, and 96 hours after drug
administration. Plasma concentrations of clindamycin were
determined using a validated LC/MS/MS method with a lower limit of
quantitation of 0.2 ng/mL.
[0100] Plasma concentrations and pharmacokinetic parameters after
administration of both formulations were highly variable.
Coefficients of variation for pharmacokinetic parameters ranged
from 88% to 154% and 51% to 127% for the Example 1 and reference
formulations. Mean plasma clindamycin concentrations after
intravaginal administration of the Inventive cream formulation were
substantially lower than those after administration of Cleocin.RTM.
as were mean values for Cmax and the areas under the curve. The
bioavailability of clindamycin from the Inventive cream formulation
was 7.52% of that produced by Cleocin.RTM. based on Cmax and, 12.4%
of that produced by Cleocin.RTM. based on AUC.sub.0-t or
AUC.sub..infin.. See FIG. 1 for the results.
[0101] The results demonstrate that systemic exposure to
clindamycin after intravaginal administration of the Inventive
Vaginal Cream 2% was approximately 12% of that after administration
of Cleocin.RTM. Vaginal Cream 2%.
[0102] The formulation of Example 1, namely clindamycin Vaginal
Cream 2% was compared with the Cleocin.RTM. Vaginal Cream 2% in
patients with bacterial vaginosis (BV). The study involved a
multicenter, randomized, single-blind, parallel group study having
540 patients.
[0103] In the study, therapeutic cure was defined as having all 4
Amsel Criteria resolved (normal vaginal discharge, vaginal
pH<4.7, <20% clue cells on wet mount, and negative "Whiff"
test) and having a Nugent score less than 4 at study endpoint. The
therapeutic cure rate was the primary efficacy outcome for patients
in this study.
[0104] The results of the study are set forth below and involve 1)
The Therapeutic Cure Rate--See FIG. 2, and 2) The Primary and
Secondary Efficacy Outcome-see FIG. 3.
[0105] The results of this study demonstrated that one dose of the
formulation of Example 1 (clindamycin Vaginal Cream, 2%) was
statistically equivalent to 7 doses of Cleocin.RTM. vaginal cream,
2% in the treatment of bacterial vaginosis based on therapeutic
cure rate for all analysis populations (Per Protocol, modified
Intent-to-Treat, and Intent-to-Treat).
[0106] Regarding the additional efficacy rates, Clinical cure,
Nugent cure, and Investigator cure rates demonstrated secondary
efficacy outcomes in this study. Clinical cure was defined as
having all 4 Amsel Criteria resolved at study endpoint. Nugent cure
was defined as having a Nugent score less than 4 at study endpoint.
Investigator cure was defined by the investigator answering "no" to
the following question at study endpoint: "In your opinion, does
the patient require additional treatment for BV at this time?" The
results are set forth in FIG. 3.
[0107] In addition, results of this study demonstrated that one
dose of the Inventive formulation was statistically equivalent to 7
doses of Cleocin.RTM. Vaginal Cream, 2% in the treatment of
bacterial vaginosis based on Clinical cure, Nugent cure, and
Investigator cure for all analysis populations (Per Protocol,
modified Intent-to-Treat, and Intent-to-Treat).
[0108] The study also demonstrated that 1.8% of 600 patients
receiving the Inventive formulation dosed over three days, as
compared to 2.7% of 1,325 patients receiving Cleocin.RTM. Vaginal
Cream, 2% dosed over seven days, discontinued therapy due to drug
related adverse events.
* * * * *