U.S. patent application number 13/416043 was filed with the patent office on 2012-07-12 for preparations for the external application of antiseptic agents and/or agents promoting the healing of wounds.
This patent application is currently assigned to Euro-Celtique S.A.. Invention is credited to Wolfgang Fleischer, Hermann Gumbel, Karen Reimer, Dieter Ruckert, Horst Winkler.
Application Number | 20120177725 13/416043 |
Document ID | / |
Family ID | 25961152 |
Filed Date | 2012-07-12 |
United States Patent
Application |
20120177725 |
Kind Code |
A1 |
Ruckert; Dieter ; et
al. |
July 12, 2012 |
PREPARATIONS FOR THE EXTERNAL APPLICATION OF ANTISEPTIC AGENTS
AND/OR AGENTS PROMOTING THE HEALING OF WOUNDS
Abstract
The present invention relates to liposomal pharmaceutical
preparations which include active agents such as antiseptic agents,
wound-healing agents, or combinations thereof, useful in the
treatment of external wounds. The active agents are encapsulated in
liposomes, and the liposomes are incorporated in pharmaceutical
preparations such as liquids, ointments, gels, lotions, or creams
capable of delivering the active agents to external wound sites.
The invention further relates to methods of preparation of the
liposomes and the pharmaceutical preparations, and to methods of
treatment of external wounds and ophthalmic infections.
Inventors: |
Ruckert; Dieter; (Tuhingen,
GE) ; Gumbel; Hermann; (Rodermark-Waldacker, DE)
; Fleischer; Wolfgang; (Ingelheim, DE) ; Reimer;
Karen; (Limburg, DE) ; Winkler; Horst;
(Limburg, DE) |
Assignee: |
Euro-Celtique S.A.
|
Family ID: |
25961152 |
Appl. No.: |
13/416043 |
Filed: |
March 9, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12814182 |
Jun 11, 2010 |
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13416043 |
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09561748 |
Apr 28, 2000 |
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12814182 |
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09123152 |
Jul 27, 1998 |
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09561748 |
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08903839 |
Jul 31, 1997 |
5863556 |
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09123152 |
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08293877 |
Sep 19, 1994 |
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08903839 |
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Current U.S.
Class: |
424/450 ;
424/644; 424/667; 424/78.07; 514/389; 514/718; 514/731;
514/735 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 17/02 20180101; A61K 9/127 20130101; A61P 31/00 20180101 |
Class at
Publication: |
424/450 ;
424/644; 514/731; 514/718; 514/735; 424/667; 424/78.07;
514/389 |
International
Class: |
A61K 9/127 20060101
A61K009/127; A61K 31/05 20060101 A61K031/05; A61K 31/085 20060101
A61K031/085; A61K 31/055 20060101 A61K031/055; A61P 31/00 20060101
A61P031/00; A61K 31/79 20060101 A61K031/79; A61K 31/4166 20060101
A61K031/4166; A61P 17/02 20060101 A61P017/02; A61P 27/02 20060101
A61P027/02; A61K 33/28 20060101 A61K033/28; A61K 33/18 20060101
A61K033/18 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 20, 1993 |
DE |
G9312509.7 |
Claims
1. A pharmaceutical preparation for external application comprising
an antiseptic agent, a wound-healing agent, or a combination
thereof, encapsulated in a plurality of liposomes.
2. A pharmaceutical preparation according to claim 1, further
comprising a pharmaceutically acceptable vehicle, wherein a portion
of said antiseptic agent or said wound-healing agent, or said
combination thereof contained in the preparation is not
encapsulated in said liposomes.
3. A pharmaceutical preparation according to claim 2, wherein at
least the greatest part of said antiseptic agent or said wound
healing promoting agent, or said combination thereof, is
encapsulated inside the liposomes.
4. A pharmaceutical preparation according to claim 1 wherein said
antiseptic agent is selected from the group consisting of metal
compounds such as mercury compounds, phenol derivatives such as
thymol, eugenol and hexachlorophene, detergents, iodine and iodine
complexes.
5. A pharmaceutical preparation according to claim 4 wherein said
antiseptic agent is povidone iodine.
6. A pharmaceutical preparation according to claim 1 wherein said
wound-healing agent is selected from the group consisting of
allantoin, an azulene compound, a compound from the vitamin B
series, and combinations of the foregoing.
7. A pharmaceutical preparation according to claim 1 wherein the
preparation contains at least one antiseptic and at least one wound
healing promoting agent.
8. A pharmaceutical preparation according to claim 1 wherein said
liposomes are of a substantially uniform size in the range from
about 20 to about 20,000 nm.
9. A pharmaceutical preparation according to claim 8 wherein said
liposomes are of a substantially uniform size in the range from
about 50 to about 4,000 nm.
10. A pharmaceutical preparation according to claim 8 wherein said
liposomes are of a substantially uniform size in the range from
about 500 to about 2,500 nm.
11. A pharmaceutical preparation according to claim 8 wherein said
liposomes are of a substantially uniform size of about 1,000 nm
diameter.
12. A pharmaceutical preparation according to claim 2 wherein the
preparation releases said antiseptic agent, said wound-healing
agent, or combination thereof, in an environment of use over an
extended time period.
13. A pharmaceutical preparation according to claim 12 wherein said
extended time period comprises several hours duration.
14. A pharmaceutical preparation according to claim 12 wherein the
preparation releases said antiseptic agent, said wound-healing
agent, or combination thereof, at approximately the same release
rate over the release time period.
15. A pharmaceutical preparation according to claim 2 further
comprising at least one anesthetically active agent.
16. A pharmaceutical preparation according to claim 2 further
comprising conserving agents and consistency forming additives.
17. A pharmaceutical preparation according to claim 2, wherein said
vehicle is a liquid and said preparation is in the form of a
solution or dispersion comprising liposomes.
18. A pharmaceutical preparation according to claim 17, wherein
said preparation is in the form of a pharmaceutical drop
preparation.
19. A pharmaceutical preparation according to claim 2, wherein said
vehicle comprises a hydrophilic, lipophilic, or amphophilic cream
base and said preparation is in the form of a cream.
20. A pharmaceutical preparation according to claim 2, in the form
of a pharmaceutical oil in water or a water in oil lotion.
21. A pharmaceutical preparation according to claim 2, wherein said
vehicle is an ointment base and the preparation is in the form of a
pharmaceutical ointment.
22. A pharmaceutical preparation according to claim 2, wherein said
vehicle is a gel base and the preparation is in the form of a
pharmaceutical gel.
23. A pharmaceutical preparation according to claim 22, wherein
said vehicle is a nonalcoholic hydrogel base.
24. A pharmaceutical preparation according to claim 2, wherein the
pharmaceutical preparation is in the form of a pharmaceutical
eyedrop formulation; wherein said liposomes comprise a
pharmaceutically acceptable liposome membrane forming substance;
wherein said antiseptic agent comprises a 0.1 to 2% PVP iodine
solution at least most of which is encapsulated within said
liposomes; and wherein said liposomes are of substantially uniform
size between about 50 and about 4,000 nM, and said formulation may
additionally comprise customary additives, adjuvants and auxiliary
substances of a pharmaceutical eyedrop formulation.
25. A pharmaceutical preparation according to claim 24 wherein said
liposomes are of substantially uniform size, with diameters of
about 1,000 nm.
26. A method of preparing a liposomal pharmaceutical formulation
comprising the steps of: dissolving a liposome forming agent in a
solvent in a suitable container; evaporating said solvent to form a
lipid film on the inner surface of said container; adding a
quantity of PVP iodine solution with said lipid film therein to
form a mixture; agitating said mixture to produce liposomes;
separating said liposomes; dispersing said liposomes in a sodium
chloride buffer solution; and freeze-drying said dispersion.
27. A method of preparing a liposomal pharmaceutical formulation
according to claim 26, further comprising the step of filtering
said dispersion or said mixture through a high pressure filtering
means subsequent to liposome formation.
28. A method of treating external wounds comprising the steps of:
applying an antiseptically active amount of a pharmaceutical
preparation to an external wound, wherein said pharmaceutical
preparation comprises an antiseptic agent, a wound-healing agent,
or a combination thereof, encapsulated in a plurality of liposomes
dispersed in a pharmaceutically acceptable vehicle.
29. A method of treating eye infections comprising the steps of:
applying an antiseptically effective dose of a pharmaceutical
preparation to the eye of a mammal having an eye infection, wherein
said pharmaceutical preparation comprises an antiseptic agent, a
wound-healing agent, or a combination thereof, encapsulated in a
plurality of liposomes and dispersed in a pharmaceutically
acceptable vehicle.
30. A method of treating eye infections as recited in claim 29.
wherein said pharmaceutical preparation is in the form of a
pharmaceutical eyedrop formulation; wherein said liposomes comprise
a pharmaceutically acceptable liposome membrane forming substance;
wherein said antiseptic agent comprises a 0.1 to 2% PVP iodine
solution at least most of which is encapsulated within said
liposomes; and wherein said liposomes are of substantially uniform
size between about 50 and about 4,000 nm, and said formulation may
additionally comprise customary additives, adjuvants and auxiliary
substances of a pharmaceutical eyedrop formulation.
Description
BACKGROUND OF THE INVENTION
[0001] The present application is a continuation of U.S.
application Ser. No. 12/814,182 filed Jun. 11, 2010, which is a
continuation of U.S. application Ser. No. 09/561,748 filed Apr. 28,
2000, now abandoned, which is a continuation of U.S. application
Ser. No. 09/123,152 filed Jul. 27, 1998, now abandoned, which is a
divisional of U.S. application Ser. No. 08/903,839 filed Jul. 31,
1997, now U.S. Pat. No. 5,863,556, which is a continuation of U.S.
application Ser. No. 08/293,877 filed Sep. 19, 1994, now abandoned,
the disclosure of each of which is incorporated by reference herein
in its entireties.
[0002] The invention concerns preparations for the external
application of agents with antiseptic and/or wound healing
promoting properties. The preparations are specifically applied to
wounds, skin, mucous membranes and mucosa-like unkeratinized
epithelial tissues of humans and animals.
[0003] A plurality of different antibiotic and antiseptic agents
are known for the topical treatment of infectious maladies. A
decisive disadvantage of antibiotic agents is that the infecting
bacteria show primary resistances, and can acquire secondary
resistances, against these agents. Further, antibiotics quite often
lead to patient sensitivity, especially after prolonged treatment.
The use of antiseptics such as povidone iodine, also known as
polyvidone iodine or PVP iodine, i.e. the
poly(1-vinyl-2-pyrrolidin-2-one)-iodine complex, can inhibit the
formation of resistances to antiseptic or antibiotic agents by
infecting bacteria. Antiseptic agents are also much more rarely
allergenic when used in patients as compared to antibiotics.
[0004] In the scientific literature liposomes have quite often been
disclosed as drug carriers. A non-exhaustive list comprises the
following, more recent publications:
[0005] Hoekstra, H. J., Van Baare, J., Dutrieux, R. P.: Evaluation
of topical therapy and wound healing. European Burn Association 5th
Congress, Brighton, England, 1993;
[0006] Neuhann, T., Sommer, G.: Erfahrungen mit Jod-Povidon zur
Behandlung der Reratokonjunctivitis epidemica. Z. prakt. Augenh. 1
(1980), p. 65;
[0007] Pleyer, U., Schmidt, K., Thiel, H. J. (eds.): Liposomes in
Ophthalmology and Dermatology. Hippbkrates Verlag Stuttgart,
1993;
[0008] Prufer, K., Sterntaerg, B.: Liposomen in der Medizin--Eine
aktuelle Bestandsaufnahme. Z. arzt. Fortbildung 88 (1994), pp.
257-256;
[0009] Rubas, W., Schreier, H.: Liposomen: Fortschritt in
Herstellungs-Technologie and Therapie Pharmazie in unserer Zeit, 6
(1991) pp. 255-270;
[0010] Schreier, H., Bouwstra, J.:. Liposomes as topical drug
carriers: dermal and transdermal drug delivery. (Submitted);
and
[0011] Shell, J. W.: Ophthalmic drug delivery systems. Surv.
Opthalmol. 29 (1984), 117.
[0012] Further, the team of Hoekstra et al. in Beverwijk,
Netherlands, has reported on animal experiments with silver
sulfadiazine, a chemotherapeutic agent, encapsulated in liposomes
and applied to experimental wounds. The results appear to show
agent enrichment at the wound bottom and reduced silver resorption,
compared with customary silver sulfadiazine ointments.
[0013] However, although a lot of attention has been paid for quite
some time to liposomes as drug carriers, there appears to be no
prior art relating to liposomes as carriers of antiseptic or wound
healing promoting agents for external applications.
OBJECTS AND SUMMARY OF THE INVENTION
[0014] An object of the instant invention is to provide a
well-tolerated, easily applicable antiseptic or wound healing
promoting preparation, which provides protracted release and
protracted topical effect of the active agent.
[0015] A further object of the present invention is to provide a
method of producing a pharmaceutically acceptable liposome
preparation including an active agent (e.g. an antiseptic agent or
a wound-healing agent).
[0016] Another object of the present invention is related to the
treatment of eye infections using a liposomal pharmaceutical
preparation containing an antiseptic agent.
[0017] It is a further object of the present invention to provide a
method of treating external wounds using a liposomal pharmaceutical
formulation which formulation includes an antiseptic agent, a
wound-healing promoting agent, or a combination thereof as active
ingredients.
[0018] According to the invention the technical objects are
attained in that the preparation comprises at least one antiseptic
and/or wound healing promoting agent in the form of a liposome
preparation.
[0019] In accordance with the above-stated objectives and others,
the present invention is directed in part to a pharmaceutical
preparation for external application which preparation contains an
antiseptic agent, a wound-healing agent, or a combination thereof,
encapsulated in a plurality of liposomes.
[0020] An important aspect of the invention is related to the
surprising fact that liposomes are highly suited as carriers for
antiseptic agents, especially for povidone iodine, and for agents
promoting the healing of wounds.
[0021] In certain preferred embodiments, a portion of the
antiseptic agent or wound-healing agent or combination thereof is
not encapsulated in the liposomes.
[0022] In certain preferred embodiments, the antiseptic agent may
be selected from mercury compounds, phenol derivatives such as
thymol, eugenol and hexachlorophene, detergents, iodine and iodine
complexes, or mixtures of the foregoing. A particularly preferred
embodiment contains povidone iodine as the antiseptic agent.
[0023] The wound-healing agent promotes healing of injured tissue.
In certain embodiments of the invention, the wound-healing agent is
selected from the group consisting of allantoin, an azulene
compound, a compound from the vitamin B series, or combinations
thereof.
[0024] A preferred embodiment of the invention contains at least
one antiseptic agent and at least one wound-healing agent.
[0025] Liposome size is also an important aspect of the invention.
Preferably, the liposomes in the pharmaceutical preparation are in
the range from about 20 to about 20,000 nm, more preferably from
about 50 to about 4,000 nm, even more preferably from about 500 to
about 2,500 nm, and most preferably the liposomes are of a uniform
diameter of about 1,000 nm.
[0026] The pharmaceutical preparation according to the invention
will preferably release the antiseptic agent or wound-healing agent
or combination thereof over an extended time period, more
preferably over an extended time period of several hours duration
(e.g., about 2 to about 12 hours). A particularly preferred
embodiment releases the antiseptic agent or wound-healing agent at
the same release rate over the extended time period.
[0027] A preferred pharmaceutical preparation according to the
present invention preferably includes at least one anesthetically
active agent.
[0028] The pharmaceutical preparation may also include additional
conserving or preservative agents, and consistency forming
additives that are currently known to one of ordinary skill in the
pharmaceutical art.
[0029] The pharmaceutical preparation of the present invention may
take a variety of different forms according to the vehicle used. In
a preferred embodiment, the vehicle is a liquid and the preparation
is in the form of a solution or a dispersion comprising liposomes.
A particularly preferred embodiment where the pharmaceutical
preparation is in the form of a liquid pharmaceutical drop
preparation.
[0030] In yet another embodiment the vehicle is in the form of a
cream base and the resultant pharmaceutical preparation is in the
form of a cream. Other embodiments of the present invention include
the pharmaceutical preparation in the form of an oil in water or
water in oil lotion, an ointment, or a gel (preferably a hydrogel
base).
[0031] Another preferred embodiment of the invention is a
pharmaceutical preparation in the form of a pharmaceutical eyedrop
formulation prepared with liposomes encapsulating an antiseptic
agent (e.g., PVP iodine solution), and wherein said liposomes are
of substantially uniform size. The formulation may additionally
comprise customary additives, adjuvants and auxiliary substances of
a pharmaceutical eyedrop formulation.
[0032] The present invention is further directed towards a method
of preparing a liposomal pharmaceutical formulation comprising the
steps of dissolving a liposome forming agent in a solvent in a
suitable container; evaporating the solvent to form a lipid film on
the surface of the container; adding a quantity of PVP iodine
solution to said container with the lipid film therein to form a
mixture; agitating said mixture to produce liposomes; separating
the liposomes and dispersing the liposomes in a sodium chloride
buffer solution; and freeze-drying the resultant dispersion.
Additionally, the method described may include the further step of
filtering the dispersion through a high pressure filtering means
subsequent to liposome formation.
[0033] The invention also relates to a method of treating external
wounds comprising the steps of applying a pharmaceutical
preparation to an external wound, wherein the pharmaceutical
preparation comprises an antiseptic agent, a wound-healing agent,
or a combination thereof, encapsulated in a plurality of liposomes,
and a pharmaceutically acceptable vehicle.
[0034] Additionally, the invention relates to a method of treating
eye infections comprising the steps of applying a dose of a
pharmaceutical preparation to the eye of a mammal having an eye
infection, wherein the pharmaceutical preparation comprises an
antiseptic agent, a wound-healing agent, or a combination thereof,
encapsulated in a plurality of liposomes, and a pharmaceutically
acceptable vehicle. In a preferred embodiment, the pharmaceutical
preparation is in the form of a pharmaceutical eyedrop
formulation.
[0035] Further advantageous embodiments of the invention will
become apparent from the following paragraphs.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The liposome preparations according to this invention permit
protracted release of the agent or agents, and provide an extended
and topical activity at the desired locus of action by interaction
with cell surfaces.
[0037] Experiments and research carried out by the instant
inventors appear to show that, even more unexpectedly, the
preparations according to this invention do not only contain the
active agent (e.g. povidone iodine) encapsulated in liposomes;
there is also some amount of active agent (e.g. antiseptic agent,
wound-healing agent) which is not contained inside the
liposomes.
[0038] The preparations according to the present invention often
show a marked initial effect which is observed in addition to the
slower, protracted release of the active agent from the liposomes.
Without wishing to be bound to any theoretical explanation, it is
presently assumed that in addition to active agent encapsulated
inside the liposomes, some active agent is present outside of the
liposomes, and probably loosely bound to the outer surfaces of the
liposomes. This could be due to association of active agent
molecules with the liposomal membrane, or it could be due to active
agent molecules forming a layer on the liposomal surface, which
layer partly or even fully coats the liposome externally. The type
and amount of this initial agent effect can, for example, be
influenced by varying the concentration of the active agent.
[0039] Liposome preparations according to this invention thus make
it possible to achieve effects which cannot be provided by
customary preparations such as solutions, ointments etc.
[0040] The active agent used in the preparations of the present
invention may be selected from well-known agents which are
classified, e.g., as antiseptic agents, wound-healing agents, and
the like. Preferred antiseptic agents comprise the well-known
pharmaceutical substances providing fast effect, a broad range of
activity, low systemic toxicity and good tissue compatibility. They
can e.g. be selected from the group comprising metal compounds,
phenolic compounds, detergents, iodine and iodine complexes. A
specifically preferred antiseptic agent is povidone iodine.
[0041] Preferred wound-healing agents comprise substances which
have been described in the literature for such application.
Preferred wound-healing agents include substances known to promote
epithelization. These include vitamins, specifically from the
vitamin B group, allantoin, azulenes, and mixtures thereof, and
other agents well known in the art having similar properties.
[0042] In preferred embodiments, the liposome preparations
containing antiseptic and/or wound-healing agents can comprise
further agents such as anaesthetic agents. Inventive preparations
can also contain customary further agents, including adjuvants and
additives, conserving agents or consistency forming agents such as
viscosity adjusting additives, emulgators etc.
[0043] The amphophilic substances generally known in prior art to
form liposome membranes can be employed in the context of the
invention as long as they are pharmaceutically acceptable for the
intended application. Presently, liposome forming systems
comprising lecithin are preferred. Such systems can comprise
hydrogenated soy bean lecithin besides cholesterol and disodium
succinate-hexahydrate. It is presently specifically preferred to
use hydrogenated soy bean lecithin as the sole membrane forming
agent.
[0044] The known prior art methods for forming liposome structures
can generally be used in the context of the invention. Broadly,
these methods comprise mechanical agitation of a suitable mixture
containing the membrane forming substance and water or an aqueous
solution. Filtration through suitable membranes is preferred in
forming a substantially uniform liposome size.
[0045] The size of the liposomes can vary over generally from about
20 to about 20,000 nm. Liposomes with diameters from about 50 to
about 4,000 nm are preferred and liposomes of approximately 1,000
nm diameter are presently most preferred.
[0046] One presently preferred field of application is in
ophthalmology, e.g., in the treatment of bacterial and viral
keratoconjunctivitis, and the pre-operative antiseptic
prophylaxis.
[0047] A presently highly preferred use of the inventive liposome
preparations is in the local treatment of infections of the frontal
part of the eye, especially when the liposome preparations contain
povidone iodine. Also in this indication, the inventive antiseptic
preparations, especially those containing PVP iodine, have the
great advantage of not causing resistances and lead to much less
allergic reactions, while permitting a very cost-efficient therapy
with a broad spectrum of effect. A povidone iodine liposome
preparation according to this invention is e.g. effective against
adenovirus, the most frequent cause of viral conjunctivitis. This
effect is not provided by antibiotic agents.
[0048] A pharmaceutical preparation incorporating the liposomes of
the present invention can provide extended release of an agent
(e.g., an antiseptic agent; wound-healing agent) in an environment
of use over an extended period of time. Such a time period may be,
for example, of several hours duration. More preferably, the time
period is in the range of about 4 to about 30 hours duration, and
most preferably, from about 12 to about 24 hours duration.
[0049] Further, a liposome preparation of antiseptic agent or a
microbicidal agent such as povidone iodine provides protracted
release of the agent, e.g., from liposomes located in the frontal
part of the eye. This leads to extended effect of the antimicrobial
substance, and thus less frequent application, as compared with the
customary antiseptic eyedrop preparations.
[0050] Preparations according to this invention forms, including
solutions, dispersions, lotions, ointments and gels.
[0051] Generally, the amount of active agents in an inventive
preparation will be determined by the desired effect on the one
hand and the carrying capacity of the liposome preparation for the
agent on the other hand.
[0052] Broadly, a solution or dispersion of active agent in an
inventive liposome preparation can range between the lower limit of
effectiveness of the agent and the solubility or dispersability
limit of the agent in the respective solvent or dispersant.
[0053] Similar considerations broadly limit the amount of agent in
liquids, lotions, creams, ointments or gels, or other such
preparations capable of furthering the usefulness of the
invention.
[0054] More specifically, for an antiseptic such as povidone
iodine, a solution or dispersion in an inventive liposome
preparation can contain from about 0.1 to about 10 g of agent in
approximately 100 g of preparation. Such a preparation will then
typically contain from about 1 to about 5 g of liposome membrane
forming substance especially lecithin per 100 g of preparation.
[0055] In a lotion, which can be a hydrophilic, amphophilic or a
lipophilic lotion, a typical range of active agent will be from
about 0.5 to about 10 g agent, and from about 3 to about 8 g,
preferably about 5 g of liposome membrane forming agent such as
hydrogenated soy bean lecithin, per 100 g of lotion. In the case of
a hydrophilic lotion, electrolyte solution will often be used in
preparing the liposome containing lotion. A lipophilic lotion will
often be made from the agent, a membrane forming substance and
lipophilic formation agents such as medium chain length
triglycerides etc.
[0056] Hydrophilic, lipophilic, or amphophilic creams are capable
of preparation in accordance with the invention. A hydrophilic
cream comprising an inventive liposome preparation will generally
comprise between 0.1 and 10 g agent, such as povidone iodine,
together with between about 1 and 10 g membrane forming substance
and further typical oil in water (0/W) cream forming additives, per
100 g of cream.
[0057] A comparable amphophilic cream according to the invention
will have similar contents of agent and membrane forming substance
such as lecithin, and will have the typical further additives of an
amphophilic cream.
[0058] A hydrophilic ointment according to the invention can
broadly comprise from about 0.1 to about 10 g of active agent and
from about 1 to about 10 g liposome membrane forming substance such
as lecithin, together with typical prior art ointment basis
substances such as Macrogol.TM. and water, in 100 g of
ointment.
[0059] A non-alcoholic hydrogel according to the invention could
broadly comprise from about 1 to about 5 g agent such as povidone
iodine, approximately 2 g lecithin and gel forming substances such
as Carbopol.TM., with pH-adjusting agent and water to form 100 g of
hydrogel.
[0060] More specific formulations are notable from the embodiment
example.
[0061] One preferred method for producing the liposomes of the
present invention can generally be described as follows:
[0062] The lipid membrane forming components, e.g. lecithin, are
dissolved in a suitable solvent such as chloroform or a 2:1 mixture
of methanol and chloroform and are filtered under sterile
conditions. Then, a lipid film is produced on a sterile high
surface substrate, such as glass beads, by controlled evaporation
of the solvent. In some cases, it can be quite sufficient to form
the film on the inner surface of the vessel used in evaporating the
solvent, without using a specific substrate to increase the
surface.
[0063] An aqueous system is prepared from electrolyte components
and the one or more active agents to be incorporated in the
liposome preparation. Such an aqueous system can, for example,
comprise 10 mmol/1 sodium hydrogen phosphate and 0.9% sodium
chloride, at pH 7.4; the aqueous system will further comprise at
least the desired amount of the active agent, which in the
embodiment examples is povidone iodide. Often, the aqueous system
will comprise an excess amount of agent or agents.
[0064] The liposomes are generally formed by agitating said aqueous
system in the presence of said film formed by the lipid components.
At this stage, further additives can be added to improve liposome
formation; for example, sodium cholate can be added. Liposome
formation can also be influenced by mechanical action such as
pressure filtration rough, for example, polycarbonate membranes, or
centrifuging. Generally, the raw liposome dispersion will be
washed, for example, with electrolyte solution as used in preparing
the above-described solution of the active agent.
[0065] When liposomes with the required size distribution have been
obtained and washed, they can be redispersed in an electrolyte
solution as already described, often also comprising sugars such as
saccharose or a suitable sugar substitute. The dispersion can be
freeze-dried, and it can be lyophilized. It can, prior to use, be
reconstituted by addition of water and suitable mechanical
agitation at the transition temperature of the lipid component,
which for hydrogenated soy bean lecithin is e.g. about 55.degree.
C.
[0066] In the following Examples, hydrogenated soy bean lecithin
(EPISURON.TM. 200 SH obtainable from Lukas Meyer, Germany or
PHOSPOLIPON.TM. 90 H obtainable from Nattermann Phospholipid GmbH,
Germany) was used. However, other pharmaceutically acceptable
liposome membrane forming substances can be used instead, and the
person skilled in the art will find it easy to select suitable
alternative liposome forming systems from what is described in
prior art.
DETAILED DESCRIPTIONS OF THE PREFERRED EMBODIMENTS
[0067] The features and advantages of this invention will become
notable in more detail from the ensuing description of preferred
embodiments. In these embodiments, which include a best mode,
povidone iodine is exemplified as an antiseptic agent. This should
not, however, be construed as a restriction of this invention to
antiseptic agents or, among antiseptic agents, to povidone iodine,
although such preparations are specifically preferred.
EXAMPLE I
[0068] In a 1000 ml glass flask, provided with glass beads for
increased surface, 51.9 mg cholesterol and 213 mg hydrogenated soy
bean lecithin were dissolved in a sufficient amount of a mixture of
methanol and chloroform in a 2:1 ratio. The solvent was then
evaporated under a vacuum until a film was formed on the inner
surface of the flask and on the glass beads.
[0069] 2.4 g PVP iodine (containing about 10% available iodine)
were separately dissolved in 12 ml water.
[0070] Again in a separate vessel, 8.77 g sodium chloride and 1.78
g Na2HPOH 2H20 were dissolved in 400 ml water. Further water was
added up to a total volume of 980 ml, and then, approximately 12 ml
1N hydrochloric acid were added to adjust pH to 7.4. This solution
was then topped up with water to produce exactly 1000 ml.
[0071] In a fourth vessel, 900 mg saccharose and 57 mg disodium
succinate were dissolved in 12 ml water.
[0072] The PVP iodine solution was then added to the lipid film in
the flask and the mixture was shaken until the film dissolved. This
produced liposome formation from the hydrated lipids in the flask.
The product was centrifuged and the supernatant liquid was
discarded. Then a sufficient quantity of saccharose solution was
added to produce 12 ml of solution and the product was again
centrifuged. Afterwards the supernatant liquid was again discarded.
At this stage, a further washing step, using the sodium chloride
buffer solution could be used.
[0073] After the last centrifugation step and discarding of the
supernatant, a sufficient quantity of sodium chloride buffer
solution was added to produce 12 ml of solution, and the liposomes
were homogeneously distributed therein. The product was then
distributed into vials each containing 2 ml liposome dispersion,
and the vials were then subjected to a freeze-drying step.
[0074] After the freeze-drying, each vial comprised about 40 mg
solids.
[0075] The method of Embodiment Example I has a minor disadvantage
in that the PVP iodine solution used, due to the high percentage of
solids, is rather viscous and thus more difficult to handle.
EXAMPLE II
[0076] In a 2000 ml flask provided with glass beads to increase
surface, 173 mg hydrogenated soy bean lecithin and 90 mg disodium
succinate were dissolved in approximately 60 ml of a
methanol/chloroform mix in a 2:1 ratio. The solvent was removed
under vacuum until a film was formed.
[0077] 4 g PVP iodine (10% available iodine) were dissolved in 40
ml of the sodium chloride buffer solution described in Embodiment
Example I, and were added to the lipid film in the flask. The flask
was then shaken until the film dissolved and liposomes were
formed.
[0078] The product was centrifuged and the supernatant liquid was
discarded.
[0079] To the thus produced liposome pellet, further sodium
chloride buffer solution was added to produce 40 ml of solution,
and the centrifuging step was repeated. The supernatant was again
discarded. At this stage, this washing step could be repeated where
necessary.
[0080] After the final centrifuging and decanting step, sodium
chloride buffer solution was again added to the precipitated
liposomes to produce 40 ml of homogeneous dispersion. The
homogenous dispersion was then distributed into vials, each vial
containing about 2 ml liposome dispersion, and the vials were then
subjected to a freeze-drying step. This produced approximately 200
mg freeze-dried solids per vial.
[0081] From the freeze-dried solids of Examples I and II, further
preparations were made as described in subsequent embodiment
Examples and Test Reports.
[0082] Like that of Embodiment Example 1, the above-described
method uses a hydrating step after film formation in the presence
of organic solvents and aims at inclusion rates of from about 5 to
about 15%. These methods generally produce rather large and often
multilamellar liposomes.
[0083] The above-described methods can be modified by a high
pressure filtering step through a suitable membrane such as a
polycarbonate membrane after the raw liposomes have been formed or
after any of the subsequent washing steps or directly by using high
pressure homogenization. This produces much smaller, unilamellar
liposomes at increased amounts of encapsulated agent.
[0084] Instead of high pressure homogenization, other prior art
methods known to provide small uniform sized liposomes can be
employed.
EXAMPLE III
[0085] A hydrophilic (0/W) cream was prepared from 10 g
hydrogenated soy bean lecithin/PVP iodine liposomes as described in
Embodiment Example II; these were mixed with 4 g Polysorbate
40.TM., 8 g cetylstearyl alcohol, 8 g glycerol, 24 g white
vaseline, and water to produce 100 g of hydrophilic cream.
EXAMPLE IV
[0086] An amphophilic cream was prepared from 10 g hydrogenated soy
bean lecithin/povidone iodine liposomes as described in Embodiment
Example II; 7.5 g medium chain length triglyceride, 7 g
polyoxyethyleneglycerol monostearate, 6 g cetylstearyl alcohol, 8 g
pro-pylene glycol, 25 g white vaseline, and water ad 100 g.
EXAMPLE V
[0087] A hydrophilic ointment which can be rinsed off with water
was prepared using 10 g of liposomal PVP iodine as described in
Embodiment Example II, 55 g Macrogol 400.TM., 25 g Macrogol
4000.TM., and water ad 100 g.
EXAMPLE VI
[0088] A hydrogel was prepared from 4 g liposomal PVP iodine as
described in Embodiment Example II, 0.5 g Carbopol 980 NF.TM.,
sodium hydroxide ad pH 7, water ad 100 g.
[0089] Further modifications of the above-described embodiments are
envisaged.
[0090] Thus, the creams of Embodiment Examples III and IV can have
an additional content of an agent known to promote the healing of
wounds, such as allantoin. Such an agent will be added in a
pharmaceutically useful concentration, in the case of allantoin in
the range of 0.1 to 0.5 g, per 100 g of cream. The wound healing
agent can be incorporated in the cream base, in which case it will
largely be outside the liposomes. It can, however, be partly or
mostly incorporated in the liposomes, in which case it will be
added at a corresponding suitable stage of the liposome preparation
method.
[0091] Similar alternatives are easily envisaged on the basis of
the further Embodiment Examples.
[0092] It is also possible to prepare embodiments similar to the
above-described ones, which comprise an agent capable of promoting
the healing of wounds instead of, and not in addition to, the
antiseptic agent as e.g. povidone iodine disclosed in the above
Embodiment Examples. Presently, it is however preferred to use a
wound healing promoting agent (if at all) in addition to an
antiseptic agent.
[0093] For application of the inventive preparations to a patient,
known systems can be used, such as pneumatic pump applicators,
two-chamber gas pressure packs etc.
[0094] In a pneumatic pump applicator, a bellows device is provided
between an upstream and a downstream valve, both valves operating
one way in the same direction. A supply of pharmaceutical
preparation, such as an ointment or gel, is contained in a
reservoir upstream of the valves-and-bellows device.
[0095] When compressing the bellows, the downstream valve opens and
permits a dosed amount of preparation to leave the device for
application. When the bellows is extended, this valve shuts and
prevents reentry of the preparation. At the same time, the upstream
valve opens and permits preparation from the reservoir to enter
into the bellows, for release through the downstream valve upon the
next compression step of the bellows.
[0096] The reservoir is sealed by a closure element which can move
through the reservoir like a piston moves in a cylinder. By the
stepwise emptying of the reservoir, this closure element is sucked
into the reservoir, so that the remaining amount of pharmaceutical
preparation in the reservoir is always sealed off, while at the
same time the reservoir can be emptied.
[0097] Such a device is useful for pasty preparations, creams,
ointments etc.
[0098] In a two-chamber gas pressure pack, the pharmaceutical
preparation is contained in a bag of flexible plastics film
material. Often, this is high pressure polyethylene.
[0099] The bag is contained inside a gas tight pressure vessel
which further contains a supply of pressurizing gas, very often a
compressed inert gas like nitrogen.
[0100] The plastic film bag has only one outlet, which is
gas-tightly connected to the interior wall of the pressure vessel,
surrounding a single opening thereof. The pressurized gas in the
vessel tends to compress the bag, driving the pharmaceutical
preparation inside the bag out through the opening of the bag and
thus through the opening of the vessel. A valve and, in case,
spray-head device is provided in the vessel mouth. Operating the
valve releases a spray mist, a jet of liquid or a portion of
flowable solid such as cream. Using such a system, solutions,
emulsions, creams, ointments and gels, dosed and applied.
[0101] Dosing inventive preparations efficiency and acceptability
tests were then carried out, as follows:
Test I
[0102] This was an in-vitro-test of the bactericidal effect
provided by an inventive povidone iodine liposome preparation. The
test was based on the quantitative suspension test as described in
"Richtlinien der Deutschen Gesellschaft fur hygiene and
Mikrobiologie", 1989. In this test, the bactericidal agent is used
to kill staphylococcus aureus (ATCC 29213), a major problem in
hospital hygiene.
[0103] The liposome preparation used was that of Embodiment Example
I. At different contact times between 1 and 120 minutes, the
minimum concentration of the preparation in water was determined
which was capable of killing the staphylococci.
[0104] The results are shown in Table 1.
TABLE-US-00001 TABLE I Contact Time (Minutes) Bactericidal
Concentration 1, 2, 3, 4 .gtoreq.0.060% 5, 30, 60 120
.gtoreq.0.015% 120 .gtoreq.0.007%
[0105] The results show that at short contact times (between 1 and
4 minutes) the bactericidal concentration is as low as 0.06% and
that at long contact times (120 minutes) the bactericidal
concentration can be as low as 0.007%.
Test II
[0106] The second test was a placebo-controlled clinical study of
the local acceptability (at the eye) of an inventive povidone
iodine liposome preparation. An eyedrop formulation was made using
the liposomes of Embodiment Example II. It was tried on 15 male
test persons. The inventive preparation was always used on one eye
of the test person, with physiological sodium chloride solution
added as a comparison to the respective other eye.
[0107] Specifically, each test person received one drop of PVP
iodine liposome preparation in the right eye and one drop of
physiological sodium chloride solution in the left eye, and this
was twice repeated at hourly intervals. After 5, 30, 65, 95, 125
and 150 minutes as well as after 24 hours after the first
application, symptoms were determined. These symptoms included
hyperaemia, as measured with a slit/lamp microscope; burning;
itching, and tear flow. Each symptom was measured according to a 4
point score with 0 corresponding to no symptom, 1 corresponding to
a low degree, 2 corresponding to a medium degree and 3
corresponding to a strong degree of symptom appearance.
[0108] A sum score was calculated from the degree scores of all
four symptoms and the 7 determination time points. The sum score
could thus vary between 0 (=0 times 0 times 0) and 84 (=4 times 3
times 7).
[0109] The test persons were between 21 and 36 years old, with an
average of 30 years of age. All test persons were healthy and not
under medication during the test. Specifically, any illnesses of
the eye and of the thyroid were excluded.
[0110] One test person was not evaluated for sum score since one
control of symptoms after 150 minutes was missed.
[0111] The results are notable from Table II.
[0112] Overall, the sum score on both eyes was extremely low. It is
surprising that on average, the sum score for the eyes treated with
the povidone iodine liposome preparation was even lower than that
for the eyes receiving physiological sodium chloride solution.
TABLE-US-00002 TABLE II PVP-I-Liposomes Sum score Number of test
persons Phys. NaCl-Solution 0 11 6 1 3 6 2 0 2 3-84 0 0 Average
0.21 0.71 Standard Deviation 0.43 0.73 Median 0 1 p-Value 0.02
[0113] Eleven test persons treated with the invention's povidone
iodine liposome preparation showed no symptoms whatsoever. Three
test persons had slight hyperaemia, one felt some very slight
burning (this is the above-mentioned test person who could not be
evaluated for sum score). On the contrary, only six test persons
exhibited no symptoms after receiving physiological sodium chloride
solution. Four test persons experienced burning, one of them at two
subsequent time points. One test person experienced slight burning
and itching of the left eye. A total of four test persons showed
some hyperaemia.
[0114] The examples provided are not meant to be exclusive. Many
other variations of the present invention will be obvious to those
skilled in the art, and are contemplated to be within the scope of
the appended claims.
* * * * *