TITLE OF INVENTION: SILDENAFIL SOLUTIONS AND METHODS OF
MAKING AND USING SAME
TECHNICAL FIELD
[0001] Various exemplary embodiments of the invention relate to pharmaceutical
compositions containing sildenafil citrate as an active ingredient and to methods of
producing and/or administering such compositions.
BACKGROUND ART
[0002] Sildenafil as citrate is FDA and EMEA approved for treatment of erectile
dysfunction and pulmonary arterial hypertension (PAH).
[0003] There are also reports that sildenafil citrate is used for off-label indications
including, but not limited to, prevention of high-altitude pulmonary edema associated with
altitude sickness, treating lung fibrosis, primary pulmonary hypertension, secondary
pulmonary hypertension, hypoxia induced pulmonary hypertension, neonatal pulmonary
hypertension, pediatric pulmonary hypertension, nonoperable chronic thromboembolic
pulmonary hypertension, severe coronary artery disease, age-related macular degeneration,
brachial artery flow-mediated dilatation (in type 2 diabetes), Raynaud's syndrome, anal
fissures, postmenopausal female sexual dysfunction, female sexual arousal disorder, digital
ulcers secondary to systemic sclerosis, migraine, premature ejaculation, sickle-cell disease
with pulmonary hypertension, achalasia (esophageal motility dysfunction), severe digital
ischemia, recurrent ischemic priapism, severe lymphatic formation, congestive heart failure,
diastolic dysfunction, tunical fibrosis, multiple sclerosis, intrauterine growth restriction,
chronic pelvic pain, Alzheimer's disease, stroke, preeclampsia, gastroparesis, glucose
dyscontrol in diabetes, primary dysmenorrheal pain, for increasing exercise capacity during
hypoxia, increasing uterine artery blood flow and endometrial thickness to promote in-vitro
fertilization (IVF).
[0004] Sildenafil citrate has also been proposed as a treatment for prostate cancer,
pancreatic cancer, ovarian cancer, stomach cancer, obesity, Crohn's disease, spastic
esophageal disorder, reduction of alcohol induced gastric damage and other conditions.
[0005] Sildenafil citrate is commonly marketed as VIAGRA ® (for treatment of erectile
dysfunction) and REVATIO ® (for treatment of pulmonary hypertension), both
manufactured by Pfizer Pharmaceuticals. Generic versions of sildenafil citrate are also
available. VIAGRA ® is commonly supplied as 25, 50 or 100 mg tablets and is to be taken
not more than once per day 0.5 to 4 hours prior to intercourse. REVATIO ® is most often
supplied as 20 mg tablets to be taken 3 times daily. REVATIO ® is also available in
injectable form as a clear colorless, sterile, ready to use solution containing 10 mg of
sildenafil citrate per 12.5 ml of solution. Each ml of solution contains 1.124 mg sildenafil
citrate, 50.5 mg dextrose and water for injection.
[0006] The injectable form of REVATIO ® is most often administered intravenously.
This route of administration is practical in a hospital setting but impractical outside a
hospital or clinic setting.
[0007] In the EU sildenafil citrate is also available as an oral suspension at a
concentration of 10 mg/ml. REVATIO ® POS (powder for oral suspension) is supplied by
Pfizer to be made up into an oral suspension. Additional ingredients in the POS include
colloidal silicon dioxide, sucralose, sorbitol, sodium benzoate, sodium citrate, flavor and
xanthan gum. The active ingredient in suspension has a slower absorption rate than would
be expected for a solution with a similar concentration. In addition, the presence of some of
the additional ingredients makes this product difficult to tolerate for people with known
sensitivities to these ingredients.
[0008] Whether provided as tablets or oral suspension, sildenafil citrate exhibits an
absolute bioavailability of about 41% and is reported to result in maximum observed plasma
concentrations within 30 to 120 minutes following oral dosing in a fasted state. The rate of
absorption is reportedly reduced if taken with a high fat meal.
[0009] According to the US package insert for VIAGRA®, solubility of
sildenafil citrate in water is 3.5 mg/ml. The EMEA CHMP Assessment Report for Vizarsin
(International Nonproprietary Name: sildenafil) indicates that it is insoluble in ethanol,
chloroform and acetone, but soluble in methanol and dimethylsulfoxide (DMSO). The
Jordanian Pharmaceutical Manufacturing Co. reports that sildenafil citrate is about 3.5 times
less soluble in ethanol than in water (~ 1 mg/ml). The low water solubility of
sildenafil citrate and/or its high presystemic elimination each independently contribute to its
low oral bioavailability.
SUMMARY OF INVENTION
[0010] A broad aspect of the invention relates to use of sildenafil citrate as a
pharmaceutically active ingredient.
[0011] One aspect of some embodiments of the invention relates to increasing
bioavailability of sildenafil citrate. In some exemplary embodiments of the invention,
bioavailability of sildenafil citrate is increased by providing the sildenafil citrate in solution
at a concentration of 7, 10, 20, 25, 30, 35, 40, or 45 mg/ml or intermediate or greater
concentrations. As used in this specification and the accompanying claims, the terms "in
solution," "dissolved," "soluble," and variations thereof, indicate transparency under light
with no particles visible to the naked eye.
[0012] One aspect of some embodiments of the invention relates to dissolving the
sildenafil citrate in water mixed with one or more alcohols. In some exemplary
embodiments of the invention, the one or more alcohols include ethanol. In some
exemplary embodiments of the invention, a ketone, (e.g. acetone) is provided with the water
and alcohol. In some exemplary embodiments of the invention, the solution is delivered to
a patient as a spray. In some embodiments, the spray is delivered to the trachea and/or
lungs using a nebulizer or a metered dose inhaler.
[0013] Another aspect of some embodiments of the invention relates to treatment
methods for erectile dysfunction which rely on dosages of sildenafil citrate which are less
than half of what the specific patient is used to taking. In some exemplary embodiments of
the invention, dissolution of the sildenafil citrate and/or increased absorption due to the
rapid uptake of the carrier contributes to the dosage reduction. According to various
exemplary embodiments of the invention the administration route is oral or buccal.
[0014] It will be appreciated that the various aspects described above relate to solution
of technical problems related to the low bioavailability of sildenafil citrate in solid or
suspension formulations. Specifically, it is believed that the low solubility of sildenafil
citrate tablets and/or suspension under physiologic conditions contributes to elimination of a
significant amount of the ingested material without absorption.
[0015] Alternatively or additionally, it will be appreciated that the various aspects
described above relate to solution of technical problems related to the relatively long time
between drug administration and onset of desired therapeutic action. Specifically,
experienced subjects reported half the time (or less) for the same therapeutic effect when
using a solution as described above compared to a tablet form of sildenafil citrate.
[0016] Alternatively or additionally, it will be appreciated that the various aspects
described above relate to solution of technical problems related to reducing the effective
dose of sildenafil citrate. Specifically, half the dose (or less) of sildenafil citrate in a
solution as described above provides the same therapeutic effect compared to a tablet form
or suspension form of sildenafil citrate.
[0017] Alternatively or additionally, it will be appreciated that the various aspects
described above relate to solution of technical problems related to mitigation of unwanted
side effects of sildenafil citrate.
[0018] In some exemplary embodiments of the invention there is provided a
pharmaceutical composition including: (a) a liquid carrier including water and at least 20%
of at least one alcohol; and (b) sildenafil citrate dissolved in the liquid carrier at a
concentration of at least 7 mg/ml. In some embodiments, the liquid carrier includes at least
5% water. Alternatively or additionally, in some embodiments the liquid carrier includes at
least 30% water. Alternatively or additionally, in some embodiments the concentration of
sildenafil citrate dissolved in the liquid carrier is at least 12.5 mg/ml. Alternatively or
additionally, in some embodiments the concentration of sildenafil citrate dissolved in the
liquid is at least 20 mg/ml. Alternatively or additionally, in some embodiments the at least
one alcohol includes ethanol. Alternatively or additionally, in some embodiments the liquid
carrier includes a ketone. Alternatively or additionally, in some embodiments the ketone
includes acetone. Alternatively or additionally, in some embodiments the liquid carrier
includes more than 3% ketone. Alternatively or additionally, in some embodiments the
concentration of the sildenafil citrate dissolved in the liquid is at least 25 mg/ml.
Alternatively or additionally, in some embodiments, the pharmaceutical composition
includes a flavoring agent. Alternatively or additionally, in some embodiments the
pharmaceutical composition includes a bitterness blocking agent.
[0019] In some exemplary embodiments of the invention, there is provided an oral
dosage form including: an outer coating; and a liquid core including a pharmaceutical
composition as described hereinabove.
[0020] In some exemplary embodiments of the invention, there is provided buccal
dosage form including: a carrier containing a pharmaceutical composition as described
hereinabove; and a wrapper adapted to prevent evaporation of the liquid carrier during
storage.
[0021] In some exemplary embodiments of the invention, there is provided treatment
kit including: a container holding a plurality of doses of a pharmaceutical composition as
described hereinabove; and a measuring device calibrated for measurement of a single dose
from the container.
[0022] In some exemplary embodiments of the invention, there is provided treatment
kit including: one or a plurality of single doses of a pharmaceutical composition as
described hereinabove, each of the single doses contained in a separate container; and
packaging material adapted to hold the separate containers.
[0023] In some exemplary embodiments of the invention there is provided a method
including: (a) placing sildenafil citrate in a combination consisting essentially of one or
more alcohols and water to produce a mixture; and (b) heating the mixture to produce a
solution of the sildenafil citrate with a concentration of at least 7 mg/ml.
[0024] In some embodiments, the heating is to a temperature of at least 65 °C.
Alternatively or additionally, in some embodiments the heating is to a temperature not
exceeding 85 °C. Alternatively or additionally, in some embodiments the heating is
conducted in an open container. Alternatively or additionally, in some embodiments the
heating is conducted in a closed container. Alternatively or additionally, in some
embodiments the solution of the sildenafil citrate has a concentration of at least 12.5 mg/ml.
Alternatively or additionally, in some embodiments the one or more alcohols includes
ethanol. Alternatively or additionally, in some embodiments the combination of one or
more alcohols and water includes at least 20% alcohol. Alternatively or additionally, in
some embodiments the combination of one or more alcohols and water includes at least 5%
water. Alternatively or additionally, in some embodiments a volume of the solution after
heating is substantially the same as a volume of the mixture prior to heating. Alternatively
or additionally, in some embodiments a volume of the solution after heating is significantly
less than a volume of the mixture prior to heating. Alternatively or additionally, in some
embodiments the method includes cooling the solution and adding alcohol and/or water.
[0025] In some exemplary embodiments of the invention there is provided a method
including: (a) providing a first volume of a ketone; (b) adding a second volume consisting
essentially of one or more alcohols and water to produce a total volume of solution; and
(c) dissolving sildenafil citrate at a concentration of at least 7 mg/ml with respect to the total
volume.
[0026] In some embodiments, the method includes heating the solution at a
temperature not less than 5° C below the boiling point of the ketone. Alternatively or
additionally, in some embodiments the heating is to a temperature at least 5° C above a
boiling point of the ketone. Alternatively or additionally, in some embodiments the heating
is to a temperature at least 10° C above a boiling point of the ketone. Alternatively or
additionally, in some embodiments the method includes removing at least 25% of the
ketone. Alternatively or additionally, in some embodiments the sildenafil citrate in the
solution has a concentration of at least 25 mg/ml. Alternatively or additionally, in some
embodiments the one or more alcohols includes ethanol. Alternatively or additionally, in
some embodiments the combination of one or more alcohols and water includes at least
2 0% alcohol. Alternatively or additionally, in some embodiments the combination of one
or more alcohols and water includes at least 5% water. Alternatively or additionally, in
some embodiments a volume of the solution after heating is 50% or less of the volume of
the solution prior to heating. Alternatively or additionally, in some embodiments the
method includes cooling the solution and adding alcohol(s) and/or water to a total alcohol
concentration of at least 34%.
[0027] In some exemplary embodiments of the invention, there is provided a
pharmaceutical composition including: (a) a liquid carrier including water, ethanol, and less
than 20% acetone; and (b) sildenafil citrate dissolved in the liquid carrier at a concentration
of at least 10 mg/ml.
[0028] In some exemplary embodiments of the invention there is provided
pharmaceutical composition including: (a) a liquid carrier consisting essentially of water
and at least 20% of at least one alcohol; and (b) sildenafil citrate dissolved in the liquid
carrier at a concentration of at least 7 mg/ml. In some embodiments the liquid carrier
includes at least 5% water. Alternatively or additionally, in some embodiments the liquid
carrier includes at least 30% water. Alternatively or additionally, in some embodiments the
concentration of sildenafil citrate dissolved in the liquid carrier is at least 12.5 mg/ml.
Alternatively or additionally, in some embodiments the concentration of sildenafil citrate
dissolved in the liquid is at least 20 mg/ml. Alternatively or additionally, in some
embodiments the at least one alcohol includes ethanol. Alternatively or additionally, in
some embodiments the liquid carrier includes a ketone.
[0029] Alternatively or additionally, in some embodiments the ketone includes
acetone. Alternatively or additionally, in some embodiments the liquid carrier includes
more than 3% ketone. Alternatively or additionally, in some embodiments the
concentration of the sildenafil citrate dissolved in the liquid is at least 25 mg/ml.
Alternatively or additionally, in some embodiments the pharmaceutical composition
includes a flavoring agent. Alternatively or additionally, in some embodiments the
pharmaceutical composition includes a bitterness blocking agent.
[0030] In some exemplary embodiments of the invention, there is provided an oral
dosage form including: an outer coating and a liquid core, including a pharmaceutical
composition as described hereinabove.
[0031] In some exemplary embodiments of the invention, there is provided buccal
dosage form including: a carrier containing a pharmaceutical composition as described
hereinabove; and a wrapper adapted to prevent evaporation of the liquid carrier during
storage.
[0032] In some exemplary embodiments of the invention, there is provided treatment
kit including: a container holding a plurality of doses of a pharmaceutical composition as
described hereinabove, and a measuring device calibrated for measurement of a single dose
from the container.
[0033] In some exemplary embodiments of the invention, there is provided treatment
kit including: a plurality of single doses of a pharmaceutical composition as described
hereinabove, each of the single doses contained in a separate container; and packaging
material adapted to hold the separate containers.
[0034] In some exemplary embodiments of the invention, there is provided a
pharmaceutical composition including: (a) a liquid carrier consisting essentially of water,
ethanol, and less than 20% acetone; and (b) sildenafil citrate dissolved in the liquid carrier
at a concentration of at least 10 mg/ml.
[0035] Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art to which this
invention belongs. Although suitable methods and materials are described below, methods
and materials similar or equivalent to those described herein can be used in the practice of
the present invention. In case of conflict, the patent specification, including definitions, will
control. All materials, methods, and examples are illustrative only and are not intended to
be limiting.
[0036] As used herein, the terms "comprising" and "including" or grammatical
variants thereof are to be taken as specifying inclusion of the stated features, integers,
actions or components without precluding the addition of one or more additional features,
integers, actions, components or groups thereof. This term is broader than, and includes the
terms "consisting of and "consisting essentially of as defined by the Manual of Patent
Examination Procedure of the United States Patent and Trademark Office. Thus, any
recitation that an embodiment "includes" or "comprises" a feature is a specific statement
that sub embodiments "consist essentially of and/or "consist of the recited feature.
[0037] The phrase "adapted to" as used in this specification and the accompanying
claims imposes additional structural limitations on a previously recited component.
[0038] The term "method" refers to manners, means, techniques and procedures for
accomplishing a given task including, but not limited to, those manners, means, techniques
and procedures either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of chemistry and/or pharmacology.
[0039] Percentages (%) of solvents (e.g., water and/or alcohols and/or ketones)
indicate preparing a total volume (T) by measuring a volume (X) of a first liquid and adding
a second liquid until the total volume teaches T. For example, to prepare one liter of a 70%
ethanol solution 736.8 ml of 95% ethanol is measured and water is added to a total volume
of 1 liter. Such a solution is also referred to here as 70:30 ethanokwater or 70% EtOH.
[0040] For determining percentages of components after heating GC/MS (Gas
Chromatography /Mass Spectroscopy) is employed and weight percentages are determined
based upon areas below curves of relevant peaks. Throughout the specification, if GC/MS
was used it is so indicated.
[0041] Concentrations of sildenafil citrate are indicated as mg/ml of the relevant liquid
at room temperature unless otherwise indicated.
BRIEF DESCRIPTIONS OF THE DRAWINGS
[0042] In order to understand the invention and to see how it may be carried out in
practice, embodiments will now be described, by way of non-limiting example only, with
reference to the accompanying figures. In the figures, identical and similar structures,
elements or parts thereof that appear in more than one figure are generally labeled with the
same or similar references in the figures in which they appear. Dimensions of components
and features shown in the figures are chosen primarily for convenience and clarity of
presentation and are not necessarily to scale. The attached figures are:
[0043] Fig. 1 is a simplified flow diagram of a preparation method according to some
embodiments of the invention;
[0044] Fig. 2 is a simplified flow diagram of a preparation method according to some
embodiments of the invention;
[0045] Fig. 3 is an NMR (Nuclear Magnetic Resonance) plot of a liquid
pharmaceutical composition of sildenafil citrate according to an exemplary embodiment of
the invention aligned with a plot of sildenafil citrate powder; and
[0046] Fig. 4 is a simplified flow diagram of a method according to some exemplary
embodiments of the invention.
DESCRIPTION OF EMBODIMENTS
[0047] Embodiments of the invention relate to solutions of sildenafil citrate and to
methods of preparing and/or using such solutions.
[0048] Specifically, some embodiments of the invention can be used to treat erectile
dysfunction. In some embodiments, treatment of erectile dysfunction with a solution
according to an exemplary embodiment of the invention contributes to a reduction in dosage
of sildenafil citrate and/or a reduction in time between administration and onset of
therapeutic effect and/or a reduction in unwanted side effects.
[0049] The principles and operation of solutions and/or methods according to
exemplary embodiments of the invention may be better understood with reference to the
drawings and accompanying descriptions.
[0050] Before explaining at least one embodiment of the invention in detail, it is to be
understood that the invention is not limited in its application to the details set forth in the
following description or exemplified by the Examples. The invention is capable of other
embodiments or of being practiced or carried out in various ways. Also, it is to be
understood that the phraseology and terminology employed herein is for the purpose of
description and should not be regarded as limiting.
Exemplary composition
[0051] In some exemplary embodiments of the invention, there is provided a
pharmaceutical composition including a liquid carrier including water and at least 20%, at
least 22 .5%, at least 25%, at least 25% or at least 30%> of at least one alcohol with sildenafil
citrate dissolved in the liquid carrier at a concentration of at least 7 mg/ml. The fact that it
is possible to prepare such a composition is surprising since the solubility of sildenafil
citrate in both water and alcohols which are suitable for use in pharmaceutical compositions
(i.e., alcohols that are considered "safe" for human consumption) is well below 7 mg/ml.
One example of an alcohol suitable for use in a pharmaceutical composition is ethanol
(EtOH).
[0052] Alternatively or additionally, in some embodiments the liquid carrier includes
at least 5%, at least 10%>, at least 20%, at least 30%, at least 40% or at least 50% water. In
some embodiments of the invention, the amount of sildenafil citrate dissolved in the liquid
carrier is at least 12.5 mg/ml, at least 20 mg/ml, at least 25 mg/ml, at least 30 mg/ml, at least
40 mg/ml, at least 50 mg/ml or at least 60 mg/ml. Alternatively or additionally, in some
embodiments the amount of sildenafil citrate dissolved in the liquid carrier is less than 125
mg/ml, less than 100 mg/ml, less than 70 mg/ml, less than 60 mg/ml, less than 50 mg/ml or
less than 45 mg/ml.
[0053] For liquid pharmaceutical compositions in general, a small dosage volume can
contribute to patient acceptance. This general preference among patients contributes to an
incentive for manufacturers to produce compositions with high concentrations of sildenafil
citrate (e.g., 18 mg/ml or higher).
[0054] In some exemplary embodiments of the invention, the liquid carrier includes a
ketone (e.g., acetone). In some embodiments, the amount of ketone is less than the amount
of water and/or ethanol in the liquid carrier. Some ketones are incompatible with glass or
plastic containers during prolonged storage. For this reason, although their presence in a
pharmaceutical composition is acceptable, there is no incentive to increase the amount of
ketone. Among those embodiments of the invention which include a ketone (e.g., acetone),
concentrations of at least 2.5%, at least 3%, at least 4%, at least 5%, at least 6%, at least
7 .5%, at least 10%> or at least 15%> or intermediate or greater concentrations are employed.
Alternatively or additionally, of those embodiments of the invention which include a ketone
(e.g., acetone), concentrations of less than 50%, less than 25%, less than 15%, less than
10% , less than 7.5%, less than 5%, less than 4% or less than 3% or intermediate or lesser
concentrations are employed.
Exemplary oral dosage forms
[0055] Some exemplary embodiments of the invention incorporate a liquid
pharmaceutical composition as described above into a non-liquid dosage form. For
example, an oral dosage form according to some embodiments of the invention includes an
outer coating and a liquid core including a pharmaceutical composition as described above.
Oral dosage forms of this type are provided as, for example, gel caps or capsules.
[0056] Experimental data presented below in Example 5 (Table 3) demonstrate that 1
to 2 ml of liquid volume is sufficient to deliver a physiologically effective dose (20 mg to
30 mg) of sildenafil citrate in solution. However, the solutions employed in example 5 were
relatively dilute. Increasing the concentration of sildenafil citrate in solution reduces the
volume required for delivery of the same physiologically effective dose proportionately.
For example, a 40 mg/ml solution requires only 0.5 ml to deliver a 20 mg dose. One to two
gel caps can easily contain 0.5 ml of liquid volume.
Exemplary buccal dosage forms
[0057] Some exemplary embodiments of the invention incorporate a liquid
pharmaceutical composition as described above into buccal dosage form. It is well
established that delivery of physiologically active substances through the oral mucosa can
be faster and/or more effective than delivery of the same substances through the stomach
and/or intestines. Some embodiments of the invention relate to a buccal dosage form
including a carrier containing a pharmaceutical composition as described above provided in
a wrapper adapted to prevent evaporation of the liquid carrier of the composition during
storage. According to various exemplary embodiments of the invention the carrier is
provided as paper, cardboard, nonwoven fabric or a wafer (e.g. starch base).
[0058] In some embodiments, the solid substrate is provided as a chewable material
such as, for example, an edible wax or chewing gum. In some embodiments, the chewable
material is impregnated with a liquid pharmaceutical composition as described above.
Alternatively or additionally, in some embodiments the chewable material surrounds a core
including a liquid pharmaceutical composition as described above.
[0059] Again experimental data presented below in Example 5 (Table 3) demonstrate
that 1 to 2 ml of liquid volume is sufficient to deliver a physiologically effective dose
(20 mg to 30 mg) of sildenafil citrate in solution. If a 40 mg/ml solution is employed only
0.5 ml of liquid volume provides a 20 mg dose. A 0.5 ml liquid volume can easily be
provided in 1 to 2 pieces of conventional chewing gum, liquid centered chewing gum, or
wax "candies."
[0060] Chewing gum containing sildenafil citrate is described at least in U.S. Patents
6,531,1 14 and 6,592,850, each of which is fully incorporated by reference.
[0061] Liquid centered chewing gum is described at least in US patent application
publications 20100203191 and 20100209553 and in US patent 7,556,487 each of which is
fully incorporated herein by reference.
Exemplary treatment kits
[0062] In some exemplary embodiments of the invention, a liquid pharmaceutical
composition is provided in a treatment kit. In some embodiments, the treatment kit includes
packaging material and/or instructions for use. In some exemplary embodiments of the
invention, the instructions for use provide guidance on switching from a dose of sildenafil
citrate solid to a lower dose of sildenafil in solution.
[0063] In some embodiments, the treatment kit includes a container holding one or a
plurality of doses of a liquid pharmaceutical composition as described above and a
measuring device calibrated for measurement of a single dose from the container.
According to various exemplary embodiments of the invention, the measuring device is
configured as a cup, a spoon, or as the cap of the container. In some embodiments,
calibration markings are provided (e.g., in teaspoons or ml). Optionally, the measuring
device is to be totally filled (e.g. a spoon) one or more times. A measuring device which is
to be filled completely during use can prevent accidentally exceeding the recommended
dose. However, experimental data presented below in Example 5 (Table 3) suggests that
many patients will be taking 2 to 3 times less sildenafil citrate in solution than they would
consume in conventional tablet form. This means that even if they were to exceed the
recommended liquid dosage by as much as 50%, the risk is expected to be low.
[0064] In some embodiments, the treatment kit includes a plurality of single doses of a
liquid pharmaceutical composition as described above. According to these embodiments,
each of the single doses is contained in a separate container and the kit includes packaging
material adapted to hold said separate containers.
[0065] For example, in some embodiments of this type, the kit is configured as a box
containing single dose ampoules (e.g., of glass or wax). A kit of this type may also be
configured to hold the ampoules in an ordered array (e.g., in a line). Provision of cardboard
or paper dividers between ampoules may contribute to a reduction in breakage during
transport and/or storage.
[0066] In some embodiments, the treatment kit is configured as a package of chewing
gum with each piece of gum providing a single dose of sildenafil citrate. According to
various exemplary embodiments of the invention the chewing gum is provided as sticks of
conventional chewing gum, as cushions or as cubes. Cushions or cubes of gum are coated
in some embodiments of the invention. Alternatively or additionally, cushions or cubes of
gum are filled with a liquid center including a pharmaceutical composition according to an
embodiment of the invention as described above.
[0067] In some embodiments, the treatment kit includes a nebulizer and a plurality of
doses of a liquid pharmaceutical composition as described above and a measuring device
calibrated for measurement of a single dose from the container to be administered via the
nebulizer. According to various exemplary embodiments of the invention the measuring
device is configured as described above. In certain embodiments, the nebulizer is not
provided in the kit.
[0068] In some embodiments, the treatment kit includes a metered dose inhaler
containing a plurality of doses of a liquid pharmaceutical composition as described above.
[0069] It is expected that delivery of a liquid pharmaceutical composition as described
above via a nebulizer or metered dose inhaler will contribute to an additional reduction in
the dosage which produces a therapeutic effect.
Exemplary palatability considerations
[0070] Sildenafil citrate is bitter. Conventional solid dosage forms, such as tablets, are
typically swallowed quickly so that they are not tasted by the patient being treated. Oral
administration of a liquid composition as described above and/or buccal administration of a
dosage form including such a liquid composition make it more likely that the users will be
sensitive to the bitter taste of sildenafil citrate.
[0071] In some exemplary embodiments of the invention, inactive ingredients are
added to the composition to address this issue.
[0072] In some exemplary embodiments of the invention, a liquid pharmaceutical
composition as described above includes a flavoring agent. Flavoring agents include, but
are not limited to essential oils (e.g. lemon oil), sweeteners (e.g. sugars or sugar substitutes),
glutamates, esters and aldehydes. Alternatively or additionally, in some embodiments a
liquid pharmaceutical composition as described above includes a bitterness blocking agent.
Essential oils of tarragon (e.g., Artemesia dracunculus) and/or basil (e.g., Ocium basilicum)
have been found to be useful in blocking the bitterness of sildenafil citrate.
[0073] In some exemplary embodiments of the invention, 1 drop/ml of oil of tarragon,
oil of basil or a combination thereof is sufficient to block the bitter taste of a liquid
composition as described hereinabove and herein below (Example 5). In some
embodiments, an increase in the concentration of sildenafil citrate in the composition
contributes to a need to increase the amount of tarragon and/or basil oil in order to achieve
the desired bitterness blocking effect.
[0074] As used in this specification and the accompanying claims the term "essential
oil of tarragon" indicates CAS (Chemical Abstract Service) registry number 8016-88-4.
[0075] As used in this specification and the accompanying claims the term "essential
oil of basil" indicates CAS (Chemical Abstract Service) registry number 8015-73-4.
[0076] Alternatively or additionally, in some embodiments of the invention, one or
more inactive ingredients are added to provide a pleasant aroma and/or flavor (i.e. flavoring
agent). For example, lemon oil, vanilla extract, oil of peppermint, oil of wintergreen,
cinnamon, chocolate extract and rum extract are employed in various exemplary
embodiments of the invention.
[0077] As used in this specification and the accompanying claims the term "bitterness
blocking agent" indicates an ingredient which masks the bitter taste of sildenafil citrate. In
some exemplary embodiments of the invention, the bitterness blocking agent serves also as
a flavoring agent. In other exemplary embodiments of the invention, the bitterness blocking
agent does not impart a perceptible flavor.
[0078] Exemplary liquid pharmaceutical compositions embodying the invention
described hereinabove include alcohol and water. This makes them easily miscible with
essential oils and/or alcohol based extracts in the relevant amounts.
First exemplary method of preparation
[0079] Fig. 1 is a simplified flow diagram of an exemplary method for preparing a
liquid pharmaceutical composition as described above indicated generally as 100. Depicted
exemplary method 100 includes placing 110 sildenafil citrate in a combination consisting
essentially of one or more alcohols and water to produce a mixture and heating 120 the
mixture to produce a solution of sildenafil citrate with a concentration of at least 7 mg/ml.
[0080] As used in this specification and the accompanying claims the phrase
"consisting essentially of water and one or more alcohols" indicates that other ingredients
may be present but that none of these other ingredients would be expected to account for the
amount of sildenafil citrate dissolved in the carrier beyond the expected solubility calculated
based on the amount of water and alcohol(s). For example, "consisting essentially of water
and at least one alcohol" allows for inclusion of acetone at significant concentrations
because sildenafil citrate is considered to be insoluble in acetone. Conversely, "consisting
essentially of water and at least one alcohol" precludes significant concentrations of
dimethyl formamide or DMSO because sildenafil citrate is considered soluble in these
solvents.
[0081] As used in this specification and the accompanying claims the phrase
"pharmaceutical composition" precludes use of ingredients which are recognized as toxic or
unsafe for human consumption in the amount needed to formulate a single dosage form of
sildenafil citrate.
[0082] In some embodiments, the at least one alcohol includes ethanol. In some
embodiments, alcohol is the primary alcohol. In some embodiments, ethanol is
substantially the only alcohol.
[0083] Alternatively or additionally, in some embodiments the combination of
alcohol(s) and water includes at least 20%, at least 30%, at least 32.5%, at least 35%, at
least 37.5%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least
80% , at least 90%, at least 95% alcohol(s) or intermediate or greater percentages of the one
or more alcohols.
[0084] Alternatively or additionally, in some embodiments the combination of
alcohol(s) and water includes at least 5%, at least 10%, at least 20%, at least 30%, at least
40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at
least 80% water or intermediate or greater percentages.
[0085] In some exemplary embodiments of the invention, heating 120 is to a
temperature of at least 55 °C, at least 60 °C, at least 65 °C, at least 70 °C, at least 75 °C, or
intermediate or higher temperatures.
[0086] Alternatively or additionally, in some embodiments heating 120 is to a
temperature not exceeding 100 °C, 95 °C, not exceeding 90 °C, not exceeding 85 °C, not
exceeding 80 °C, not exceeding 75 °C or intermediate or lower temperatures.
[0087] In some exemplary embodiments of the invention, heating 120 is conducted in
an open container. In some embodiments, an open container permits evaporation of one or
more components of the mixture. In other exemplary embodiments of the invention,
heating 120 is conducted in a closed container or under a condenser. In some embodiments,
the closed container/condenser contributes to a decrease in evaporation (relative to similar
heating in an open container).
[0088] In some embodiments, the solution resulting from heating 120 has a sildenafil
citrate concentration of at least 10.0 mg/ml, at least 12.5 mg/ml, at least 15.0 mg/ml, at least
17.5 mg/ml, at least 20.0 mg/ml, at least 22.5 mg/ml, at least 25.0 mg/ml or intermediate or
higher concentrations.
[0089] In some embodiments, a volume of the solution after heating 120 is
substantially the same (not depicted) as a volume of the mixture prior to heating ( 110). One
way to achieve this is to conduct heating 120 in a closed container or under a condenser.
[0090] In other exemplary embodiments of the invention, a volume of the solution
after heating 120 is significantly reduced 123 relative to the mixture prior to heating ( 110).
One way to achieve this is to conduct heating 120 in an open container at a temperature at
which one or more components of the mixture have a significant vapor pressure.
[0091] In the depicted exemplary embodiment, method 100 includes adding 140
alcohol and/or water and/or cooling the solution 130 (e.g. to room temperature). In some
embodiments, cooling is performed by simply allowing the solution to cool. In some
embodiments, adding 140 includes adding a mixture of alcohol and water at a desired ratio.
In some embodiments, adding 140 serves to adjust the total alcohol concentration to a
desired level. In some embodiments, the mixture of alcohol and water added 140 is the
same ratio in which sildenafil citrate was originally placed 110. For example, in some
embodiments, sildenafil citrate is placed 110 in 70% EtOH, and adding 140 also employs
70% EtOH. In other exemplary embodiments of the invention, the mixture of alcohol and
water added 140 is not the same ratio in which sildenafil citrate was originally placed 110.
[0092] Alternatively or additionally, in some embodiments method 100 includes
adding 150 inactive ingredients (e.g. flavoring agents and/or bitterness blockers as
described above). Although adding 140 and adding 150 are depicted separately for clarity,
they are conducted as a single step in many embodiments. Essential oils are easily miscible
in alcohol/water combinations so that inactive ingredients can be incorporated into an
alcohol/water combination employed at 140.
Second exemplary method of preparation
[0093] Fig. 2 is a simplified flow diagram of an exemplary method for preparing a
liquid pharmaceutical composition as described above indicated generally as 200. Depicted
exemplary method 200 includes providing 210 a first volume of a ketone and adding 220 a
second volume consisting essentially of one or more alcohols and water (e.g., as a
combination or mixture) to produce a total volume of solution and dissolving 225 sildenafil
citrate at a concentration of at least 7 mg/ml, at least 10 mg/ml or at least 12.5 mg/ml with
respect to the total volume. According to various exemplary embodiments of the invention
dissolving 225 is in said first volume at 210 and/or in said total volume at 220. It is
important to note that in many embodiments of method 200, all of the sildenafil citrate goes
into solution without heating. MR assays (see Fig. 3 and Example 4) confirmed that
sildenafil citrate was unchanged by dissolution.
[0094] Some embodiments of method 200 include heating 230 the solution at a
temperature not less than 10 °C below the boiling point, not less than 5 °C below the boiling
point, not less than 2.5 °C below the boiling point, not less than the boiling point of the
ketone or intermediate or higher temperatures. Alternatively or additionally, in some
embodiments method 200 includes heating to a temperature at least 5° C above a boiling
point, at least 7.5 0 C above a boiling point, at least 10° C above a boiling point, at least
15° C above a boiling point of said ketone or intermediate or higher temperatures.
[0095] In some embodiments, method 200 includes continuing 240 heating 230 until at
least 25%, at least 50%, at least 55%, at least 60%, at least 70%, at least 80%, at least 85%,
at least 90%, at least 95%, at least 97.5%, at least 99%, at least 99.5% , at least 99.75% or
intermediate or greater percentages of the ketone evaporate.
[0096] In other exemplary embodiments of the invention, at least 25%, at least 50%, at
least 55%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%,
at least 97.5%, at least 99%, at least 99.5%, at least 99.75% or intermediate or greater
percentages of the ketone are removed by evaporation without heating (e.g., by application
of vacuum).
[0097] In other exemplary embodiments of the invention, at least 25%, at least 50%, at
least 55%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%,
at least 97.5%, at least 99%, at least 99.5%, at least 99.75% or intermediate or greater
percentages of the ketone are removed by solvent extraction.
[0098] In some embodiments, the sildenafil citrate in solution at 220 has a
concentration of at least 25 mg/ml, at least 30 mg/ml, at least 35 mg/ml, 40 mg/ml, at least
50 mg/ml, at least 55 mg/ml or intermediate or higher concentrations.
[0099] In some embodiments, the alcohol in the second volume (220) includes ethanol,
is primarily ethanol or is substantially all ethanol.
[0100] Alternatively or additionally, in some embodiments the combination of one or
more alcohols and water in the second volume (220) includes at least 20 % alcohol, at least
30% alcohol, at least 32.5% alcohol, at least 35% alcohol, at least 37.5% alcohol, at least
40% alcohol or intermediate or greater percentages. Alternatively or additionally, in some
embodiments the combination of an alcohol and water in the second volume (220) includes
at least 60%, at least 62.5%, at least 65%, at least 67.5%, at least 70%, at least 72.5%, at
least 7 5% water or intermediate or greater percentages.
[0101] In some embodiments, a volume of the solution after heating 230 is 50% or less
of the volume of the solution prior to heating.
[0102] In the depicted exemplary embodiment, method 200 includes cooling 250 (e.g.,
to room temperature) the solution and/or adding 260 an alcohol and/or water to a total
alcohol concentration of at least 20%, at least 30%>, at least 34%, at least 40%, at least 50%,
at least 60%, at least 62.5%, at least 65%, at least 67.5%, at least 70.0%, at least 72.5%, at
least 7 5% or intermediate concentrations. Adding 260 is similar to adding 140 (Fig. 1) as
described hereinabove and similar considerations apply. In some embodiments, cooling is
performed by simply allowing the solution to cool.
[0103] In some embodiments, inactive ingredients are added 270. Adding 270 is
similar to adding 150 (Fig. 1) as described hereinabove and similar considerations apply.
Additional exemplary compositions
[0104] Some embodiments of the invention relate to a pharmaceutical composition
including a liquid carrier with water, ethanol, and less than 30% acetone and sildenafil
citrate dissolved in the liquid carrier at a concentration of at least 10 mg/ml, at least 20
mg/ml, at least 25 mg/ml, at least 30 mg/ml, at least 35 mg/ml, at least 40 mg/ml, at least 45
mg/ml, at least 50 mg/ml, at least 55 mg/ml or intermediate or greater concentrations. In
some embodiments, the concentration of acetone is less than 25% or less than 20%.
[0105] In some embodiments, the ethanol concentration is less than 90%, less than
80%, less than 70%, less than 60%, less than 50%, less than 45%, less than 40%, less than
3 5%, less than 30% or less than 25%. Alternatively or additionally, in some embodiments
the composition contains at least 5%, at least 10%, at least 20%, at least 30%, at least 40%,
at least 50%, at least 52.5%, at least 55%, at least 60%, at least 70% or intermediate or
greater percentages of water.
[0106] In some embodiments, the acetone concentration is well below 20%. For
example, acetone levels in the range of 5 to 7%were achieved (see Table 2 in Example 3).
[0107] Some embodiments of the invention relate to a pharmaceutical composition
including a liquid carrier consisting essentially of water and at least one alcohol and
sildenafil citrate dissolved in the liquid carrier at a concentration of at least 7 mg/ml.
According to various exemplary embodiments of the invention the at least one alcohol
includes ethanol, is primarily ethanol or is substantially only ethanol. Alternatively or
additionally, in some embodiments the carrier includes residual ketone (e.g., acetone) from
a preparation method which employs a ketone. An exemplary method 200 employing a
ketone is described hereinabove in the context of Fig. 2 .
[0108] Some embodiments of the invention relate to a pharmaceutical composition
including sildenafil citrate in a liquid carrier and a bitterness blocker comprising one or
more essential oils derived from a plant selected from the group consisting of tarragon and
basil. In some embodiments, the sildenafil citrate is in solution. In other embodiments the
sildenafil is in suspension.
[0109] These additional exemplary composition types are also provided as buccal
dosage forms and/or treatment kits as described above in additional exemplary
embodiments of the invention.
Exemplary treatment method
[0110] Fig. 4 is a simplified flow diagram of an exemplary treatment method for
erectile dysfunction indicated generally as 400.
[0111] Depicted exemplary method 400 includes identifying 410 a patient taking a
customary dose of sildenafil citrate in solid form for erectile dysfunction and treating 420
said patient for erectile dysfunction with sildenafil citrate in solution using a reduced dose
which is less than 50% of the customary dose.
[0112] In some exemplary embodiments of the invention, the sildenafil citrate is in
solution in a liquid carrier including one or more alcohols and water. According to various
exemplary embodiments of the invention the one or more alcohols include ethanol, include
primarily ethanol or is substantially all ethanol.
[0113] Alternatively or additionally, in some embodiments the liquid carrier includes a
ketone (e.g., acetone).
[0114] According to various exemplary embodiments of the invention the reduced
dose is delivered in a volume of less than 15 ml, less than 10 ml, less than 5 ml, less than 3
ml, less than 2 ml or intermediate or smaller volumes. According to various exemplary
embodiments of the invention administration of the reduced dose is via an oral or a buccal
route. Buccal dosage forms and/or treatment kits as described hereinabove are a convenient
way to provide the reduced dose.
[0115] It is expected that during the life of this patent many dosage forms for
pharmaceutically active ingredients in liquid form will be developed and the scope of the
invention is intended to include all such new dosage forms apriori.
[0116] Alternatively or additionally, it is expected that during the life of this patent
many carriers for buccal administration of pharmaceutically active ingredients will be
developed and the scope of the invention is intended to include all such carriers apriori.
[0117] As used herein the term "about" refers to ± 10 %.
[0118] Although the invention has been described in conjunction with specific
embodiments thereof, it is evident that many alternatives, modifications and variations will
be apparent to those skilled in the art. Accordingly, it is intended to embrace all such
alternatives, modifications and variations that fall within the scope of the appended claims.
[0119] Specifically, a variety of numerical indicators have been utilized. It should be
understood that these numerical indicators could vary even further based upon a variety of
engineering principles, materials, intended use and designs incorporated into the various
embodiments of the invention. Additionally, components and/or actions ascribed to
exemplary embodiments of the invention and depicted as a single unit may be divided into
subunits. Conversely, components and/or actions ascribed to exemplary embodiments of
the invention and depicted as sub-units/individual actions may be combined into a single
unit/action with the described/depicted function.
[0120] Alternatively, or additionally, features used to describe a method can be used to
characterize an apparatus and features used to describe an apparatus can be used to
characterize a method.
[0121] It should be further understood that the individual features described
hereinabove can be combined in all possible combinations and sub-combinations to produce
additional embodiments of the invention. The examples given above are exemplary in
nature and are not intended to limit the scope of the invention.
[0122] Each recitation of an embodiment of the invention that includes a specific
feature, part, component, module or process is an explicit statement that additional
embodiments not including the recited feature, part, component, module or process exist.
[0123] Specifically, the invention has been described in the context of ethanol and
water, or ethanol, water and acetone but might also be used with other alcohols and/or other
ketones.
[0124] All publications, references, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by reference into the specification, to
the same extent as if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein by reference. In addition,
citation or identification of any reference in this application shall not be construed as an
admission that such reference is available as prior art to the present invention.
[0125] The terms "include," and "have" and their conjugates as used herein mean
"including but not necessarily limited to."
[0126] Additional objects, advantages, and novel features of various embodiments of
the invention will become apparent to one ordinarily skilled in the art upon examination of
the following examples, which are not intended to be limiting. Additionally, each of the
various embodiments and aspects of the present invention as delineated hereinabove and as
claimed in the claims section below finds experimental support in the following examples.
EXAMPLES
[0126] Reference is now made to the following examples, which together with the
above descriptions; illustrate the invention in a non limiting fashion.
EXAMPLE 1:
[0126] Preparation of sildenafil citrate solutions at high concentration.
[0126] In order to demonstrate the feasibility of dissolving sildenafil citrate at high
concentrations in a combination of solvents that are considered separately as poor solvents
for the compound, a series of ten experiments using ethanol (EtOH), water and acetone in
various proportions was conducted. In each of experiments 1 to 6, 250 mg of sildenafil
citrate (Teva Pharmaceuticals; Israel) was dissolved in a mixture of acetone and
EtOH/water as indicated in Table 1 and heated at 70 to 77 °C for 10 minutes in an open
container.
[0126] In experiment 7 - 10, 150 - 250 mg of sildenafil citrate (Teva Pharmaceuticals;
Israel) was dissolved in 70% EtOH/water and heated at 70 to 77 °C for 10 minutes in a
closed container. Results presented in Table 1 indicate that it is possible to achieve initial
concentrations of 12.5 mg/ml of Sildenafil citrate in solution without heating (Experiments
1, 2 and 6) and up to 25 mg/ml with heating (Experiment 7).
[0126] In addition, as heating continued and the volume of solvent mixture decreased,
the sildenafil citrate remained in solution at concentrations as high as 35.7 mg/ml. Due to
the relative vapor pressures of the components of the liquid mixture, the relative proportion
of water in the mixture increased as the volume decreased.
[0126] Some solutions were filtered using filter paper and/or 0.22 microns membrane
filters with no visible residue. This example illustrates that the solubility of Sildenafil
citrate in EtOH/water, or EtOH/water with small amounts of residual acetone, is far greater
than its solubility in water or EtOH or acetone alone.
Table 1 : solubility of sildenafil citrate in EtOH/water mixtures with and without acetone
dissolution and heating in closed container to prevent evaporation
EXAMPLE 2 :
[0127] Stability of sildenafil citrate solutions.
[0128] The volume of each solution from experiments 1 to 7 in Example 1 was
adjusted to 10 ml with 60% EtOH (Experiment 1) or 70% EtOH (Experiments 2-7) to
produce a clear solution with a concentration of 25 mg/ml. After 24 hours all solutions
remained clear. Some of these solutions have remained clear for two years. Some solutions
were filtered using filter paper and/or 0.22 microns membrane filters with no visible
residue.
[0129] In order to assess the stability of these further they were subjected to freezing at
minus 18 °C and thawing. The solution from experiment 7 exhibited a slight degree of
sedimentation after thawing. The solutions from experiment 1 to 6 remained clear after
thawing. The solutions from experiments 3, 6, and 9 & 10 remained clear after 3 cycles of
freezing and thawing. Solutions 9 and 10 remained clear after 6 months. This example
illustrates that the solubility of sildenafil citrate is not diminished by freezing and thawing
and suggests that the solutions will have a significant shelf life (e.g. 2 years or more).
EXAMPLE 3 :
[0130] Solvent concentrations after heating.
[0131] In order to assess the solvent concentrations in the sildenafil citrate solutions
after heating, samples were sent to an independent laboratory for GC/MS (Gas
Chromatography/Mass Spectroscopy) analysis. Three samples were prepared as follows:
[0132] Sample A: 250 mg sildenafil citrate + 10 ml acetone + 10 ml 70% EtOH in
water was heated to 77 °C for 7 min., till volume reduced to 5 ml (50 mg/ml). 70% EtOH in
water was added to bring the volume to 10 ml (25 mg/ml).
[0133] Sample B : 500 mg sildenafil citrate + 10 ml acetone + 10 ml 70% EtOH in
water was heated to 77 °C for 7 min., till volume reduced to 5.1 ml (98 mg/ml). 70% EtOH
in water was added to bring the volume to 10 ml (50 mg/ml).
[0134] Sample C: 10 ml acetone + 10 ml 70% EtOH in water was heated to 77 °C for 7
min., till volume reduced to 5.3 ml. 70% EtOH in water was added to bring the volume to
10 ml.
[0135] Sample C served as a control to see if the sildenafil citrate influenced relative
evaporation rates of the different solvents.
[0136] Results presented in Table 2 indicate that small but measurable amounts of
acetone remained after heating until volume had been reduced by 75% at a temperature well
above the boiling point of acetone. The actual acetone concentration remaining in the
samples was approximately double the percentage in table 2, since the samples were diluted
after heating with an acetone free solution. Similarly, results presented in Table 2 indicate
that measurable amounts of EtOH remained after heating until volume had been reduced by
7 5% at a temperature well above the boiling point of EtOH. The actual EtOH concentration
remaining in the samples was actually much less than the percentage indicated by GC/MS,
since the samples were diluted after heating with 70% EtOH. The number in parentheses
indicates the EtOH% resulting from this dilution.
Table 2 : solvent percentages after heating as analyzed by GC/MS
[0137] Preparation of samples A and B indicates that it is possible to achieve
concentration of 50 to 100 mg/ml of sildenafil citrate in solution. The pH of solutions A, B
and C was in the range of 4.4 to 4.55.
[0138] This example illustrates that the achieved solution concentrations of sildenafil
citrate cannot be accounted for by the nominal solubility of that compound in any of the
three components of the solvent mixture.
[0139] Sample B was not stable long term. During shipping to the outside laboratory
that performed the GC/MS some sedimentation had occurred (apparently due to freezing (at
up to -55 degrees Celsius) in transit). Warming prior to testing re-dissolved the sediment.
EXAMPLE 4:
[0140] Stability of Sildenafil citrate during heating.
[0141] In order to confirm that sildenafil remained unchanged by heating in solvent
mixtures as described in Examples 1 and 3, samples that were solubilized as described
above were subject to NMR analysis using commercially available sildenafil citrate (Teva
Pharmaceuticals; Israel) dissolved in DMSO as a control.
[0142] Representative NMR results are shown in Fig. 3 . In the figure, one trace is
sildenafil citrate in solution according to an exemplary embodiment of the invention and the
other trace is the control material. The two traces are substantially identical.
[0143] This example illustrates that the protocols described above cause no chemical
change in sildenafil citrate.
EXAMPLE 5:
[0144] Exemplary case studies.
[0145] In order to evaluate the efficacy of sildenafil citrate solutions according to
exemplary embodiments of the invention in human subjects the following solutions were
prepared:
[0146] Solution 1 - sildenafil citrate was dissolved in equal volumes of 70% EtOH and
acetone and heated in an open container to allow evaporation of about 65% of the initial
volume. The resultant concentrated solution was diluted with 70% EtOH to produce a final
concentration of 20 mg/ml of sildenafil citrate.
[0147] Solution 2 - sildenafil citrate was heated in 70% EtOH in a closed container
resulting in a final concentration of 15 mg/ml of sildenafil citrate.
Table 3 : Human subjects
[0148] Subject A was a regular user of VIAGRA® 50 mg pills for approximately one
year. A 1ml dose of solution 1 according to an exemplary embodiment of the invention
produced the same therapeutic effect with a dosage reduction of 2.5X. Furthermore,
solution 1 according to an exemplary embodiment reportedly produced onset of action in 10
minutes, as opposed to approximately 30 to 40 minutes using VIAGRA® 50 mg pills.
[0149] Subject B was a regular user of VIAGRA® 100 mg pills for erectile
dysfunction. A 1.5 ml dose of solution 1 according to an exemplary embodiment of the
invention produced the same therapeutic effect with a dosage reduction of more than 3 .OX.
Subject B also reported no headaches using solution 1 according to an exemplary
embodiment of the invention although VIAGRA® pills caused headaches. Subject B also
reported onset of action in 10 - 15 minutes, about half the time it took for onset of action
using pills.
[0150] Subject C had regularly used VIAGRA® 100 mg pills over a period of 5 years.
He achieved equivalent therapeutic effect using 2 ml (30 mg active ingredient) of Solution 2
according to an exemplary embodiment of the invention. Like subject B, he reported no
headaches whereas VIAGRA ® pills caused headaches. Like the other two subjects, he
reported onset of action in 10 to 15 minutes, about half to a third of the time it took for
onset of action using VIAGRA ® pills.
[0151] These results suggest increased efficacy/unit of sildenafil citrate in solution
administered orally according to exemplary embodiments of the invention relative to
conventional tablet dosage forms. This suggests increased bioavailability. In addition,
sildenafil citrate in solution administered orally appears to produce fewer side effects. It is
not clear if this is due to the lower dosages or other factors. Alternatively or additionally,
onset of action using sildenafil citrate in solution administered orally produced a more rapid
onset of therapeutic effect than conventional solid dosage forms, despite the lower dose.
[0152] Solutions 1 and 2 contained essential oils as described above to block
bitterness. Subjects A, B and C found the taste of the solutions acceptable.
EXAMPLE 6:
[0153] Preparation of additional sildenafil citrate solutions at high concentration
[0154] In order to investigate the contribution of alcohol and water for dissolving
sildenafil citrate at high concentrations an additional series of ten experiments using ethanol
(EtOH) and water in various proportions was conducted with 50% acetone in the initial
composition. In this series of experiments, sildenafil citrate was dissolved in an initial
volume of a liquid carrier and heated at 70 to 77 °C to reduce the volume. As in Example 1,
as the volume decreased, the relative proportion of water in the mixture increased.
[0155] Results presented in table 4 indicate that it is possible to achieve a
concentration of 12.5 mg/ml to 37.5 mg/ml by adding sildenafil citrate to a mixture that is
half acetone and half 30% to 60% EtOH. No heat was required to produce solutions with
these initial concentrations in any of the experiments. Heating these mixtures until the
volume was reduced to 7 ml produced solutions with concentrations of 35 mg/ml to 107
mg/ml.
Table 4 : solubility of sildenafil citrate in EtOH/water mixtures at various ratios with acetone
[0156] This example illustrates that it is possible to decrease the amount of alcohol
used relative to Example 1.
EXAMPLE 7:
[0157] Stability of additional sildenafil citrate solutions.
[0158] The volume of each solution from experiments 1 to 10 in Example 6 was
adjusted to 10 ml with the same EtOH/water mixture used to prepare the initial
composition. In all ten experiments the resultant solution was clear. Adjusted
concentrations were 25 mg/ml to 75 mg/ml. After 24 hours at room temperature, these
solutions exhibited varying degrees of cloudiness and/or sedimentation.
[0159] This example illustrates that development of commercially relevant exemplary
embodiments based on experiments 1 to 10 in the previous example may employ stabilizing
agents to keep the sildenafil citrate in solution.
[0160] Known stabilizing agents include, but are not limited to: Diacetylated
monoglycerides, diethyl glycol monopalmitostearate, glyceryl behenate, glyceryl distearate,
glyceryl monolinoleate, glyceryl mono-oleate, glyceryl monostearate, self emulsifying
glyceryl monostearate. macrogol cetostearyl ethers, cetomacrogol 1000, 9 polyoxyl 20
cetostearyl ether, macrogol 15 hydroxystearate, macrogol lauril ethers, laureth 4,
lauromacrogol 400, macrogol monomethyl ethers, macrogol oleyl ethers, polyoxyl 10 oleyl
ether, macrogol stearates, polyoxyl 40 stearates, menfegol, mono & di glycerides,
nonoxinols, octoxinols, poloxamers, polyoxyl castor oil, polyoxyl hydrogenated castor oils,
polysorbates, propylen glycol diacetate, propylen glycol laureates, propylen glycol
dilaurate, propylen glycol mono laureate, propylen glycol monopalmitostearate, quillaia,
sorbitan esters, sucrose esters, tyloxapol, carrageenan, cellulose, ceratonia, dextrates,
ethylcellulose, gastric mucin, hyprolose, hypromellose, hypermellose phthalate,
methylcellulose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, silicas, sodium
starch glycolate, tragacanth, xanthan gum.
EXAMPLE 8:
[0161] Sildenafil citrate solutions with varying amounts of acetone. In order to
investigate the contribution of acetone for dissolving sildenafil citrate at high concentrations
an additional series of thirteen experiments using ethanol (EtOH) and water in various
proportions with relatively small amounts of acetone was conducted.
[0162] In this series of experiments, sildenafil citrate was dissolved in an initial
volume of a liquid carrier and heated at 70 to 77 °C either to dissolve the sildenafil citrate
(experiments 6 and 13) or to reduce the volume (experiment 1-5 and 7-12). In this series of
experiments, the initial volume was 10 ml and heating was continued until the volume was
reduced to 9 ml (experiments 1-5) or 7 ml (experiments 7-12). As in Example 1, as the
volume decreased, the relative proportion of water in the mixture increased.
[0163] In this series of experiments, heating was required for initial dissolution of the
sildenafil citrate at initial concentrations of 16.7 mg/ml to 50 mg/ml. Results summarized
in table 5 indicate that it was possible to achieve an initial concentration of 40 mg/ml using
10% acetone (experiment 6); 50 mg/ml using 2% to 8% acetone in 50% to 70% EtOH
(experiments 3 to 5) and 25 mg/ml using 6.3% acetone in 35% EtOH (experiment 13).
[0164] In each of the thirteen experiments in this example the sildenafil citrate was in
solution at the end of the heating.
Table 5 : solubility of sildenafil citrate in EtOH/water mixtures at various ratios with acetone
*Heated at 70-77°C only to point of dissolution
EXAMPLE 9:
[0165] Stability of low acetone sildenafil citrate solutions. The volume of each
solution from experiments 1 to 13 in Example 8 was adjusted to 10 ml with 50%
EtOH/water (experiments 1 to 4); 70% EtOH/water (experiments 5, 7, 8 and 9 to 13) and
95% EtOH/water (experiment 6). In all thirteen experiments the resultant solution was clear.
Concentrations were 25 mg/ml to 50 mg/ml.
[0166] After 24 hours at room temperature, some solutions exhibited sedimentation but
the diluted solutions from experiments 10 to 13 remained clear. This example illustrates
that it is possible to decrease the amount of acetone used relative to Example 1.
EXAMPLE 10:
[0167] Sildenafil citrate solutions without ketone. In order to investigate the
possibility of dissolving sildenafil citrate at high concentrations in alcohol/water mixtures
without a ketone, an additional series of eight experiments using ethanol (EtOH) and water
in various proportions with no acetone was conducted.
[0168] In this series of experiments, sildenafil citrate was placed in 10 ml of
EtOH/water and heated at 70 to 77 °C to dissolve the sildenafil citrate (experiments 1 to 8)
and/or to reduce the volume (experiments 1 to 5) or heated at 70 to 77 °C in a closed
container to dissolve the sildenafil citrate while preventing evaporation (experiments 6 to
8). As in Example 1, if heating was conducted in an open container, as the volume
decreased, the relative proportion of water in the mixture increased.
[0169] In this series of experiments, heating was required for initial dissolution of the
sildenafil citrate at initial concentrations of 25 mg/ml to 50 mg/ml. Results summarized in
table 6 indicate that it was possible to achieve a final concentration of 55.6 mg/ml without
acetone by performing the initial dissolution in 50% to 70% EtOH (experiments 2 and 3)
and 50 mg/ml without acetone by performing the initial dissolution 35% EtOH (experiment
7). In each of the eight experiments in this example the sildenafil citrate was in solution at
the end of the heating.
Table 6: solubility of sildenafil citrate in EtOH/water mixtures at various ratios without acetone
EXAMPLE 11:
[0170] Stability of acetone free sildenafil citrate solutions.
[0171] The volume of each solution from experiments 1 to 8 in Example 10 was
adjusted to 10 ml with 50% EtOH/water (experiments 1 and 2) and 70% EtOH/water
(experiments 3 to 5). No adjustment of volume was needed in experiments 6 to 8 . In all 8
experiments the resultant solution was clear. Concentrations were 25 mg/ml to 50 mg/ml.
After 24 - 48 hours at room temperature, some solutions exhibited sedimentation and/or
cloudiness but the diluted solution from experiment 4 remained clear.
[0172] This example illustrates that solutions of sildenafil citrate at concentrations well
above those reported in the literature for water or ethanol can be achieved using a mixture
of water and ethanol and heating.
[0173] Experiments with similar compounds such as tadalafil or vardenafil using the
same methodology described above were not successful in yielding stable solutions.

CLAIMS
What is claimed is:
1. A pharmaceutical composition comprising:
(a) a liquid carrier comprising water and at least 20% of at least one alcohol; and
(b) sildenafil citrate dissolved in said liquid carrier at a concentration of at least
7 mg/ml.
2 . A pharmaceutical composition according to claim 1, wherein said liquid carrier
comprises at least 5% water.
3 . A pharmaceutical composition according to claim 2, wherein said liquid carrier
comprises at least 30% water.
4 . A pharmaceutical composition according to claim 1, wherein said concentration of
sildenafil citrate dissolved in said liquid carrier is at least 12.5 mg/ml.
5 . A pharmaceutical composition according to claim 4, wherein said concentration of
sildenafil citrate dissolved in said liquid is at least 20 mg/ml.
6 . A pharmaceutical composition according to claim 1, wherein said at least one
alcohol includes ethanol.
7 . A pharmaceutical composition according to claim 1, wherein said liquid carrier
comprises a ketone.
8 . A pharmaceutical composition according to claim 7, wherein said ketone includes
acetone.
9 . A pharmaceutical composition according to claim 7, wherein said liquid carrier
comprises more than 3% ketone.
10. A pharmaceutical composition according to claim 8, wherein said concentration of
said sildenafil citrate dissolved in said liquid is at least 25 mg/ml.
11. An oral dosage form comprising:
an outer coating; and
a liquid core comprising a pharmaceutical composition according to claim 1.
12. A buccal dosage form comprising:
a carrier containing a pharmaceutical composition according to claim 1; and a
wrapper adapted to prevent evaporation of said liquid carrier during storage.
13. A treatment kit comprising:
a container holding a plurality of doses of a pharmaceutical composition according
to claim 1; and
a measuring device calibrated for measurement of a single dose from said container.
14. A treatment kit comprising:
a single or a plurality of single doses of a pharmaceutical composition according to
claim 1, each of said single doses contained in a separate container; and
packaging material adapted to hold said separate containers.
15. A pharmaceutical composition according to claim 1, comprising a flavoring agent.
16. A pharmaceutical composition according to claim 1, comprising a bitterness
blocking agent.
17. A method comprising:
(a) placing sildenafil citrate in a combination consisting essentially of one or
more alcohols and water to produce a mixture; and
(b) heating said mixture to produce a solution of said sildenafil citrate with a
concentration of at least 7 mg/ml.
18. A method according to claim 17, wherein said heating is to a temperature of at least
65 °C.
19. A method according to claim 17, wherein said heating is to a temperature not
exceeding 85 °C.
20. A method according to claim 17, wherein said heating is conducted in an open
container.
21. A method according to claim 17, wherein said heating is conducted in a closed
container.
22. A method according to claim 17, wherein said solution of said sildenafil citrate has a
concentration of at least 12.5 mg/ml.
23. A method according to claim 17, wherein said one or more alcohols includes
ethanol.
24. A method according to claim 17, wherein said combination of one or more alcohols
and water includes at least 20% alcohol.
25. A method according to claim 17, wherein said combination of one or more alcohols
and water includes at least 5% water.
26. A method according to claim 17, wherein a volume of said solution after heating is
substantially the same as a volume of said mixture prior to heating.
27. A method according to claim 17, wherein a volume of said solution after heating is
significantly less than a volume of said mixture prior to heating.
28. A method according to claim 17, comprising:
cooling said solution and adding alcohol and/or water.
29. A method comprising:
(a) providing a first volume of a ketone; and
(b) adding a second volume consisting essentially of one or more alcohols and water to
produce a total volume of solution; and
(c) dissolving sildenafil citrate at a concentration of at least 7 mg/ml with respect to said
total volume.
30. A method according to claim 29, comprising:
heating said solution at a temperature not less than 5 °C below the boiling point of
said ketone.
31. A method according to claim 30, wherein said heating is to a temperature at least 5 0
C above a boiling point of said ketone.
32. A method according to claim 31, wherein said heating is to a temperature at least 10
0 C above a boiling point of said ketone.
33. A method according to claim 30, comprising removing at least 25% of said ketone.
34. A method according to claim 29, wherein said sildenafil citrate in said solution has a
concentration of at least 25 mg/ml.
35. A method according to claim 29, wherein said one or more alcohols includes
ethanol.
36. A method according to claim 29, wherein said combination of one or more alcohols
and water includes at least 20% alcohol.
37. A method according to claim 29, wherein said combination of one or more alcohols
and water includes at least 5% water.
38. A method according to claim 30, wherein a volume of said solution after heating is
50% or less of the volume of the solution prior to heating.
39. A method according to claim 30, comprising:
cooling said solution and adding alcohol(s) and/or water to a total alcohol
concentration of at least 34%.
40. A pharmaceutical composition comprising:
(a) a liquid carrier comprising water, ethanol, and less than 20% acetone; and
(b) sildenafil citrate dissolved in said liquid carrier at a concentration of at least
10 mg/ml.
4 1. A pharmaceutical composition comprising:
(a) a liquid carrier consisting essentially of water and at least 20% of at least one
alcohol; and
(b) sildenafil citrate dissolved in said liquid carrier at a concentration of at least
7 mg/ml.
42. A pharmaceutical composition according to claim 41, wherein said liquid carrier
comprises at least 5% water.
43. A pharmaceutical composition according to claim 42, wherein said liquid carrier
comprises at least 30% water.
44. A pharmaceutical composition according to claim 41, wherein said concentration of
sildenafil citrate dissolved in said liquid carrier is at least 12.5 mg/ml.
45. A pharmaceutical composition according to claim 44, wherein said concentration of
sildenafil citrate dissolved in said liquid is at least 20 mg/ml.
46. A pharmaceutical composition according to claim 41, wherein said at least one
alcohol includes ethanol.
47. A pharmaceutical composition according to claim 41, wherein said liquid carrier
comprises a ketone.
48. A pharmaceutical composition according to claim 47, wherein said ketone includes
acetone.
49. A pharmaceutical composition according to claim 47, wherein said liquid carrier
comprises more than 3% ketone.
50. A pharmaceutical composition according to claim 48, wherein said concentration of
said sildenafil citrate dissolved in said liquid is at least 25 mg/ml.
51. An oral dosage form comprising:
an outer coating; and
a liquid core comprising a pharmaceutical composition according to claim 41.
52. A buccal dosage form comprising:
a carrier containing a pharmaceutical composition according to claim 41; and a
wrapper adapted to prevent evaporation of said liquid carrier during storage.
53 . A treatment kit comprising:
a container holding a plurality of doses of a pharmaceutical composition according
to claim 41; and
a measuring device calibrated for measurement of a single dose from said container.
54. A treatment kit comprising:
a plurality of single doses of a pharmaceutical composition according to claim 41,
each of said single doses contained in a separate container; and
packaging material adapted to hold said separate containers.
55. A pharmaceutical composition according to claim 41, comprising a flavoring agent.
56. A pharmaceutical composition according to claim 41, comprising a bitterness
blocking agent.
57. A pharmaceutical composition comprising:
(a) a liquid carrier consisting essentially of water, ethanol, and less than 20%
acetone; and
(b) sildenafil citrate dissolved in said liquid carrier at a concentration of at least
10 mg/ml.