HK1230870A1 - Sildenafil solutions and methods of making and using same - Google Patents

Description

Sildenafil solutions and methods of making and using the same

Technical Field

Various exemplary embodiments of the present invention relate to pharmaceutical compositions containing sildenafil citrate as an active ingredient and to methods of producing and/or administering such compositions.

Background

Sildenafil in the citrate form is approved by the FDA and EMEA for the treatment of erectile dysfunction and Pulmonary Arterial Hypertension (PAH).

Sildenafil citrate has also been reported for use in indications not approved by clinical trials including, but not limited to, prevention of high altitude disease-associated hyperplastic pulmonary edema, treatment of pulmonary fibrosis, primary pulmonary hypertension, secondary pulmonary hypertension, hypoxia-induced pulmonary hypertension, neonatal pulmonary hypertension, pediatric pulmonary hypertension, inoperable chronic thromboembolic pulmonary hypertension, severe coronary artery disease, age-related macular degeneration, brachial artery blood flow-mediated dilatation (in type 2 diabetes), raynaud's syndrome, anal fissure, postmenopausal female sexual dysfunction, female sexual arousal disorder, digital ulcer-secondary systemic sclerosis, migraine, premature ejaculation, sickle cell disease with pulmonary hypertension, achalasia (esophageal motor dysfunction), severe digital ischemia, repeated ischemic penile erectile dysfunction, peripheral vascular disorder, and other conditions including but not limited to prevention of high altitude disease, severe lymphangiogenesis, congestive heart failure, diastolic dysfunction, tunica vaginalis fibrosis, multiple sclerosis, intrauterine growth restriction, chronic pelvic pain, alzheimer's disease, stroke, preeclampsia, gastroparesis, poor blood glucose control in diabetic patients, primary dysmenorrhea pain, for increasing exercise capacity in hypoxia, increasing uterine arterial blood flow and endometrial thickness to facilitate In Vitro Fertilization (IVF).

Sildenafil citrate has also been proposed for use as a treatment for prostate cancer, pancreatic cancer, ovarian cancer, gastric cancer, obesity, crohn's disease, spastic esophageal disorders, alleviation of alcohol-induced gastric damage and other conditions.

Sildenafil citrate is usually formulated as(for treating erectile dysfunction) and(for treatment of pulmonary hypertension), both manufactured by Pfizer Pharmaceuticals. A general version of sildenafil citrate is also available.Usually in 25mg, 50mg or 100mg tablets and not more than once daily for 0.5 to 4 hours prior to intercourse.Most commonly, 20mg tablets are administered 3 times a day.It is also available as an injectable form of a clear, colorless, sterile ready-to-use solution containing 10mg of sildenafil citrate per 12.5ml of solution. Each ml of solution contained 1.124mg of sildenafil citrate, 50.5mg of dextrose and water for injection.

In injectable formMost commonly, intravenous administration is used. This route of administration is practical in a hospital setting but not feasible outside a hospital or clinical setting.

In the European Union, sildenafil citrate is also available in the form of oral suspensions at a concentration of 10 mg/ml.POS (powder for oral suspension) was supplied by Pfizer (Pfizer) to make oral suspensions. Additional ingredients in the POS include colloidal silica, sucralose, sorbitol, sodium benzoate, sodium citrate, flavoring agents, and xanthan gum. The active ingredient in the form of a suspension has a slower absorption rate than would be expected for a solution having the same concentration. Furthermore, the presence of some additional ingredients makes it difficult for people with known sensitivities to these ingredients to tolerate this product.

Whether provided in the form of tablets or oral suspensions, sildenafil citrate exhibits an absolute bioavailability of about 41% and is reported to produce maximum observed plasma concentrations within 30 minutes to 120 minutes following oral administration in the fasting state. Absorption rates are reported to decrease if high fat foods are ingested.

According to the relation toThe US drug Specification of (1), sildenafil citrate has a solubility in water of 3.5 mg/ml. EMEA CHMP assessment for Vizarsin (International Nonber: sildenafil)The report indicated that it was insoluble in ethanol, chloroform and acetone, but soluble in methanol and Dimethylsulfoxide (DMSO). Jordan pharmaceutical Manufacturing Co reports sildenafil citrate to be 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 first-pass elimination each independently contribute to its low oral bioavailability.

Disclosure of Invention

The present invention relates in a broad aspect to the use of sildenafil citrate as a pharmaceutically active ingredient.

An aspect of some embodiments of the invention relates to increasing the bioavailability of sildenafil citrate. In some exemplary embodiments of the invention, the bioavailability of sildenafil citrate is increased by providing sildenafil citrate in solution at a concentration of 7mg/ml, 10mg/ml, 20mg/ml, 25mg/ml, 30mg/ml, 35mg/ml, 40mg/ml or 45mg/ml or an intermediate or greater concentration. As used in this specification and the appended claims, the terms "in solution," "dissolved," "soluble," and variations thereof mean the transparency of the particles to light without visible to the naked eye.

An aspect of some embodiments of the invention relates to dissolving sildenafil citrate in water mixed with one or more alcohols. In some exemplary embodiments of the invention, the one or more alcohols comprise ethanol. In some exemplary embodiments of the invention, a ketone (e.g., acetone) is provided along with water and an alcohol. In some exemplary embodiments of the invention, the solution is delivered to the patient in the form of a spray. In some embodiments, the aerosol is delivered to the trachea and/or lungs using a nebulizer or metered dose inhaler.

Another aspect of some embodiments of the invention relates to a method of treatment for erectile dysfunction that relies on a dose of sildenafil citrate that is less than half of the dose that patients routinely take. In some exemplary embodiments of the invention, the dissolution of sildenafil citrate and/or the increased rate of absorption due to the fast absorption carrier facilitates a reduction in dosage. According to various exemplary embodiments of the invention, the route of administration is oral or buccal.

It will be appreciated that the above aspects relate to solutions to technical problems associated with low bioavailability of sildenafil citrate in solid or suspension formulations. In particular, it is believed that the low solubility of sildenafil citrate tablets and/or suspensions under physiological conditions promotes the elimination of large amounts of ingested material without absorption, eliminating large amounts of ingested but unabsorbed material.

Alternatively or additionally, it will be appreciated that the above aspects relate to solutions to technical problems associated with the relatively long time between administration and onset of the desired therapeutic effect. In particular, already diseased subjects report a halving (or less) time to effect for the same treatment when using the solution described above compared to sildenafil citrate in tablet form.

Alternatively or additionally, it will be appreciated that the various aspects described above relate to solutions to technical problems associated with reducing effective dosages of sildenafil citrate. In particular, half the dose (or less) of sildenafil citrate in the solution described above provides the same therapeutic effect as sildenafil citrate in tablet form or suspension form.

Alternatively or additionally, it should be appreciated that the above aspects relate to solutions to technical problems associated with alleviating undesirable side effects of sildenafil citrate.

In some exemplary embodiments of the present invention, there is provided 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 the liquid carrier at a concentration of at least 7 mg/ml. In some embodiments, the liquid carrier comprises 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 comprises ethanol. Alternatively or additionally, in some embodiments, the liquid carrier comprises a ketone. Alternatively or additionally, in some embodiments, the ketone comprises acetone. Alternatively or additionally, in some embodiments, the liquid carrier comprises more than 3% ketones. Alternatively or additionally, in some embodiments, the concentration of 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 comprises a bitter blocker.

In some exemplary embodiments of the present invention, there is provided an oral dosage form comprising: an outer coating; and a liquid core comprising a pharmaceutical composition as described above.

In some exemplary embodiments of the present invention, there is provided an oral dosage form comprising: a carrier containing a pharmaceutical composition as described above; and a wrapper adapted to prevent evaporation of the liquid carrier during storage.

In some exemplary embodiments of the invention, a therapeutic kit is provided comprising: a container holding a plurality of doses of a pharmaceutical composition as described above; and a calibrated measuring device for measuring a single dose from the container.

In some exemplary embodiments of the invention, a therapeutic kit is provided comprising: one or more single doses of a pharmaceutical composition as described above, each single dose contained in a separate container; and packaging materials suitable for holding individual containers.

In some exemplary embodiments of the invention, there is provided a method comprising: (a) placing sildenafil citrate into 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 sildenafil citrate at a concentration of at least 7 mg/ml.

In some embodiments, the heating is to a temperature of at least 65 ℃. Alternatively or additionally, in some embodiments, the heating is to a temperature of no more than 85 ℃. Alternatively or additionally, in some embodiments, the heating is performed in an open container. Alternatively or additionally, in some embodiments, the heating is performed in a closed container. Alternatively or additionally, in some embodiments, the concentration of the solution of sildenafil citrate is at least 12.5 mg/ml. Alternatively or additionally, in some embodiments, the one or more alcohols include 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, the volume of the solution after heating is substantially the same as the volume of the mixture before heating. Alternatively or additionally, in some embodiments, the volume of the solution after heating is substantially less than the volume of the mixture before heating. Alternatively or additionally, in some embodiments, the method includes cooling the solution and adding alcohol and/or water.

In some exemplary embodiments of the invention, there is provided 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 the solution; and (c) dissolving sildenafil citrate in a concentration of at least 7mg/ml relative to the total volume.

In some embodiments, the method comprises heating the solution at a temperature no less than 5 ℃ below the boiling point of the ketone. Alternatively or additionally, in some embodiments, the heating is to a temperature at least 5 ℃ above the boiling point of the ketone. Alternatively or additionally, in some embodiments, the heating is to a temperature at least 10 ℃ above the boiling point of the ketone. Alternatively or additionally, in some embodiments, the method comprises removing at least 25% of the ketone. Alternatively or additionally, in some embodiments, the sildenafil citrate has a concentration of at least 25mg/ml in solution. Alternatively or additionally, in some embodiments, the one or more alcohols include 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, the volume of the solution after heating is 50% or less of the volume of the solution before 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%.

In some exemplary embodiments of the present invention, there is provided a pharmaceutical composition comprising: (a) a liquid carrier comprising 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.

In some exemplary embodiments of the present invention, there is provided 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 the liquid carrier at a concentration of at least 7 mg/ml. In some embodiments, the liquid carrier comprises 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 comprises ethanol. Alternatively or additionally, in some embodiments, the liquid carrier comprises a ketone.

Alternatively or additionally, in some embodiments, the ketone comprises acetone. Alternatively or additionally, in some embodiments, the liquid carrier comprises more than 3% ketones. Alternatively or additionally, in some embodiments, the concentration of 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 comprises a bitter blocker.

In some exemplary embodiments of the present invention, there is provided an oral dosage form comprising: an outer coating; and a liquid core comprising a pharmaceutical composition as described above.

In some exemplary embodiments of the present invention, there is provided an oral dosage form comprising: a carrier containing a pharmaceutical composition as described above; and a wrapper adapted to prevent evaporation of the liquid carrier during storage.

In some exemplary embodiments of the invention, a therapeutic kit is provided comprising: a container holding a plurality of doses of a pharmaceutical composition as described above, and a calibrated measuring device for measuring a single dose from the container.

In some exemplary embodiments of the invention, a therapeutic kit is provided comprising: a plurality of single doses of a pharmaceutical composition as described above, each single dose contained in a separate container; and packaging materials suitable for holding individual containers.

In some exemplary embodiments of the present invention, there is provided a pharmaceutical composition comprising: (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.

Unless defined otherwise, 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 present specification, including definitions, will control. All materials, methods, and examples are illustrative only and not intended to be limiting.

As used herein, the terms "comprises" and "comprising," or grammatical variants thereof, are to be taken as specifying the inclusion of the stated features, integers, acts or components, but does not preclude the addition of one or more additional features, integers, acts, components or groups thereof. This term is broader than and includes the terms "consisting of" and "consisting essentially of", as defined by the United States Patent and Trademark Office Patent Examination guidelines. Thus, any statement that an embodiment "comprises" or "includes" a feature specifically states that the sub-embodiment "consists essentially of and/or" consists of the recited feature.

The phrase "adapted to" as used in this specification and the appended claims imposes additional structural limitations on the components previously recited.

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 by, chemical and/or pharmaceutical practitioners.

The percentage (%) of solvent (e.g., water and/or alcohol and/or ketone) represents the total volume (T) prepared by measuring the volume (X) of the first liquid and adding the second liquid until the total volume teaches T. For example, to prepare one liter of 70% ethanol solution, 736.8ml of 95% ethanol was measured and water was added to a total volume of 1 liter. Such solutions are also referred to herein as 70: 30 ethanol water or 70% EtOH.

To determine the percentage of components after heating, GC/MS (gas chromatography/mass spectrometry) was used and the weight percentage was determined from the area under the curve of the relevant peak. Throughout this specification, if GC/MS is used, it is indicated as such.

Unless otherwise indicated, the concentration of sildenafil citrate is expressed as mg/ml of the relevant liquid at room temperature.

Drawings

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 drawings. In the drawings, identical or similar structures, elements or parts thereof that appear in more than one figure are generally labeled with identical or similar reference numbers in the figures in which they appear. The dimensions of the components and features shown in the figures are chosen primarily for convenience and clarity of presentation and are not necessarily to scale. The attached drawings are as follows:

FIG. 1 is a simplified flow diagram of a method of making according to some embodiments of the invention;

FIG. 2 is a simplified flow diagram of a method of making according to some embodiments of the invention;

fig. 3 is a comparison of NMR (nuclear magnetic resonance) curves of a liquid pharmaceutical composition of sildenafil citrate in accordance with an exemplary embodiment of the present invention versus sildenafil citrate powder; and

fig. 4 is a simplified flow diagram of a method according to some exemplary embodiments of the invention.

Detailed Description

Embodiments of the present invention relate to solutions of sildenafil citrate and to methods of making and/or using such solutions.

In particular, some embodiments of the invention are useful for treating erectile dysfunction. In some embodiments, treatment of erectile dysfunction with a solution according to exemplary embodiments of the present invention results in a reduction in sildenafil citrate dosage and/or a reduction in the time between administration and onset of therapeutic effect and/or a reduction in undesirable side effects.

The principles and operation of solutions and/or methods according to exemplary embodiments of the present invention may be better understood with reference to the drawings and the accompanying description.

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 illustrated 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 compositions

In some exemplary embodiments of the invention, a pharmaceutical composition is provided comprising a liquid carrier comprising water and at least 20%, at least 22.5%, at least 25%, or at least 30% of at least one alcohol, and 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 compositions is unexpected, since the solubility of sildenafil citrate in both water and the alcohol suitable for use in pharmaceutical compositions (i.e. the alcohol considered "safe" for human consumption) is well below 7 mg/ml. One example of an alcohol suitable for use in the pharmaceutical composition is ethanol (EtOH).

Alternatively or additionally, in some embodiments, the liquid carrier comprises 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 12.5mg/ml, at least 20mg/ml, at least 25mg/ml, at least 30mg/ml, at least 40mg/ml, at least 50mg/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 125mg/ml, less than 100mg/ml, less than 70mg/ml, less than 60mg/ml, less than 50mg/ml, or less than 45 mg/ml.

Generally, for liquid pharmaceutical compositions, a small dose volume may encourage patient acceptance. This general preference among patients has prompted manufacturers to stimulate the production of compositions with high concentrations of sildenafil citrate (e.g., 18mg/ml or higher).

In some exemplary embodiments of the invention, the liquid carrier comprises 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 long term storage. For this reason, although the presence of a ketone in the pharmaceutical composition is acceptable, there is no stimulus to increase the amount of ketone. In those embodiments of the invention that include ketones (e.g., acetone), a concentration 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 an intermediate or greater concentration is employed. Alternatively or additionally, in those embodiments of the invention that include ketones (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

Some exemplary embodiments of the present 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 in the form of, for example, gel caps or capsules.

The experimental data presented in example 5 below (table 3) indicate that a liquid volume of 1ml to 2ml is sufficient to deliver a physiologically effective dose (20mg to 30mg) of sildenafil citrate in solution. However, the solution employed in example 5 was relatively dilute. Increasing the concentration of sildenafil citrate in solution proportionally decreases the volume required to deliver the same physiologically effective dose. For example, a 40mg/ml solution only needs 0.5ml to deliver a 20mg dose. One to one gel cap can easily contain a liquid volume of 0.5 ml.

Exemplary buccal dosage forms

Some exemplary embodiments of the present invention incorporate the liquid pharmaceutical compositions described above into an oral dosage form. It is recognized that delivery of a physiologically active substance through the oral mucosa may be faster and/or more effective than delivery of the same substance through the stomach and/or intestine. Some embodiments of the present invention are directed to buccal dosage forms comprising a carrier containing a pharmaceutical composition as described above provided in a wrapper suitable for preventing evaporation of the liquid carrier during storage. According to various exemplary embodiments of the present invention, the carrier is provided in the form of paper, paperboard, nonwoven, or wafers (e.g., starch substrates).

In some embodiments, the solid substrate is provided in the form of a chew material, such as an edible wax or chewing gum. In some embodiments, the chew material is impregnated with a liquid pharmaceutical composition as described above. Alternatively or additionally, in some embodiments, the chew material surrounds a core comprising a liquid pharmaceutical composition as described above.

Furthermore, the experimental data presented in example 5 below (table 3) indicate that a liquid volume of 1ml to 2ml is sufficient to deliver a physiologically effective dose (20mg to 30mg) of sildenafil citrate in solution. If a 40mg/ml solution is used, only a liquid volume of 0.5ml provides a 20mg dose. A liquid volume of 0.5ml can be readily provided in 1 to 2 pieces of conventional chewing gum, liquid center chewing gum or wax "candy".

Sildenafil citrate containing chewing gum is described in at least U.S. patents 6, 531, 114 and 6, 592, 850, each of which is incorporated by reference in its entirety.

Liquid center chewing gums are described at least in U.S. patent application publications 20100203191 and 20100209553 and in U.S. patent 7, 556, 487, each of which is incorporated herein by reference in its entirety.

Exemplary therapeutic kits

In some exemplary embodiments of the invention, the liquid pharmaceutical composition is provided in a therapeutic kit. In some embodiments, the therapeutic kit includes packaging materials and/or instructions for use. In some exemplary embodiments of the invention, the instructions for use provide guidance regarding the transition from a sildenafil dose of a non-citrate solid to a lower dose of sildenafil in solution.

In some embodiments, the therapeutic kit comprises a container holding one or more doses of a liquid pharmaceutical composition as described above and a calibrated measuring device for measuring 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 a container lid. In some embodiments, a calibration mark is provided (e.g., in a teaspoon or ml). Optionally, the measuring device will be completely filled (e.g. spoon) one or more times. A measuring device that will be completely filled during use can prevent accidental exceeding of the recommended dose. However, the experimental data presented in example 5 below (table 3) indicates that many patients will take sildenafil citrate in solution form 2 to 3 times less than they would take a conventional tablet form. This means that even if they exceed the recommended liquid dosage by as much as 50%, the risk is expected to be low.

In some embodiments, the therapeutic kit comprises a plurality of single doses of the liquid pharmaceutical composition as described above. According to these embodiments, each single dose is contained in a separate container, and the kit comprises packaging material suitable for holding said separate containers.

For example, in some embodiments of this type, the kit is configured as a box containing a single dose ampoule (e.g., glass or wax). This type of kit may also be configured to hold the ampoules in an ordered array (e.g., in a line). The provision of a cardboard or paper divider between ampoules may facilitate a reduction in breakage during transport and/or storage.

In some embodiments, the therapeutic kit is configured as a chewing gum package, wherein each tablet of gum provides a single dose of sildenafil citrate. According to various exemplary embodiments of the present invention, the chewing gum is provided in the form of a conventional stick of chewing gum, in the form of a pad or in the form of a cube. In some embodiments of the invention, the gum pads or cubes are coated. Alternatively or additionally, the pads or cubes of chewing gum are filled with a liquid center comprising a pharmaceutical composition according to embodiments of the present invention as described above.

In some embodiments, the therapeutic kit comprises a nebulizer and a plurality of doses of a liquid pharmaceutical composition as described above and a calibrated measurement device for measuring a single dose from the container administered via the nebulizer. According to various exemplary embodiments of the present invention, the measuring device is configured as described above. In certain embodiments, the nebulizer is not provided in the kit.

In some embodiments, the therapeutic kit comprises a metered dose inhaler containing a plurality of doses of a liquid pharmaceutical composition as described above.

It is expected that delivery of a liquid pharmaceutical composition as described above via a nebulizer or metered dose inhaler will result in an additional reduction in the dose that produces the therapeutic effect.

Exemplary palatability considerations

Sildenafil citrate is bitter. Conventional solid dosage forms (e.g., tablets) are typically swallowed quickly, thereby making them unpalatable by the treated patient. Oral administration liquid compositions as described above and/or buccal administration of dosage forms comprising such liquid compositions make it more likely that the user will be sensitive to the bitter taste of sildenafil citrate.

In some exemplary embodiments of the invention, inactive ingredients are added to the composition to address this problem.

In some exemplary embodiments of the invention, the liquid pharmaceutical composition comprises a flavoring agent, as described above. Flavoring agents include, but are not limited to, essential oils (e.g., lemon oil), sweeteners (e.g., sugar or sugar substitutes), glutamates, esters, and aldehydes. Alternatively or additionally, in some embodiments, the liquid pharmaceutical composition comprises a bitter blocker as described above. Essential oils of tarragon (e.g., artemisinia maculacculus) and/or basil (e.g., Ocium basilicum) have been found to block the bitter taste of sildenafil citrate.

In some exemplary embodiments of the invention, 1 drop/ml of tarragon oil, basil oil, or a combination thereof is sufficient to block the bitter taste of the liquid composition as described above and below (example 5). In some embodiments, an increase in the concentration of sildenafil citrate in the composition promotes the need to increase the amount of tarragon and/or basil oil in order to achieve the desired bitterness blocking effect.

As used in this specification and the appended claims, the term "tarragon essential oil" means CAS (chemical abstracts) accession number 8016-88-4.

As used in this specification and the appended claims, the term "basil essential oil" means CAS (chemical abstracts) accession No. 8015-73-4.

Alternatively or additionally, in some embodiments of the invention, one or more inactive ingredients are added to provide a desirable flavor and/or taste (i.e., flavor). For example, in various exemplary embodiments of the present invention, lemon oil, vanilla extract, peppermint oil, oil of wintergreen, cinnamon, chocolate extract, and rum extract are employed.

As used in this specification and the appended claims, the term "bitter blocker" means an ingredient that masks the bitter taste of sildenafil citrate. In some exemplary embodiments of the invention, the bitter blocker also acts as a flavoring agent. In other exemplary embodiments of the present invention, the bitter blocker does not impart a perceptible taste.

An exemplary liquid pharmaceutical composition embodying the invention described above comprises alcohol and water. This makes it readily miscible with relevant amounts of essential oils and/or alcoholic extracts.

First exemplary preparation method

Fig. 1 is a simplified flow diagram of an exemplary process, generally designated 100, for preparing a liquid pharmaceutical composition as described above. The depicted exemplary method 100 includes placing 110 sildenafil citrate into 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 at a concentration of at least 7 mg/ml.

As used in this specification and the appended claims, the phrase "consisting essentially of water and one or more alcohols" means that other ingredients may be present but none of these other ingredients are intended to explain that the amount of sildenafil citrate dissolved in the vehicle exceeds the expected solubility calculated from the amount of water and alcohol(s). For example, "consisting essentially of water and at least one alcohol" allows for the inclusion of significant concentrations of acetone, as sildenafil citrate is considered to be insoluble in acetone. In contrast, "consisting essentially of water and at least one alcohol" excludes significant concentrations of dimethylformamide or DMSO, as sildenafil citrate is considered soluble in these solvents.

As used in this specification and the appended claims, the phrase "pharmaceutical composition" excludes the use of ingredients recognized as being toxic or unsafe for human consumption in the amounts required to formulate a single dosage form of sildenafil citrate.

In some embodiments, the at least one alcohol comprises ethanol. In some embodiments, the alcohol is a primary alcohol. In some embodiments, ethanol is substantially the only alcohol.

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 an intermediate or greater percentage of alcohol(s).

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 an intermediate or greater percentage.

In some exemplary embodiments of the invention, the heating 120 is to a temperature of at least 55 ℃, at least 60 ℃, at least 65 ℃, at least 70 ℃, at least 75 ℃, or a temperature of intermediate or higher.

Alternatively or additionally, in some embodiments, the heating 120 is to a temperature of no more than 100 ℃, 95 ℃, no more than 90 ℃, no more than 85 ℃, no more than 80 ℃, no more than 75 ℃, or a temperature of intermediate or lower.

In some exemplary embodiments of the invention, the heating 120 is performed in an open container. In some embodiments, the open container permits evaporation of one or more components of the mixture. In other exemplary embodiments of the invention, the heating 120 is performed in a closed vessel or under a condenser. In some embodiments, the closed container/condenser promotes a reduction in evaporation (relative to similar heating in an open container).

In some embodiments, the solution resulting from heating 120 has a sildenafil citrate concentration of at least 10.0mg/ml, at least 12.5mg/ml, at least 15.0mg/ml, at least 17.5mg/ml, at least 20.0mg/ml, at least 22.5mg/ml, at least 25.0mg/ml, or a medium or higher concentration.

In some embodiments, the volume of the solution after heating 120 is substantially the same as the volume of the mixture before heating (110) (not depicted). One way to achieve this is to perform the heating 120 in a closed vessel or under a condenser.

In other exemplary embodiments of the invention, the volume of the solution after heating 120 is significantly reduced 123 relative to the mixture before heating (110). One way to achieve this is to heat 120 in an open container at a temperature at which one or more components of the mixture has a significant vapor pressure.

In the depicted exemplary embodiment, the method 100 includes adding 140 alcohol and/or water and/or cooling the solution 130 (e.g., to room temperature). In some embodiments, the cooling is performed solely by cooling the solution. In some embodiments, adding 140 includes adding a mixture of alcohol and water in a desired ratio. In some embodiments, the addition 140 is used 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 that was put in the 110 sildenafil citrate originally. For example, in some embodiments, sildenafil citrate is placed in 11070% EtOH, and addition 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 that was put into the 110 sildenafil citrate.

Alternatively or additionally, in some embodiments, the method 100 includes adding 150 inactive ingredients (e.g., a flavoring agent and/or a bitter blocker as described above). Although additions 140 and 150 are depicted separately for clarity, in many embodiments they are performed as a single step. The essential oil is readily miscible in the alcohol/water combination, such that the inactive ingredient may be incorporated into the alcohol/water combination employed at 140.

Second exemplary preparation method

Fig. 2 is a simplified flow diagram of an exemplary process, generally designated 200, for preparing a liquid pharmaceutical composition as described above. The depicted exemplary method 200 includes providing 210 a first volume of ketone and adding 220 a second volume (e.g., in combination or mixture) consisting essentially of one or more alcohols and water to produce a total volume of solution, and dissolving 225 sildenafil citrate at a concentration of at least 7mg/ml, at least 10mg/ml, or at least 12.5mg/ml relative to the total volume. According to various exemplary embodiments of the invention, dissolving 225 is at 210 in the first volume and/or dissolving 225 is at 220 in the total volume. It is important to note that in many embodiments of method 200, all of the sildenafil citrate goes into solution without heating. NMR measurements (see figure 3 and example 4) confirmed that sildenafil citrate was unchanged by dissolution.

Some embodiments of the method 200 include heating 230 the solution at a temperature no less than 10 ℃ below boiling point, no less than 5 ℃ below boiling point, no less than 2.5 ℃ below boiling point, no less than the boiling point of the ketone, or at a temperature that is intermediate or higher. Alternatively or additionally, in some embodiments, the method 200 includes heating to a temperature at least 5 ℃ above the boiling point, at least 7.5 ℃ above the boiling point, at least 10 ℃ above the boiling point, at least 15 ℃ above the boiling point of the ketone, or a temperature of or greater than.

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 an intermediate or greater percentage of the ketone evaporates.

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 an intermediate or greater percentage of the ketone is removed by evaporation without heating (e.g., by application of a vacuum).

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 an intermediate or greater percentage of the ketone is removed by solvent extraction.

In some embodiments, the sildenafil citrate in solution at 220 has a concentration of at least 25mg/ml, at least 30mg/ml, at least 35mg/ml, 40mg/ml, at least 50mg/ml, at least 55mg/ml, or a medium or higher concentration.

In some embodiments, the alcohol in the second volume (220) comprises ethanol, predominantly ethanol or substantially all ethanol.

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 an intermediate or greater percentage. Alternatively or additionally, in some embodiments, the combination of alcohol and water in the second volume (220) comprises at least 60%, at least 62.5%, at least 65%, at least 67.5%, at least 70%, at least 72.5%, at least 75% water, or an intermediate or greater percentage.

In some embodiments, the volume of the solution after heating 230 is 50% or less of the volume of the solution before heating.

In the depicted exemplary embodiment, the method 200 includes cooling 250 (e.g., to room temperature) the solution and/or adding 260 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 75%, or an intermediate concentration. The adding 260 is similar to the adding 140 (fig. 1) as described above, and similar considerations apply. In some embodiments, the cooling is performed by cooling only the solution.

In some embodiments, inactive ingredients are added 270. Adding 270 is similar to adding 150 (fig. 1) as described above, and similar considerations apply.

Further exemplary compositions

Some embodiments of the invention relate to a pharmaceutical composition comprising a liquid carrier having water, ethanol, and less than 30% acetone and sildenafil citrate dissolved in the liquid carrier at a concentration of at least 10mg/ml, at least 20mg/ml, at least 25mg/ml, at least 30mg/ml, at least 35mg/ml, at least 40mg/ml, at least 45mg/ml, at least 50mg/ml, at least 55mg/ml, or a concentration of intermediate or greater. In some embodiments, the concentration of acetone is less than 25% or less than 20%.

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 35%, 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 an intermediate or greater percentage of water.

In some embodiments, the acetone concentration is well below 20%. For example, acetone levels ranging from 5% to 7% were achieved (see table 2 in example 3).

Some embodiments of the invention relate to a pharmaceutical composition comprising 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 comprises ethanol, predominantly ethanol or substantially only ethanol. Alternatively or additionally, in some embodiments, the carrier includes residual ketone (e.g., acetone) from a manufacturing process that employs the ketone. An exemplary method 200 employing ketones is described above in the context of fig. 2.

Some embodiments of the invention relate to a pharmaceutical composition comprising sildenafil citrate and a bitter blocker comprising one or more essential oils derived from a plant selected from the group consisting of tarragon and basil in a liquid carrier. In some embodiments, the sildenafil citrate is in the form of a solution. In other embodiments, the sildenafil is in the form of a suspension.

In further exemplary embodiments of the present invention, these additional exemplary composition types are also provided in the form of buccal dosage forms and/or therapeutic kits as described above.

Exemplary methods of treatment

Figure 4 is a simplified flow diagram of an exemplary treatment for erectile dysfunction generally designated 400.

The 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 the patient for erectile dysfunction with sildenafil citrate in solution using a reduced dose of less than 50% of the customary dose.

In some exemplary embodiments of the invention, the sildenafil citrate is in solution in a liquid carrier comprising one or more alcohols and water. According to various exemplary embodiments of the invention, the one or more alcohols comprise ethanol, predominantly comprises ethanol or substantially all ethanol.

Alternatively or additionally, in some embodiments, the liquid carrier includes a ketone (e.g., acetone).

According to various exemplary embodiments of the invention, the reduced dose is delivered in a volume of less than 15ml, less than 10ml, less than 5ml, less than 3ml, less than 2ml or a volume of medium or less. According to various exemplary embodiments of the present invention, the administration of the reduced dose is via an oral or buccal route. Buccal dosage forms and/or therapeutic kits as described above are a convenient way to provide reduced dosages.

It is expected that during the life of this patent many dosage forms for pharmaceutically active ingredients will be developed in liquid form, and the scope of the present invention is intended to include all such novel dosage forms as a priori.

Alternatively or additionally, it is expected that during the life of this patent many carriers will be developed for buccal administration of pharmaceutically active ingredients, and the scope of the invention is intended to include all such carriers in the reasoning.

As used herein, the term "about" means ± 10%.

While 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 included claims.

Specifically, various numerical indicators are utilized. It should be appreciated that these numerical indicators may be further varied according to various engineering principles, materials, intended uses, and designs incorporated into various embodiments of the present invention. Additionally, components and/or actions ascribed to exemplary embodiments of the invention and depicted as a single unit may be divided into sub-units. Rather, components and/or acts that are ascribed to exemplary embodiments of the present invention and that are depicted as sub-units/single acts may be combined into a single unit/act having the described/depicted functionality.

Alternatively or additionally, features used to describe a method can be used to characterize a device, and features used to describe a device can be used to characterize a method.

It should be further understood that the various features described above can be combined in all possible combinations and sub-combinations to yield further embodiments of the invention. The examples given above are exemplary in nature and are not intended to limit the scope of the invention.

Whenever an embodiment of the present invention is described as including a particular feature, part, component, module or process, it is expressly stated that there are additional embodiments that do not include the recited feature, part, component, module or process.

In particular, the invention has been described in the context of ethanol and water, or ethanol, water and acetone, but may also be used in the form of other alcohols and/or other ketones.

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.

The terms "including" and "having," and their conjugates, as used herein, mean "including, but not necessarily limited to.

Additional objects, advantages and novel features of various embodiments of the present invention will become apparent to those skilled in the art upon examination of the following examples, which are not intended to be limiting. In addition, 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 of the invention

Reference is now made to the following examples in conjunction with the above description; the invention is shown in a non-limiting manner.

Example 1:

preparation of a high concentration sildenafil citrate solution.

To demonstrate the possibility of dissolving high concentrations of sildenafil citrate in combinations of solvents considered individually as poor solvents for the compounds, a series of ten experiments using ethanol (EtOH), water and acetone in various ratios were performed. In each of experiments 1 to 6, 250mg of sildenafil citrate (Tevapharmaceuticals; Israel) was dissolved in a mixture of acetone and EtOH/water as shown in Table 1 and heated in an open container at 70 ℃ to 77 ℃ for 10 minutes.

In experiments 7-10, 150-250mg sildenafil citrate (israel's terranean pharmaceutical) was dissolved in 70% EtOH/water and heated in a closed vessel at 70 ℃ to 77 ℃ for 10 minutes. The results presented in table 1 indicate that it is possible to achieve an initial concentration of 12.5mg/ml of sildenafil citrate in solution without heating (experiment 1, experiment 2 and experiment 6) and an initial concentration of up to 25mg/ml of sildenafil citrate in solution with heating (experiment 7).

Furthermore, as heating continues and the volume of the solvent mixture decreases, sildenafil citrate remains in solution at a concentration of up to 35.7 mg/ml. The relative proportion of water in the mixture increases as the volume decreases due to the relative vapor pressures of the components of the liquid mixture.

Some solutions were filtered using filter paper and/or 0.22 micron filter membranes with no visible residue. This example illustrates that sildenafil citrate has a much greater solubility in EtOH/water or EtOH/water with a small amount of residual acetone than in water or EtOH or acetone alone.

Table 1: solubility of sildenafil citrate in EtOH/Water mixtures with acetone and EtOH/Water mixtures without acetone

Dissolving and heating in a closed container to prevent evaporation

Example 2:

stability of sildenafil citrate solution.

The volume of each solution from experiment 1 to experiment 7 in example 1 was adjusted to 10ml with 60% EtOH (experiment 1) or 70% EtOH (experiment 2-experiment 7) to produce a clear solution at 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 micron filter membranes with no visible residue.

To analyze their stability, they were further subjected to freezing and thawing at-18 ℃. The solution from experiment 7 showed a slight sedimentation after thawing. The solutions from experiments 1 to 6 remained clear after thawing. The solutions from experiment 3, experiment 6 and experiment 9 and experiment 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 that the solution will have a significant shelf life (e.g., 2 years or more).

Example 3:

solvent concentration after heating.

To analyze the solvent concentration in the sildenafil citrate solution after heating, the samples were sent to a separate laboratory for GC/MS (gas chromatography/mass spectrometry) analysis. Three samples were prepared as follows:

sample a: 250mg sildenafil citrate +10ml acetone +10ml 70% EtOH in water was heated to 77 ℃ for 7min until the volume was reduced to 5ml (50 mg/ml). 70% EtOH in water was added to bring the volume to 10ml (25 mg/ml).

Sample B: 500mg sildenafil citrate +10ml acetone +10ml 70% EtOH in water was heated to 77 ℃ for 7min until the volume was reduced to 5.1ml (98 mg/ml). 70% EtOH in water was added to bring the volume to 10ml (50 mg/ml).

Sample C: 10ml acetone +10ml 70% EtOH in water was heated to 77 ℃ for 7min until the volume was reduced to 5.3 ml. 70% EtOH in water was added to bring the volume to 10 ml.

Sample C was used as a control to see if sildenafil citrate affected the relative evaporation rates of the different solvents.

The results presented in table 2 show that a small but measurable amount of acetone remains after heating until a 75% reduction in volume at temperatures well above the boiling point of acetone. The actual acetone concentration remaining in the sample was about twice the percentage in table 2, as the sample was diluted with acetone-free solution after heating. Similarly, the results presented in table 2 indicate that a measurable amount of EtOH remains after heating until a 75% reduction in volume at temperatures well above the boiling point of EtOH. The actual EtOH concentration remaining in the sample was actually much less than the percentage indicated by GC/MS, since the sample was diluted with 70% EtOH after heating. The numbers in parentheses indicate the% EtOH resulting from this dilution.

Table 2: percent solvent after heating as analyzed by GC/MS

The preparation of samples a and B shows that it is possible to achieve concentrations of sildenafil citrate in solution of 50mg/ml to 100 mg/ml. The pH of solution A, solution B and solution C is in the range of 4.4 to 4.55.

This example illustrates that the solution concentration of sildenafil citrate achieved cannot be explained by the nominal solubility of the compound in any of the three components of the solvent mixture.

Sample B was not stable for long periods. During transport to an external laboratory where GC/MS was performed, some settling had occurred (apparently due to freezing in transport (at up to-55 degrees celsius)). Heat was applied before testing to redissolve the sediment.

Example 4:

stability of sildenafil citrate during heating.

To confirm that sildenafil remained unchanged by heating in the solvent mixtures as described in examples 1 and 3, samples dissolved as described above were subjected to NMR analysis using commercially available sildenafil citrate (israel's stephanawa pharmaceutical) dissolved in DMSO as a control.

Representative NMR results are shown in fig. 3. In this figure, one trace is sildenafil citrate in solution according to an exemplary embodiment of the invention and the other trace is a control material. The two traces are substantially identical.

This example illustrates that the above protocol does not cause chemical changes in sildenafil citrate.

Example 5:

exemplary case study.

To evaluate the efficacy of sildenafil citrate solutions according to exemplary embodiments of the present invention in human subjects, the following solutions were prepared:

solution 1-sildenafil citrate was dissolved in the same volume of 70% EtOH and acetone and heated in an open container to allow evaporation of about 65% of the initial volume. The resulting concentrated solution was diluted with 70% EtOH to give sildenafil citrate at a final concentration of 20 mg/ml.

Solution 2-sildenafil citrate in 70% EtOH was heated in a closed container to give sildenafil citrate at a final concentration of 15 mg/ml.

Table 3: human subject

Subject A isPills are regularly taken by users for about one year. A 1ml dose of solution 1 according to an exemplary embodiment of the present invention produced the same therapeutic effect as a 2.5X dose reduction. Furthermore, solution 1 according to the exemplary embodiment reportedly produces a time to onset of action within 10 minutes, as compared to useThe pill takes about 30 to 40 minutes.

Subject B is for erectile dysfunctionRegular users of pills. A 1.5ml dose of solution 1 according to an exemplary embodiment of the present invention produced the same therapeutic effect as a dose reduction of more than 3.0X. Test subjectB also reports no headache with solution 1 according to an exemplary embodiment of the invention, butThe pill causes headache. Subject B also reported an onset of action within 10-15 minutes, which was about half the onset of action required for pill use.

Subject C has been used regularlyThe pill is taken for a period of 5 years. He achieved an equivalent therapeutic effect using 2ml (30mg active ingredient) of solution 2 according to an exemplary embodiment of the invention. As with subject B, he reported no headacheThe pill causes headache. As with the other two subjects, he reported onset of action within 10 minutes to 15 minutes for useThe desired onset of action of the pill is about one half to one third.

These results demonstrate the improved efficacy/unit of orally administered sildenafil citrate in solution according to exemplary embodiments of the present invention relative to conventional tablet dosage forms. This indicates improved bioavailability. Furthermore, sildenafil citrate in solution for oral administration appears to produce fewer side effects. Whether this is due to a lower dose or other factors is ambiguous. Alternatively or additionally, the onset of action using orally administered sildenafil citrate in solution produces a more rapid onset of therapeutic effect than conventional solid dosage forms despite the lower dose.

Solutions 1 and 2 contained essential oils as described above to block bitterness. Subjects A, B and C found the taste of the solution to be acceptable.

Example 6:

preparation of additional sildenafil citrate solution at high concentration

To investigate the effect of alcohol and water on dissolving sildenafil citrate at high concentrations, an additional series of ten experiments using ethanol (EtOH) and water in various ratios in the initial composition with 50% acetone were performed. In this series of experiments, sildenafil citrate was dissolved in the initial volume of liquid carrier and heated at 70 ℃ to 77 ℃ to reduce the volume. As in example 1, the relative proportion of water in the mixture increases as the volume decreases.

The results presented in table 4 indicate that it is possible to achieve concentrations of 12.5mg/ml to 37.5mg/ml by adding sildenafil citrate to a mixture of half acetone and half 30% to 60% EtOH. In either experiment, no heat was required to produce solutions with these initial concentrations. These mixtures were heated until the volume was reduced to 7ml, resulting in a solution with a concentration of 35mg/ml to 107 mg/ml.

Table 4: solubility of sildenafil citrate in EtOH/water mixtures with acetone in various ratios

This example illustrates that it is possible to reduce the amount of alcohol used relative to example 1.

Example 7:

stability of additional sildenafil citrate solutions.

The volume of each solution from experiment 1 to experiment 10 in example 6 was adjusted to 10ml with the same EtOH/water mixture used to prepare the initial composition. In all ten experiments, the resulting solution was clear. The adjusted concentration is 25mg/ml to 75 mg/ml. After 24 hours at room temperature, these solutions exhibited varying degrees of turbidity and/or sedimentation.

This example illustrates that a study according to the commercially relevant exemplary embodiments of experiments 1-10 in the previous examples can employ a stabilizer to maintain sildenafil citrate in solution.

Known stabilizers include, but are not limited to: diacetyl monoglyceride, diethylene glycol monopalmitoyl stearate, glyceryl behenate, glyceryl distearate, glyceryl monolinoleate, glyceryl monooleate, glyceryl monostearate, self-emulsifying glyceryl monostearate, polyethylene glycol cetearyl ether, cetostearyl alcohol 1000, 9 polyethylene glycol 20 cetearyl ether, polyethylene glycol 15 hydroxystearate, polyethylene glycol lauryl ether, lauryl alcohol ether 4, lauroyl alcohol 400, polyethylene glycol monomethyl ether, polyethylene glycol oleyl ether, polyethylene glycol 10 oleyl ether, polyethylene glycol stearate, polyethylene glycol 40 stearate, menthyl alcohol ether, mono-and diglycerides, nonoxynol, octoxynol, poloxamer, polyethylene glycol castor oil, polyethylene glycol hydrogenated castor oil, polysorbate, propylene glycol diacetate, propylene glycol laurate, propylene glycol dilaurate, propylene glycol monolaurate, propylene glycol, Propylene glycol monopalmitoyl stearate, quillaja bark, sorbitan esters, ester sucrose, tyloxapol, carrageenan, cellulose, carob, dextrates, ethylcellulose, gastric mucin, hydroxypropyl cellulose, hypromellose phthalate, methylcellulose, polyethylene oxide, polyvinyl acetate, polyvinyl alcohol, silicon dioxide, sodium starch glycolate, tragacanth, xanthan gum.

Example 8:

sildenafil citrate solutions with varying amounts of acetone. To investigate the effect of acetone on dissolving sildenafil citrate at high concentrations, a further series of thirteen experiments using ethanol (EtOH) and water in various ratios were performed with relatively small amounts of acetone.

In this series of experiments, sildenafil citrate was dissolved in the initial volume of liquid carrier and heated at 70 ℃ to 77 ℃ to dissolve sildenafil citrate (experiments 6 and 13) or reduced in volume (experiments 1-5 and 7-12). In this series of experiments, the initial volume was 10ml and heating was continued until the volume was reduced to 9ml (experiments 1-5) or 7ml (experiments 7-12). As in example 1, the relative proportion of water in the mixture increases as the volume decreases.

In this series of experiments, heating was required for initial dissolution of sildenafil citrate at an initial concentration of 16.7mg/ml to 50 mg/ml. The results summarized in table 5 indicate that it is possible to achieve an initial concentration of 40mg/ml using 10% acetone (experiment 6); initial concentrations of 50mg/ml were achieved using 2% to 8% acetone in 50% to 70% EtOH (experiment 3 to experiment 5) and 25mg/ml using 6.3% acetone in 35% EtOH (experiment 13).

In each of the thirteen experiments in this example, sildenafil citrate was in solution at the end of heating.

Table 5: solubility of sildenafil citrate in EtOH/water mixtures with acetone in various ratios

Heating at 70-77 deg.C to only the melting point

Example 9:

stability of sildenafil citrate low in acetone. With 50% EtOH/water (experiment 1 to experiment 4); the volume of each solution from experiment 1 to experiment 13 in example 8 was adjusted to 10ml with 70% EtOH/water (experiment 5, experiment 7, experiment 8 and experiment 9-experiment 13) and 95% EtOH/water (experiment 6). In all thirteen experiments, the resulting solution was clear. The concentration is 25mg/ml to 50 mg/ml.

After 24 hours at room temperature, some of the solutions appeared to settle but the dilute solutions from experiment 10 to experiment 13 remained clear. This example illustrates that it is possible to reduce the amount of acetone used relative to example 1.

Example 10:

sildenafil citrate solution without ketone. To investigate the possibility of dissolving high concentrations of dissolved sildenafil citrate in alcohol/water mixtures without ketone, a series of eight experiments using ethanol (EtOH) and water in various ratios without acetone were performed.

In this series of experiments, sildenafil citrate was placed in 10ml EtOH/water and heated at 70 ℃ to 77 ℃ to dissolve sildenafil citrate (experiments 1 to 8) and/or reduced in volume (experiments 1 to 5) or heated at 70 ℃ to 77 ℃ in a closed container to dissolve sildenafil citrate while preventing evaporation (experiments 6 to 8). As in example 1, if the heating is carried out in an open container, the relative proportion of water in the mixture increases as the volume decreases.

In this series of experiments, heating was required for initial dissolution of sildenafil citrate at initial concentrations of 25mg/ml to 50 mg/ml. The results summarized in table 6 indicate that it is possible to achieve a final concentration of 55.6mg/ml by performing an initial dissolution in 50% to 70% EtOH without acetone (experiments 2 and 3) and a final concentration of 50mg/ml by performing an initial dissolution in 35% EtOH without acetone (experiment 7). In each of the eight experiments in this example, sildenafil citrate was in solution at the end of the heating.

Table 6: solubility of sildenafil citrate in EtOH/water mixtures in various ratios without acetone

Example 11:

stability of sildenafil citrate solution without acetone.

The volume of each solution from experiment 1 to experiment 8 in example 10 was adjusted to 10ml with 50% EtOH/water (experiment 1 and experiment 2) and 70% EtOH/water (experiment 3 to experiment 5). No volume adjustment was required in experiments 6 to 8. In all 8 experiments, the resulting solution was clear. The concentration is 25mg/ml to 50 mg/ml. After 24-48 hours at room temperature, some of the solutions appeared to be settling and/or cloudy but the dilute solution from experiment 4 remained clear.

This example illustrates that a solution of sildenafil citrate with concentrations for water or ethanol much greater than those reported in the literature can be achieved using water and ethanol and heating.

Experiments with similar compounds such as tadalafil or vardenafil using the same method described above were unsuccessful in producing stable solutions.

Claims (57)

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 the liquid carrier at a concentration of at least 7 mg/ml.

2. The pharmaceutical composition of claim 1, wherein the liquid carrier comprises at least 5% water.

3. The pharmaceutical composition of claim 2, wherein the liquid carrier comprises at least 30% water.

4. The pharmaceutical composition according to claim 1, wherein the concentration of sildenafil citrate dissolved in the liquid carrier is at least 12.5 mg/ml.

5. The pharmaceutical composition according to claim 4, wherein said concentration of sildenafil citrate dissolved in said liquid is at least 20 mg/ml.

6. The pharmaceutical composition of claim 1, wherein the at least one alcohol comprises ethanol.

7. The pharmaceutical composition of claim 1, wherein the liquid carrier comprises a ketone.

8. The pharmaceutical composition of claim 7, wherein the ketone comprises acetone.

9. The pharmaceutical composition of claim 7, wherein the liquid carrier comprises more than 3% ketones.

10. The pharmaceutical composition according to claim 8, wherein the concentration of the sildenafil citrate dissolved in the liquid is at least 25 mg/ml.

11. An oral dosage form comprising:

an outer coating; and

a liquid core comprising the pharmaceutical composition of claim 1.

12. An oral dosage form comprising:

a carrier containing the pharmaceutical composition of claim 1; and a wrapper adapted to prevent evaporation of the liquid carrier during storage.

13. A therapeutic kit comprising:

a container holding a plurality of doses of the pharmaceutical composition of claim 1; and

a calibrated measuring device for measuring a single dose from the container.

14. A therapeutic kit comprising:

a single or multiple single doses of a pharmaceutical composition according to claim 1, each of said single doses contained in a separate container; and a packaging material adapted to hold the individual containers.

15. The pharmaceutical composition of claim 1, comprising a flavoring agent.

16. The pharmaceutical composition of claim 1, comprising a bitter blocker.

17. A method, comprising:

(a) placing sildenafil citrate into 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 at a concentration of at least 7 mg/ml.

18. The method of claim 17, wherein the heating is to a temperature of at least 65 ℃.

19. The method of claim 17, wherein the heating is to a temperature of no more than 85 ℃.

20. The method of claim 17, wherein the heating is performed in an open container.

21. The method of claim 17, wherein the heating is performed in a closed vessel.

22. The method of claim 17, wherein the solution of the sildenafil citrate has a concentration of at least 12.5 mg/ml.

23. The method of claim 17, wherein the one or more alcohols comprise ethanol.

24. The method of claim 17, wherein the combination of one or more alcohols and water comprises at least 20% alcohol.

25. The method of claim 17, wherein the combination of one or more alcohols and water comprises at least 5% water.

26. The method of claim 17, wherein the volume of the solution after heating is substantially the same as the volume of the mixture before heating.

27. The method of claim 17, wherein the volume of the solution after heating is substantially less than the volume of the mixture before heating.

28. The method of claim 17, comprising:

cooling the 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 the solution; and

(c) sildenafil citrate is dissolved in a concentration of at least 7mg/ml relative to the total volume.

30. The method of claim 29, comprising:

heating the solution at a temperature no less than 5 ℃ below the boiling point of the ketone.

31. The method of claim 30, wherein the heating is to a temperature at least 5 ℃ above the boiling point of the ketone.

32. The method of claim 31, wherein the heating is to a temperature at least 10 ℃ above the boiling point of the ketone.

33. The method of claim 30, comprising removing at least 25% of the ketone.

34. The method of claim 29, wherein the sildenafil citrate has a concentration of at least 25mg/ml in the solution.

35. The method of claim 29, wherein the one or more alcohols comprise ethanol.

36. The method of claim 29, wherein the combination of one or more alcohols and water comprises at least 20% alcohol.

37. The method of claim 29, wherein the combination of one or more alcohols and water comprises at least 5% water.

38. The method of claim 30, wherein the volume of the solution after heating is 50% or less of the volume of the solution before heating.

39. The method of claim 30, comprising:

the solution is cooled and alcohol(s) and/or water are added 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 the liquid carrier at a concentration of at least 10 mg/ml.

41. 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 the liquid carrier at a concentration of at least 7 mg/ml.

42. The pharmaceutical composition according to claim 41, wherein the liquid carrier comprises at least 5% water.

43. The pharmaceutical composition according to claim 42, wherein the liquid carrier comprises at least 30% water.

44. The pharmaceutical composition according to claim 41, wherein the concentration of sildenafil citrate dissolved in the liquid carrier is at least 12.5 mg/ml.

45. The pharmaceutical composition according to claim 44, wherein the concentration of sildenafil citrate dissolved in the liquid is at least 20 mg/ml.

46. The pharmaceutical composition according to claim 41, wherein the at least one alcohol comprises ethanol.

47. The pharmaceutical composition of claim 41, wherein the liquid carrier comprises a ketone.

48. The pharmaceutical composition of claim 47, wherein the ketone comprises acetone.

49. The pharmaceutical composition according to claim 47, wherein the liquid carrier comprises more than 3% ketones.

50. The pharmaceutical composition according to claim 48, wherein the concentration of the sildenafil citrate dissolved in the liquid is at least 25 mg/ml.

51. An oral dosage form comprising:

an outer coating; and

a liquid core comprising the pharmaceutical composition of claim 41.

52. An oral dosage form comprising:

a carrier containing the pharmaceutical composition of claim 41; and a wrapper adapted to prevent evaporation of the liquid carrier during storage.

53. A therapeutic kit comprising:

a container holding a plurality of doses of the pharmaceutical composition of claim 41; and

a calibrated measuring device for measuring a single dose from the container.

54. A therapeutic kit comprising:

a plurality of single doses of the pharmaceutical composition of claim 41, each of the single doses contained in a separate container; and a packaging material adapted to hold the individual containers.

55. The pharmaceutical composition of claim 41, comprising a flavoring agent.

56. The pharmaceutical composition of claim 41, comprising a bitter blocker.

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 the liquid carrier at a concentration of at least 10 mg/ml.