WO2023037394A1 - A pharmaceutical composition of sildenafil and a formulation thereof - Google Patents

A pharmaceutical composition of sildenafil and a formulation thereof Download PDF

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Publication number
WO2023037394A1
WO2023037394A1 PCT/JO2021/050012 JO2021050012W WO2023037394A1 WO 2023037394 A1 WO2023037394 A1 WO 2023037394A1 JO 2021050012 W JO2021050012 W JO 2021050012W WO 2023037394 A1 WO2023037394 A1 WO 2023037394A1
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Prior art keywords
pharmaceutical composition
agent
sildenafil
weight
combination
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PCT/JO2021/050012
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French (fr)
Inventor
Hanan KAKISH
Sharifeh ABU ALI
Areej ABUSHAMALAH
Fadi ALATRASH
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Amman Pharmaceutical Industries Company
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Priority to PCT/JO2021/050012 priority Critical patent/WO2023037394A1/en
Publication of WO2023037394A1 publication Critical patent/WO2023037394A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present disclosure relates to novel pharmaceutical compositions and formulations for treating erectile dysfunction, and more particularly to a novel pharmaceutical composition and formulation of sildenafil or a pharmaceutically acceptable salt thereof.
  • Penile erection is a complicated physiological process that involves the blood vessel system, as well as the endocrine and nervous systems.
  • Patients suffering from erectile dysfunction (“ED”) are increasing due to many reasons such as the expanded life span, the increase of adult diseases, change of diet, the increase of industrial and traffic accidents, and the increase of mental stress and physical fatigue resulting from complicated modem life could contribute to aggravate this manifestation.
  • Sildenafil is one of the widely known medications that are used to temporarily treat ED, and is mainly formulated as oral tablets or as intravenous injection. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (“cGMP”) specific phosphodiesterase type 5 (“PDE5”) which regulates the blood flow in the penis.
  • cGMP cyclic guanosine monophosphate
  • PDE5 phosphodiesterase type 5
  • the oral gel formulation provides a similar bioavailability of sildenafil in a human body compared to a commercially available approved 100 mg film-coated tablet of sildenafil.
  • the pharmaceutical composition may include sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water.
  • the pharmaceutical composition may further include a coloring agent.
  • the pharmaceutically acceptable salt may include sildenafil citrate.
  • the gelling and thickening agent may be a carbomer polymer having a grade selected from a group including 71G, 971, 971P, 974, 974P, 934, 934P, or combinations thereof.
  • the water miscible co-solvent may be propylene glycol, glycerin, or a combination thereof.
  • the taste masking agent may be a sorbitol solution, mannitol, or a combination thereof.
  • the sweeting agent may be sucralose, sodium saccharine, or a combination thereof.
  • the flavoring agent may be peppermint oil, orange oil, or a combination thereof or any other suitable flavoring agent.
  • the neutralizing agent may be sodium hydroxide, potassium hydroxide, ethanolamine, or a combination thereof.
  • the pharmaceutical composition may include from about 1.5% to about 3.5% by weight sildenafil or its pharmaceutically acceptable salt.
  • the pharmaceutical composition may include from about 0.5% to about 2% by weight gelling and thickening agent.
  • the pharmaceutical composition may include from about 15% to about 30% by weight water miscible co-solvent.
  • the pharmaceutical composition may include from about 5% to about 10% by weight taste masking agent.
  • the pharmaceutical composition may include from about 0.01% to about 0.4% by weight favoring agent.
  • the neutralizing agent adjusts the pH of the pharmaceutical composition from about 4 to about 8.
  • the pharmaceutical composition may include from about 0.005% to about 0.02% by weight coloring agent.
  • the pharmaceutical composition is for use in treating ED. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 illustrates a flowchart of a method of preparing an oral gel formulation of a composition of sildenafil or a pharmaceutically acceptable salt thereof in accordance with embodiments of the present disclosure.
  • FIG. 2 illustrates mean plasma concentrations of sildenafil in human blood plasma after taking the oral gel formulation prepared in accordance with embodiments of the present disclosure and the commercially available Reference sildenafil 100 mg film-coated tablets.
  • Embodiments of the present disclosure provide a pharmaceutical composition for treating ED, the composition may include sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water.
  • the pharmaceutical composition may further include a coloring agent.
  • the pharmaceutically acceptable salt may include sildenafil citrate.
  • the gelling and thickening agent may be a carbomer polymer having a grade selected from a group including 71 G, 971, 97 IP, 974, 974P, 934, 934P, or combinations thereof.
  • carbomers designated with the letter ‘P’ are the pharmaceutical grade polymers for oral or mucosal contact products.
  • Table (1) illustrates characteristics of possible carbomer polymers.
  • the water miscible co-solvent may be propylene glycol, glycerin, or a combination thereof.
  • the taste masking agent may be a sorbitol solution, mannitol, or a combination thereof.
  • the sweeting agent may be sucralose, sodium saccharine, or a combination thereof.
  • the flavoring agent may be peppermint oil, orange oil, or a combination thereof, or any other suitable flavoring agent.
  • the neutralizing agent may be sodium hydroxide, potassium hydroxide, ethanolamine, or a combination thereof.
  • the pharmaceutical composition may include from about 1.5% to about 3.5% by weight sildenafil or its pharmaceutically acceptable salt.
  • the pharmaceutical composition may include from about 0.5% to about 2% by weight gelling and thickening agent.
  • the pharmaceutical composition may include from about 15% to about 30% by weight water miscible co-solvent.
  • the pharmaceutical composition may include from about 5% to about 10% by weight taste masking agent.
  • the pharmaceutical composition may include from about 0.1% to about 1.0% by weight sweetening agent. [044] In some embodiments, the pharmaceutical composition may include from about 0.01% to about 0.4% by weight favoring agent.
  • the neutralizing agent adjusts the pH of the pharmaceutical composition from about 4 to about 8.
  • the pharmaceutical composition may include from about 0.005% to about 0.02% by weight coloring agent.
  • the pharmaceutical composition is for use in treating ED.
  • Embodiments of the present disclosure further provide an oral gel formulation including the pharmaceutical composition as described above.
  • FIG. 1 illustrates a flowchart of a method of preparing an oral gel formulation of a pharmaceutical composition including sildenafil or a pharmaceutically acceptable salt thereof
  • the method may include the steps of hydrating a gelling and thickening agent (0.8-1.2%) to provide a first mixture (process block 1-1); dispersing the sildenafil or its pharmaceutical acceptable salt (citrate salt around 2.8%) in a water miscible co-solvent (23-28%) to provide a second mixture (process block 1-2); dissolving a sweetening agent (0.3-0.5%) , a taste masking agent (6-8%), a flavoring agent (0.02-0.2%), a neutralizing agent, and a coloring agent (0.007-0.015%) in water to provide a third mixture (process block 1-3); and mixing the first, second, and third mixtures together to obtain an oral gel, followed by adjusting the pH to of the gel to become within a range from about 5 to about 7 (process block 1-4).
  • Example 1 illustrates a flowchart
  • FIG. 2 is showing the bioavailability of sildenafil in a human blood plasma after taking the oral gel formulation prepared in accordance with embodiments of the present disclosure and the commercially available reference sildenafil 100 mg film-coated tablets (VIAGRA).
  • a comparative randomized, single dose, two-way crossover open label study to determine the bioequivalence of sildenafil 100 mg after an oral administration to healthy adults under fasting conditions was conducted to compare the absorption and disposition kinetics of the oral gel formulation of the present disclosure relative to the commercially available reference 100 mg film-coated tablet.
  • Each healthy male subject received an oral dose of the assigned formulation, according to a randomization scheme, administered with 240 ml of water.
  • Subject assigned for the oral gel formulation have administered the gel quantity filled in the sachet to have an equivalent amount of 100 mg Sildenafil as per the film coated tablet of the reference product, Viagra tablets.
  • the two periods were separated by at least seven-day washout interval from the first study drug administration.
  • FIG. 2 illustrates Sildenafil means after a single dose administration for both treatments; the oral gel formulation of 100 mg sildenafil prepared in accordance with embodiments of the present disclosure and the commercially available reference sildenafil 100 mg film-coated tablets.
  • Cmax and for AUC proves comparable plasma concentrations of sildenafil. Since plasma levels are a meaningful surrogate for pharmacodynamic action and adverse events, this demonstrates that an equivalent therapeutic activity and tolerance is to be expected from the oral gel formulation as compared to film-coated tablets.
  • Table (3) [057] The analytical methods used to determine the stability of the oral gel formulation were stability indicating validated methods capable of separating the intact compound of interest from decomposition products or from potentially interfering substances. The used methods were the USP pharmacopeia methods used for the sildenafil tablets.
  • Tables 5 and 6 summarize the validation results of the method of analysis used for assay and degradation, respectively.
  • Amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub-ranges such as 1 to 3, 2 to 4, etc.
  • the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

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Abstract

There is provided a pharmaceutical composition including sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water. There is also provide an oral gel formulation containing the pharmaceutical composition, for use in treating erectile dysfunction as a bioequivalent formulation to the commercially available reference film coated 100 mg tablets.

Description

A PHARMACEUTICAL COMPOSITION OF SILDENAFIL AND A FORMULATION THEREOF
TECHNICAL FIELD
[01] The present disclosure relates to novel pharmaceutical compositions and formulations for treating erectile dysfunction, and more particularly to a novel pharmaceutical composition and formulation of sildenafil or a pharmaceutically acceptable salt thereof.
BACKGROUND INFORMATION
[02] Penile erection is a complicated physiological process that involves the blood vessel system, as well as the endocrine and nervous systems. Patients suffering from erectile dysfunction (“ED”) are increasing due to many reasons such as the expanded life span, the increase of adult diseases, change of diet, the increase of industrial and traffic accidents, and the increase of mental stress and physical fatigue resulting from complicated modem life could contribute to aggravate this manifestation.
[03] Sildenafil is one of the widely known medications that are used to temporarily treat ED, and is mainly formulated as oral tablets or as intravenous injection. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (“cGMP”) specific phosphodiesterase type 5 (“PDE5”) which regulates the blood flow in the penis.
[04] Some adults do not tolerate taking medications in solid oral dosage forms for reasons such as swallowing difficulties. Therefore, they tend to take medications formulated in a dosage form that are more tolerable for them. Attempts to provide alternative formulations for Sildenafil have been conducted in the art. For instance, Kamagra, is a commercially available oral gel formulation of Sildenafil, but no clinical or pharmacokinetic studies were conducted to show the bioavailability of Sildenafil compared to the approved tablets dosage form. Therefore, its safety or efficacy are not proven.
[05] Other attempts have been done in the art to provide a topical gel formulation of Sildenafil for other uses. For example, a study conducted by Koray Gusroy et al. in 2013 discloses a topical gel formulation of Sildenafil for wound healing. As another example, a study by Shabaan K. Osman was conducted in 2016 to provide a topical gel formulation of sildenafil.
[06] The prior art solutions do not provide an oral gel formulation of sildenafil or any of its pharmaceutically acceptable salts that provide a similar bioavailability of sildenafil in the human body compared to 100 mg film coated tablet.
SUMMARY
[07] Therefore, it is an object of the present disclosure to provide a pharmaceutical composition of sildenafil or a pharmaceutically acceptable salt thereof.
[08] It is another object of the present disclosure to provide an oral gel formulation of the pharmaceutical composition of sildenafil or its pharmaceutically acceptable salt.
[09] In aspects of the present disclosure, the oral gel formulation provides a similar bioavailability of sildenafil in a human body compared to a commercially available approved 100 mg film-coated tablet of sildenafil.
[010] In aspects of the present disclosure, the pharmaceutical composition may include sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water.
[OH] In some aspects, the pharmaceutical composition may further include a coloring agent.
[012] In aspects of the present disclosure, the pharmaceutically acceptable salt may include sildenafil citrate.
[013] In aspects of the present disclosure, the gelling and thickening agent may be a carbomer polymer having a grade selected from a group including 71G, 971, 971P, 974, 974P, 934, 934P, or combinations thereof.
[014] In aspects of the present disclosure, the water miscible co-solvent may be propylene glycol, glycerin, or a combination thereof. [015] In aspects of the present disclosure, the taste masking agent may be a sorbitol solution, mannitol, or a combination thereof.
[016] In aspects of the present disclosure, the sweeting agent may be sucralose, sodium saccharine, or a combination thereof.
[017] In aspects of the present disclosure, the flavoring agent may be peppermint oil, orange oil, or a combination thereof or any other suitable flavoring agent.
[018] In aspects of the present disclosure, the neutralizing agent may be sodium hydroxide, potassium hydroxide, ethanolamine, or a combination thereof.
[019] In some aspects, the pharmaceutical composition may include from about 1.5% to about 3.5% by weight sildenafil or its pharmaceutically acceptable salt.
[020] In some aspects, the pharmaceutical composition may include from about 0.5% to about 2% by weight gelling and thickening agent.
[021] In some aspects, the pharmaceutical composition may include from about 15% to about 30% by weight water miscible co-solvent.
[022] In some aspects, the pharmaceutical composition may include from about 5% to about 10% by weight taste masking agent.
[023] In some aspects, the pharmaceutical composition may include from about 0.01% to about 0.4% by weight favoring agent.
[024] In some aspects, the neutralizing agent adjusts the pH of the pharmaceutical composition from about 4 to about 8.
[025] In some aspects, the pharmaceutical composition may include from about 0.005% to about 0.02% by weight coloring agent.
[026] In aspects of the present disclosure, the pharmaceutical composition is for use in treating ED. BRIEF DESCRIPTION OF THE DRAWINGS
[027] The present disclosure will now be described with reference to the accompanying drawing, which illustrates embodiments of the present disclosure, and in which:
[028] FIG. 1 illustrates a flowchart of a method of preparing an oral gel formulation of a composition of sildenafil or a pharmaceutically acceptable salt thereof in accordance with embodiments of the present disclosure.
[029] FIG. 2 illustrates mean plasma concentrations of sildenafil in human blood plasma after taking the oral gel formulation prepared in accordance with embodiments of the present disclosure and the commercially available Reference sildenafil 100 mg film-coated tablets.
DETAILED DESCRIPTION
[030] Embodiments of the present disclosure provide a pharmaceutical composition for treating ED, the composition may include sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water. In some embodiments, the pharmaceutical composition may further include a coloring agent.
[031] In some embodiments of the present disclosure, the pharmaceutically acceptable salt may include sildenafil citrate.
[032] In embodiments of the present disclosure, the gelling and thickening agent may be a carbomer polymer having a grade selected from a group including 71 G, 971, 97 IP, 974, 974P, 934, 934P, or combinations thereof.
[033] In general, carbomers designated with the letter ‘P’, e.g. Carbopol 971P, are the pharmaceutical grade polymers for oral or mucosal contact products. Table (1) illustrates characteristics of possible carbomer polymers. Table (1)
Carbopol Polymerization/Residual Viscosity, cP
Polymer solvent (0.5 wt% at pH 7.5)
Figure imgf000006_0001
[034] In embodiments of the present disclosure, the water miscible co-solvent may be propylene glycol, glycerin, or a combination thereof.
[035] In embodiments of the present disclosure, the taste masking agent may be a sorbitol solution, mannitol, or a combination thereof.
[036] In embodiments of the present disclosure, the sweeting agent may be sucralose, sodium saccharine, or a combination thereof.
[037] In embodiments of the present disclosure, the flavoring agent may be peppermint oil, orange oil, or a combination thereof, or any other suitable flavoring agent.
[038] In embodiments of the present disclosure, the neutralizing agent may be sodium hydroxide, potassium hydroxide, ethanolamine, or a combination thereof.
[039] In some embodiments, the pharmaceutical composition may include from about 1.5% to about 3.5% by weight sildenafil or its pharmaceutically acceptable salt.
[040] In some embodiments, the pharmaceutical composition may include from about 0.5% to about 2% by weight gelling and thickening agent.
[041] In some embodiments, the pharmaceutical composition may include from about 15% to about 30% by weight water miscible co-solvent.
[042] In some embodiments, the pharmaceutical composition may include from about 5% to about 10% by weight taste masking agent.
[043] In some embodiments, the pharmaceutical composition may include from about 0.1% to about 1.0% by weight sweetening agent. [044] In some embodiments, the pharmaceutical composition may include from about 0.01% to about 0.4% by weight favoring agent.
[045] In some embodiments, the neutralizing agent adjusts the pH of the pharmaceutical composition from about 4 to about 8.
[046] In some embodiments, the pharmaceutical composition may include from about 0.005% to about 0.02% by weight coloring agent.
[047] In embodiments of the present disclosure, the pharmaceutical composition is for use in treating ED.
[048] Embodiments of the present disclosure further provide an oral gel formulation including the pharmaceutical composition as described above.
[049] The disclosure is now further illustrated on the basis of examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only; they are not intended to be exhaustive or to limit the disclosure to the precise form disclosed.
Example 1
Preparation of the oral gel formulation
[050] Reference in this example is made to FIG. 1, which illustrates a flowchart of a method of preparing an oral gel formulation of a pharmaceutical composition including sildenafil or a pharmaceutically acceptable salt thereof, the method may include the steps of hydrating a gelling and thickening agent (0.8-1.2%) to provide a first mixture (process block 1-1); dispersing the sildenafil or its pharmaceutical acceptable salt (citrate salt around 2.8%) in a water miscible co-solvent (23-28%) to provide a second mixture (process block 1-2); dissolving a sweetening agent (0.3-0.5%) , a taste masking agent (6-8%), a flavoring agent (0.02-0.2%), a neutralizing agent, and a coloring agent (0.007-0.015%) in water to provide a third mixture (process block 1-3); and mixing the first, second, and third mixtures together to obtain an oral gel, followed by adjusting the pH to of the gel to become within a range from about 5 to about 7 (process block 1-4). Example 2
Bioequivalence of the oral gel formulation with the film-coated tablets of sildenafil
[051] Reference in this example is being made to FIG. 2, which is showing the bioavailability of sildenafil in a human blood plasma after taking the oral gel formulation prepared in accordance with embodiments of the present disclosure and the commercially available reference sildenafil 100 mg film-coated tablets (VIAGRA).
[052] A comparative randomized, single dose, two-way crossover open label study to determine the bioequivalence of sildenafil 100 mg after an oral administration to healthy adults under fasting conditions was conducted to compare the absorption and disposition kinetics of the oral gel formulation of the present disclosure relative to the commercially available reference 100 mg film-coated tablet. Each healthy male subject received an oral dose of the assigned formulation, according to a randomization scheme, administered with 240 ml of water. Subject assigned for the oral gel formulation have administered the gel quantity filled in the sachet to have an equivalent amount of 100 mg Sildenafil as per the film coated tablet of the reference product, Viagra tablets. The two periods were separated by at least seven-day washout interval from the first study drug administration. 30 subjects were admitted the night before the study drug administration, supervised for at least 10 hours of overnight fasting, and confined until collecting the 24-hour sample. Safety/adverse events, laboratory evaluation, ECG, physical examination and vital signs. The study was conducted according to the “Declaration of Helsinki”.
[053] Point estimates and the 90% Confidence Intervals for sildenafil transformed ratios (Test/Reference) were within the accepted limits of 80.00%-125.00% for Cmax: 92.51 (80.90-105.79) % and for AUC(I 97.01 (90.99- 103.43)% showing bioequivalency of the oral gel formulation to the commercially available reference film coated 100 mg tablets. Table 2 illustrates the summary of the pharmacokinetics parameters of sildenafil from the oral gel Formulation compared to reference available tablets after a single dose administration for both treatments; wherein Test Product refers to the oral gel formulation of 100 mg sildenafil prepared in accordance with embodiments of the present disclosure Reference Product refers to VIAGRA 100 mg sildenafil film coated tablet. Table (2)
Figure imgf000009_0001
[054] FIG. 2 illustrates Sildenafil means after a single dose administration for both treatments; the oral gel formulation of 100 mg sildenafil prepared in accordance with embodiments of the present disclosure and the commercially available reference sildenafil 100 mg film-coated tablets. The point estimates mentioned above for Cmax and for AUC(I proves comparable plasma concentrations of sildenafil. Since plasma levels are a meaningful surrogate for pharmacodynamic action and adverse events, this demonstrates that an equivalent therapeutic activity and tolerance is to be expected from the oral gel formulation as compared to film-coated tablets.
Example 3
Stability of the oral gel formulation
[055] Stability studies were conducted in accordance to ICH Q1A (R2). Long term stability for at least 24 months at 30°C and 35% relative humidity was done in addition to accelerated stability for 6 months conducted at 40°C and not more than 25% relative humidity on three batches to confirm the product stability.
[056] The assay results of sildenafil in samples stored at different storage conditions remained within the specifications throughout the time periods monitored and there was no significant decrease in its concentration throughout the time periods monitored. The results of determination of degradation products of sildenafil in the tested samples show that the percentage of these products were below the assigned allowable limits at the long term & accelerated stability studies. The oral gel formulation was also shown to be microbially stable with no significant decrease seen in the dissolution of sildenafil from the oral gel during the 24 months long term stability or the accelerated stability. Tables 3 and 4 summarize the stability data at different conditions
Table (3)
Figure imgf000010_0001
[057] The analytical methods used to determine the stability of the oral gel formulation were stability indicating validated methods capable of separating the intact compound of interest from decomposition products or from potentially interfering substances. The used methods were the USP pharmacopeia methods used for the sildenafil tablets.
[058] Tables 5 and 6 summarize the validation results of the method of analysis used for assay and degradation, respectively.
Table (5)
Figure imgf000011_0001
Table (6)
Figure imgf000012_0001
[059] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof.
[060] In describing and claiming the present invention, the following terminology is used.
[061] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
[062] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defector equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
[063] Amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub-ranges such as 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as “less than approximately 4.5,” which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described.
[064] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.
[065] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.
[066] As used herein, the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

Claims

CLAIMS What is claimed is:
1. A pharmaceutical composition comprising sildenafil or a pharmaceutically acceptable salt thereof, a gelling and thickening agent, a water miscible co-solvent, a taste masking agent, a sweetening agent, a flavoring agent, a neutralizing agent, and water.
2. The pharmaceutical composition of claim 1, further comprising a coloring agent.
3. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt comprises sildenafil citrate.
4. The pharmaceutical composition of claim 1, wherein the gelling and thickening agent comprises a carbomer polymer having a grade selected from a group comprising 71G, 971, 97 IP, 974, 974P, 934, 934P, or combinations thereof.
5. The pharmaceutical composition of claim 1, wherein the water miscible co-solvent comprises propylene glycol, glycerin, or a combination thereof.
6. The pharmaceutical composition of claim 1, wherein the taste masking agent comprises a sorbitol solution, mannitol, or a combination thereof.
7. The pharmaceutical composition of claim 1, wherein the sweeting agent comprises sucralose, sodium saccharine, or a combination thereof.
8. The pharmaceutical composition of claim 1, wherein the flavoring agent comprises peppermint oil, or orange oil or a combination thereof, or any other suitable flavoring agent.
9. The pharmaceutical composition of claim 1, wherein the neutralizing agent comprises sodium hydroxide, potassium hydroxide, ethanolamine, or a combination thereof.
10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 1.5% to about 3.5% by weight sildenafil or its pharmaceutically acceptable salt. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 0.5% to about 2% by weight gelling and thickening agent. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 15% to about 30% by weight water miscible co-solvent. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 5% to about 10% by weight taste masking agent. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 0.01% to about 0.4% by weight favoring agent. The pharmaceutical composition of claim 1, the neutralizing agent adjusts the pH of the pharmaceutical composition from about 4 to about 8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition may include from about 0.005% to about 0.02% by weight coloring agent. Use of the pharmaceutical composition of claim 1 for treating erectile dysfunction. An oral gel formulation comprising the pharmaceutical composition of claim 1.
PCT/JO2021/050012 2021-09-13 2021-09-13 A pharmaceutical composition of sildenafil and a formulation thereof WO2023037394A1 (en)

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US20050042177A1 (en) * 2003-07-23 2005-02-24 Elan Pharma International Ltd. Novel compositions of sildenafil free base
US20110244050A1 (en) * 2008-12-12 2011-10-06 Siegfried Rhein S.A. De C.V. Pulsed-release sildenafil composition and method for preparing said composition
US20160287593A1 (en) * 2015-04-03 2016-10-06 Insys Development Company, Inc. Sildenafil sublingual spray formulations
US20190282591A1 (en) * 2018-03-16 2019-09-19 Blue Goose Drugs Inc. Finasteride and sildenafil compositions and applications
US20200222544A1 (en) * 2014-12-09 2020-07-16 Aquestive Therapeutics, Inc. Linear polysaccharide based film products
US20210052591A1 (en) * 2017-12-26 2021-02-25 Ftf Pharma Private Limited Liquid oral formulations for pde v inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050042177A1 (en) * 2003-07-23 2005-02-24 Elan Pharma International Ltd. Novel compositions of sildenafil free base
US20110244050A1 (en) * 2008-12-12 2011-10-06 Siegfried Rhein S.A. De C.V. Pulsed-release sildenafil composition and method for preparing said composition
US20200222544A1 (en) * 2014-12-09 2020-07-16 Aquestive Therapeutics, Inc. Linear polysaccharide based film products
US20160287593A1 (en) * 2015-04-03 2016-10-06 Insys Development Company, Inc. Sildenafil sublingual spray formulations
US20210052591A1 (en) * 2017-12-26 2021-02-25 Ftf Pharma Private Limited Liquid oral formulations for pde v inhibitors
US20190282591A1 (en) * 2018-03-16 2019-09-19 Blue Goose Drugs Inc. Finasteride and sildenafil compositions and applications

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