WO2023037394A1 - Composition pharmaceutique de sildénafil et formulation de celui-ci - Google Patents

Composition pharmaceutique de sildénafil et formulation de celui-ci 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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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
agent
sildenafil
weight
combination
Prior art date
Application number
PCT/JO2021/050012
Other languages
English (en)
Inventor
Hanan KAKISH
Sharifeh ABU ALI
Areej ABUSHAMALAH
Fadi ALATRASH
Original Assignee
Amman Pharmaceutical Industries Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amman Pharmaceutical Industries Company filed Critical Amman Pharmaceutical Industries Company
Priority to PCT/JO2021/050012 priority Critical patent/WO2023037394A1/fr
Publication of WO2023037394A1 publication Critical patent/WO2023037394A1/fr

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Classifications

    • 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Reproductive Health (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant du sildénafil ou un sel pharmaceutiquement acceptable de celui-ci, un agent gélifiant et épaississant, un co-solvant miscible dans l'eau, un agent masquant le goût, un agent édulcorant, un agent aromatisant, un agent neutralisant et de l'eau. L'invention concerne également une formulation de gel oral contenant la composition pharmaceutique, destinée à être utilisée dans le traitement d'un dysfonctionnement érectile en tant que formulation bioéquivalente aux comprimés pelliculés à 100 mg de référence disponibles dans le commerce.
PCT/JO2021/050012 2021-09-13 2021-09-13 Composition pharmaceutique de sildénafil et formulation de celui-ci WO2023037394A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JO2021/050012 WO2023037394A1 (fr) 2021-09-13 2021-09-13 Composition pharmaceutique de sildénafil et formulation de celui-ci

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JO2021/050012 WO2023037394A1 (fr) 2021-09-13 2021-09-13 Composition pharmaceutique de sildénafil et formulation de celui-ci

Publications (1)

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WO2023037394A1 true WO2023037394A1 (fr) 2023-03-16

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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
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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