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WO2009074995A1 - Compositions à croquer de citrate de sildénafil au goût masqué - Google Patents

Compositions à croquer de citrate de sildénafil au goût masqué Download PDF

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Publication number
WO2009074995A1
WO2009074995A1 PCT/IN2008/000049 IN2008000049W WO2009074995A1 WO 2009074995 A1 WO2009074995 A1 WO 2009074995A1 IN 2008000049 W IN2008000049 W IN 2008000049W WO 2009074995 A1 WO2009074995 A1 WO 2009074995A1
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WO
WIPO (PCT)
Prior art keywords
sildenafil
composition
sildenafil citrate
taste
complex
Prior art date
Application number
PCT/IN2008/000049
Other languages
English (en)
Inventor
Shailesh Singh
Dhanraj Amin
Mohan Goud
Original Assignee
Ajanta Pharma Limited
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 Ajanta Pharma Limited filed Critical Ajanta Pharma Limited
Publication of WO2009074995A1 publication Critical patent/WO2009074995A1/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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61P15/16—Masculine contraceptives

Definitions

  • the present invention provides novel chewable immediate release compositions comprising sildenafil citrate wherein the bitter taste of sildenafil has been masked by forming a sildenafil mask complex
  • the masking agent comprises of a mixture of polyacrylic resin, carbomer and powdered microcrystalline cellulose.
  • the sildenafil gets entrapped in the polyacrylic resin which has free exchange sites and a cationic exchange occurs.
  • the carbomer serves as a binder to strengthen the complex formation whereas the powdered microcrystalline cellulose is a filler.
  • the said composition further comprises other excipients like mannitol which serves as the base for a chewable tablet, disintegrants, binders, lubricants, glidants and flavours.
  • Sildenafil citrate is a selective inhibitor of cyclic guanosine monophosphate (cGMP)- specific phosphodiesterase type 5 (PDE5), commercially developed by Pfizer, Inc. as VIAGRA R .
  • Sildenafil citrate is designated chemically as l-[[3-(6,7-dihydro-l-methyl-7- oxo-3-propyl-lH-pyrazolo[4,3- ⁇ pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl piperazine citrate, having a molecular weight of 666.7, and the following chemical structure:
  • Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/ml in water.
  • NO nitric oxide
  • cGMP cyclic guanosine monophosphate
  • Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5, which is responsible for degradation of cGMP in the corpus cavernosum.
  • sildenafil When sexual stimulation causes local release of NO, inhibition of PDES by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
  • sildenafil citrate has a very bitter taste and hence tablets such as Viagra R , which are commercially available are film coated.
  • the film coating masks any bitter taste in the mouth and these tablets have to be taken with water.
  • chewable tablets which are usually uncoated, there is a need to mask the bitter taste of sildenafil as they are chewed and remain in contact with the taste receptors in the mouth for a longer period of time.
  • formulations relating to various processes used for taste masking of ingredients are known priori art.
  • US Patent No. 6,197,348 describes a dosage form that utilizes encapsulated particles coated with polymers, such as Eudragit RS and Eudragit RL.
  • Taste masking is achieved as a result of the polymer coatings and a liquid suspending medium having a pH that is adjusted to a point where the active ingredient is insoluble.
  • the thickness and type of coating is not sufficient for taste masking.
  • EP 0458751 discloses compositions containing a core that includes a cyclic amino acid compound.
  • the core is coated with polymeric film forming compounds and hydrophilic fats' fatty acids and waxes.
  • US Patent No. 4,800,087 discloses a taste masked composition in a chewable dosage form having a controlled release profile.
  • the invention utilizes a combination of polymers to achieve a taste masking coating suitable for incorporation into a chewable dosage form.
  • the composition contains microcapsules which are composed of an active ingredient and a polymer mixture coating having a sufficient elasticity to withstand chewing.
  • the polymeric coating mixture includes one high temperature film forming copolymer and one low temperature film forming copolymer.
  • US Patent No. 6,139,865 discloses a taste masked microcapsule composition of water soluble active ingredients.
  • the water soluble active ingredients are coacervated in the polymeric material.
  • This technique suffers from several disadvantages. For example, the technique requires the use of hydrocarbons and other organic solvents, such as; cyclohexane. These solvents are explosive and present problems in large scale manufacturing.
  • US Application 2002/064563 discloses a taste masked composition of topiramate and a process for its preparation. The process includes preparing core particles which include the active ingredient topiramate, coating with a taste masked mixture to form coated particles, and drying the coated particles.
  • US Patent No. 6,106,861 discloses a multiparticulate disintegrating tablet which includes excipients and an active ingredient in the form of microcrystals. Only a limited number of active ingredients can be commercially made in the form of microcrystals, and specifically, amorphous powders cannot be utilized in this process.
  • WO 01/35930 discloses a process for taste masking by granulation of the active ingredient with an aqueous admixture that includes a neutral methacrylic acid ester copolymers and a binder. Taste masking can only be achieved for moderately bitter and poorly soluble active ingredients, but is ineffective for highly bitter and/or soluble active ingredients.
  • US Patent No. 5,084,278 describes a chewable taste masked pharmaceutical composition having a controlled release profile.
  • the composition comprises microcapsules with are made up of an active ingredient core coated with a polymer mixture.
  • the coating includes a blend of ethyl cellulose and polymethacrylic acid ester copolymers.
  • US Patent No. 6,136,347 describes a pharmaceutical composition which comprises microcapsules wherein the active ingredient is microencapsulated within the microcapsule wall.
  • the active ingredient is present as an anhydrate or its free base fond.
  • the composition further utilizes an oily suspension as a vehicle for suspending microparticles coated with a combination of water soluble and water insoluble polymers' thus preventing the interaction of water.
  • this dosage form suffers from the disadvantage of poor acceptability due to a sand/oily feel in the mouth. Additionally, it needs a vehicle for reconstitution to be supplied along with the microcapsules It is evident that there is a commercial need for a pharmaceutical dosage form that effectively provides taste masking, without alteration of the release profile.
  • the prior art fails to describe a pharmaceutical composition with a taste masking coating that provides for immediate release of the encapsulated active ingredient in solution, without the problems of leaching or swelling when exposed to an aqueous media in suspension at the typical pH of saliva.
  • US Patent No. 6,221,402 assigned to Pfizer discloses a rapidly releasing and taste masking pharmaceutical dosage form for sildenafil and a process for the preparation of the same.
  • this product uses an inner and outer coating wherein the inner coating coats the granules of sildenafil citrate and comprises of Eudragit NE30D, the outer coating comprising of two layers one made up of Eudragit ElOO and the other being a sugar coating layer.
  • WO 04/087111 assigned to Ranbaxy discloses oral taste masked pharmaceutical compositions that include a core having an active ingredient coated with a mixture of polymeric film forming binders and inorganic carriers. Also provided are processes for preparing the oral taste masked pharmaceutical composition.
  • WO 04/022037 assigned to Ranbaxy relates to taste masked dosage forms utilizing low amounts of taste masking polymer, and simple and economical processes for the preparation of the taste masked dosage forms.
  • the taste-masked dosage form includes one or more drugs and one or more cationic polymers synthesized from dimethylaminoethyl methacrylate and neutral methacrylic acid esters.
  • the wt/wt ratio of the drug to polymer is less than about one to two.
  • US Application 2006/0159758 relates to coating compositions for taste masking and methods for applying the coating compositions to dosage forms to mask the taste of a medicinal substance.
  • the taste masking coating compositions generally include a copolymer of acrylate and methacrylate with a quaternary ammonium group in combination with sodium carboxymethylcellulose and a polyvinyl alcohol-polyethylene glycol copolymer.
  • a taste masked pharmaceutical composition of sildenafil citrate that includes use of a polyacrylic resin where in a cationic exchange occurs.
  • a polyacrylic resin where in a cationic exchange occurs.
  • the ready mix comprises of a polyacrylic resin which is cationic in nature. In addition it comprises carbomer and powdered cellulose.
  • the polyacrylic resin does not belong to the class of methacrylic acid esters. It has free binding sites wherein the sildenafil citrate gets exchanged.
  • the active pharmaceutical ingredient may be one or more of antibiotics, antihistamines, antiarthritics, anti psychotics, tranquillizers, antidiabetics, antipyretics, antiulcerants, antiasthmatics, antihypertensives, antianxiety, nonsteroidal antiinflammatory active ingredients and salts thereof.
  • the active pharmaceutical ingredient may be one or more of clarithromycin, ciprofloxacin, acetaminophen, bambuterol, olanzapine, ranitidine, sildenafil, cefodoxime, amoxycillin, erythromycin, chlorpheniramine, cefuroxime and salts thereof.
  • the active pharmaceutical ingredient may be present in the range of from about 5% w/w to about 90% w/w.
  • the cationic polyacrylic resin comprising the ready mix does not belong to the methacrylate class of polymers and may be present in a concentration ranging from about 10% w/w to about 90°/0 w/w.
  • the other excipients include mannitol which forms the base for chewable tablets.
  • the concentration range for mannitol may vary from about 5% w/w to about 15% w/w.
  • the composition may further include one or more pharmaceutically acceptable excipients which includes disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.
  • disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride
  • sweetners like aspartame sucralose and sucrose
  • flavors like monoammonium glycerrhizinate
  • a process for the preparation of an oral taste masked composition of sildenafil citrate using an ion-exchange mechanism to mask the bitter taste of the drug includes forming a mask complex of sildenafil citrate by using Instacoat MK 9014 by using an aqueous process to obtains taste masked granules which are suitably sized followed by aqueous granulation of the masked complex with various excipients and then lubrication of the final mass before compression into tablets using suitable tooling.
  • a method of treating a condition for which an active pharmaceutical ingredient is prescribed includes administering a taste masked pharmaceutical composition that includes a taste masked chewable tablet formulation.
  • the present invention provides obvious benefits being simple and fast operational process for manufacturing said oral solid extended release pharmaceutical composition. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • the present invention provides taste masked chewable tablet compositions for bitter tasting drugs like sildenafil citrate.
  • the said composition comprises the bitter drug sildenafil citrate in the form of a mask complex which is achieved by using a cationic exchange resin.
  • the drug gets exchanged with the free sites in the polyacrylic cationic resin to form a taste masked complex.
  • This taste masked complex is then incorporated into a formulation.
  • the other excipients used to arrive at the final composition include disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.
  • pharmaceutically acceptable derivative means various pharmaceutical equivalent isomers, enantiomers, complexes, hydrates, polymorphs, and etc. of metoprolol succinate.
  • composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, and pellets, comprising metoprolol succinate or pharmaceutically acceptable derivatives thereof.
  • terapéuticaally effective amount means an amount of the drug, which is capable of eliciting a physiological response in a human patient. More specifically, the term “therapeutically effective amount” means the amount of drug, which is capable of treating erectile dysfunction and related disorders.
  • the medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule, a tablet, micro-tablets, granules or pellets filled in capsule formulation, typically an extended or modified release tablet formulation substantially as hereinafter further described.
  • a formulation according to the present invention provides a taste masked chewable dosage form, preferably tablets comprising taste masked sildenafil citrate or pharmaceutically acceptable derivatives thereof along with other pharmaceutically acceptable excipients wherein the taste masking is achieved through an ion-exchange mechanism
  • a preferred embodiment of the present invention is a chewable tablet formulation comprising a pharmaceutically active agent (sildenafil citrate) along with suitable excipients.
  • a pharmaceutically active agent sildenafil citrate
  • suitable excipients for taste masking the bitter taste of sildenafil citrate by using an ion-exchange mechanism.
  • the taste masked chewable tablet dosage form of sildenafil citrate according to the present invention may be formulated by mixing the drug with a polyacrylic cationic exchange resin that is commercially available as INSTAMASK R .
  • This ready mix commercially available product comprises of a polyacrylic resin (cationic) ion-exchange resin, carbomer and powdered cellulose.
  • the composition of the present invention may also comprise some drug that is not taste masked and added directly.
  • the other excipients used include disintegrants like croscarmellose sodium, pH adjusters like citric acid monohydrate and sodium chloride, fillers like microcrystalline cellulose (Vivapur 102), sweetners like aspartame sucralose and sucrose, flavors like monoammonium glycerrhizinate, glidants and lubricants like magnesium stearate, talc and colloidal silicon dioxide (Aerosil), binders like PVP and colours.
  • the present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as herein before described.
  • sildenafil citrate The total dose of sildenafil citrate is divided into two halves with one half being taste masked. The remaining half dose is added as such directly into the composition. This is done by mixing sildenafil citrate and Instacoat MK 9014 in purified water for 30 minutes, followed by stirring for a period of about 4 hours. The suspension is then centrifuged and dried in a fluidized bed drier. The resulting sildenafil citrate - Instacoat MK 9014 masked complex is sifted through Sieve No. 40.
  • This dried masked complex is then granulated in a Rotary Mixer Granulator along with the remaining 50% sildenafil citrate, mannitol, microcrystalline cellulose, citric acid monohydrate, sodium chloride, aspartame, monoammonium glycerrhizinate, sucralose, sucrose, croscarmellose sodium and colours for a period of 15 minutes. All excipients are passed through Sieve No. 40 before use.
  • the binder solution comprising povidone (PVPK30) in isopropyl alcohol is added to the dry mix and the mass granulated to obtain suitable granules.
  • the granules are dried in a fluidized bed drier and sifted through Sieve No. 20.
  • the granules are then transferred to an octagonal blender and mixed for 2 minutes.
  • the granules are lubricated by addition of croscarmellose sodium, colloidal silicon dioxide, purified talc and flavours are mixed in the octagonal blender for 15 minutes. All excipients added at the lubrication stage are passed through Sieve No. 60. After blending of lubricants is completed for 15 minutes, magnesium stearate passed through Sieve No. 60 is added to the octagonal blender and the resulting mass is further mixed for 5 minutes. The lubricated mass is then compressed into tablets using suitable tooling.
  • a flow chart depicting the process of manufacture is diagrammatically given below:
  • sildenafil citrate mask complex a part of sildenafil citrate with Instacoat MK 9014 in purified water to form a sildenafil citrate mask complex.
  • the resultant complex is dried and sized.
  • This complex is then mixed with the remaining 50% sildenafil citrate, mannitol, microcrystalline cellulose, citric acid monohydrate, sodium chloride, aspartame, monoammonium glycerrhizinate, sucralose, sucrose, croscarmellose sodium and colours for a period of 15 minutes.
  • the dry mix is granulated with a binder solution of povidone (PVPK30) in isopropyl alcohol, dried in a fluidized bed drier and sifted.
  • povidone PVPK30
  • the granules are lubricated by addition of croscarmellose sodium, colloidal silicon dioxide, purified talc and flavours and mixed in the octagonal blender for 15 minutes, followed by addition of magnesium stearate and further mixing for 5 minutes.
  • the lubricated mass is then compressed into tablets using suitable tooling.

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Abstract

La présente invention concerne des compositions pharmaceutiques solides à croquer comprenant du citrate de sildénafil. Ledit citrate de sildénafil est un médicament très amer, si bien que les comprimés classiques comprennent un revêtement pelliculaire permettant d'améliorer son apparence esthétique et son acceptabilité. Lesdits comprimés à croquer sont généralement non revêtus, d'où la nécessité de masquer le goût amer du sildénafil afin de garantir leur acceptabilité par les patients. La présente invention parvient à masquer le goût du citrate de sildénafil grâce à l'utilisation d'une résine échangeuse d'ions qui forme un complexe et masque le goût amer du sildénafil. On incorpore ensuite le complexe de sildénafil au goût masqué d'échange d'ions à d'autres excipients, afin de formuler un comprimé à croquer en utilisant des arômes et d'autres ingrédients.
PCT/IN2008/000049 2007-12-10 2008-01-25 Compositions à croquer de citrate de sildénafil au goût masqué WO2009074995A1 (fr)

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IN2416MU2007 2007-12-10
IN2416/MUM/2007 2007-12-10

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011030351A2 (fr) 2009-09-03 2011-03-17 Rubicon Research Private Limited Compositions pharmaceutiques au goût masqué
WO2013077533A1 (fr) * 2011-11-25 2013-05-30 한국유나이티드제약 주식회사 Comprimés de citrate de sildénafil à croquer dans lesquels l'amertume est masquée, et procédé de fabrication associé
KR20140077658A (ko) * 2012-12-14 2014-06-24 한미약품 주식회사 포스포다이에스터라제-5 억제제를 포함하는 츄정
WO2014209022A1 (fr) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Formule de comprimé à mâcher comprenant du tadalafil ou l'un de ses sels pharmaceutiquement acceptables
CN104352461A (zh) * 2013-04-28 2015-02-18 南京海融医药科技有限公司 他达拉非的口服药物制剂
CN112826802A (zh) * 2021-01-22 2021-05-25 上海普康药业有限公司 一种枸橼酸西地那非咀嚼片及其制备方法
CN113413388A (zh) * 2021-06-30 2021-09-21 上海奥全生物医药科技有限公司 含有枸橼酸西地那非的药物组合物、制备方法及其应用
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate

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US20040228830A1 (en) * 2003-01-28 2004-11-18 Collegium Pharmaceutical, Inc. Multiparticulate compositions of milnacipran for oral administration
WO2006000232A1 (fr) * 2004-06-29 2006-01-05 Fertin Pharma A/S Chewing-gum liberant un alcaloide du tabac
WO2006011044A1 (fr) * 2004-07-22 2006-02-02 Pfizer Products Inc. Compositions a base de cyclodextrine amorphe
US20070092553A1 (en) * 2005-10-21 2007-04-26 Pfab Lp Compositions and methods of making rapidly dissolving lonically masked formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040228830A1 (en) * 2003-01-28 2004-11-18 Collegium Pharmaceutical, Inc. Multiparticulate compositions of milnacipran for oral administration
WO2006000232A1 (fr) * 2004-06-29 2006-01-05 Fertin Pharma A/S Chewing-gum liberant un alcaloide du tabac
WO2006011044A1 (fr) * 2004-07-22 2006-02-02 Pfizer Products Inc. Compositions a base de cyclodextrine amorphe
US20070092553A1 (en) * 2005-10-21 2007-04-26 Pfab Lp Compositions and methods of making rapidly dissolving lonically masked formulations

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011030351A2 (fr) 2009-09-03 2011-03-17 Rubicon Research Private Limited Compositions pharmaceutiques au goût masqué
WO2011030351A3 (fr) * 2009-09-03 2011-06-30 Rubicon Research Private Limited Compositions pharmaceutiques au goût masqué
WO2013077533A1 (fr) * 2011-11-25 2013-05-30 한국유나이티드제약 주식회사 Comprimés de citrate de sildénafil à croquer dans lesquels l'amertume est masquée, et procédé de fabrication associé
KR20140077658A (ko) * 2012-12-14 2014-06-24 한미약품 주식회사 포스포다이에스터라제-5 억제제를 포함하는 츄정
KR101953735B1 (ko) 2012-12-14 2019-03-04 한미약품 주식회사 포스포다이에스터라제-5 억제제를 포함하는 츄정
CN104352461A (zh) * 2013-04-28 2015-02-18 南京海融医药科技有限公司 他达拉非的口服药物制剂
KR20150002453A (ko) * 2013-06-28 2015-01-07 한미약품 주식회사 타다라필 또는 이의 약학적으로 허용가능한 염을 포함하는 저작정 제제
WO2014209022A1 (fr) * 2013-06-28 2014-12-31 Hanmi Pharm. Co., Ltd. Formule de comprimé à mâcher comprenant du tadalafil ou l'un de ses sels pharmaceutiquement acceptables
KR102239291B1 (ko) 2013-06-28 2021-04-14 한미약품 주식회사 타다라필 또는 이의 약학적으로 허용가능한 염을 포함하는 저작정 제제
US11179331B1 (en) 2020-04-21 2021-11-23 Cure Pharmaceutcai Holding Corp Oral soluble film containing sildenafil citrate
CN112826802A (zh) * 2021-01-22 2021-05-25 上海普康药业有限公司 一种枸橼酸西地那非咀嚼片及其制备方法
CN113413388A (zh) * 2021-06-30 2021-09-21 上海奥全生物医药科技有限公司 含有枸橼酸西地那非的药物组合物、制备方法及其应用
CN113413388B (zh) * 2021-06-30 2022-11-15 上海奥全生物医药科技有限公司 含有枸橼酸西地那非的药物组合物、制备方法及其应用

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