OA17536A - Tadalafil free base-containing film dosage form containing polyethylene glycol-based polymer and/or vinyl pyrrolidone-based polymer as dispersion stabilizer - Google Patents
Tadalafil free base-containing film dosage form containing polyethylene glycol-based polymer and/or vinyl pyrrolidone-based polymer as dispersion stabilizer Download PDFInfo
- Publication number
- OA17536A OA17536A OA1201500410 OA17536A OA 17536 A OA17536 A OA 17536A OA 1201500410 OA1201500410 OA 1201500410 OA 17536 A OA17536 A OA 17536A
- Authority
- OA
- OAPI
- Prior art keywords
- free base
- based polymer
- tadalafil free
- tadalafil
- film
- Prior art date
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- 229960000835 tadalafil Drugs 0.000 title claims abstract description 83
- 239000012458 free base Substances 0.000 title claims abstract description 73
- 239000006185 dispersion Substances 0.000 title claims abstract description 70
- 239000003381 stabilizer Substances 0.000 title claims abstract description 56
- IEHKWSGCTWLXFU-IIBYNOLFSA-N Tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 title claims abstract 20
- 229920000642 polymer Polymers 0.000 title claims description 99
- 239000002202 Polyethylene glycol Substances 0.000 title claims description 52
- 229920001223 polyethylene glycol Polymers 0.000 title claims description 52
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 title claims description 34
- 239000002552 dosage form Substances 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 238000009472 formulation Methods 0.000 claims abstract description 13
- 239000000178 monomer Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 14
- 229920001577 copolymer Polymers 0.000 claims description 11
- 239000004094 surface-active agent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 229920001519 homopolymer Polymers 0.000 claims description 9
- 239000004014 plasticizer Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 11
- 239000003205 fragrance Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- WOXKDUGGOYFFRN-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 WOXKDUGGOYFFRN-IIBYNOLFSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 25
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 229940068984 Polyvinyl Alcohol Drugs 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 239000004373 Pullulan Substances 0.000 description 3
- 229920001218 Pullulan Polymers 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 235000019423 pullulan Nutrition 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XTXRWKRVRITETP-UHFFFAOYSA-N vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 3
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 2
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 2
- 230000036328 Free drug Effects 0.000 description 2
- 210000000214 Mouth Anatomy 0.000 description 2
- 229940069328 Povidone Drugs 0.000 description 2
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 2
- 229940005550 Sodium alginate Drugs 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000004815 dispersion polymerization Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- -1 magnésium stéarate Polymers 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 2
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N 2-Pyrrolidone Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229940084030 CARBOXYMETHYLCELLULOSE CALCIUM Drugs 0.000 description 1
- 229960001631 Carbomer Drugs 0.000 description 1
- 229940113118 Carrageenan Drugs 0.000 description 1
- 229940117229 Cialis Drugs 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M Dioctyl sodium sulfosuccinate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229960000878 Docusate Sodium Drugs 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 229920000219 Ethylene vinyl alcohol Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940014259 Gelatin Drugs 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 206010053317 Hydrophobia Diseases 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 229960001021 Lactose Monohydrate Drugs 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 210000002200 Mouth Mucosa Anatomy 0.000 description 1
- 229960000502 Poloxamer Drugs 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 229950008882 Polysorbate Drugs 0.000 description 1
- 229940033134 Talc Drugs 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 Triacetin Drugs 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000004715 ethylene vinyl alcohol Substances 0.000 description 1
- 229960005191 ferric oxide Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 229910000460 iron oxide Inorganic materials 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004301 light adaptation Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001888 polyacrylic acid Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical group CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
Abstract
The present disclosure relates to a film formulation for oral administration, containing tadalafil free base and a method of preparing the same, and a film may be provided with maximized dispersion stability of tadalafil free base in the film by the addition of a dispersion stabilizing agent in small amounts without unique fragrance or favor that may appear when other dispersion stabilizing agents known in the art are used, and an extremely low likelihood that a reagglomeration phenomenon of tadalafil free base particles will occur, and an amount of bubbles generated may be significantly reduced during a production process.
Description
The présent disclosure relates to a film formulation containing tadalafil free base as an active ingrédient and a method of preparing the same. More particularly, the présent disclosure relates to a tadalafil free base-containing film with content uniformity and dispersion uniformity and a method of producing a tadalafil free basecontaining film with content uniformity and dispersion uniformity.
The présent application claims priority to Korean Patent Application No. 102013-0040084 filed in the Republic of Korea on April 11, 2013, the disclosure of which is incorporated herein by reference.
BACKGROUND ART
An active ingrédient of Cialis , tadalafil, has been used to treat male erectile dysfunction. Prescription information of Cialis® describes this product as almondshaped tablets for oral administration, coated with a film containing tadalafil and the following inactive ingrédients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnésium stéarate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide and triacetin (see http://pi.lilly.com/us/cialis-pi.pdf).
The chemical désignation of tadalafil is (6R-trans)-6-(l,3-benzodioxol-5-yl)2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[r,2':l,6]pyrido[3,4-b]indole-l,4-dione. Tadalafil(CAS# 171596-29-5) has a structure represented as below:
Tadalafil is a solid that is practically insoluble in water, and is known as being slightly soluble in some organic solvents such as methanol, éthanol and acetone. U.S. Patent No. 6,841,167 discloses having a water solubility of about 2 μ g per 1 milliliter (mL) of water at 25°C.
When tadalafil is produced in an insufficient dissolved state or in a dispersed or suspended state, a layer séparation of a film preparing solution and non-uniformity of an active ingrédient may occur due to strong water repellency. Such layer séparation and non-uniformity takes place in processes of preparing the film preparing solution, and delivering for coating of the film preparing solution, and drying after coating.
In an attempt to overcome poor water solubility resulting from strong hydrophobicity of tadalafil, many technologies were applied. U.S. Patent No. 6,841,167 reports a pharmaceutical formulation containing a mixture of tadalafil in a free drug form with a diluent, a lubricant, a hydrophilic binder and disintegrant. Also, U.S. Patent No. 6,821,975 discloses a free drug particulate form of tadalafil comprising particles of a compound wherein at least 90% of the particles hâve a particle size of less than about 40 microns, limiting a particle size of tadalafil.
However, these methods ail focus on improvement in solubility of tadalafil, and there is a need for an attempt to overcome strong hydrophobie properties of tadalafil.
DISCLOSURE
Technical Problem
The présent disclosure is directed to providing a tadalafil free base-containing film preparing solution in which a dispersion stabilizing agent is présent in a smaller amount than a compound conventionally used as a dispersion stabilizing agent, the dispersion stabilizing agent selected to allow uniform dispersion in a film without a reagglomeration phenomenon, rather than substantially dissolving tadalafil free base, and a film, and a method of preparing a tadalafil free base-containing film using the dispersion stabilizing agent.
Technical Solution
To achieve the object, the présent disclosure provides a tadalafil free basecontaining film in which a polyethyleneglycol-based polymer, a vinylpyrrolidonebased polymer, or mixtures thereof is included in a tadalafil free base-containing film formulation as a dispersion stabilizing agent, and its film preparing solution, and their preparing methods.
More particularly, the présent disclosure provides a tadalafil free basecontaining film in which a film formulation includes tadalafil free base as an active ingrédient, and a polyethyleneglycol-based polymer, a vinylpyrrolidone-based polymer, or mixtures thereof as a dispersion stabilizing agent.
Also, the présent disclosure provides a tadalafil free base-containing film preparing solution including a tadalafil free base as an active ingrédient, and a polyethyleneglycol-based polymer, a vinylpyrrolidone-based polymer, or mixtures thereof as a dispersion stabilizing agent.
Tadalafil free base is very difficult to préparé a film in an aqueous solution state due to strong hydrophobicity. Therefore, instead of overcoming strong hydrophobicity of tadalafil free base, the présent disclosure is intended to make use of it. The présent disclosure is based on fmdings that a film containing a desired content of tadalafil free base with a thickness and a size suitable for individual dose adaptation as well as desired properties may be obtained by dispersing (or suspending) tadalafil free base in a polymer solution based on strong hydrophobicity of tadalafil free base, rather than substantially dissolving tadalafil free base in a polymer solution.
In particular, when a polyethyleneglycol-based polymer, a vinylpyrrolidonebased polymer, or mixtures thereof is used as the dispersion stabilizing agent to disperse (or suspend) tadalafil free base, even a small amount may maximize dispersion stability of tadalafil free base in a film and eliminate or reduce the likelihood that a reagglomeration phenomenon of tadalafil free base particles will occur after a film preparing solution is prepared, as well as significantly reducing an amount of bubbles generated during a production process. Further, the présent disclosure is based on fmdings that excellence consists in being free of unique fragrance or favor appearing when other dispersion stabilizing agents (and/or surfactants) known in the art, for example, sodium lauryl sulfates (S LS) are used.
In the présent disclosure, the film may be also called a strip, an orally dissolving film (ODF), or an orally disintegrating film (ODF), and represents a formulation that is adhered to and dissolves in the oral cavity, to be exact, on the tongue or the oral mucosa membrane, or under the tongue. The film formulation according to the présent disclosure has advantages of taking a dose without drinking water and being convenient to carry with.
As used herein, dispersing (or suspending) rather than substantially ,y~ dissolving represents that 15 wt% or less, preferably 10 wt% or less, more preferably 7 wt% or less, even more preferably 4 wt% or less, most preferably 2 wt% or less of the total tadalafil free base is dissolved in the polymer solution.
In the film formulation according to the présent disclosure, because tadalafil free base does not substantially dissolve, it does not interact with a film forming polymer, and it is predicted that this is as one of the factors causing the resulting film to exhibit désirable properties, but the présent disclosure is not limited to this theory.
In the présent disclosure, it is characterized in that a polyethyleneglycol-based polymer and/or a vinylpyrrolidone-based polymer is used as the dispersion stabilizing agent to uniformly disperse tadalafil free base in the film. When a polyethyleneglycol-based polymer and/or vinylpyrrolidone-based polymer is used as the dispersion stabilizing agent, not only are there effects of maximizing the dispersion stability in the film while not dissolving tadalafil free base, but also eliminating or reducing the likelihood that a reagglomeration phenomenon of tadalafil particles will occur after a film solution is prepared.
In the présent disclosure, the polyethyleneglycol-based polymer represents a homopolymer or a copolymer of a monomer expressed by the following chemical formula 1 :
[Chemical formula 1]
where R is hydrogen or an alkyl group having 1-6 carbon atoms, and the alkyl group represents linear or branched saturated lower aliphatic hydrocarbon, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl and n pentyl groups, and most preferably, R is hydrogen. When R is hydrogen in the above formula, the monomer expressed by the above chemical formula is polyethylene glycol (PEG).
The 'n' is an integer of from 1 to 300, preferably from 5 to 100, more preferably from 10 to 50, and most preferably from 11 to 35.
The homopolymer of the monomer expressed by the above chemical formula 1 represents a polymer formed from the monomer expressed by the above chemical formula 1 alone, and the copolymer of the monomer expressed by the above chemical formula 1 represents a polymer consisting of the monomer expressed by the above chemical formula 1 and other monomer that can be copolymerized with the monomer.
In the présent disclosure, the monomer expressed by the above chemical formula 1 and other désirable monomer that can be copolymerized with the monomer include vinyl alcohol-based, and the vinyl alcohol-based polymer includes, for example, polyvinyl alcohol, polyvinyl acetate, ethylene vinyl alcohol, most preferably polyvinyl alcohol.
In the présent disclosure, a most préférable example of the monomer expressed by the above chemical formula 1 is polyethylene glycol, and in this case, the polyethyleneglycol-based polymer may be a polyethylene glycol homopolymer or a polyethylene glycol copolymer. Also, a most préférable example of the polyethylene glycol copolymer is polyvinyl alcohol-polyethylene glycol.
The polyethyleneglycol-based polymer may hâve a molecular weight in the range between 200 g/mol and 10,000,000 g/mol, but in the case of a homopolymer, the molecular weight may be preferably between 200 g/mol and 35,000 g/mol, more preferably between 200 g/mol and 10,000 g/mol, and most preferably between 200 g/mol and 600 g/mol. When the polyethyleneglycol-based polymer having the molecular weight of less than 200 g/mol or more than 35,000 g/mol is used, it is difficult to maximize the dispersion stability of tadalafil ffee base, and the likelihood of reagglomeration will occur is high. For example, according to a particular embodiment, where polyethyleneoxide (PEO) having a chemical structure similar to the polyethyleneglycol-based polymer but a relatively high molecular weight is used as the dispersion stabilizing agent, it is impossible to disperse tadalafil free base stably and effectively, as opposed to the case where the polyethyleneglycol-based polymer is used as the dispersion stabilizing agent.
The polyethyleneglycol-based polymer exists as a liquid or solid at room condition (25°C), and when the molecular weight is higher than or equal to 700 g/mol, it exists as a solid in flakes or powder form at room condition (25°C) and the melting point increases in proportion to the molecular weight, and when the molecular weight is less than 700 g/mol, it exists as a liquid at room condition (25°C). For the polyethyleneglycol-based polymer, in the présent disclosure, a liquid polyethyleneglycol-based polymer is preferably used as the dispersion stabilizing agent, and a solid polyethyleneglycol-based polymer may be used after it becomes a liquid by heating at the température higher than or equal to the melting point. The polyethyleneglycol-based polymer in a liquid state or changed to a liquid state may uniformly disperse tadalafil free base in an aqueous solution without a separate organic solvent.
In the présent disclosure, the vinylpyrrolidone-based polymer represents a homopolymer or a copolymer containing N-vinyl-2-pyrrolidone as a monomer. The vinylpyrrolidone homopolymer represents a polymer formed from N-vinyl-2pyrrolidone alone, and the vinylpyrrolidone copolymer represents a polymer consisting of N-vinyl-2-pyrrolidone and other monomer that can be copolymerized with N-vinyl-
2-pyrrolidone.
In the présent disclosure, other monomer that can be copolymerized with Nvinyl-2-pyrrolidone is a vinyl acetate-based polymer, and the vinyl acetate-based polymer is most preferably vinyl acetate.
In the présent disclosure, the vinylpyrrolidone-based polymer preferably includes, for example, polyvinylpyrrolidone or a vinylpyrrolidone-vinyl acetate copolymer.
In the présent disclosure, the vinylpyrrolidone-based polymer and/or the polyethyleneglycol-based polymer as the dispersion stabilizing agent may be présent in an amount of from 0.2 wt% to 20 wt%, more preferably from 0.3 wt% to 10 wt%, and most preferably from 2 wt% to 5 wt% based on the total weight of the dried film. For example, when the vinylpyrrolidone-based polymer and/or the polyethyleneglycolbased polymer as the dispersion stabilizing agent is présent less than 0.1 wt%, a reagglomeration phenomenon of tadalafil free base particles occurs in the resulting film and uniform dispersion of tadalafil free base is impossible, and when the vinylpyrrolidone-based polymer and/or the polyethyleneglycol-based polymer as the dispersion stabilizing agent is présent more than 20 wt%, it is uneconomical and unique favor and fragrance may appear by the addition of an excessive amount of the vinylpyrrolidone-based polymer and/or the polyethyleneglycol-based polymer.
In the présent disclosure, by the use of the vinylpyrrolidone-based polymer and/or polyethyleneglycol-based polymer as the dispersion stabilizing agent, an amount of other additives used may be reduced, for example, additives added to disperse tadalafil free base between polymer chains more stably beyond the simple suspension of free base of tadalafil in the polymer solution, to reduce agglomération of tadalafil free base particles, or to inhibit layer séparation. For example, the total amount of use of a dispersion stabilizing agent, a plasticizer, and a surfactant necessary to préparé the film may be reduced. Thus, the total content of the dispersion stabilizing agent, the plasticizer, and the surfactant may be from 1 wt% to 90 wt%, more preferably from 1 wt% to 70 wt%, even more preferably from 1 wt% to 50 wt%, and most preferably from 10 wt% to 15 wt% based on the total weight of the dried film. Also, the content of the vinylpyrrolidone-based polymer and/or the polyethyleneglycol-based polymer as the dispersion stabilizing agent may be from 5 wt% to 90 wt%, most preferably from 10 wt% to 20 wt% based on the total weight of the surfactant, the plasticizer, and the dispersion stabilizing agent used to préparé the film. When the content is less than 5 wt% or more than 90 wt%, it is difficult to stably disperse tadalafil free base. The plasticizer included in the film preparing solution according to the présent disclosure includes, but is not limited to, for example, glycerin, sorbitol, propylene glycol, or mixtures thereof. Also, the surfactant and/or the dispersion stabilizing agent included in the film preparing solution according to the présent disclosure include, but are not limited to, for example, polysorbate, polyoxyethylenealkylether, polyoxyethylene castor oil, polyoxyethyelenstearate, docusatesodium, sodium lauryl sulfate, sorbitanester, or mixtures thereof.
The présent disclosure is characterized by preparing a film formulation with maximized dispersion stability by dispersing (suspending) tadalafil free base in the polymer solution based on strong hydrophobicity of tadalafil free base rather than substantially dissolving tadalafil free base in the polymer solution. Thus, preferably 90 wt% or more, more preferably 95 wt% or more, and even more preferably 98 wt% or more of a solvent is water to keep tadalafil free base from being dissolved. Taking into account various aspects such as a thickness and a drying rate of the film when applying the film preparing solution, and viscosity of the film preparing solution, an amount of solvents used in producing the film is preferably from 0.7 parts by weight to 4 parts by weight, more preferably from 1.3 parts by weight to 3.3 parts by weight, per 1 part by weight of film constituent materials remaining after drying.
As the polymer used to form the film used in the présent disclosure, for the purpose of the présent disclosure, it is more preferred to use a polymer having viscosity of 15 cp or less (preferably between 1 cp and 15 cp) as measured in a 2 wt% aqueous solution. That is, when this polymer is used, it is more preferred in terms of a production process as previously noted and the properties of the resulting film, and besides, there is an advantage of rapid disintegration in the oral cavity. More preferably, an example of the polymer of 15 cp or less includes pullulan, low density hydroxypropyl cellulose, low density hydroxypropyl methylcellulose.
However, for another purpose of the présent disclosure (for example, to increase the strength of the film), it is more preferred to use a small amount of a high viscosity polymer having viscosity of 50 cp or more (preferably between 50 cp and 10,000 cp) as measured in a 2 wt% aqueous solution (together with the polymer of 15 cp or less), and in this case, the content of the high viscosity polymer of 50 cp or more is preferably 20 wt% or less, more preferably 10 wt% or less, even more preferably 5 wt% or less, and most preferably 3 wt% or less per the total weight of the film after drying. More preferably, an example of the polymer of 50cp or more includes xanthan gum, propylene glycol alginate, sodium alginate, alginic acid, hydroxypropyl methylcellulose, hydroxypropyl cellulose, guar gum, and carboxymethyl cellulose sodium. The polymer used for forming the film in the présent disclosure includes, but is not limited to, for example, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xanthan gum, pullulan, sodium alginate, propylene glycol alginate, povidone, poloxamer, polyvinylalcohol, alginic acid, carrageenan, carbomer, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, gelatin, or mixtures thereof.
Therefore, as a particular embodiment, the présent disclosure provides a film or a film preparing solution including tadalafil free base, a vinylpyrrolidone-based polymer and/or a polyethyleneglycol-based polymer as a dispersion stabilizing agent, and hydroxypropyl cellulose, and by this combination, the objects of the présent disclosure may be achieved more effectively. More preferably, the présent disclosure provides a film including 10 wt% to 30 wt% of tadalafil free base, 0.2 wt% to 20 wt% of a vinylpyrrolidone-based polymer and/or a polyethyleneglycol-based polymer as a dispersion stabilizing agent, and 20 wt% to 80 wt% of hydroxypropyl cellulose, based on the total weight of the dried film.
Also, in the présent disclosure, the film preparing solution may include a sweeting agent, a fragrance, or a coloring agent.
The présent disclosure provides a method of producing a tadalafil free basecontaining film by which a tadalafil free base-containing film is produced by drying a polymer solution having tadalafil free base dispersed therein by the addition of a vinylpyrrolidone-based polymer and/or a polyethyleneglycol-based polymer as a dispersion stabilizing agent.
The film according to the présent disclosure may be produced by drying the polymer solution in which tadalafil free base is dispersed by the addition of the vinylpyrrolidone-based polymer and/or the polyethyleneglycol-based polymer as the dispersion stabilizing agent. More preferably, the film is produced by drying the film preparing solution containing dissolved polymer according to the présent disclosure in which water more than or equal to 90 wt% of a solvent is used and 10 wt% to 30 wt% of tadalafil free base is dispersed using 0.2 wt% to 20 wt% of the dispersion stabilizing agent based on the total weight of the dried film, and the content of the polymer may be from 20 wt% to 80 wt% per the total weight of the dried film. Even more preferably, the film according to the présent disclosure may additionally include a plasticizer, a surfactant and/or a dispersion stabilizing agent as well as the vinylpyrrolidone-based polymer and/or polyethyleneglycol-based polymer dispersion stabilizing agent, and the total content of the vinylpyrrolidone-based polymer and/or polyethyleneglycol-based polymer dispersion stabilizing agent, and the plasticizer, the surfactant, and/or the dispersion stabilizing agent may be from 1 wt% to 90 wt% based on the total weight of the dried film.
Advantageous Effects
According to the présent disclosure, a film may be provided with maximized dispersion stability of tadalafil free base in the film by the addition of a small amount of a polyethyleneglycol-based polymer as a dispersion stabilizing agent without unique fragrance or favor that may appear when other dispersion stabilizing agents known in the art are used, and an extremely low likelihood that a reagglomeration phenomenon of tadalafil free base particles will occur, and an amount of bubbles generated may be significantly reduced during a production process.
MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the embodiments of the présent disclosure will be described in detail to assist the understanding of the présent disclosure. The présent disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth below. Rather, these embodiments are provided so that this disclosure will fully convey the scope of the présent disclosure to one of ordinary skill in the art.
< Préparation of a tadalafîl free base-containing film formulation >
A tadalafîl free base-containing film formulation was prepared as follows. A plasticizer, an additive, a sweeting agent, a surfactant, and a dispersion stabilizing agent were added to purified water, and agitated to dissolve or disperse in the purified water, and tadalafîl free base was added thereto. Subsequently, homogenization was performed using a homogenizer (Ultra turrax T-25, IKA). A polymer was added thereto, and homogenization was performed using the same homogenizer. Subsequently, gas was removed from the film preparing solution at 45°C under a vacuum condition, and after cooling to room température, coating was performed with an optimum thickness on a polyethylene (PE) film. Subsequently, drying was performed at 80°C to préparé a film formulation containing tadalafîl free base.
<Test examples 1 - 14. Comparison of dispersion stability based on a type of a dispersion stabilizing agent added>
A film was produced by the same method as that of the above described préparation of a tadalafîl free base-containing film formulation, varying the ingrédients included in the film and their content as shown in the following table 1, and a resuit of measuring dispersion stability of tadalafîl free base in the film was indicated in RSD % (relative standard déviation).
RSD % was determined by cutting the resulting bulk film to predetermined size and area, and measuring how uniformly tadalafîl free base is distributed through analysis of the content of tadalafîl free base included in each tailored film.
[Table 1]
| EXAMPLE | | st r—1 | bLD I-1 | 00 «—i LH | un CN | Ch o i-1 | m cd «—< | p i-4 | 00 ô | | 0Ό0Τ | p | xp œ* O O t-4 O | ||||||||||
en t-4 | cD | co rH LH | un CN | Ch o t-4 | en ld* «—< | p «-4 | co o | O ô o t-4 | t-4 t-4 | ||||||||||||
CN t—< | b> CD t-1 | 00 «—i un | LH CN | στ o t-4 | m CO 1—i | p i-4 | 00 o | Q Ô O i-4 | Ch CN | ||||||||||||
t—l t-4 | bLD t-4 | 00 «—1 LH | un CN | σι ô t-4 | m LD t-4 | p i-4 | 00 o | O O O t-4 | CN en | ||||||||||||
O T™< | >· LO t-4 | 00 t-4 LH | LH CN | Ch o t-f | en CD r4 | O «—i | 00 o | O ό o ï-4 | (h (Ni | ||||||||||||
en | bLD t-4 | 00 t-4 LH | un CN | Ch O t-4 | CH CD t—i | p 1-4 | 00 o | O o o i-4 | CN en | ||||||||||||
co | bLD t-4 | co t-1 LH | un N | Ch Ô r-H | m LD r-< | p i-4 | 00 o | O o Q i-4 | b' en | ||||||||||||
b- | bLD t-1 | 00 t—< LH | un CN | Ch O t-4 | m CD t-4 | O i-4 | 00 o | O O o i-1 | en ô | ||||||||||||
LD | r> LD t-4 | 00 t-4 LH | LH CN | Ch Ô t-4 | en CD t-4 | p i-4 | 00 o | O o o i-4 | ch ô | ||||||||||||
m | bLO t*4 | 00 t-4 LH | LH CN | <h o t-4 | m CD t—I | p i-4 | 00 ô | O Ô O i-4 | ch en | ||||||||||||
b* LD t—I | 00 t—< LH | LD CN | en ô i-I | m CD »—< | O f4 | co o | O o o i-4 | un ô | |||||||||||||
| COMPARATIVE EXAMPLE | | m | t-4 t< t-4 | O cri LD | CN t-4 t—I | i—l en r—4 | i-4 i-4 | un | O o o i-4 | un | ||||||||||||
CN | t-4 r< «—1 | CN O LD | CN t-4 t-4 | bcn | p »-4 | 00 o | O ô o i-4 | en ’xf | |||||||||||||
r-1 | t-f r< t-4 | p cri | CN t-4 r-I | p t-4 CN | p i-4 | 00 un | O O O i-4 | Ch on | |||||||||||||
ë < Q ί | IPOLYETHYLENE GLYCOL | | IPOLYETHYLENE GLYCOL | | IPOLYETHYLENE OXIDE | | IPOLYVINYLPYRROLIDONE (POVIDONE) | | |POLYVINYLALCOHOL-POLYETHYLENEGLYCOL copolymer | | IHYDROXYETHYL CELLULOSE | | |HYDROXYETHYLMETHYL CELLULOSE | | IPOLYOXYETHYLENE CASTOR OIL | | IPOLYOXYETHYLENE STEARATE | | ITRIETHYL CITRATE | | IVINYLPYRROUDONE-VINYLACETATE COPOLYMER | | IPOLYOXYETHYLENEALKYLETHER | | IGLYCERIN | | ITTTANIUM OXIDE | | ISUCRALOSE | | IPOLYSORBATE 80 | | |T0TAL | | IC0NTENT RSD% | | 1— Z LU >; O en |
As a resuit, as can be seen in the above table 1, when a polyethyleneglycol based polymer was included as a dispersion stabilizing agent, good dispersion stability was exhibited, and when polyethylene glycol was used as a dispersion stabilizing agent (Example 4), RSD% was found to be 0.5, and when a polyvinyl alcoholpolyethylene glycol copolymer was used as a dispersion stabilizing agent (Example 7), RSD% was found to be 0.9. Also, when a vinylpyrrolidone-based polymer was used as a dispersion stabilizing agent, good dispersion stability was exhibited, and when polyvinylpyrrolidone was used as a dispersion stabilizing agent (Example 6), RSD% was found to be 0.9, and when a vinylpyrrolidone-vinyl acetate copolymer was used as a dispersion stabilizing agent (Example 13), RSD% was found to be 1.1. These results show significant lower RSD% than the case where a dispersion stabilizing agent is not included (i.e., Comparative examples 1 - 3) and the case where compounds other than a polyethyleneglycol-based polymer or a vinylpyrrolidonebased polymer are included as a dispersion stabilizing agent (i.e., Examples 5, 8 - 12, 14). Thus, when a polyethyleneglycol-based polymer or a vinylpyrrolidone-based polymer is used as a dispersion stabilizing agent, it results in stable dispersion of tadalafil free base in a film and consequential good stability, from which it is expected that a layer séparation or a progressive reagglomeration phenomenon will not occur.
INDUSTRIAL APPLICABILITY
According to the présent disclosure, a film may be provided with maximized dispersion stability of tadalafil free base in the film by the addition of a small amount of a polyethyleneglycol-based polymer as a dispersion stabilizing agent without unique fragrance or favor that may appear when other dispersion stabilizing agents known in the art are used, and an extremely low likelihood that a reagglomeration phenomenon of tadalafil free base particles will occur, and an amount of bubbles generated may be significantly reduced during a production process.
Claims (13)
- WHAT IS CLA1MED IS:1. A tadalafil free base-containing film, in which a film formulation containing tadalafil free base as an active ingrédient comprises a polyethyleneglycol-based polymer, a vinylpyrrolidone-based polymer, or mixtures thereof as a dispersion stabilizing agent.
- 2. The tadalafil free base-containing film according to claim 1, wherein the polyethyleneglycol-based polymer is a homopolymer or a copolymer of a monomer expressed by the following chemical formula 1 :[Chemical formula 1 ] where R is hydrogen or an alkyl group having 1 - 6 carbon atoms, and n is an integer of from 1 to 300.
- 3. The tadalafil free base-containing film according to claim 2, wherein the homopolymer has a molecular weight of from 200 g/mol to 10,000 g/mol.
- 4. The tadalafil free base-containing film according to claim 2, wherein the monomer is polyethylene glycol (PEG) in which R in the chemical formula 1 is hydrogen.
- 5. The tadalafil free base-containing film according to claim 2, wherein the polyethyleneglycol-based polymer is a polyvinyl alcohol-polyethylene glycol copolymer.
- 6. The tadalafil free base-containing film according to claim 1, wherein the vinylpyrrolidone-based polymer is a homopolymer or copolymer of vinylpyrrolidone.
- 7. The tadalafil free base-containing film according to claim 6, wherein the vinylpyrrolidone-based polymer is polyvinylpyrrolidone or a vinylpyrrolidone-vinyl acetate copolymer. ν''
- 8. The tadalafil free base-containing film according to claim 1, wherein the dispersion stabilizing agent is présent from 0.2 wt% to 20 wt% based on a total weight of a dried film.
- 9. The tadalafil free base-containing film according to claim 1, wherein a total content of a surfactant, a plasticizer, and a dispersion stabilizing agent is from 1 wt% to 90 wt% based on a total weight of a dried film.
- 10. The tadalafil free base-containing film according to claim 9, wherein the polyethyleneglycol-based polymer, the vinylpyrrolidone-based polymer, or mixtures thereof is présent from 5 wt% to 90 wt% based on the total content of the surfactant, the plasticizer, and the dispersion stabilizing agent.
- 11. A tadalafil free base-containing film preparing solution, comprising: tadalafil free base as an active ingrédient; and a polyethyleneglycol-based polymer, a vinylpyrrolidone-based polymer, or mixtures thereof as a dispersion stabilizing agent.
- 12. The tadalafil free base-containing film preparing solution according to claim 11, wherein 90% or more of the film preparing solution is water.
- 13. A method of preparing a tadalafil free base-containing film, comprising:drying a polymer solution in which tadalafil free base is dispersed by the addition of a polyethyleneglycol-based polymer, a vinylpyrrolidone-based polymer, or mixtures thereof as a dispersion stabilizing agent,
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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KR10-2013-0040084 | 2013-04-11 |
Publications (1)
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OA17536A true OA17536A (en) | 2017-02-10 |
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