WO2015186929A1 - Film à désintégration orale contenant du tadalafil, et son procédé de fabrication - Google Patents

Film à désintégration orale contenant du tadalafil, et son procédé de fabrication Download PDF

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Publication number
WO2015186929A1
WO2015186929A1 PCT/KR2015/005429 KR2015005429W WO2015186929A1 WO 2015186929 A1 WO2015186929 A1 WO 2015186929A1 KR 2015005429 W KR2015005429 W KR 2015005429W WO 2015186929 A1 WO2015186929 A1 WO 2015186929A1
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WO
WIPO (PCT)
Prior art keywords
film
oral disintegrating
tadalafil
disintegrating film
oral
Prior art date
Application number
PCT/KR2015/005429
Other languages
English (en)
Korean (ko)
Inventor
신새벽
최원재
황상욱
김훈택
곽용규
Original Assignee
에스케이케미칼주식회사
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.)
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Application filed by 에스케이케미칼주식회사 filed Critical 에스케이케미칼주식회사
Publication of WO2015186929A1 publication Critical patent/WO2015186929A1/fr

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Classifications

    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to an orally disintegrating film containing a tadalafil and a method for manufacturing the same, and more particularly, it is possible to include a pharmacologically effective amount of tadalafil in a small size and a thin film, and is easy to handle and take. It relates to an oral disintegrating film showing high solubility and good drug expression and a method for producing the same.
  • Tadalaf i l is a drug used to treat erectile dysfunction and is commercially available as a tablet for oral administration of Cialis 15.
  • the erectile dysfunction treatment is in the form of tablets, it is quite inconvenient to take orally without water.
  • oral disintegrating film containing the drug is easy to carry and take, can be expected to disintegrate rapidly in the oral cavity and rapid expression of the active ingredient. Accordingly, attempts have been made to prepare erectile dysfunction drugs in the form of oral disintegrating films.
  • tadalafil is poorly soluble drugs is because commercial ⁇ 1: Tablets (commercially available reference product) of Cialis passions indicate the efficacy expressed the same level of 25 to the mouth as to maintain different other with drugs equivalent contrast the solubility of the necessary forms A disintegrating film should be prepared. Accordingly, the inventors have found that the solubility of tadalafil is equivalent to that of the reference drug.
  • the present invention has been completed by developing a tadalafil-containing oral disintegrating film that can satisfy the above requirements.
  • a tadalafil-containing oral disintegrating film that can satisfy the above requirements.
  • the present invention to provide an oral disintegrating film comprising a tadalafil and a method for producing the same.
  • the present invention to achieve the above object is tadalafil; One or more solubilizers; And it provides an oral disintegrating film comprising at least one film-forming polymer.
  • Fig. 1 is a graph showing the results of a Cialis definition comparative dissolution test that is an orally disintegrating film of the present invention and a commercial tablet.
  • the present invention relates to tadalafil; One or more solubilizers; And at least one film forming polymer.
  • Oral disintegration film in the present invention refers to a formulation to be taken by disintegrating in the oral cavity after being placed on the tongue, it can be easily taken without water.
  • Oral disintegrating film of the present invention contains tadalafil as a pharmacologically active ingredient.
  • the tadalafil is a drug of the phosphodiesterase (PDE5) inhibitor family and is used as a erectile dysfunction treatment agent.
  • PDE5 phosphodiesterase
  • Tadalafil a selective, reversible inhibitor of cGMP-specific PDE5
  • Tadalafil is currently marketed as Cialis tablets. Therefore, the oral disintegrating film of the present invention can be usefully used to treat erectile dysfunction.
  • the tadalafil may be included in an amount of 0.1 to 100 mg, preferably 2.5 to 20 mg per sheet of 10 cm 2 film.
  • the tadalafil may be included in an amount of 5 to 75% by weight, preferably 10 to 30% by weight based on the total weight of the film.
  • the oral disintegrating film of the present invention includes at least one solubilizer.
  • the solubilizer serves to increase the solubility of tadalafil to increase the bioavailability.
  • the solubilizing agent is preferably a plastic cap polylactam polyvinyl acetate-polyethylene glycol copolymer (commercial product name: Plus solution (Soluplus) ®; Manufacturer: BASF Corporation).
  • the solubilizer may be included in the film in a weight ratio of 1: 0.25 to 1: 10, preferably in a weight ratio of 1: 1 to 1: 6 based on the tadalafil.
  • the solubilizer may be included in an amount of 1 to 50% by weight, preferably 10 to 40% by weight, based on the total weight of the film.
  • the oral disintegrating film of the present invention comprises at least one film forming polymer.
  • the film forming polymer is preferably a hydrophilic polymer, more preferably carboxymethylsalose sodium.
  • the film forming polymer may be included in an amount of 10 to 80% by weight, preferably 20 to 40% by weight, based on the total weight of the film.
  • the oral disintegrating film of the present invention may further include other pharmaceutically acceptable additives within a range not impairing the object of the present invention.
  • the pharmaceutically acceptable additive may be selected from the group consisting of excipients, plasticizers, emulsifiers, sweeteners, fragrances, antioxidants, and combinations thereof, the amount of which may be appropriately adjusted according to needs and purposes.
  • one or more components selected from the group consisting of calcium phosphate, microcrystalline salose, lactose pregelatinized starch, and mixtures thereof may be used, for example, calcium phosphate.
  • the excipient may be used in an amount of 2 to 50 weight percent>, preferably 5 to 30 weight percent based on the total weight of the film.
  • Plasticizers serve to give flexibility and flexibility to films made of polymers so that they are not easily broken.
  • the plasticizer include glycerin, propylene glycol, ethylene glycol, polyethylene glycol, sorbbi, xylyl, malty, erythri, tributyl citrate, triethyl citrate, triacetin, and glycerol triacetate.
  • One or more components selected from the group consisting of acceptable alcohols (e.g. ethanol), mannites and combinations thereof may be used.
  • glycerin may be used in an amount of 5 to 40 wt%, preferably 10 to 30 wt%, based on the total weight of the film.
  • the emulsifier one or more components selected from the group consisting of polysorbate, sorbitan oleate, sodium lauryl sulfate, polyoxyethylene hardened castor oil, polyoxyethylene octylphenyl 5 ether, and mixtures thereof may be used.
  • polysorbate polysorbate.
  • the emulsifier may be used in an amount of 0.01 to 8% by weight, preferably 0.2 to 4% by weight based on the total weight of the film.
  • Sweeteners play a role in controlling taste.
  • the sweetening agent one or more ingredients selected from the group consisting of sucralose, 10 aspartame, sodium saccharin, stevioside, riboudioside, tomatin (thaumat in " acesulfame potassium and combinations thereof) may be used. It may be for example sucralose.
  • the sweetener may be used in an amount of 0.1 to 10% by weight, preferably 0.5 to 5% by weight, based on the total weight of the film.
  • Fragrances have the right fragrance to reduce discomfort.
  • the fragrance may be one or more ingredients selected from the group consisting of men, camphor, peppermint and mixtures thereof, for example, men.
  • the fragrance is based on the total weight of the film, from 0.01 to 10 weight 3 ⁇ 4. , Preferably in an amount of 0.5 to 5 weight 3 ⁇ 4.
  • the antioxidants include butyl ated hydroxytoluene (BHT), butyl ated hydroxy ani sole (BHA), ascorbyl palmitate, ascorbic acid, tocopherol and its One or more components selected from the group consisting of mixtures may be used, for example ⁇ .
  • the antioxidant may be used in an amount of 0.001 to 5% by weight, preferably 25 to 0.01% by weight, based on the total weight of the film.
  • one oral disintegrating film of the present invention containing about 20 mg of tadalafil in a size of 10 cm 2 was dissolved in about 10 mL of water.
  • the oral disintegrating film of the present invention has a weight of 80 to 160 mg after the drying of the film based on the size of about 10 cm 2 , the thickness is 0.05 to 0.5 mm, small size and thin thickness, easy to carry Do.
  • the present invention comprises the steps of (1) dissolving at least one solubilizer and at least one film-forming polymer in a solvent, dispersing tadalafil therein to prepare a coating stock solution; And (2) degassing the coating stock solution prepared above, applying it to a process film, and then drying to prepare an oral disintegrating film.
  • the manufacturing method of the oral disintegrating film according to the present invention will be described in detail.
  • the coating stock solution is prepared by dissolving at least one solubilizer and at least one film-forming polymer in a solvent, and dispersing tadalafil therein.
  • the solvent used in the step (1) is water; an organic solvent selected from the group consisting of ethanol, acetone, ethyl acetate and a mixture thereof; Or a mixed solvent thereof, and preferably a water, or a mixed solvent of water and ethanol.
  • the solvent may be used in an amount of 200 mg to 500 mg based on the case of producing a film of about 10 cm 2 size.
  • step (1) The type and amount of solubilizer and film forming polymer used in step (1) are the same as described above.
  • the step (1) may further include a pharmaceutically acceptable additive in the coating stock solution, the pharmaceutically acceptable additive is in the group consisting of excipients, plasticizers, emulsifiers, sweeteners, fragrances, antioxidants and mixtures thereof Can be selected. Specific types and usage amounts of the additives are the same as described above.
  • the coating 5 undiluted solution prepared in step (1) is degassed, coated on a process film, and dried to prepare an oral disintegrating film.
  • the coating stock solution is applied to the process film in a thickness of 100 to 1,000 ⁇ according to a conventional method of preparing a film formulation. Subsequently, the process film to which the coating ' stock solution is applied is dried for 5 minutes to 1 hour to evaporate the solvent. Then, if necessary, the oral disintegrating film of the present invention can be prepared by peeling the dried film and then cutting it to an appropriate size, for example, about 2 to 15 cm 2 .
  • the process film may be a suitable process film used in the pharmaceutical field, such as polyethylene terephthalate process film, polyethylene terephthalate film coated with silicone or Teflon, polyethylene 5 film.
  • the oral disintegrating film of the present invention is small in size and thin in thickness, which is convenient to carry, and does not need to be ingested with water, and is easy to take.
  • it contains a solubilizer that dissolves rapidly in the oral cavity and serves to increase the solubility of tadalafil, it can be expected to express the same efficacy as a commercially available control drug. Accordingly, it will be useful in the treatment of erectile dysfunction: on the basis of the following examples to the present invention will be described in more detail.
  • Example 1 Preparation of Oral Disintegrating Film Containing Tadalafil Oral disintegrating film was prepared according to the ingredients and contents shown in Table 1 below.
  • carboxymethyl salolose sodium (CMC-Na, obtained by Ashland) as a polymer and polyvinyl caprolactam-polyvinylacetate- polyethylene glycol copolymer (Soluplus, obtained by BASF) as a solubilizer was dissolved in water, glycerin as a plasticizer (from LG H & H), calcium phosphate as an excipient (Cal ipharm A, obtained from Innophos), polysorbate as an emulsifier (Tween 80, obtained from Merck) And sucralose (available from Splenda) as a sweetener was added and mixed uniformly. A tadalafil was added thereto and dispersed to prepare a coating stock solution.
  • CMC-Na carboxymethyl salolose sodium
  • Soluplus obtained by BASF
  • the coating solution thus prepared was degassed by stirring under vacuum, and the film was coated with polyethylene terephthalate process (obtained by SKC Co., Ltd.) using a film-coating apparatus manufactured by ENT. The thickness was applied uniformly. Then, the solvent was removed by drying for 10 to 20 minutes at a temperature of 8C C or more. The dried film was peeled from the polyethylene terephthalate process film and cut to a size of about 10 cm 2 to prepare an oral disintegrating film of the present invention. It was then packaged using an aluminum pouch. The weight after drying of the thus prepared film was about 120 mg.
  • Comparative Examples 1 and 2 Preparation of oral disintegrating film containing tadalafil According to the components and contents shown in Table 1 below was prepared oral disintegrating film in the same manner as in Example 1. At this time, the solubilizer was not used in Comparative Example 1, and HPC was used instead of SoluPlus in Comparative Example 2.
  • Comparative Example 1 and Example 1 can be seen that the dissolution rate is faster than commercial tablets due to the nature of the oral disintegrating film.
  • Experimental Example 2 Solubility Comparison Test of Oral Disintegrating Film and Commercial Tablet A solubility comparison test of 20 mg of Cialis tablets, which are commercial tablets of oral disintegrating films prepared according to Examples 1 and Comparative Examples 1 and 2 and tadalafil, was performed as follows. It was carried out as follows. It also comes with solubility for 20 mg of tadalafil for comparison Compared.
  • One oral disintegrating film, one tablet of commercial tablets and 20 mg of tadalafil were added to 10 mL of water, and then completely disintegrated for 10 minutes, and then the solubility was measured.
  • solubility about 2 mL of the dispersion was taken, centrifuged, the supernatant was obtained, filtered, and measured by liquid chromatography.
  • the remaining dispersion was placed in a shaking incubator (37 ° C.) incubator for 60 minutes and the solubility was measured again in the same manner as above. The results are shown in Table 2 below.
  • Example 2 As shown in Table 2, the orally disintegrating film of Example 1 exhibited similar tadalafil solubility as Cialis tablets. On the other hand, oral disintegrating films of Comparative Examples 1 and 2 exhibited solubility of only about 1/10 of the film of Example 1.
  • Experimental Example 3 Bioavailability Evaluation Test of Oral Disintegrating Films and Commercial Tablets A bioavailability evaluation test of 20 mg of Cialis tablets, a commercial tablet of oral disintegrating films prepared according to Examples 1 and 1 and Comparative Example 1, was given below. It was carried out as follows.
  • the orally disintegrating film of the present invention exhibits a similar bioavailability as Cialis tablets and can be expected to be equivalent to the expression of the drug. Therefore, it can be usefully used for the treatment of erectile dysfunction symptoms.

Abstract

La présente invention concerne un film à désintégration orale comprenant du tadalafil, un ou plusieurs types de solubilisateurs, et un ou plusieurs types de polymères filmogènes, ainsi qu'un procédé pour sa fabrication. Le film à désintégration orale selon la présente invention a de petites dimensions et une faible épaisseur, de façon à être commode à porter, et est facile à prendre car il n'a pas besoin d'être absorbé avec de l'eau. De même, le film non seulement se désintègre rapidement à l'intérieur de la bouche, mais encore on peut s'y fier pour présenter des effets médicamenteux favorables, car il contient un solubilisateur qui fonctionne par une augmentation de la solubilité du tadalafil, et peut donc être utilisé utilement pour traiter les symptômes du dysfonctionnement érectile.
PCT/KR2015/005429 2014-06-02 2015-05-29 Film à désintégration orale contenant du tadalafil, et son procédé de fabrication WO2015186929A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020140066888A KR20150138671A (ko) 2014-06-02 2014-06-02 타달라필을 함유하는 구강 붕해 필름 및 이의 제조방법
KR10-2014-0066888 2014-06-02

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090047330A1 (en) * 2007-08-17 2009-02-19 Ramesh Bangalore Oral fast dissolving films for erectile dysfunction bioactive agents
KR20110041412A (ko) * 2009-10-15 2011-04-21 (주)씨엘팜 Ｐｄｅ5 억제제를 함유하는 구강 용해성 필름
US20110263606A1 (en) * 2010-04-26 2011-10-27 Horst Zerbe Solid oral dosage forms comprising tadalafil
KR20130003511A (ko) * 2011-06-30 2013-01-09 중앙대학교 산학협력단 약제학적 활성 성분을 함유하는 경구용 속붕해성 필름 및 이의 제조 방법
US20130189343A1 (en) * 2012-01-20 2013-07-25 Markus Krumme Transmucosal administration system for a pharmaceutical drug

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090047330A1 (en) * 2007-08-17 2009-02-19 Ramesh Bangalore Oral fast dissolving films for erectile dysfunction bioactive agents
KR20110041412A (ko) * 2009-10-15 2011-04-21 (주)씨엘팜 Ｐｄｅ5 억제제를 함유하는 구강 용해성 필름
US20110263606A1 (en) * 2010-04-26 2011-10-27 Horst Zerbe Solid oral dosage forms comprising tadalafil
KR20130003511A (ko) * 2011-06-30 2013-01-09 중앙대학교 산학협력단 약제학적 활성 성분을 함유하는 경구용 속붕해성 필름 및 이의 제조 방법
US20130189343A1 (en) * 2012-01-20 2013-07-25 Markus Krumme Transmucosal administration system for a pharmaceutical drug

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