WO2019059652A1 - Préparation pharmaceutique à goût masqué et administrée par voie orale et sa méthode de préparation - Google Patents

Préparation pharmaceutique à goût masqué et administrée par voie orale et sa méthode de préparation Download PDF

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Publication number
WO2019059652A1
WO2019059652A1 PCT/KR2018/011077 KR2018011077W WO2019059652A1 WO 2019059652 A1 WO2019059652 A1 WO 2019059652A1 KR 2018011077 W KR2018011077 W KR 2018011077W WO 2019059652 A1 WO2019059652 A1 WO 2019059652A1
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sucrose
taste
lipids
drug
emulsion
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PCT/KR2018/011077
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English (en)
Korean (ko)
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이윤석
이재민
송찬우
송상병
노인환
정기원
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경상대학교 산학협력단
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    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a pharmaceutical preparation for orally administrable taste and a preparation method thereof, wherein the form of the pharmaceutical preparation may be a liquid preparation or a mouth disintegration film.
  • the orally administered drug may be in the form of a solid, such as a capsule, a caplet, or a tablet, a liquid form such as a solution, a syrup, an emulsion or a suspension, or a liquid form such as a tablet, a chewable tablet, And various oral dissolution preparations.
  • taste is an important indicator and it is very important in the pharmaceutical industry to mask the unpleasant taste when taking it.
  • Many pharmaceutical companies have tried various efforts to develop bitter taste-masked formulations while sufficiently exhibiting the drug's efficacy. They have tried to coat raw drug particles, form molecular complexes between drugs and other substances, Or the like as a taste masking agent or by minimizing dissolution by acupuncture or the like.
  • the liquid preparations can be swallowed easily, unlike the other dosage preparations, and thus can be used for infants, And furthermore, when it is necessary to administer a large amount of drug, the liquid form is advantageous over the chewable dosage form.
  • a general problem associated with a liquid preparation is that it shields the unpleasant taste such as bitter taste, argin taste, rough taste, pungent taste of the raw drug when the pharmacologically active agent is administered in a liquid dosage form.
  • a method of attempting shielding using various sweeteners or fragrances or a separate process such as coating a raw material to form a shielding film against a raw material of a drug.
  • Korean Patent Laid-Open Publication No. 2010-0135316 discloses a conventional technique for shielding the taste of a liquid agent, in which, in order to shield the bitter taste of a raw material drug, the taste of the raw drug is added by a method of adding a sweetener,
  • this method has a limitation in shielding with a sweetener or a fragrance in the case of a drug having a severe irritation to an arine taste drug or oral mucosa, and a flavoring system for a drug is often applied to other drugs It can not be applied to the case.
  • US Patent Application Publication 2008/0044454 discloses a method of coating a raw material drug with an active material using various coating techniques and putting it into a film forming agent so as to shield the bitter taste, Since the manufacturing process is complicated and the liquid agent is manufactured after coating the active material, there is a high possibility that the drug is released into the solution through the coating film through the heating, mixing and dissolving processes during the liquid agent manufacturing process, There is a disadvantage that it may be deteriorated.
  • Orodispersible Tablet which developed a solid oral disintegration form, is one of the new drug delivery systems.
  • ODT Orodispersible Tablet
  • the oral disintegration film is a drug-loaded formulation in thin film formulations, and the oral disintegrating film formulation provides several advantages over conventional solid dosage forms, liquids, and oral disintegrating tablets. That is, since the oral disintegrating film preparation can be taken without water, it is very useful not only for the elderly who have difficulties in taking tablets or capsules but also for children, persons with disabilities, patients lying in bed, busy modern people, It is estimated that disintegration is more advanced than any existing formulations. Particularly, when the drug is absorbed into the buccal mucosa, the first pass of the liver can be avoided.
  • the buccal disintegration film has an advantage that it can be applied to drugs that are highly metabolized in the liver among the drugs absorbed from the digestive tract. Therefore, many efforts have been made to manufacture oral disintegrating film formulations of various techniques for the physical properties of the film and compliance with the patient's taking.
  • WO 2001/70194 discloses a method for producing a readily consumable oral consumable film by adsorbing an active ingredient to an ion exchange resin as a taste-masking agent This method has disadvantages in that the ion exchange resin is contained in the water-soluble polymer and scratches are generated during the film forming, resulting in poor merchantability and inferior productivity due to complicated operations.
  • US Patent Application 2008/0044454 discloses a method for coating a raw drug with an active substance using various coating techniques and then injecting it into a film forming agent to mask bitter taste, Coating process, so that the manufacturing process is complicated and the film is produced after the coating of the active material, so that the coating layer is damaged in the film production process and the taste shielding function may be deteriorated.
  • the inventors of the present invention have been studying a method of shielding the taste of a liquid drug, and as a new pharmaceutical formulation for oral administration, a shielding film for a drug substance is formed during the liquid preparation process,
  • the inventors of the present invention have completed the present invention by disclosing a method of shielding the taste of a raw material drug by forming a shielding film in a raw material material during the film manufacturing process without further processing Respectively.
  • the drug is a taste masked liquid containing the drug substance distributed in the lipid classes.
  • step 1 Adding lipids to a water-soluble solution and heating at a temperature above the melting point of the lipids to form an emulsion (step 1);
  • step 2 Adding a raw drug to the emulsion of step 1 (step 2); And
  • the present invention also provides a method of producing the taste masked liquid agent.
  • the flavor-blocking agent is a flavor-masked oral disintegration film containing a drug substance dispersed in the lipids.
  • step 1 Adding lipids to a water-soluble solution and heating at a temperature above the melting point of the lipids to form an emulsion (step 1); And
  • the present invention also provides a method for producing the taste-masked oral disintegration film.
  • the pharmaceutical preparation for oral administration of the present invention has a remarkable advantage in that the drug is distributed in the inner phase of the emulsion (lipid phase) so that the unpleasant taste of the drug is shielded through the liquid agent in which the matrix of the lipid and the drug is suspended
  • oral disintegration film type pharmaceutical preparations for oral administration are advantageous in that the raw material drugs are distributed in the lipids and thus the taste blocking effect of the raw drug is remarkably excellent.
  • the manufacturing method of the liquid agent has an advantage that it can apply the equipment and the process for manufacturing the existing liquid agent as it is, and the taste shielding (lipid coating) for the drug raw material is one-stop solution solution can be provided.
  • a method for producing an oral disintegration film is a one-stop solution method in which lipids that block the taste of a raw material drug are formed at the same time as a film is produced, There is an advantage that a film can be produced.
  • Example A-1 shows an optical microscope photograph of Example A-1.
  • Example 3 is a photograph of the surface of the oral disintegration film produced according to Example B-12 of the present invention, observed using a scanning electron microscope (SEM)
  • Example 4 is a photograph of the surface of the oral disintegration film produced according to Example B-13 of the present invention, observed using a scanning electron microscope (SEM)
  • FIG. 5 is a photograph of the surface of the oral disintegration film produced according to Comparative Example B-3 of the present invention, using a scanning electron microscope (SEM).
  • the pharmaceutical preparations for oral administration in which the taste is masked may be more specifically described.
  • the pharmaceutical preparations for oral administration may be in the form of a liquid or a mouth disintegration film.
  • the present invention is a.
  • a raw drug distributed in the lipid species wherein the taste masking agent is a taste masking agent.
  • the liquid agent of the present invention is a liquid agent in which the taste of a raw material drug is shielded to improve the feeling of use and satisfaction and convenience of taking in patients (particularly, children).
  • the liquid agent according to the present invention includes lipids.
  • the lipids are used for shielding the taste of the raw drug. By distributing the raw drug to the lipids, the taste of the raw drug can be physically shielded when taken.
  • the above-mentioned lipids can be formed simultaneously with the production of a liquid preparation.
  • the lipid which is a component of the above-mentioned lipids, is placed in a solution containing a water-soluble solvent and heated to 70 ° C to form an emulsion.
  • the raw drug can be distributed in lipids to form a suspension liquid.
  • the above-mentioned lipids are produced by using lipids having a melting point of 40 ° C or higher and lower than 100 ° C.
  • the lipids may be liquefied during storage at room temperature after the production of the liquid agent, resulting in a problem of deteriorating the physical stability of the liquid agent, ° C., the water is vaporized because the melting point of the above-mentioned lipids is higher than the boiling point of water, so that the weight ratio of the solution and the lipids is varied, which may make it difficult to control the manufacturing conditions of the liquid agent.
  • the lipids may be used as GELUCIRE 44/14 having a melting point of 44 ° C.
  • lipids having a hydrophilic-lipophilic balance (HLB) of 0 to 16 are used.
  • hydrophilic lipophilic balance is a value indicating the degree of affinity with respect to water and oil. Of the values of 0 to 20, values closer to 0 indicate good lipophilicity, and values closer to 20 indicate hydrophilicity.
  • HLB hydrophilic / lipophilic balance
  • the lipid may be prepared from at least one lipid selected from the group consisting of fatty acid glycerides, PEG fatty acid esters, and sugar surfactants.
  • the fatty acid may be a fatty acid having 10 to 30 carbon atoms, and more preferably a fatty acid having 12 to 22 carbon atoms.
  • the fatty acid glyceride may be mono-, di-, triglyceride, or a combination thereof, and the PEG fatty acid ester may be mono-, diester or a mixture thereof.
  • fatty acid glycerides or PEG fatty acid esters of said lipids glycerol mono as stearate (Glycerol monostearate), glycerol di-behenate (Glycerol dibehenate), glyceryl behenate (Glyceryl behenate)
  • glycerol monostearate Glycerol monostearate
  • glycerol di-behenate Glycerol dibehenate
  • glyceryl behenate Glyceryl behenate
  • Comp erythritol Compritol) ® 888 ATO
  • C8-18 glycerides (C8-18glycerides) as a gel Lucy LES (Gelucire) ® 43/01
  • lauroyl polyoxyl -32 glycerides as (lauroyl polyoxyl-32 glycerides) gel Lucy LES (Gelucire) ® 44/14 la
  • the saccharide surfactant may be selected from the group consisting of sucrose monostearate, sucrose distearate, sucrose mono-distearate, sucrose monopalmitate, But are not limited to, Sucrose dipalmitate, Sucrose monolaurate, Sucrose dilaurate, Sucrose monooleate, Sucrose dioleate, It is also possible to use one or more of sucrose monocaprate, sucrose dicaprate, sucrose monocaprylate, sucrose dicaprylate, sucrose monomyristate, Sucrose dimyristate, Sucrose monolinolenate and Sucrose monolinolenate, dilinolenate, and the like.
  • the above-mentioned lipid classes may be sucrose esters of the following Table 1, but are not limited thereto.
  • Type HLB Content of major fatty acids (% by weight) Ester composition (% by weight) shape Monoester Di (di), tri (tri), polyester Sucrose Stearate D-1803F 3 About 70 About 20 About 80 P " D-1805 5 70 30 70 P " D-1807 7 70 40 60 P " D-1809 9 70 50 50 P " D-1811 11 70 55 45 P " D-1811F 11 70 55 45 P " D-1815 15 70 70 360 P " D-1816 16 70 75 25 P Sucrose palmitate D-1615 15 80 70 30 P " D-1616 16 80 80 20 P Sucrose laurate D-1216 16 95 80 20 P
  • the liquid preparation of the present invention may be a form in which a raw material drug is mixed with a lipid.
  • the raw drug may be uniformly mixed with lipids to form a matrix, but since the portion of the raw drug exposed to the outside is remarkably small, the dissolution rate in the mouth is temporarily reduced by the lipids, The taste shielding effect is remarkably excellent.
  • the raw drug suspended in the liquid preparation of the present invention may be in the form of being formed in the lipids.
  • the raw drug is shielded from the outside by lipids, and the taste of the drug can be completely blocked by the lipids, thereby remarkably excelling in the taste shielding effect of the drug.
  • the liquid agent according to the present invention includes a raw drug distributed in the above-mentioned lipids.
  • the drug substance may be a diabetic drug having an unpleasant taste; An insomnia remedy; Genitourinary therapy; Obesity remedy; Enzymes; Peptic ulcer solvent; Jinhae expectorant; A therapeutic agent for skin diseases; Antistatic agent; Antidepressants; Antihistamines; Antipyretic analgesics; Hormone preparations; Therapeutic agents for circulation; Therapeutic agent for digestive tract disorders; Psychotropic solvent; Erectile dysfunction treatment; A therapeutic agent for osteoporosis; Arthritis remedy; Antiepileptics; Muscle relaxants; Brain function improvers; A therapeutic agent for schizophrenia; Immunosuppressants; Antiviral agents, anti-malarial therapeutic agents, anti-tuberculosis agents, antibiotics; Anticancer agents; Anticancer adjuvants; Vaccines; Mouthwash; Anemia treatment agent; Constipation remedy; vitamin; Nutrients; Lactic acid bacteria preparation; Comprehensive cold medicine; And a health functional food.
  • the raw drug may also be selected from the group consisting of dexibuprofen, ibuprofen, naproxen, flurbiprofen, phosphodiesterase-5 inhibitor, but are not limited to, trimebutine, nicotine, varenicline, oseltamivir, prednisolone, donepezil, desmopressin, meclizine, entecavir, but are not limited to, entecavir, lamivudine, abacavir, atazanavir, zidovudine, cobicistat, stavudine, didanosine, dolutegravir, (eg, dolutegravir), darunavir, efavirenz, etravirine, elvitegravir, emtricitabine, fosamprenavir, indinavir indinavir, lopinavir, nevirapine,
  • the present invention relates to a pharmaceutical composition comprising raltegravir, r
  • liquid agent of the present invention may contain additives.
  • the additive may be at least one selected from the group consisting of sweeteners, flavors, stabilizers, and pH adjusters. In this way, it can contain various flavors or aromas while at the same time shielding the taste.
  • the sweetener to be used as the additive may be selected from the group consisting of sugar, glucose, maltose, oligosaccharide, galactose, starch, sorbitol, maltitol, phosgene, xylitol, erythritol, hydrogenated starch, mannitol, trehalose, aspartame, acesulfamate, sucralose,
  • a sweetener which is at least one selected from the group consisting of saccharin salt, neo-time, thaumatin, tothomic mixture, cyclamate salt, tothmine, nahan and extract, licorice extract, stevioside, May be used, but the sweetening agent is not limited thereto.
  • the above-mentioned flavor used as the additive may include strawberry flavor essence, lemon flavor essence, banana flavor essence, strawberry incense cotton, lemon incense cotton, grape incense cotton, banana incense cotton or orange incense cotton, peppermint, cinnamon, menthol, Mint, peach flavor, cherry flavor, vanillin flavor, and raspberry flavor, but the flavor is not limited thereto.
  • the pH adjusting agent used as the additive may be selected from the group consisting of citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid, Succinic acid, sodium dihydrogen phosphate, monosodium phosphate, disodium dihydrogen pyrophosphate, acid citrate salts, amino acid hydrochlorides, Sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine, sodium bicarbonate, sodium carboxymethylcellulose, carbonate, l-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate, calcium carbonate, and the like.
  • the pH adjusting agent is not limited thereto.
  • step 1 Adding lipids to a water-soluble solution and heating at a temperature above the melting point of the lipids to form an emulsion (step 1);
  • step 2 Adding a raw drug to the emulsion of step 1 (step 2); And
  • the present invention also provides a method of producing the taste masked liquid agent.
  • the method for producing a liquid agent according to the present invention is a one-stop solution method in which a shielding film can be formed on a raw material drug during the production of a liquid agent, There is an advantage that this shielded liquid agent can be manufactured.
  • step 1 is a step of adding lipids to an aqueous solution and heating at a temperature above the melting point of the lipids to form an emulsion.
  • the water-soluble solution may be purified water as a solvent, but not limited thereto, and other conventional water-soluble solvents may be used.
  • the step 1 may further include adding an additive to the solution.
  • the additive may be at least one selected from the group consisting of sweeteners, flavors, stabilizers, and pH adjusters.
  • the sweetener is included to add flavor to the taste of the liquid or to further enhance the taste shielding effect.
  • the sweetener may be selected from, for example, sugars, glucose, maltose, oligosaccharides, galactose, starch, sorbitol, maltitol, phytonutrients, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfamoyl, At least one member selected from the group consisting of salt, neo-time, thaumatin, tothomic mixture, cyclamate salt, tothmine, nahan and extract, licorice extract, stevioside, enzyme-treated stevioside, neohesperidin and monelin But is not limited thereto.
  • the sweetener is preferably contained in an amount of 0.1 to 40% based on the total weight of the solution.
  • the flavoring agent is included to add a flavor suitable for the liquid agent or to further enhance the taste shielding effect.
  • the flavors include, for example, strawberry incense, lemon incense essence, banana incense essence, strawberry incense cotton, lemon incense cotton, grape incense cotton, banana incense cotton or orange incense cotton, peppermint, cinnamon, menthol, At least one selected from the group consisting of peach flavor, cherry flavor, vanillin flavor and raspberry flavor may be used, but the flavor is not limited thereto.
  • the flavoring agent is preferably contained in an amount of 0.01 to 10% based on the total weight of the solution.
  • the pH adjusting agent used as the additive may be selected from the group consisting of citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid, Succinic acid, sodium dihydrogenphosphate, monosodium phospate, disodium dihydrogen pyrophosphate, acid citrate salts, amino acid hydrochlorides, Sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine, sodium bicarbonate, sodium carboxymethylcellulose, carbonate, l-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate (cal cadmium carbonate, and cadmium carbonate.
  • the pH adjusting agent is not limited thereto.
  • step 1 lipids are added to the aqueous solution, and the emulsion is formed by heating the lipids above the melting point of the lipids.
  • the lipids have a melting point of 40 ° C or higher and lower than 100 ° C.
  • the lipids may be liquefied during storage at room temperature after the production of the liquid agent, resulting in a problem of deteriorating the physical stability of the liquid agent, ° C., the water is vaporized because the melting point of the above-mentioned lipids is higher than the boiling point of water, so that the weight ratio of the solution and the lipids is varied, which may make it difficult to control the manufacturing conditions of the liquid agent.
  • the lipids may be used as GELUCIRE 44/14 having a melting point of 44 ° C.
  • the lipid may be prepared from at least one lipid selected from the group consisting of fatty acid glycerides, PEG fatty acid esters, and sugar surfactants.
  • the fatty acid may be a fatty acid having 10 to 30 carbon atoms, and more preferably a fatty acid having 12 to 22 carbon atoms.
  • the fatty acid glyceride may be mono-, di-, triglyceride, or a combination thereof, and the PEG fatty acid ester may be mono-, diester or a mixture thereof.
  • fatty acid glycerides or PEG fatty acid esters of said lipids glycerol mono as stearate (Glycerol monostearate), glycerol di-behenate (Glycerol dibehenate), glyceryl behenate (Glyceryl behenate)
  • glycerol monostearate Glycerol monostearate
  • glycerol di-behenate Glycerol dibehenate
  • glyceryl behenate Glyceryl behenate
  • Comp erythritol Compritol) ® 888 ATO
  • C8-18 glycerides (C8-18glycerides) as a gel Lucy LES (Gelucire) ® 43/01
  • lauroyl polyoxyl -32 glycerides as (lauroyl polyoxyl-32 glycerides) gel Lucy LES (Gelucire) ® 44/14 la
  • the saccharide surfactant may be selected from the group consisting of sucrose monostearate, sucrose distearate, sucrose mono-distearate, sucrose monopalmitate, But are not limited to, Sucrose dipalmitate, Sucrose monolaurate, Sucrose dilaurate, Sucrose monooleate, Sucrose dioleate, It is also possible to use one or more of sucrose monocaprate, sucrose dicaprate, sucrose monocaprylate, sucrose dicaprylate, sucrose monomyristate, Sucrose dimyristate, Sucrose monolinolenate and Sucrose monolinolenate, dilinolenate, and the like.
  • the lipids are preferably contained in an amount of 1 to 40% by weight based on the total weight of the aqueous solution.
  • the weight of the lipid is less than 1% by weight based on the total weight of the aqueous solution, it is difficult to distribute the raw drug on the lipid, The shielding effect may be deteriorated. If the weight of the lipids exceeds 40% by weight based on the total weight of the aqueous solution, the dissolution rate may be excessively delayed.
  • the step 2 is a step of injecting a raw material drug into the emulsion of the step 1 so that the raw material drug is distributed in the phase of the lipids.
  • step 2 it is preferable that the drug substance is distributed in the phase of lipids of the emulsion.
  • the drug substance may be a diabetic drug having an unpleasant taste; An insomnia remedy; Genitourinary therapy; Obesity remedy; Enzymes; Peptic ulcer solvent; Jinhae expectorant; A therapeutic agent for skin diseases; Antistatic agent; Antidepressants; Antihistamines; Antipyretic analgesics; Hormone preparations; Therapeutic agents for circulation; Therapeutic agent for digestive tract disorders; Psychotropic solvent; Erectile dysfunction treatment; A therapeutic agent for osteoporosis; Arthritis remedy; Antiepileptics; Muscle relaxants; Brain function improvers; A therapeutic agent for schizophrenia; Immunosuppressants; Antiviral agents, anti-malarial therapeutic agents, anti-tuberculosis agents, antibiotics; Anticancer agents; Anticancer adjuvants; Vaccines; Mouthwash; Anemia treatment agent; Constipation remedy; vitamin; Nutrients; Lactic acid bacteria preparation; Comprehensive cold medicine; And a health functional food.
  • the raw drug may also be selected from the group consisting of dexibuprofen, ibuprofen, naproxen, flurbiprofen, phosphodiesterase-5 inhibitor, but are not limited to, trimebutine, nicotine, varenicline, oseltamivir, prednisolone, donepezil, desmopressin, meclizine, entecavir, but are not limited to, entecavir, lamivudine, abacavir, atazanavir, zidovudine, cobicistat, stavudine, didanosine, dolutegravir, (eg, dolutegravir), darunavir, efavirenz, etravirine, elvitegravir, emtricitabine, fosamprenavir, indinavir indinavir, lopinavir, nevirapine, A group consisting of raltegravir, ritonavir, rilp
  • the step 3 is a step for cooling the emulsion added with the raw drug after the step 2.
  • step 3 it is preferable that the temperature of the emulsion to which the raw drug is added is lowered while stirring to cool it to room temperature.
  • the above-mentioned manufacturing method is advantageous in that a taste-masked liquid agent can be produced without a further process by a one-stop solution method in which lipids surrounding the raw material are formed simultaneously with the formation of a liquid agent.
  • the flavor-blocking agent is a flavor-masked oral disintegration film containing a drug substance dispersed in the lipids.
  • the oral disintegration film of the present invention is a mouth disintegration film in which the taste of a raw material drug is shielded and convenience of taking is improved.
  • the oral disintegration film according to the present invention comprises lipids.
  • the lipids are used for shielding the taste of the raw drug. By distributing the raw drug to the lipids, the taste of the raw drug can be physically shielded when taken.
  • the lipids can be formed at the same time as the preparation of the oral disintegration film.
  • the lipid which is a component of the above-mentioned lipids, is placed in a solution containing a water-soluble solvent and heated to 70 ° C to form an emulsion. After the drug substance is distributed in the lipid phase of the emulsion, And then dried to form lipids and lipid disintegration film containing the drug substance distributed therein.
  • the above-mentioned lipids are produced by using lipids having a melting point of 40 ° C or higher and lower than 100 ° C.
  • the lipids may be liquefied during storage at room temperature after the preparation of the oral disintegration film, resulting in separation of the oil phase from the film or softening of the film.
  • the melting point is 100 ° C or higher, the melting point of the above-mentioned lipids is higher than the boiling point of water, so that water is vaporized and the weight ratio of the solution and the lipids is varied, so that it is difficult to control the production conditions of the film.
  • the lipids may be used as GELUCIRE 44/14 having a melting point of 44 ° C.
  • lipids having a hydrophilic-lipophilic balance (HLB) of 0 to 16 are used.
  • hydrophilic lipophilic balance is a value indicating the degree of affinity with respect to water and oil. Of the values of 0 to 20, values closer to 0 indicate good lipophilicity, and values closer to 20 indicate hydrophilicity.
  • HLB hydrophilic / lipophilic balance
  • the lipids may be selected from the group consisting of Glycerol monostearate, Glycerol dibehenate, Glyceryl behenate, COMPRITOL 888, Gelucire 43/01, GELUCIRE 44/14, GELUCIRE 44/14, GELUCIRE 50/13, LABRAFRL M2130 CS, glyceryl palmitostearate (PRECIROL ATO 5), beads wax Beeswax, carnauba wax, and sugar-based surfactants.
  • the saccharide surfactant may be selected from the group consisting of sucrose monostearate, sucrose distearate, sucrose mono-distearate, sucrose monopalmitate, Sucrose dipalmitate, Sucrose monolaurate, Sucrose diraurate, Sucrose monooleate, Sucrose dioleate, Sucrose dipalmitate, Sucrose monocaprate, Sucrose dicaprate, Sucrose monocaprylate, Sucrose dicaprylate, Sucrose monomyristate, Sucrose monocarboxylate, , Sucrose dimyristate, sucrose monolinolenate, and sucrose di Tease carbonate may be at least one selected from the group consisting of (Sucrose dilinolenate).
  • the above-mentioned lipids may be sucrose esters of the following Table 2, but are not limited thereto.
  • Type HLB Content of major fatty acids (% by weight) Ester composition (% by weight) shape Monoester Di (di), tri (tri), polyester Sucrose Stearate D-1803F 3 About 70 About 20 About 80 P " D-1805 5 70 30 70 P " D-1807 7 70 40 60 P " D-1809 9 70 50 50 P " D-1811 11 70 55 45 P " D-1811F 11 70 55 45 P " D-1815 15 70 70 360 P " D-1816 16 70 75 25 P Sucrose palmitate D-1615 15 80 70 30 P " D-1616 16 80 80 20 P Sucrose laurate (sucrose) D-1216 16 95 80 20 P
  • the oral disintegration film of the present invention may be a form in which the raw material drug is mixed with lipid streams.
  • the raw drug may be uniformly mixed with lipids to form a matrix, but since the portion of the raw drug exposed to the outside is remarkably small, the dissolution rate in the mouth is temporarily reduced by the lipids, The taste shielding effect is remarkably excellent.
  • the oral disintegration film of the present invention may be in the form of a raw material drug formed in lipids.
  • the raw drug is shielded from the outside by lipids, and the taste of the drug can be completely blocked by the lipids, thereby remarkably excelling in the taste shielding effect of the drug.
  • the oral disintegration film according to the present invention includes a raw drug distributed in the above lipid classes.
  • the drug substance may be a diabetic drug having an unpleasant taste; An insomnia remedy; Genitourinary therapy; Obesity remedy; Enzymes; Peptic ulcer solvent; Jinhae expectorant; A therapeutic agent for skin diseases; Antistatic agent; Antidepressants; Antihistamines; Antipyretic analgesics; Hormone preparations; Therapeutic agents for circulation; Therapeutic agent for digestive tract disorders; Psychotropic solvent; Erectile dysfunction treatment; A therapeutic agent for osteoporosis; Arthritis remedy; Antiepileptics; Muscle relaxants; Brain function improvers; A therapeutic agent for schizophrenia; Immunosuppressants; Antiviral agents, anti-malarial therapeutic agents, anti-tuberculosis agents, antibiotics; Anticancer agents; Anticancer adjuvants; Vaccines; Mouthwash; Anemia treatment agent; Constipation remedy; vitamin; Nutrients; Lactic acid bacteria preparation; Comprehensive cold medicine; And a health functional food.
  • the raw drug may also be selected from the group consisting of dexibuprofen, ibuprofen, naproxen, flurbiprofen, phosphodiesterase-5 inhibitor, but are not limited to, trimebutine, nicotine, varenicline, oseltamivir, prednisolone, donepezil, desmopressin, meclizine, entecavir, but are not limited to, entecavir, lamivudine, abacavir, atazanavir, zidovudine, cobicistat, stavudine, didanosine, dolutegravir, (eg, dolutegravir), darunavir, efavirenz, etravirine, elvitegravir, emtricitabine, fosamprenavir, indinavir indinavir, lopinavir,
  • the pharmaceutical composition of the present invention is a pharmaceutical composition comprising at least one compound selected from the group consisting of nev
  • the oral disintegration film of the present invention may contain additives.
  • the additive may shield the taste of the raw material drug, may include various flavors or fragrances, and may facilitate the production of the film .
  • the additive may be at least one selected from the group consisting of a polymer, a plasticizer, a sweetener, a flavor, a stabilizer, and a pH adjuster. In this way, it may contain various flavors or aromas while at the same time shielding the taste, and may also assist in the production of the film.
  • the polymer used as the additive is a film-forming agent for forming a film, and examples thereof include pullulan, gelatin, pectin, low viscosity pectin, hydroxypropylmethylcellulose, low viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose Cellulose, carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein,
  • the water-soluble polymer may be at least one water-soluble polymer selected from the group consisting of water, a water-soluble polymer, a water-soluble polymer, a separation product, jane, levan, elscan, gluten, acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum,
  • the plasticizer used as the additive may be selected from the group consisting of glycerin fatty acid ester, sucrose fatty acid ester, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, , Starch syrup, glycerin, triacetin, glycerol oleate, triethyl citrate, and a medium chain fatty acid.
  • the plasticizers are not limited thereto.
  • the sweetener used as the additive may be selected from sugar, glucose, maltose, oligosaccharide, galactose, starch, sorbitol, maltitol, phosgene, xylitol, erythritol, hydrogenated starch, mannitol, trehalose, aspartame, acesulfamate, sucralo
  • oats saccharin salts, neo time, thaumatin, tothmine mixture, cyclamate salt, tothmine, nahan and extract, licorice extract, stevioside, enzyme-treated steviosides, neohesperidin and monelin
  • the sweetener is not limited thereto.
  • the above-mentioned flavor used as the additive may include strawberry flavor essence, lemon flavor essence, banana flavor essence, strawberry incense cotton, lemon incense cotton, grape incense cotton, banana incense cotton or orange incense cotton, peppermint, cinnamon, menthol, Mint, peach flavor, cherry flavor, vanillin flavor, and raspberry flavor may be used, but the flavor is not limited to this.
  • the pH adjusting agent used as the additive may be selected from the group consisting of citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid, Succinic acid, sodium dihydrogenphosphate, monosodium phospate, disodium dihydrogen pyrophospate, acid citrate salts, amino acid hydrochlorides, Sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine, sodium bicarbonate, sodium carboxymethylcellulose, carbonate, l-lysine carbonate, arginine carbonate, amorphous calcium carbonate, calcium carbonate (calc ium carbonate, and the like.
  • the flavor is not limited to this.
  • step 1 Adding lipids to a water-soluble solution and heating at a temperature above the melting point of the lipids to form an emulsion (step 1); And
  • the present invention also provides a method for producing a taste-masked oral disintegration film.
  • the method for producing an oral disintegration film according to the present invention is a one-stop solution method for forming a shielding film on a raw material drug during the process of manufacturing an oral disintegration film, There is an advantage that the oral disintegration film having a taste can be easily manufactured without the use of the above-mentioned method.
  • an oral disintegration film effectively shielding the unpleasant taste such as bitter taste, arginine taste, rough taste, bitter taste, etc. of the raw material drug can be produced, and thereby the raw drug can be more easily taken.
  • step 1 is a step of adding lipids to an aqueous solution and heating the lipid to a temperature above the melting point of the lipids to form an emulsion.
  • the water-soluble solution may be purified water as a solvent, but not limited thereto, and other conventional water-soluble solvents may be used.
  • the step 1 may further include adding an additive to the solution.
  • the additive is poly, and at least one selected from the group consisting of plasticizers, sweeteners, flavors, stabilizers, and pH adjusters may be used.
  • the polymer may be a water-soluble polymer used as a conventional film-forming agent.
  • the polymer may be selected from, for example, pullulan, gelatin, pectin, low viscosity pectin, hydroxypropylmethylcellulose, low viscosity hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyvinylalcohol, But are not limited to, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, carrageenan, modified starch, casein, whey protein isolate, soy protein isolate, But is not limited to, at least one selected from the group consisting of gluten, acacia gum, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum and agar.
  • the polymer is preferably contained in an amount of 30 to 85% based on the total weight of the solution.
  • plasticizer among the additives is included to control the flexibility of the film.
  • plasticizers include, for example, glycerin fatty acid esters, sucrose fatty acid esters, lecithin, enzyme-treated lecithin, polysorbate, sorbitan fatty acid ester, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol, propylene glycol, At least one selected from the group consisting of glycerin, triacetin, glycerol oleate, sucrose fatty acid ester and medium chain fatty acid may be used, but the plasticizer is not limited thereto.
  • the plasticizer is preferably contained in an amount of 0.1 to 30% based on the total weight of the solution.
  • the sweetener among the additives is included in order to add a flavor suited to the taste of the oral disintegration film or to further enhance the taste shielding effect.
  • the sweetener may be selected from, for example, sugars, glucose, maltose, oligosaccharides, galactose, starch, sorbitol, maltitol, phytonutrients, xylitol, erythritol, hydrogenated starch syrup, mannitol, trehalose, aspartame, acesulfamoyl, At least one member selected from the group consisting of salt, neo-time, thaumatin, tothomic mixture, cyclamate salt, tothmine, nahan and extract, licorice extract, stevioside, enzyme-treated stevioside, neohesperidin and monelin But is not limited thereto.
  • the sweetener is preferably contained in an amount of 0.1 to 40% based on the total weight of the solution.
  • the flavors among the above additives are included to add a flavor appropriate to the mouth disintegration film or to further enhance the taste shielding effect.
  • the flavors include, for example, strawberry incense, lemon incense essence, banana incense essence, strawberry incense cotton, lemon incense cotton, grape incense cotton, banana incense cotton or orange incense cotton, peppermint, cinnamon, menthol, At least one selected from the group consisting of peach flavor, cherry flavor, vanillin flavor and raspberry flavor may be used, but the flavor is not limited to this.
  • the flavoring agent is preferably contained in an amount of 0.01 to 10% based on the total weight of the solution.
  • the pH adjusting agent used as the additive may be selected from the group consisting of citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid, adipic acid, Succinic acid, sodium dihydrogenphosphate, monosodium phospate, disodium dihydrogen pyrophospate, acid citrate salts, amino acid hydrochlorides, Sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium sesquicarbonate, sodium glycine, sodium bicarbonate, sodium carboxymethylcellulose, carbonate, l-lysine carbonate, arginene carbonate, amorphous calcium carbonate, calcium carbonate (calc ium carbonate, and the like.
  • the flavor is not limited to this.
  • step 1 lipids are added to the aqueous solution, and the emulsion is formed by heating the lipids above the melting point of the lipids.
  • the lipids have a melting point of 40 ° C or higher and lower than 100 ° C.
  • the lipids may be liquefied during storage at room temperature after the preparation of the oral disintegration film, resulting in separation of the oil phase from the film or softening of the film.
  • the melting point is 100 ° C or higher, the melting point of the above-mentioned lipids is higher than the boiling point of water, so that water is vaporized and the weight ratio of the solution and the lipids is varied, so that it is difficult to control the production conditions of the film.
  • the lipids may be used as GELUCIRE 44/14 having a melting point of 44 ° C.
  • the lipids are selected from the group consisting of Glycerol monostearate, Glycerol dibehenate, Glyceryl behenate, COMPRITOL 888, Gelucire 43/01, GELUCIRE ) 44/14, GELUCIRE 44/14, GELUCIRE 50/13, LABRAFRL M2130 CS, glyceryl palmitostearate (PRECIROL ATO 5), beeswax (Beeswax ), Carnauba wax, and sugar-based surfactants.
  • the saccharide surfactant may be selected from the group consisting of sucrose monostearate, sucrose distearate, sucrose mono-distearate, sucrose monopalmitate, Sucrose dipalmitate, Sucrose monolaurate, Sucrose diraurate, Sucrose monooleate, Sucrose dioleate, Sucrose dipalmitate, Sucrose monocaprate, Sucrose dicaprate, Sucrose monocaprylate, Sucrose dicaprylate, Sucrose monomyristate, Sucrose monocarboxylate, , Sucrose dimyristate, sucrose monolinolenate, and sucrose di Tease carbonate may be at least one selected from the group consisting of (Sucrose dilinolenate).
  • the lipids are preferably contained in an amount of 1 to 40% by weight based on the total weight of the aqueous solution.
  • the weight of the lipid is less than 1% by weight based on the total weight of the aqueous solution, it is difficult to distribute the raw drug on the lipid, There is a problem that the shielding effect is lowered. If the weight of the lipids exceeds 40 wt% of the total weight of the aqueous solution, it is difficult to form the film, May occur.
  • the step 2 is a step of injecting the raw drug into the emulsion of the step 1 so that the raw drug is distributed in the lipid phase.
  • step 2 it is preferable that the drug substance is distributed in the phase of lipids of the emulsion.
  • the drug substance may be a diabetic drug having an unpleasant taste; An insomnia remedy; Genitourinary therapy; Obesity remedy; Enzymes; Peptic ulcer solvent; Jinhae expectorant; A therapeutic agent for skin diseases; Antistatic agent; Antidepressants; Antihistamines; Antipyretic analgesics; Hormone preparations; Therapeutic agents for circulation; Therapeutic agent for digestive tract disorders; Psychotropic solvent; Erectile dysfunction treatment; A therapeutic agent for osteoporosis; Arthritis remedy; Antiepileptics; Muscle relaxants; Brain function improvers; A therapeutic agent for schizophrenia; Immunosuppressants; Antiviral agents, anti-malarial therapeutic agents, anti-tuberculosis agents, antibiotics; Anticancer agents; Anticancer adjuvants; Vaccines; Mouthwash; Anemia treatment agent; Constipation remedy; vitamin; Nutrients; Lactic acid bacteria preparation; Comprehensive cold medicine; And a health functional food.
  • the raw drug may also be selected from the group consisting of dexibuprofen, ibuprofen, naproxen, flurbiprofen, phosphodiesterase-5 inhibitor, but are not limited to, trimebutine, nicotine, varenicline, oseltamivir, prednisolone, donepezil, desmopressin, meclizine, entecavir, but are not limited to, entecavir, lamivudine, abacavir, atazanavir, zidovudine, cobicistat, stavudine, didanosine, dolutegravir, (eg, dolutegravir), darunavir, efavirenz, etravirine, elvitegravir, emtricitabine, fosamprenavir, indinavir indinavir, lopinavir,
  • the pharmaceutical composition of the present invention is a pharmaceutical composition comprising at least one compound selected from the group consisting of nev
  • the method for producing the oral disintegration film of the present invention preferably further comprises cooling and drying the emulsion after the emulsion is heated after step 2.
  • the preparation method is a one-stop solution method in which a lipid surrounding the raw material is formed simultaneously with the formation of an oral disintegration film, and a mouth-shrinking film having a taste can be produced without further processing.
  • Xanthan Gum is swollen in water, carboxymethyl cellulose (CMC) is swollen in water to another beaker, and the temperature of the two solutions is then brought to 60 ° C.
  • CMC carboxymethyl cellulose
  • Glycerin is dissolved in water at 60 ° C to prepare a solution, and white sugar and sorbitol are dissolved in the solution, and the thickener of step 1 is added thereto.
  • Step 3 Encapsulation of lipid and drug
  • the lipid After the lipid is heated to 80 DEG C and melted, the molten lipid is rapidly stirred, the drug is added, and stirring is continued until the drug is sufficiently dissolved. 15 ml of water is added little by little to make an emulsion, and the temperature is lowered to 60 ° C with rapid stirring.
  • step 3 The emulsion produced in step 3 is rapidly stirred, the syrup prepared in step 2 is added, and then stirred rapidly. Cool the preparation to 30 ° C and add other excipients.
  • Example A liquid agent was prepared in the same manner as in Example A-1, except that each component in Example A-1 was changed as shown in the following Tables 3 and 4.
  • Example A-1 The components in Example A-1 were varied as shown in the following Table 3, and in the emulsion preparation of Step 3 in Example A-1, the lipid was heated to 80 DEG C to melt, and the molten lipid A solution was prepared by performing the same procedure as in Example A-1, except that the process of rapidly stirring and loading the drug was omitted.
  • Example A-8 Example A-9
  • Example A-10 Increasing agent / Sweetener White sugar 40 40 40 Sorbitol 27.5 27.5 27.5 Sweetener Sucral Rose 0.1 0.1 Enzyme treatment Stevia 0.1 Acidic Malic acid 0.2 0.2 0.2 Incrementer Xanthan gum 0.4 0.4 " CMC 0.6 0.6 " Carrageenan 0.6 Plasticizer glycerin One One One pH adjusting agent Citric acid 0.4 0.4 0.4 Flavor Grape incense One " Strawberry incense 0.5 One " Chrysanthemum 0.5 drug Ibuprofen 1.2 1.2 1.2 Lipid Beeswax 1.8 " Carnauba wax 1.8 " Castor wax 1.8 Purified water Suitable amount Suitable amount Suitable amount Total (mL) 100.00 100.00 100.00 100.00
  • Example A-1 Example A-2 Comparative Example A-1 flavor ++++ ++++ ++
  • Xanthan Gum is swollen in water, carboxymethyl cellulose (CMC) is swollen in water to another beaker, and the temperature of both solutions is then brought to 60 ° C.
  • CMC carboxymethyl cellulose
  • Glycerin is dissolved in water at 60 ° C to prepare a solution, and white sugar and sorbitol are dissolved in the solution, and the thickener of step 1 is added thereto.
  • Step 3 Encapsulation of lipid and drug
  • step 3 The emulsion produced in step 3 is rapidly stirred, the syrup prepared in step 2 is added, and then stirred rapidly. Cool the preparation to 30 ° C and add other excipients.
  • Example A liquid agent was prepared in the same manner as in Example A-11, except that the respective components in Example A-11 were changed as shown in the following Tables 6 and 7.
  • Example A-11 The components in Example A-11 were changed as shown in the following Table 6, and the process of melting and heating the lipids by heating to 80 DEG C in the tanning process of Step 3 in Example A-11, A liquid agent was prepared by performing the same procedure as in Example A-11, except that the process of rapidly stirring and loading the drug was omitted.
  • Example A-11 Example A-13 Comparative Example A-2 flavor ++++ ++++ +
  • Xanthan Gum is swollen in water, carboxymethyl cellulose (CMC) is swollen in water to another beaker, and the temperature of both solutions is then brought to 60 ° C.
  • CMC carboxymethyl cellulose
  • Glycerin is dissolved in water at 60 ° C to prepare a solution, and white sugar and sorbitol are dissolved in the solution, and the thickener of step 1 is added thereto.
  • Step 3 Encapsulation of lipid and drug
  • step 3 The emulsion produced in step 3 is rapidly stirred, the syrup prepared in step 2 is added, and then stirred rapidly. Cool the preparation to 30 ° C and add other excipients.
  • a liquid agent was prepared in the same manner as in Example A-21, except that each component in Example A-21 was changed as shown in Tables 9 and 10 below.
  • Example A-21 The components in Example A-21 were varied as shown in Table 9 below, and in the emulsion preparation process of Step A-21 of Example A-21, the process of melting and heating the lipid to 80 DEG C and the process of melting the molten lipid A liquid agent was prepared in the same manner as in Example A-21, except that the process of rapidly stirring and loading the drug was omitted.
  • the liquid preparations prepared in Examples A-21, A-26 and Comparative Example A-3 were administered to 6 subjects in an amount of 5 mL of the solution, And recorded. At this time, for accurate evaluation of the taste, the subjects rinsed the mouth with distilled water before taking the liquid.
  • the evaluation results of the liquid agents prepared in Examples A-21, A-26 and A-3 are shown in Table 11 below.
  • the degree of bitter taste was expressed as follows.
  • Example A-21 Example A-26 Comparative Example A-3 flavor +++ +++ +
  • Xanthan Gum is swollen in water, carboxymethyl cellulose (CMC) is swollen in water to another beaker, and the temperature of both solutions is then brought to 60 ° C.
  • CMC carboxymethyl cellulose
  • Glycerin is dissolved in water at 60 ° C to prepare a solution, and white sugar and sorbitol are dissolved in the solution, and the thickener of step 1 is added thereto.
  • Step 3 Encapsulation of lipid and drug
  • the lipid After the lipid is heated to 80 DEG C and melted, the molten lipid is rapidly stirred, the drug is added, and stirring is continued until the drug is sufficiently dissolved. 15 ml of water is added little by little to make an emulsion, and the temperature is lowered to 60 ° C with rapid stirring.
  • step 3 The emulsion produced in step 3 is rapidly stirred, the syrup prepared in step 2 is added, and then stirred rapidly. Cool the preparation to 30 ° C and add other excipients.
  • a liquid agent was prepared in the same manner as in Example A-31, except that the respective components in the above Example A-31 were changed as shown in the following Tables 12 and 13.
  • Example A-31 The procedure of Example A-31 was repeated except that the components in Example A-31 were changed as shown in Table 12 below and the lipid was heated to 80 [deg.
  • a liquid agent was prepared in the same manner as in Example A-31 except that the process of rapidly stirring and loading the drug was omitted.
  • Example A-31 Example A-32 Comparative Example A-4 flavor ++++ ++++ +
  • Example A-1 the liquid preparations of Example 1 and Comparative Example 1 were stained using the liposoluble means III dye, and the particles were observed under an optical microscope, (Example A-1) and Fig. 2 (Comparative Example A-1).
  • the liquid agent of the present invention minimizes direct contact of the drug with the oral cavity or the digestive system upon administration and that the drug is present in the lipid matrix, thereby effectively shielding bitter taste and arginine taste.
  • Example B-1 (% by weight)
  • Example B-2 (% by weight) Comparative Example B-1 (% by weight)
  • Carrageenan 1.24 5.24 1.30 Triethanol citrate 4.13 4.13 4.30 Sodium hydrogencarbonate 18.24 18.24 19.00
  • Example B-3 (% by weight)
  • Example B-4 (% by weight) Comparative Example B-2 (% by weight)
  • Pullulan 74.16 74.16 82.40 Carrageenan 9.80 1.80 2.00 Triethanol citrate 3.60 3.60 4.00 Citric acid 1.80 1.80 2.00
  • Peppermint incense 2.25 2.25 2.50 Barrenicin tartrate 0.40 0.40 0.40 saccharin 6.03 6.03 6.70 Sucrose stearate (D-1807) 1.96 9.96 - Sum 100 100 100 100
  • Example B-5 (% by weight)
  • Example B-6 (% by weight)
  • Example B-7 (% by weight)
  • Example B-8 (% by weight)
  • Pullulan 36.83 26.83 36.83 36.80 Carrageenan 1.30 1.30 2.30 1.30 Triethanol citrate 1.30 1.30 1.30 1.30 Citric acid 1.00 1.34 1.34 1.00 Orange incense 2.00 2.40 2.40 2.00
  • Example B-9 (% by weight) Example B-10 (% by weight) Example B-11 (% by weight) Comparative Example B-4 (% by weight) Pullulan 45.43 25.43 42.55 25.43 Carrageenan 2.50 2.50 3.72 2.50 Triethanol citrate 2.00 2.00 2.30 2.00 Sodium hydrogencarbonate - - 2.66 - Citric acid 2.00 2.00 - 2.00 Strawberry incense 2.00 2.00 4.50 2.00 Trimebutine 26.07 26.07 - 26.07 Oseltamivir - - 26.07 - Aspartame - - - - Stevioside 4.00 4.00 - 4.00 Sucralose - - 4.50 - Gelucire 50/13 pellets 16.00 - - - Gelucire 44/14 - 36.00 - - Oleic acid - - - 36.00 Sucrose stearate (D-1805) - - 13.70 - Sum 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100
  • Example B-3 (% by weight) Example B-12 (% by weight) Example B-13 (% by weight) Pullulan 47.96 44.66 29.66 Carrageenan 1.30 1.30 1.30 Triethanol citrate 13.0 1.30 1.30 Citric acid 1.34 1.34 1.34 Orange incense 2.40 2.40 2.40 Dexibupropene 30.00 30.00 30.00 Acesulfame K 4.00 4.00 4.00 Precirol ato 5 - 15.00 30.00 Sum 100 100 100 100 100 100
  • Step 1 Pullulan and other excipients in the weight% of the above table were added to purified water and stirred to form an aqueous solution. Lipids were added to the aqueous solution in the kind and weight% of the lipid disclosed in Example B-1 of Table 15. [ Concretely, 3.36% by weight of Precirol ato 5, 3.36% by weight of Compritol 888 ato and 9.28% by weight of Gelucire 44/14 were added and heated to 95 ° C to form an emulsion.
  • Step 2 5% by weight of nicotine as a raw drug was added to the emulsion and mixed with the emulsion so that nicotine was distributed in the lipid phase.
  • Step 3 The emulsion was placed on top, cooled and dried to prepare a taste-masked oral disintegration film having the composition of the above table.
  • Example B-1 the lipids added in Step 1 were performed in the same manner as in Example B-1 except that 12% by weight of sucrose stearate ((D-1809) was used, To prepare a flavor-masked oral disintegration film.
  • step 1 of Example B-1 the lipids were changed to 1.96% by weight of sucrose stearate ((D-1807) and in step 2 the raw drug was changed to 4% by weight of barrenicin tartaric acid was performed in the same manner as in Example B-1 to prepare a taste-masked oral disintegration film having the above-mentioned composition.
  • Step 1 of Example B-1 the lipids were changed to 9.96 wt% sucrose stearate ((D-1807) and the raw drug was changed to 4 wt% barrenicin tartaric acid in step 2 was performed in the same manner as in Example B-1 to prepare a taste-masked oral disintegration film having the above-mentioned composition.
  • Example B-1 the lipids were run with 16.74% by weight of Gelucire 43/01 pellets in Step 1, and in Example B-1 except that the raw drug was changed to 36.83% of dexibupropene in Step 2.
  • Example B-1 was prepared in the same manner as in Example B-1 except that in Step 1, the lipids were run with 26.00 wt% of Precirol ato 5, and the raw drug was changed to 36.83% of dexibupropene in Step 2. The same procedure was followed to prepare a taste-masked oral disintegration film having the composition of the above table.
  • Example B-1 in the same manner as in Example B-1 except that in Step 1, the lipids were run with 15.00 wt% of Geleol pellets and the raw drug was changed to 36.83% of bipopen in Step 2 To prepare a taste-masked oral disintegration film having the composition of the above table.
  • Example B-1 except that in step 1 the lipids were 15.64 wt% Precirol ato 5 and 1.36 wt% Gelucire 44/14 and in step 2 the raw drug was changed to 36.60% ibuprofen A taste-masked oral disintegration film having the composition of the above table was prepared in the same manner as in Example B-1.
  • Example B-1 was prepared in the same manner as in Example B-1 except that in Step 1, the lipids were changed to 16.0 wt% of Gelucire 50/13 pellets, and the raw drug was changed to 26.07% To prepare a flavor-masked oral disintegration film having the composition of the above table.
  • Example B-1 was prepared in the same manner as in Example B-1, except that in Step 1, the lipids were changed to 36.00 wt% of Gelucire 44/14 and the raw drug was changed to 26.07% The same procedure was followed to prepare a taste-masked oral disintegration film having the composition of the above table.
  • Example B-1 was prepared in the same manner as in Example B-1 except that in Step 1, the lipids were changed to 13.70 wt% of sucrose stearate (D-1805), and the raw drug in Step 2 was changed to 26.07% of oseltamivir. -1 to prepare a taste-masked oral disintegrating film having the composition of the above table.
  • Example B-1 was prepared in the same manner as in Example B-1 except that in Step 1, the lipids were changed to 15% by weight of Precirol ato 5, and the raw drug was changed to 30.00% of dexibupropene in Step 2. The same procedure was followed to prepare a taste-masked oral disintegration film having the composition of the above table.
  • Example B-1 was prepared in the same manner as in Example B-1, except that in Step 1, the lipids were changed to 30% by weight of Precirol ato 5, and the raw drug was changed to 30.00% of dexibupropene in Step 2. The same procedure was followed to prepare a taste-masked oral disintegration film having the composition of the above table.
  • Step 1 Pullulan and other excipients were added to purified water and stirred to prepare a water-soluble solution. Then, 5 wt% of nicotine was added to the aqueous solution as a raw material drug, uniformly mixed, and then degassed using a centrifuge.
  • Step 2 The solution of Step 1 was pre-heated, and then cooled and dried to prepare a mouth rinse film having the composition shown in the above table.
  • Comparative Example B-1 an oral debonding film having the composition of the above table was prepared by performing the same procedure as in Comparative Example B-1, except that the nicotine in Step 2 was changed to barrenicin tartaric acid.
  • Comparative Example B-1 an oral debonding film having the composition of the above table was prepared by performing the same procedure as in Comparative Example B-1, except that the nicotine in Step 2 was changed to dexibupropene.
  • Example B-10 a taste-masked oral disintegration film having the composition of the above table was prepared by performing the same procedure as in Example B-10 except that the lipids were changed to oleic acid in Step 1.
  • Example B-1 Example B-2 Comparative Example B-1 flavor +++ +++ +
  • Example B-3 Example B-4 Comparative Example B-2 flavor +++ ++++ +
  • Example B-12 Example B-13 Comparative Example B-3 flavor ++ +++ +
  • the oral disintegration film of the present invention has a higher bitter taste shielding effect than the oral disintegration film produced by Comparative Example B-3.
  • Example B-12, Example B-13, and Comparative Example B-3 which were prepared containing dexibupropene and acesulfame K drugs, were examined by scanning electron microscopy (SEM) The surface shape was confirmed, and the results are shown in Figs. 3 to 3, respectively.
  • Example B-10 prepared by using Gelucire 44/14 having a melting point of 40 ⁇ ⁇ as a lipid and the oral disintegration film prepared by using oleic acid having a melting point of 14 ⁇ ⁇ as a lipid (Comparative Example B-4), a state change with time after the production was confirmed, which is shown in Table 23 below.
  • Example B-10 No phase change No change in status No change in status No change in status Comparative Example B-4 No change in status No change in status
  • the film is softened Separation of oil phase from film
  • Example B-10 As shown in Table 23, in the case of the oral disintegration film produced by Example B-10, it was maintained for a long time without changing the state after production, whereas in the case of the oral disintegration film produced by Comparative Example B-4, It can be seen that the film is softened after 12 hours and the oil is separated.
  • the pharmaceutical preparations for oral administration in which the taste of the present invention is shielded and the preparation method thereof can be usefully used for drug formulation in the pharmaceutical industry.

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  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une préparation pharmaceutique à goût masqué et administrée par voie orale et sa méthode de préparation, et la préparation pharmaceutique peut se présenter sous la forme d'un liquide ou d'un film à désintégration orale et a un effet remarquablement excellent de masquage du goût d'un médicament brut. De plus, une méthode de préparation de liquide permet d'utiliser un équipement de préparation de liquide et des procédés existants, et permet une solution unique permettant de masquer le goût (enrobage lipidique) d'une matière première de médicament pendant les procédés de préparation de liquide. En outre, une méthode de préparation de film à désintégration orale, qui est une méthode de solution unique permettant à des lipides masquant le goût d'un médicament brut de se former simultanément à la préparation du film, permet de préparer un film à goût masqué et à désintégration orale sans procédés supplémentaires.
PCT/KR2018/011077 2017-09-19 2018-09-19 Préparation pharmaceutique à goût masqué et administrée par voie orale et sa méthode de préparation WO2019059652A1 (fr)

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KR10-2017-0120367 2017-09-19

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990086232A (ko) * 1998-05-26 1999-12-15 신재형 쓴맛이 은폐된 록시스로마이신 경구용 약물 조성물 및 그의 제조방법
KR20040016202A (ko) * 2002-08-16 2004-02-21 주식회사 제이알팜 쓴맛이 차폐된 히드로코르티손 경구용 약제 조성물 및 그제조방법
KR20040021957A (ko) * 2002-09-06 2004-03-11 주식회사종근당 쓴맛이 은폐된 세프포독심 프록세틸 제제
US20040058896A1 (en) * 2000-12-07 2004-03-25 Rango Dietrich Pharmaceutical preparation comprising an active dispersed on a matrix
KR20130135611A (ko) * 2012-06-01 2013-12-11 동아에스티 주식회사 Ｐｄｅ-5 억제제를 포함하는 고미 개선된 경구용 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990086232A (ko) * 1998-05-26 1999-12-15 신재형 쓴맛이 은폐된 록시스로마이신 경구용 약물 조성물 및 그의 제조방법
US20040058896A1 (en) * 2000-12-07 2004-03-25 Rango Dietrich Pharmaceutical preparation comprising an active dispersed on a matrix
KR20040016202A (ko) * 2002-08-16 2004-02-21 주식회사 제이알팜 쓴맛이 차폐된 히드로코르티손 경구용 약제 조성물 및 그제조방법
KR20040021957A (ko) * 2002-09-06 2004-03-11 주식회사종근당 쓴맛이 은폐된 세프포독심 프록세틸 제제
KR20130135611A (ko) * 2012-06-01 2013-12-11 동아에스티 주식회사 Ｐｄｅ-5 억제제를 포함하는 고미 개선된 경구용 조성물

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