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WO2014163215A1 - Composition pharmaceutique ayant un goût amer masqué - Google Patents

Composition pharmaceutique ayant un goût amer masqué Download PDF

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Publication number
WO2014163215A1
WO2014163215A1 PCT/KR2013/002698 KR2013002698W WO2014163215A1 WO 2014163215 A1 WO2014163215 A1 WO 2014163215A1 KR 2013002698 W KR2013002698 W KR 2013002698W WO 2014163215 A1 WO2014163215 A1 WO 2014163215A1
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Prior art keywords
sugar
bitter taste
pharmaceutical composition
active ingredient
sugar alcohol
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Ceased
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PCT/KR2013/002698
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English (en)
Korean (ko)
Inventor
이동하
한정오
권석영
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Jeil Pharmaceutical Co Ltd
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Jeil Pharmaceutical Co Ltd
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Publication date
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Priority to PCT/KR2013/002698 priority Critical patent/WO2014163215A1/fr
Publication of WO2014163215A1 publication Critical patent/WO2014163215A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to a pharmaceutical composition comprising a pharmacologically active ingredient having a bitter taste and a method for producing the same. Specifically, the present invention relates to a pharmaceutical composition comprising shielding bitter taste of a medicine having a bitter taste when taken through crystallization of sugars and sugar alcohols.
  • a technique for masking bitter taste is essential.
  • the sweetener can be masked to some extent by including various sweeteners in the formulation, It is well known in the art that it cannot effectively mask the bitter taste.
  • oral disintegrating tablets ODT
  • oral disintegration as an alternative oral dosage form
  • Special formulations such as Had Film (ODF) and dry syrup can be considered, but with such special formulations, the need to mask bitter taste is higher. That is, for example, in the case of oral disintegrating tablets, since the tablets must disintegrate while staying in the oral cavity, there is a need for additional technical means to avoid the patient's bitter taste during the oral residence time.
  • EP1536774A1 discloses a pharmaceutical formulation which masks the bitter taste of an active ingredient using a cationic polymer synthesized from dimethylaminoethyl methacrylate and a neutral methacrylic acid ester.
  • WO1998 / 43675 discloses an oral pharmaceutical composition in which carrageenan, chondroitin sulfate, or dextran sulfate are used in close contact with donepezil hydrochloride to form an electrical interaction, thereby preventing the dissolution of donepezil hydrochloride in saliva.
  • the pharmaceutical composition includes granules, powders, syrups and the like.
  • WO2000 / 12135 discloses a pharmaceutical composition in which polyvinylpyrrolidone and / or copolyvidone is used to reduce the irritation and bitter taste of donepezil hydrochloride.
  • European patent application publication EP1411899A2 discloses a chewed tablet with a bitter taste masked using Carbomer 934, Carbomer 971, Carbomer 974, PEG-5M and mixtures thereof.
  • Korean Patent No. 1188594 discloses a technique for blocking the bitter taste of sildenafil citrate by reducing the solubility of the active ingredient by using an alkalizing agent such as sodium hydroxide in connection with the rapid disintegrating film preparation in the oral cavity.
  • EP1809251A2 discloses a technique for blocking bitter taste by forming a core containing an active ingredient and a film by solvent coacervation on the core in relation to oral disintegrating tablet (ODT). It is.
  • the bitter taste shielding technique according to the prior art has a disadvantage that the effect of masking the bitter taste is not satisfactory, or the lowering of the dissolution rate occurs when the bitter taste shielding effect is achieved, or the manufacturing process is complicated. Existed. Therefore, there is a strong demand for new technical means that can achieve effective bitterness shielding effect in a relatively simple process.
  • the present invention with respect to a variety of active ingredients having a bitter taste, it is an object of the present invention to provide a pharmaceutical composition and a method of manufacturing the masked bitter taste of the active ingredient.
  • the pharmaceutical composition of the present invention may be in a conventional oral dosage form, and may be configured in a special formulation such as oral disintegrating tablet.
  • the present invention discloses the following solutions.
  • a pharmaceutical composition with a masked bitter taste comprising a sugar alcohol and a sugar.
  • the pharmaceutical composition is masked bitter taste, characterized in that the sugar is present in crystallized form with sugar alcohol.
  • the sugar alcohol is selected from xylitol, mannitol, sorbitol, maltitol, erythritol, pentitol, arabitol, ribitol, galactitol, lactitol, a bitter taste masked pharmaceutical
  • the composition is disclosed.
  • the pharmaceutical composition is masked bitter taste, characterized in that the sugar is selected from sucrose, lactose, maltose, sucralose, trehalose or cellobiose.
  • the active ingredient is donepezil, granistron, lamosetron, lamosetrone, palosetron, ondansetron, sildenafil, tadalafil, eudenafil, vardenafil, mirodenafil, keto
  • a bitter taste masked pharmaceutical composition is disclosed that is selected from propene, ibuprofen, dexibuprofen or Ecabet or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition is characterized in that the oral disintegrating tablet, bitter taste masked pharmaceutical composition is disclosed.
  • the sugar alcohol is selected from xylitol, mannitol, sorbitol, maltitol, erythritol, pentitol, arabitol, ribitol, galactitol, lactitol is disclosed.
  • the method is characterized in that the sugar is selected from sucrose, lactose, maltose, sucralose, trehalose or cellobiose.
  • the present invention it is possible to provide a pharmaceutical composition in which the bitter taste of various active ingredients is masked in a relatively simple process, and the pharmaceutical composition according to the present invention is made in a relatively simple process, which is extremely compared with the prior art. Efficient manufacturing is possible.
  • Figure 1 shows the DSC results of donepezil, sucralose, mannitol and a mixture of these three materials, and lyophilisate.
  • Figure 4 shows the FT-IR results of donepezil, physical mixture, lyophilisate used in lyophilization of Example 2.
  • 5 and 6 show the FT_IR results of the lyophilisate prepared by changing the sugars, sugar alcohols.
  • Figure 7 shows the XRD results of tablets made of donepezil, mannitol, sucralose, physical mixture, lyophilisate, lyophilisate.
  • the present invention relates to a means for masking bitter taste in making an active ingredient having a bitter taste into an oral dosage form.
  • the present inventors have found that when the active ingredient having a bitter taste is used as an oral dosage form, crystallization of sugar and sugar alcohol to form a crystalline complex of the active ingredient-sugar-sugar alcohol effectively masks the bitter taste. .
  • the present invention will be described in detail.
  • an active ingredient having a bitter taste means a drug having a bitter taste as a pharmacologically active drug.
  • the bitterness masking means disclosed in the present invention can be applied to a variety of active ingredients, such active ingredients are not limited, for example, donepezil, granistron, lamosetron, lamosetron, palocet Drugs such as ron, ondansetron, sildenafil, tadalafil, eudenafil, vardenafil, mirodenafil, ketoprofen, ibuprofen, dexibuprofen or ecabet.
  • the bitter taste shielding means disclosed in the present invention is considered to be applicable to various active ingredients, because it is not considered to be mediated by chemical interaction with the active ingredient, as described below.
  • sucrose in the present invention is not limited, but disaccharides such as sucrose, lactose, maltose, sucralose, trehalose or cellobiose are preferable.
  • sucrose alcohol as used in the present invention is not limited, xylitol, mannitol, sorbitol, maltitol, erythritol, pentitol, arabitol, ribitol, galactitol, lactitol and the like can be used.
  • sugars and sugar alcohols mentioned above are present in the crystallized state, as mentioned below, to achieve the effect of masking bitter taste. Therefore, as long as the sugar and sugar alcohol can be present in the crystallized state, it is included in the scope of the technical idea of the present invention, it should be noted that other sugars or sugar alcohols other than the above-mentioned sugar or sugar alcohol can be used. .
  • the presence of sugar and sugar alcohol in a crystallized state means that the present inventors have invented as a means of masking the bitter taste in the present invention.
  • the state is converted to. That is, for example, by dissolving and / or dispersing in a solvent with an active ingredient having a sugar and sugar alcohol with a bitter taste, and then lyophilized and tableting to form a crystalline complex with the sugar and sugar alcohol.
  • the present inventors have come to the present invention by obtaining a novel knowledge that the bitter taste of the active ingredient is masked by including the active ingredient having a bitter taste in such a crystalline complex of sugar-sugar alcohol.
  • crystallization of sugars and sugar alcohols is disclosed as a means of masking bitter taste.
  • the solubility of the active ingredient in order to mask the bitter taste of the active ingredient, the solubility of the active ingredient by coating the active ingredient with various polymers, forming a solid dispersion, or using an electrostatic interaction between the active ingredient and the bitter taste shielding material. Attempts have been made to lower.
  • the present inventors have obtained the knowledge that the bitter taste can be masked by using sugars and sugar alcohols which are widely used as excipients even without using the above method. More specifically, it has been surprisingly found that sugars and sugar alcohols are not included in the pharmaceutical composition as simple sweeteners, but they mask the bitter taste by employing a manufacturing process that can form crystalline complexes.
  • sugars and sugar alcohols form crystalline complexes.
  • the sugar and sugar alcohol are present in the amorphous form, that is, in the form of a liquid amorphous form.
  • the manufacturing process is performed to form a crystallized complex of sugar and sugar alcohol, thereby forming a crystalline complex of sugar-sugar alcohol to mask the bitter taste of the active ingredient.
  • the crystalline complex of the active ingredient-sugar-sugar alcohol is formed by lyophilizing sugar, sugar alcohol and active ingredient dissolved and / or dispersed in a solvent.
  • a crystalline complex of an active ingredient-sugar-sugar alcohol is formed, and an active ingredient having a bitter taste is present inside the crystalline complex, thereby making the bitter of the active ingredient bitter.
  • the taste is masked, that is, the dissolution of the active ingredient contained in the crystalline complex is delayed, thereby masking the bitter taste inherent in the active ingredient. That is, in the present invention, it should be noted that the bitter taste is masked by the presence of sugars and sugar alcohols in the crystalline complex state, rather than simply included in the pharmaceutical composition as a sweetener.
  • sugars can be used as the sugar, but disaccharides such as sucrose, lactose, maltose, sucralose, trehalose or cellobiose can be used.
  • the sugar in the present invention must form a crystalline complex with a sugar alcohol, that is, exist in such a way as to form a co-crystal with a sugar alcohol, for which a disaccharide consisting of two sugar molecules is suitable. to be.
  • a sugar alcohol capable of crystallizing with a sugar may be used as the sugar alcohol.
  • xylitol mannitol, sorbitol, maltitol, erythritol, tracerol, arabitol , Ribitol, galactitol, lactitol and the like can be used.
  • the content of sugar is preferably 0.01 to 2.0: 1.0 ratio of sugar: active ingredient
  • the content of sugar alcohol is preferably 0.1 to 20.0: 1.0 ratio of sugar alcohol: active ingredient.
  • the sugar-sugar alcohol-active component is determined by dissolving and / or dispersing it in a solvent together with an active ingredient having a sugary taste and a sugar alcohol, and then lyophilizing and tableting the same.
  • the sugar-sugar alcohol-active component is determined by dissolving and / or dispersing it in a solvent together with an active ingredient having a sugary taste and a sugar alcohol, and then lyophilizing and tableting the same.
  • it forms a sex complex it may be possible to crystallize by other means.
  • lyophilization method is recommended in that it does not form a crystalline complex of sugar and sugar alcohol.
  • bitter taste is masked while the pharmaceutical composition of the present invention is in the oral cavity. That is, the mechanism by which humans feel bitter taste in the oral cavity is not yet clear, but it is assumed that the active ingredient expresses bitter taste by binding to taste receptor proteins present in the tongue root, and the sugar-sugar alcohol-effectiveness of the present invention.
  • the crystalline complex of the components is believed to block the binding of the active ingredient with a bitter taste or a specific moiety of the active ingredient to the gastric taste receptor protein.
  • the present invention can be applied to any active ingredient, and therefore, it is different from the bitter taste shielding means in the prior art in which the bitter taste shielding means should be changed according to the active ingredient.
  • the manufacturing method of this invention can employ
  • sugars and sugar alcohols are dissolved and / or dispersed together with a suitable solvent such as an active ingredient having a bitter taste in a solvent.
  • the solvent may be 100% by weight or more relative to the active ingredient, and an amount suitable for dissolving the active ingredient, sugar and sugar alcohol is sufficient.
  • sugar and sugar alcohol are present in a liquid amorphous form.
  • the lyophilization then transforms the sugar and sugar alcohol into the form of a crystalline complex. Through this process, the sugar alcohol and sugar form a crystalline complex with each other, and it is assumed that the active ingredient having a bitter taste is present in the sugar-sugar alcohol crystalline complex.
  • a further technical feature of the present invention is that by controlling the water activity through lyophilization, it is possible to control the deterrence, fluidity and stability of the oral disintegrating tablet produced with the degree of bitterness shielding.
  • the water activity (Aw) is expressed as the ratio of the maximum water vapor pressure (Po) of pure water to the water vapor pressure (Ps) of the lyophilizer at any temperature, which indicates that the free water contained in the lyophilizer is It acts as a standard to measure the extent to which it is included.
  • Po maximum water vapor pressure
  • Ps water vapor pressure
  • the stability of the lyophilized formulation was confirmed to be influenced by the free water, not the water content including both the combined and free water present in the formulation, and to control the water activity.
  • the concept of is related to the occurrence of mass deviation due to disturbance, sticking, and fluidity problems during tableting. To date, no correlation between the water activity of lyophilized formulations and the above problems has been reported.
  • control of the water activity can be carried out by controlling the drying process, it will be possible to select the lyophilization conditions for each process while measuring the water activity.
  • oral disintegrating tablets with a bitter taste are contained, containing donepezil or a pharmacologically acceptable salt thereof as an active ingredient.
  • Donepezil or its pharmacologically acceptable salts are a treatment for dementia of the cholinesterase inhibitor family It is a drug used to treat dementia in the form of Alzheimer's disease.
  • Donepezil is a drug that reversibly inhibits acetylcholine degrading enzymes, such as acetylcholinesterase and butylcholinesterase.Alzheimer's, in which acetylcholine, a neurotransmitter, is lowered compared to normal people through gastric inhibitory function Increasing acetylcholine in the brain of sexually demented patients activates cholinergic neurons in the brain.
  • Formulations for administering donepezil to patients include oral disintegrating tablets (ODTs), oral disintegrating films (ODFs), dry syrups, jelly or patches, including conventional oral dosage forms such as tablets, capsules or solutions.
  • ODTs oral disintegrating tablets
  • ODFs oral disintegrating films
  • dry syrups dry syrups
  • jelly or patches including conventional oral dosage forms such as tablets, capsules or solutions.
  • the special formulation of is known, as the special formulation is taking into account that donepezil is mainly administered to elderly patients with dementia, taking into account the need for a dosage form with increased convenience than conventional dosage forms.
  • the elderly patients suffering from dementia have a strong tendency to show a sense of rejection when taking the drug, so in order to increase compliance with medication, special formulations such as syrups containing dry syrup, oral disintegrating tablets, and oral disintegrating films are used. According to the finding that it is preferable, the above-mentioned special formulations have been developed.
  • WO1998 / 43675 discloses an oral pharmaceutical composition in which carrageenan, chondroitin sulfate, or dextran sulfate are used in close contact with Donepezil hydrochloride to form an electrical interaction, thereby preventing the dissolution of Donepezil hydrochloride in saliva.
  • the pharmaceutical composition includes granules, powders, syrups and the like.
  • WO2000 / 12135 discloses a pharmaceutical composition in which polyvinylpyrrolidone and / or copolyvidone is used to reduce the irritation and bitter taste of donepezil hydrochloride.
  • Korean Patent No. 867639 discloses donepezil hydrochloride, which is shielded by high concentration by coating donepezil hydrochloride with a water-insoluble polymer.
  • the method disclosed in the prior art has a disadvantage in that the dissolution rate is low when the high-blocking effect is incomplete or the high-blocking effect appears, and furthermore, there is a disadvantage in that the manufacturing process is complicated. Therefore, the development of a new technical means for effective high rice shielding in a more efficient manufacturing process is urgently required.
  • oral disintegrating tablets containing donepezil as an active ingredient are disclosed.
  • oral disintegrating tablet containing donepezil for example, donepezil as an active ingredient and containing sugar and sugar alcohol
  • sugar and sugar alcohol and donepezil form a crystalline complex
  • An oral disintegrating tablet is disclosed which is present.
  • the orally disintegrating tablets are prepared by dissolving donepezil and sugars such as sucralose and sugar alcohols such as mannitol in water, and then lyophilizing and tableting them. Oral disintegrating tablets are disclosed, such oral disintegrating tablets may mask the donepezil-specific bitter or irritant taste (Arin).
  • sucralose forms a crystalline complex with mannitol, and so-called sucralose-mannitol-donepezil hydrochloride crystal is present in the crystalline complex.
  • sucralose-mannitol-donepezil hydrochloride crystal is present in the crystalline complex.
  • oral disintegrating tablets containing various active ingredients were prepared.
  • the active ingredient, sugar, and sugar alcohol were dissolved and / or dispersed in the solvent shown in the following table, and then lyophilized according to the conditions shown in the following table.
  • An appropriate amount of the additive was mixed with the lyophilized powder and then compressed into tablets.
  • Example 12 Active ingredient (g) Donepezil Hydrochloride 1.0 Donepezil Hydrochloride 1.0 Donepezil Hydrochloride 1.0 Donepezil Hydrochloride 1.0 Donepezil Hydrochloride 1.0 Solvent (mL) Purified water 30 Purified water 30 Purified water 30 Purified water 30 Purified water 30 Purified water 30 Purified water 30 Sugar (g) Sucrose 0.4 Lactose 0.4 Maltose 0.4 Sucralose 0.4 Sucralose 0.4 Sucralose 0.4 Sugar alcohol (g) Mannitol 5.0 Mannitol 5.0 Mannitol 5.0 Sorbitol 5.0 Maltitol 5.0 Xylitol 5.0 Freeze drying condition Temperature increase and dry while maintaining 1.5 Pa pressure over 48h from -40 °C to 30 °C Temperature increase and dry while maintaining 1.5 Pa pressure over 48h from -40 °C to 30 °C Temperature increase and dry while
  • oral disintegrating tablets were prepared by various methods other than lyophilization, and general direct blow, dry granulation, or wet granulation methods were used so that sugars and sugar alcohols did not form crystalline complexes.
  • oral disintegrating tablets are prepared by dissolving and / or dispersing the active ingredient, the sugar and the sugar alcohol in the solvents described in the following table, and preparing the granules according to the conditions described in the following table and mixing the appropriate amount of the additives. Prepared.
  • freeze-dried granules were prepared in the same manner as in the above-mentioned preparation method by varying the freeze-drying time based on the formulation of Example 2.
  • sucralose sucralose DSC
  • donpezil_FD Donepezil lyophilisate DSC
  • sucralose_FD sucralose DSC
  • Each component_FD DSC of each freeze-dried product prepared by changing the same amount of sugars or sugar alcohols as in the preparation method of Example 2
  • Example 1 0.3979 Example 2 0.3661 Example 3 0.3191 Example 4 0.4029 Example 5 0.4095 Example 6 0.3446 Example 7 0.4114 Example 8 0.3911 Example 9 0.3483 Example 10 0.1741 Example 11 0.1091 Example 12 0.0901 Comparative Example 1 0.1769 Comparative Example 2 0.1759 Comparative Example 3 0.1384 Comparative Example 4 0.3798 Comparative Example 5 0.2660 Comparative Example 6 0.6662 Comparative Example 7 0.8329 Comparative Example 8 0.8981
  • Example 1 23 42 radish 4.3 Example 2 22 42 radish 4.5 Example 5 19 37 radish 3.8 Example 7 23 42 radish 5.3 Example 8 20 41 radish 4.7 Example 11 22 40 radish 5.0 Comparative Example 6 24 48 U 7.9 Comparative Example 7 23 49 U 6.8 Comparative Example 8 25 47 U 8.5
  • the present invention it is possible to mask the intrinsic bitter taste of the active ingredient having a bitter taste through the sugar crystallized with the sugar alcohol, which can be achieved only by the process of dissolving, drying and tableting the active ingredient, It does not require a compression molding machine or a fluid-bed coater or spray dryer, which has manufacturing advantages.

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Abstract

L'invention concerne une composition pharmaceutique contenant un ingrédient actif de goût amer qui est une composition pharmaceutique ayant un goût amer masqué, contenant de l'alcool de sucre et du sucre. La composition pharmaceutique, selon la présente invention, forme un composite cristallin avec du sucre, de l'alcool de sucre et l'ingrédient actif de goût amer, et fournissant de cette façon un effet masquant le goût amer.
PCT/KR2013/002698 2013-04-02 2013-04-02 Composition pharmaceutique ayant un goût amer masqué Ceased WO2014163215A1 (fr)

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PCT/KR2013/002698 WO2014163215A1 (fr) 2013-04-02 2013-04-02 Composition pharmaceutique ayant un goût amer masqué

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WO2016126592A1 (fr) * 2015-02-02 2016-08-11 Axim Biotechnologies, Inc. Complexe de cannabinoïdes et d'alcools de sucre et ses procédés de fabrication et d'utilisation
CN108785247A (zh) * 2018-08-06 2018-11-13 成都通德药业有限公司 一种注射用盐酸雷莫司琼的制备方法
CN113350291A (zh) * 2020-03-04 2021-09-07 广东东阳光药业有限公司 一种乙酰胆碱酯酶抑制剂的组合物及其制备方法

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KR20050071889A (ko) * 2004-01-05 2005-07-08 신일제약주식회사 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상조성물
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KR100867639B1 (ko) * 2007-06-08 2008-11-10 (주)다산메디켐 고미가 차폐된 염산 도네페질-함유 입자, 이를 포함하는약학 조성물, 및 이들의 제조방법
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016126592A1 (fr) * 2015-02-02 2016-08-11 Axim Biotechnologies, Inc. Complexe de cannabinoïdes et d'alcools de sucre et ses procédés de fabrication et d'utilisation
CN108785247A (zh) * 2018-08-06 2018-11-13 成都通德药业有限公司 一种注射用盐酸雷莫司琼的制备方法
CN113350291A (zh) * 2020-03-04 2021-09-07 广东东阳光药业有限公司 一种乙酰胆碱酯酶抑制剂的组合物及其制备方法

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