Classifications

• • 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
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • 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
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

• the present invention relates to a pharmaceutical composition for internal use, wherein an unpleasant taste of a drug having an unpleasant taste such as bitter taste, puckery taste, acid taste, etc. is reduced and its ease of taking is improved.
• the pharmaceutical composition has such a characteristic that the unpleasant taste is significantly inhibited and reduced on taking it and control of the dose is simple and, therefore, it is a pharmaceutical composition suited particularly for a child drug dosage form.
• a dry syrup prepared by adding water on taking is effective for manufacturing a preparation by using drugs which are unstable in water. Furthermore, the dry syrup is often used as a child dosage form because of its flexibility of the dose and good ease of taking.
• the dry syrup includes, for example, those converted into a solution and those converted into a suspension, when adding water.
• the form is selected according to physical properties such as solubility of the drug, and purpose in the preparation effect such as sustained release.
• the form of a suspending syrup obtained by forming the drug into solid particles wherein the taste of the drug is masked out by any method, and dispersing the solid particles.
• an object of the present invention is to provide a pharmaceutical composition, which can be easily taken without feeling an unpleasant taste of a drug by adding water to the drug having the unpleasant feel such as bitter taste before use, and which is superior in dissolution in the gastrointestinal tract.
• the present inventors have intensively studied constantly to attain the above object, and found that, by taking drug-containing particles wherein the taste of the drug is masked out in a state of being dispersed and included in a jelly, it is possible to take even a drug, which is freely soluble in water and has a comparatively strong bitter taste, in a state where the bitter taste is sufficiently masked out without feeling the bitter taste.
• a pharmaceutical composition suiting the above object can be prepared by combining a drug, wherein its unpleasant taste is masked out to such a degree that intrinsic bioavailability of the drug is not adversely affected, with a gelling agent capable of being converted rapidly into a form of agar (jelly) when adding water.
• the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising a drug-containing substance wherein an unpleasant taste of the drug is masked out, and a gelling agent.
• the pharmaceutical composition is converted into a jelly-like preparation containing the above drug-containing substance when being added to water.
• the pharmaceutical composition of the present invention can be taken as a jelly-like preparation by adding water before use. That is, the present invention makes it possible to conduct masking of a drug having particularly strong bitter taste, which could not be sufficiently attained by the form of a suspending syrup according to the prior art, by taking, as a form on taking, the form of jelly wherein the drug whose unpleasant taste is masked out are dispersed and included.
• the pharmaceutical preparation of the present invention even if masking of the drug-containing substance is insufficient for securing the bioavailability thereby to cause leakage of the drug in the mouth on taking, diffusion of the drug is inhibited because a medium is in the form of jelly and, furthermore, the drug-containing substance is taken in a state of being surrounded by a jelly and is hardly remained in the mouth. Therefore, appearance of the bitter taste derived from the drug is prevented. Since the jelly component is quickly diluted after transferring to the gastrointestinal tract, an influence is not exerted on the dissolution of the drug from the drug- containing substance and the release characteristics as a drug-containing substance unit are maintained, thereby to ensure the bioavailability of the drug.
• the pharmaceutical composition of the present invention is a preparation prepared before use, which is used in combination with water in a proper amount before use, unlike a coated drug such as conventional sugar-coated tablet, film-coated tablet, etc., it is possible to control the dose and is optimum for application to a child drug. Furthermore, the form of a jelly is easily taken and is also useful as an oral dosage form to infants, patients suffering from dysphagia, and aged persons. Brief Description of Drawings
• Fig. 1 shows the solution out curve of the jelly composition of Example 11.
• Fig. 2 shows the solution out curve of the jelly composition of Example 14. Mode for Carrying out the Invention
• the pharmaceutical composition of the present invention will be described hereinafter.
• the particle diameter or particle size distribution of the drug show a value measured by the sieving method employed in Japanese Pharmacopoeia unless otherwise stated.
• the drug to be used in the pharmaceutical composition according to the present invention is not specifically limited, but examples thereof include preferably drug which affords an unpleasant taste such as bitter taste, puckery taste, acid taste, etc., to the subject, and more preferably water-freely soluble drug which is easily dissolved in the mouth.
• the unpleasant taste of the drug is masked out to some extent by the prior art and the remaining unpleasant taste of the drug, which can not be completely masked out, is covered by taking the form of a jelly. Therefore, the present invention is particularly useful for a drug which is not sufficiently masked out by the prior art because of strong unpleasant taste and/or high water solubility.
• the drug includes, for example, antimicrobial drug which is generally considered to be bitter (e.g. pyridonecarboxylic acid synthetic antimicrobial drug, etc.); antibiotic which is generally considered to be bitter [for example, penicillin antibiotic (e.g. bacampicillin, etc.), cephem antibiotic (e.g. cepaclor, cefotiam hexetil hydrochloride, cefteram pivoxil, etc.), macrolide antibiotic (e.g. erythromycin, clarithromycin, josamycin, etc.) and other antibiotic (e.g. tetracycline, chloramphenicol, etc.) (including embodiments of salts thereof); antitussive/expectorant (e.g.
• the pyridonecarboxylic acid synthetic antimicrobial drug is particularly preferred.
• the pyridonecarboxylic acid antimicrobial drug is generally referred to as newquinolone and examples thereof include synthetic antimicrobial drugs such as enoxacin, norfloxacin, ofloxacin, levofloxacin, cyprofloxacin, lomefloxacin, tosufloxacin, nadifloxacin, grepafloxacin, trovafloxacin and acid addition salts thereof.
• the acid addition salt include, for example, inorganic salt such as hydrochloride, nitrate, etc. and organic acid salt such as salts of citric acid, salicylic acid, tosylic acid, mesylic acid, etc. These drugs may also be an anhydrate or a hydrate.
• the above drugs are freely soluble in water and have strong bitter taste.
• grepafloxacin had such a problem that masking is not easily conducted by a conventional method and is insufficient because of low threshold value of bitter taste, such as 1 ⁇ g/ml, and high water solubility. Therefore, the drug used in the present invention is preferably a drug which is insufficiently masked out by the conventional method because the threshold value of bitter taste is low (ranging from several to several tens ⁇ g/ml) and the drug is freely soluble in water.
• the drug is preferably grepafloxacin described above, more preferably grepafloxacin hydrochloride, and particularly preferably grepafloxacin hydrate.
• threshold value of bitter taste means a minimum concentration (w/v) of the drug wherein human generally feels bitter. For example, it can be determined from a minimum drug concentration of a test solution wherein at least one of subjects felt bitter after the subjects contain each of aqueous solutions (10 ml) of various drug concentrations in the mouth for 10 seconds.
• the masking method include the following method:
• the hydrogel matrix base used herein includes, for example, gelatinized starch, partially gelatinized starch, gelatin, powdered acacia, methylcellulose, carmellose (carboxymethylcellulose) , carmellose sodium (carboxymethylcellulose sodium), hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, low substituted hydroxypropylcellulose, sodium alginate, pullulan, dextrin, starch, pectin, carmellose calcium (carboxymethylcelllose calcium) or the like.
• the wax matrix base includes, for example, hydrogenated castor oil, hydrogenated soybean oil, glycerin fatty esters, sorbitan fatty esters or the like.
• the porous polymer includes, for example, nonionic synthetic absorbent such as polystyrene, porous silica or the like.
• the ion exchange resin includes, for example, cation exchanger such as styrenesulfonic acid strong acidic cation exchange resin, acrylic weak-acidic cation exchange resin, methacrylic cation exchange resin, methacrylic acid copolymer (e.g. Eudragit L, etc.), carboxyvinyl polymer, zeolites, synthetic zeolite, Permtite, etc.; anion exchager such as styrenic strong- basic ion exchange resin, acrylic acid weak-basic ion exchange resin, hydrated iron oxide gel, etc.
• cation exchanger such as styrenesulfonic acid strong acidic cation exchange resin, acrylic weak-acidic cation exchange resin, methacrylic cation exchange resin, methacrylic acid copolymer (e.g. Eudragit L,
• the film-coating base and encapsulating base include, for example, polymers such as water-soluble polymer, water-insoluble polymer, acid-soluble polymer, enteric polymer, etc.
• the water-soluble polymer includes, for example, powdered acacia, gelatin, sodium alginate, methylcellulose, carmellose, carmellose sodium, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, etc.
• the water-insoluble polymer includes, for example, ethylcellulose, purified shellac, waxes, etc.
• the acid-soluble polymer includes, for example, aminoalkyl Methacrylate Copolymer E, polyvinyl acetal diethylaminoacetate, etc.
• the enteric polymer includes, for example, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid copolymer, cellulose acetate phthalate, etc.
• the drug-containing substance wherein the unpleasant taste of the drug is masked out which is obtained by the method described above, preferably has a granular form such as powder, fine granule, granule, etc.
• any of per se known method can be used, and examples thereof include extrusion granulating method, crush granulating method, fluidized bed granulating method, centrifugal granulating method, rolling granulating method, high-speed stir granulating method, etc.
• extrusion granulating method crush granulating method
• fluidized bed granulating method fluidized bed granulating method
• centrifugal granulating method rolling granulating method
• high-speed stir granulating method etc.
• fluidized bed, centrifugal flow, air-permeable coating pan, high-speed stirring or a combination type equipment thereof can be used and a suitable equipment can be selected according to the shape, size and production method.
• the particle diameter of the drug-containing substance can be appropriately set according to the unpleasant taste (e.g. bitter taste, etc.) of the drug or the degree of masking. Since the drug-containing substance is finally taken in a state of being surrounded by a jelly, it is not necessary to pursue refining of particles for the purpose of improving the dispersion of the particles and avoiding foreigness, like the case of the dosage form of syrup. It is possible to use the drug-containing substance having a particle diameter of up to about 2 mm and the particle diameter is not specifically limited, but is usually from 50 to 1800 ⁇ m, preferably from 75 to 1500 ⁇ m, and more preferably from 100 to 1000 ⁇ m. According to the desired particle diameter of the drug-containing substance, the masking method can be appropriately selected.
• the drug-containing substance in the form of fine particles having a particle diameter of up to 300 ⁇ m (usually from 75 to 300 ⁇ m, and preferably from 100 to 250 ⁇ m) is prepared
• a method of preparing wax matrix type fine particles using a method of dispersing a drug in a fatty acid ester of glycerol base there can be preferably employed a method of preparing wax matrix type fine particles using a method of dispersing a drug in a fatty acid ester of glycerol base.
• the resulting fine particles can also be film-coated by using a water- insoluble coating agent such as pH-depending dissolution type polymer.
• the fatty acid ester of glycerol base includes, for example, glyceryl monostearate, citric acid and fatty acid esters of glycerol, glyceryl monobehenate, etc.
• the water-soluble coating agent such as pH-depending dissolution type polymer includes, for example, aminoalkyl Methacrylate Copolymer E, Methacrylic acid Copolymer L, Methacrylic acid Copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, etc.
• the mixing ratio of the drug to fatty acid ester of glycerol in the fine particles, and the amount of the coating agent vary depending on the kind of the drug, i.e. degree of the bitter taste of the drug and its release characteristics and, therefore, they are appropriately selected according to them.
• the amount of the fatty acid ester of glycerol to be mixed with 1 part by weight of the drug contained in the fine particles is not less than 1.5 parts by weight, preferably not less than 2.5 parts by weight, and more preferably not less than 4 parts by weight.
• the upper limit of the amount of the fatty acid ester of glycerol in such a case is about 15 parts by weight.
• the proportion of the coating film component based on 100% by weight of the core particles is usually from 10 to 100% by weight, preferably from 10 to 80% by weight, and more preferably from 10 to 60% by weight.
• the above drug-containing substance can be prepared by the following method. First, the drug is molten or dispersed in a molten fatty acid ester of glycerol. Then, this melt is dropped on a disc rotating at high speed, using a proper liquid delivery pump. The dropped melt is splashed by a centrifugal force of the disc and then solidified with cooling during the dropping to obtain microspherical particles. Then, a solution containing a coating film component is sprayed from a spray gun with allowing to flow the resulting microspherical particles in a fluidized bed granulator to form microspherical coated particles.
• a masking method of including a drug in gel beads such as water-insoluble alginate beads there can be preferably used a masking method of including a drug in gel beads such as water-insoluble alginate beads.
• the content of the drug can be usually set within a range from 10 to 90% by weight based on 100% by weight of the drug-containing substance, optionally. When the content is too small, penetration of water into beads is accelerated and release of the drug is promoted. Therefore, in the case of the drug which is freely soluble in water, the content is not less than 20% by weight, preferably from 20 to 90% by weight, and more preferably from 30 to 80% by weight.
• the above drug-containing substance can be prepared, for example, by the following method. First, a drug is dispersed in an aqueous solution of sodium alginate. Then, the resulting suspension is added dropwise in an aqueous solution containing a calcium salt such as calcium chloride. The added liquid droplets are immediately solidified by the reaction between alginic acid and calcium ions, thereby to form beads including the drug therein. The resulting beads are collected, washed and then dried to obtain masked particles (drug- containing substance).
• the resulting masked particles may also be coated with the above proper coating agent, if necessary.
• the water-soluble polymer such as gelatin, acacia, etc.
• gelling agent used in the pharmaceutical composition of the present invention, those requiring any treatment such as heating, cooling, etc. in the case of gelation are not suitable, but those having a property capable of gelling quickly at normal temperature when adding water are desirable.
• the gelling agent having such physical properties is preferably a polymer capable of causing crosslinking gelation in the presence of polyvalent metallic ions.
• gelling agent used in the present invention includes not only those composed of a single component, but also those capable of causing gelation by using two or more components in combination.
• the polymer capable of causing crosslinking gelation by an action of the polyvalent metallic ions includes, for example, alginate, pectic acid salt, etc.
• alginate an alginate is preferred.
• the salt of the alginic acid and pectic acid includes, for example, salt of alkali metal such as sodium, potassium, etc.; salt of alkali earth metal such as calcium, etc.; or partially esterified one thereof.
• a sodium salt of alginic acid or pectic acid, particularly sodium alginate has great value in use because it is widely used as a viscous agent or a gelling agent in the field of foods and those having different molecular weights are commercially available.
• the viscosity in the form of an aqueous solution is defined.
• the viscosity of sodium alginate used in the present invention is from 20 to 1000 cP, preferably from 50 to 800 cP, and more preferably from 80 to 800 cP, in terms of the viscosity of an aqueous 1% solution at 20 °C (using a rotary viscometer at 30 rpm).
• sodium alginate a product having ultra- low viscosity defined as a viscosity of an aqueous 10% solution is commercially available. In the case of those having too low viscosity, it is difficult to obtain strong gel intensity. On the other hand, in the case of those having high viscosity, it becomes difficult to dissolve when adding water. In both cases, it becomes disadvantageous for masking of the drug.
• sodium alginate is classified into various grades according to a composition ratio of mannuronic acid to guluronic acid as a constituent unit of the polymer, that is ratio M/G.
• the ratio M/G is large. That is, in the case of those containing a large amount of mannuronic acid, a soft gel is liable to be obtained and the ratio M/G is small. That is, in the case of those containing a small amount of mannuronic acid, a hard gel is liable to be obtained.
• the ratio M/G of commercially available sodium alginate is from 0.3 to 2.5. In the present invention, a jelly having desired hardness can be prepared even when using any sodium alginate having the hardness within this range.
• the ratio M/G can be determined according to the method of Haug et al. (A. Haug et al., Carbohydrate Research 32, (1974) 217-225).
• polyvalent metallic ion examples include ions of salt of alkali earth metal such as magnesium, calcium, etc.; and ions of salt of divalent /trivalent metal such as aluminum, iron, copper, zinc, etc. Among them, calcium ion is preferred as an additive of the medicine.
• Examples of the supply component of the calcium ion include calcium salt of inorganic acid, such as calcium chloride, calcium sulfate, calcium monohydrogenphosphate, calcium carbonate, etc.; and calcium salt of organic acid, such as calcium lactate, calcium gluconate, calcium citrate, etc.
• a salt which is neutral and insoluble in water, such as calcium sulfate, calcium citrate, monohydrogenphosphate, calcium carbonate, etc. among them, since ions are not emitted only by adding water, it becomes necessary to add an acid for dissolving the salt. Therefore, in the present invention, it is also possible to add an organic acid such as citric acid, adipic acid, glucono- ⁇ -lactone acid, etc.
• the gelling agent It is very important for the gelling agent to form a homogeneous jelly as fast as possible when adding water. Since the gelation in the case of using sodium alginate and a calcium salt as the gelling agent occurs in the following two stages, that is (i) hydration of sodium alginate and (ii) formation of a salt with calcium ions, partial gelation of alginic acid occurs in the case where sodium alginate has high viscosity and a long time is required for hydration or dissociation of the calcium salt occurs too fast, resulting in heterogeneous jelly.
• the resultant is composed of two phases, i.e. hard gel and a liquid portion and dissolution of the drug is sometimes accelerated.
• the gelation reaction can be delayed by adding sodium citrate or sodium pyrophosphate which has an chelete action to calcium ions.
• the hardness of the jelly to be formed when water is mixed with the pharmaceutical composition comprising a drug-containing substance wherein an unpleasant taste of the drug is masked out, and a gelling agent according to the present invention is not specifically limited.
• the jelly preferably has a hardness enough to endure elasticity for shape retention.
• a hardness of the jelly can be controlled by appropriately selecting/controlling the kind and amount of the gelling agent, as a principal factor, as well as amount of water to be added on taking.
• sodium alginate and a calcium salt when using sodium alginate and a calcium salt as the gelling agent, it is a mixing ratio of sodium alginate to water that decides the hardness of the jelly.
• the amount of sodium alginate to be mixed with water so as to obtain a jelly having a proper hardness varies depending on the specification viscosity and ratio M/G, but is from about 0.2 to 5% by weight, preferably from about 0.5 to 3% by weight, and more preferably from about 0.5 to 2% by weight.
• the hardness of the jelly includes, for example, hardness of the jelly thus prepared.
• the pharmaceutical composition of the present invention is provided in a solid state and water is added by users, the dose is set by previously defining the amount of water to be added on taking in the manufacturing of the preparation.
• the proper amount of the calcium salt is from 0.1 to 1.5 mol, preferably from 0.1 to 1 mol, and more preferably from 0.2 to 0.7 mol, per mol (molecular weight per carboxyl group: 198) of sodium alginate.
• a water-insoluble calcium salt it is necessary to select an organic acid required for dissociation of it and to set the amount of the organic acid, carefully, because not only control of the gelation rate but also the taste of the jelly are influenced by them.
• the gelling agent in the present invention preferably contains the sodium alginate and calcium salt describe above as a principal component, and may also contain organic acids, chelating agents, sweeteners (e.g. purified sucrose, saccharin sodium, thaumatin, aspartame, etc.) and flavors (e.g. cherry flavor, strawberry flavor, orange flavor, etc.).
• sweeteners e.g. purified sucrose, saccharin sodium, thaumatin, aspartame, etc.
• flavors e.g. cherry flavor, strawberry flavor, orange flavor, etc.
• the mixing ratio of the drug-containing substance to the gelling agent is set by generally evaluating in view of the feel on taking, bitter taste, etc., considering the volume of the jelly formed by adding water on taking, and the amount of the drug- containing substance dispersed therein.
• the amount of the drug-containing substance drug particles
• the amount of the gelling agent is too large, since the resulting jelly has rough feel to the tongue and the particles are often made contacted with the tongue, there is a possibility of the appearance of the bitter taste, unfavorably, which is not preferred.
• the amount of the gelling agent is too large, the requisite amount of water increases and it becomes difficult to take.
• proper weight ratio of the drug-containing substance to the gelling agent is from 1:0.01 to 1:2, preferably from 1:0.025 to 1:1.2, and more preferably from 1:0.025 to 1:0.8, in terms of the amount of sodium alginate contained in the gelling agent.
• the pharmaceutical composition of the present invention is basically composed of two components, i.e. a drug-containing substance wherein the bitter taste of the drug is masked out, and a gelling agent, and these components may be separately packaged and mixed before use. In the manufacturing of the preparation, these components may be mixed after preparing separately. Alternatively, a preparation can be manufactured by mixing the drug-containing substance with the gelling agent component and granulating the mixture, or coating the drug-containing substance (in the granular form) with the gelling agent component.
• the pharmaceutical composition of the present invention includes any of these embodiments.
• the present invention further includes the following embodiments .
• a pharmaceutical composition comprising a drug- containing substance wherein an unpleasant taste of the drug is masked out, and a gelling agent.
• composition according to (3) wherein the drug-containing substance has a form of fine particles obtained by dispersing the drug in a fatty acid ester of glycerol base and said fine particles may be coated with a coating agent of one or more of a water- soluble polymer, a water-insoluble polymer, an acid- soluble polymer and an enteric polymer.
• the pharmaceutical composition according to (3), wherein the drug-containing substance in which the unpleasant taste of the drug is masked out is a substance in the form of fine particles obtained by including the drug in alginate beads.
• a mixing ratio by weight of the drug-containing substance to the gelling agent is from 1:0.01 to 1:2 in terms of a proportion of sodium alginate contained in the gelling agent.
• the drug is an antimicrobial drug or antibiotic having a bitter taste.
• a method of producing a pharmaceutical composition wherein unpleasant taste of the drug is masked out which comprises (1) preparing a drug-containing substance in which the unpleasant taste is masked out, (2) preparing a gelling agent capable of gelling at normal temperature when added to water, and (3) mixing the drug-containing substance and the gelling agent.
• a method of administering a drug having unpleasant taste to humans which comprises mixing a drug-containing substance in which the unpleasant taste is masked out and a gelling agent capable of gelling at normal temperature when added to water, adding the mixture to water under stirring and taking the resulting composition orally.
• Example 1 The following Examples further illustrate the pharmaceutical composition of the present invention in detail, but the present invention is not limited by these Examples .
• Example 1
• (A) Drug-containing substance After 90g of fatty acid ester of glycerol was molten at about 100 °C, 10 g of grepafloxacin hydrochloride was added and dispersed therein by using a homogenizer after sufficiently compatibilizing. The resultant was granulated with cooling on a rotary table under the conditions of a revolving speed of 2000 rpm to obtain 100 g of homogeneous microspherical particles (average particle diameter: about 150 ⁇ m) .
• Example 2 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml of water with a few minutes of stirring to obtain a jellylike composition wherein the drug-containing particles are dispersed.
• Example 2 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml of water with a few minutes of stirring to obtain a jellylike composition wherein the drug-containing particles are dispersed.
• Example 2 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml of water with a few minutes of stirring to obtain a jellylike composition wherein the drug-containing particles are disper
• Example 3 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml Of water with a few minutes of stirring to obtain a jelly- like composition wherein the drug-containing particles are dispersed.
• Example 3 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml Of water with a few minutes of stirring to obtain a jelly- like composition wherein the drug-containing particles are dispersed.
• Example 3 100 g of the drug-containing particles and 202 g of the powder of the gelling agent, thus obtained, were mixed to obtain a powdered composition of the present invention. To 1.5 g of the composition was added 5 ml Of water with a few minutes of stirring to obtain a jelly- like composition wherein the drug-containing particles
• Gelling agent 800 g of sodium alginate, 80 g of calcium gluconate, 80 g of citric acid and 18.3 kg of powdered sucrose were mixed and then granulated by rotary fluidized bed granulator (New Marumerizer, manufactured by Fuji Paudal Co.,Ltd.) to obtain 19.26 kg of a granulated powder (average particle diameter: about 20 ⁇ m) of a gelling agent.
• Example 3 After 500 g of the microspherical particles obtained in Example 3 were charged in a rotary fluidized bed granulation coating equipment (NQ-125, manufactured by Fuji Paudal Co., Ltd.) and the inlet-air temperature and product temperature were controlled to 60 °C and 30- 40 °C, respectively, 1500 g of 25 % Methacrylic acid Copolymer LD suspension [containing 1000 g of Eudragit L30D55, (manufactured by Rohm Pharma Co., Ltd.), 30 g of triehyl citrate and 290 g of purified water] was sprayed on the microspherical particles, and then dried to obtain a coated powder (average particle diameter: about 200 to 250 ⁇ m) .
• NQ-125 manufactured by Fuji Paudal Co., Ltd.
• Example 3 After 500 g of the microspherical particles obtained in Example 3 were charged in a rotary fluidized bed granulation coating equipment (NQ-125, manufactured by Fuji Paudal Co., Ltd.) and the inlet-air temperature and product temperature were controlled to 60 °C and 35- 40 °C, respectively, ethylcellulose (Aquacoat made of FMC: manufactured by Asahi Chemical Industry Co., Ltd.) was sprayed on the microspherical particles in the proportion of 25 to 100% to obtain a coated powder (average particle diameter: about 200 to 250 ⁇ m) .
• ethylcellulose Aquacoat made of FMC: manufactured by Asahi Chemical Industry Co., Ltd.
• Gelling agent 400 g of sodium alginate, 20 g of calcium carbonate, 200 g of adipic acid, 20 g of a flavor, 2 g of a colorant Food Red No. 2 and 11650 g of purified sucrose were mixed to obtain a gelling agent powder.
• Example 3 After 500 g of the microspherical particles obtained in Example 3 were charged in a rotary fluidized bed granulation coating equipment (NQ-125, manufactured by Fuji Paudal Co., Ltd.) and the inlet-air temperature and product temperature were controlled to 60 °C and 35- 40 °C, respectively, a mixed film of ethylcellulose (Aquacoat made of FMC: manufactured by Asahi Chemical Industry Co., Ltd.) and hydroxypropylmethylcellulose (TC- 5E, manufactured by Shin-Etsu Chemical Co., Ltd.) was sprayed on the microspherical particles in the proportion of 25 to 100% to obtain a coated powder (average particle diameter: about 200 to 250 ⁇ m) .
• B Gelling agent
• Example 7 400 g of sodium alginate, 40 g of calcium monohydrogenphosphate, 200 g of adipic acid, 20 g of a flavor, 2 g of a colorant Food Red No. 2 and 11650 g of purified sucrose were mixed to obtain a gelling agent powder. 500 g of the drug-containing particles and 10000 g of the gelling agent powder, thus obtained, were mixed to obtain a powdered composition for jelly preparation of the present invention. To 5 g of the powdered composition was added 10 ml of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• Example 7 400 g of sodium alginate, 40 g of calcium monohydrogenphosphate, 200 g of adipic acid, 20 g of a flavor, 2 g of a colorant Food Red No. 2 and 11650 g of purified sucrose were mixed to obtain a gelling agent powder. 500 g of the drug-containing particles and 10000 g of the gel
• (A) Drug-containing substance After 500 g of the microspherical particles obtained in Example 3 were charged in a rotary fluidized bed granulation coating equipment (NQ-125, manufactured by Fuji Paudal Co., Ltd.) and the inlet-air temperature and product temperature were controlled to 60 °C and 35-40 °C, respectively, a mixed film of Aquacoat made of FMC (manufactured by Asahi Chemical Industry Co., Ltd.) and mannitol (manufactured by Kyowa Hakko Kogyo Co., Ltd.) was sprayed on the microspherical particles in the proportion of 25 to 100% to obtain a coated powder (average particle diameter: about 200 to 250 ⁇ m) .
• a mixed film of Aquacoat made of FMC manufactured by Asahi Chemical Industry Co., Ltd.
• mannitol manufactured by Kyowa Hakko Kogyo Co., Ltd.
• Example 8 In addition to 100 g of the microspherical particles (drug-containing substance) obtained in Example 3, 8 g of sodium alginate, 0.8 g of calcium sulfate, 8 g of citric acid, 0.2 g of a strawberry flavor, 0.02 g of a colorant Food Red No.
• Example 10 In addition to 100 g of the microspherical particles (drug-containing substance) obtained in Example 3, 8 g of sodium alginate, 0.8 g of calcium citrate, 8 g of citric acid, 0.2 g of a strawberry flavor, 0.02 g of a colorant Food Red No. 2 and 183 g of powdered sucrose were charged in a flow granulating equipment (MP-01) and the inlet-air temperature and product temperature were controlled to 60 °C and 35-40 °C, respectively, the mixture was granulated and dried using a 5% solution of hydroxypropylmethylcellulose (HPMC) as a binder to obtain a powdered composition for preparation of jelly (average particle diameter: about 250 ⁇ m) according to the present invention. To 1 g of the powdered composition was added 2 ml of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• HPMC hydroxypropylmethylcellulose
• Example 11 After 500 g of the microspherical particles (drug- containing substance) obtained in Example 3 were charged in a centrifugal coating granulator (CF-360, manufactured by Freund Industry Co.,Ltd.), the particles were granulated with scattering a mixed powder containing 40 g of sodium alginate, 4 g of calcium citrate, 40 g of citric acid, 1 g of a strawberry flavor, 0.1 g of a colorant Food Red No. 2 and 915 g of powdered sucrose using 150 g of purified water, and then dried to obtain a granulated composition for preparation of jelly according to the present invention. To 2 g of the granulated composition was added 4 ml of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• CF-360 centrifugal coating granulator
• Example 13 After 395 g of the drug-containing particle obtained by a similar method to Example 12 were charged in a centrifugal coating granulator (CF-360, manufactured by Freund Industry Co., Ltd.), 1690 g of an aminoalkyl Methacrylate Copolymer E solution (7%) containing 140 g of aminoalkyl Methacrylate Copolymer E (Eudragit ElOO) and 60 g of talc in a mixture solution of ethanol (1400g) and purified water (400g) was sprayed on the above particles to obtain a coated particle (drug-containing substance) .
• CF-360 centrifugal coating granulator
• the particles were granulated with scattering a gelling agent component containing 80 g of sodium alginate, 8 g of calcium monohydrogen phosphate, 16 g of citric acid, 50 g of adipic acid, 4 g of strawberry flavor, 0.4 g of a colorant Food Red No. 2 and 1840 g of powdered sucrose to obtain a gelling agent composition (granule diameter; 1000 to 2500 ⁇ m) of the present invention.
• CF-360 centrifugal coating granulator
• Example 14 After 400 g of the drug-containing particles obtained by a similar method to Example 12 were charged in a flow granulating equipment (NQ-125, manufactured by Fuji Paudal Co., Ltd.), and the inlet-air temperature and product temperature were controlled to 60 °C and 30 to 40 °C, respectively, 80 g of a methacrylic acid copolymer LD solution (25 %) [a mixed suspension containing 1000 g of Eudragit L30D55 (manufactured by Rohm Pharma Co., Ltd.), 30 g of triethyl citrate and 290 g of purified water] was sprayed on the particles to obtain a coated particle (drug-containing substance).
• a methacrylic acid copolymer LD solution 25 %
• the particules were granulated with scattering a gelling component containing 80 g of sodium alginate, 8 g of calcium monohydrogen phosphate, 16 g of sodium citrate, 50 g of adipic acid, 4 g of a strawberry flavor, 0.4 g of a colorant Food Red No. 2 and 1840 g of powdered sucrose to obtain a gelling agent composition (granule diameter; 850 to 2000 ⁇ m) of the present invention.
• CF-360 centrifugal coating granulator
• Example 15 To 1 g of the composition was added 3 mL of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• Example 15 To 1 g of the composition was added 3 mL of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• a granulate was obtained by using 130 g of purified water with scattering a mixture of 120 g of grepafloxacin hydrochloride, 200 g of purified sucrose and 280 g of corn starch.
• Example 16 Drug-containing substance After 1080 g of purified sucrose was charged in a centrifugal coating granulator (CF-360, manufactured by Freund Industry Co., Ltd.), a granulate was obtained by using 250 g of purified water with scattering a mixture of 1350 g of grepafloxacin hydrochloride and 400 g of lactose.
• CF-360 centrifugal coating granulator
• the resulting granule was dried at 50 °C and sieved to obtain spherical particles having a particle diameter of 0.25 to 2 mm. Subsequently, 2800 g of the resulting particles were coated with hydroxypropylmethylcellulose and an ethylcellulose solution (containing 52 g of hydroxypropylmethylcellulose (HPMC TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.), 139 g of ethylcellulose "ETHOCEL STD 10CPS” (manufactured by Dow Chemical Co.), 19 g of fatty acid ester of glycerol ("Myvacet 9-40T", manufactured by Koyo Shokai Co.
• a granulate was obtained by using 110 g of hydroxypropylcellulose (3 %) with scattering 500 g of powdered sucrose and dried at 50 °C for 12 hours to obtain a granular particle having diameter of 500 to 1000 ⁇ m.
• 900 g of the resulting granular particles were charged in a centrifugal flow type coating granular, and a hydroxypropylmethylcellulose solution (5%) containing 50 g of hydroxypropylmethylcellulose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd. ) in 475 g of ethanol and 475 g of purified water was sprayed on the particles, and dried at 60 °C and sieved to obtain a spherical particle having a particle diameter of 500 to 1000 ⁇ m.
• a hydroxypropylmethylcellulose solution 5%) containing 50 g of hydroxypropylmethylcellulose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd. ) in 475 g of ethanol and 475 g of purified water was sprayed on the particles, and dried at 60 °C and sieved to obtain a spherical particle having a particle diameter of 500 to 1000 ⁇ m.
• Methacrylate Copolymer E (Eudragit E 100, manufactured by Rhom Pharma Co., Ltd.) in 810 g of ethanol and 90 g of purified water was coated on the resulted particles in the proportion of 5 to 50 % to obtain a double coated particle. The resulted particles were dried at 40 °C and sieved to obtain drug-containing particles having a particle diameter of 500 to 2000 ⁇ m.
• B Gelling agent
• Example 18 To 1.5 g of the resulted composition were added 3 ml of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• Example 18 To 1.5 g of the resulted composition were added 3 ml of water with a few minutes of stirring to obtain a jelly-like composition wherein the drug-containing particles are dispersed.
• a centrifugal coating granular CF-360, manufactured by Freund Industry Co., Ltd.
• a gelling agent component containing 80 g of sodium alginate, 8 g of calcium monohydrogenphosphate, 16 g of sodium citrate, 50 g of citric acid, 4 g of a strawberry flavor, 0.4 g of a colorant Food Red No.3 and 1840 g of powdered sucrose by using purified water as a binder to obtain a gelling agent composition having a particle diameter 1000 to 2500 ⁇ m according to the present invention.
• the pharmaceutical compositions of the present invention can be prepared.
• a jelly-like sample was prepared by mixing 5 g of the powdered composition with 10 ml of water (at normal temperature of 15 to 25
• Jelly compositions prepared in Example 11 and Example 14 were subjected to a dissolution out test according to a dissolution test method, the second method (paddle method) of the Japanese Pharmacopoeia.
• control samples which contain the drug-containing substance only (50 mg as the drug) without containing the gelling agent in the respective compositions of Example 11 and 14, were subjected to the same dissolution test.
• the control sample for the composition of Example 11 corresponds to the drug- containing substance obtained in Example 4
• the control sample for the composition of Example 14 corresponds to the coated product obtained by coating methacrylic acid copolymer LD on the drug-containing substance prepared in Example 12.
• the results are shown in Figs. 1 and 2. From the results, it was proved that the solution rate of the drug-containing substance only is not almost affected by the jelly composition. The results show that the pharmaceutical composition of the present invention is useful for masking the drug flavor under the condition that the absorption of the drug is not almost affected.
• Industrial Applicability The present invention makes it possible to conduct masking of a drug having unpleasant taste by taking, as a form on taking, the form of jelly wherein the drug whose unpleasant taste is masked out are dispersed and included.
• composition of the present invention is used in combination with water in a proper amount when administered, unlike a coated drug such as conventional sugar-coated tablet, film-coated tablet, etc., it is possible to control the dose and is optimum for application to a child drug. Furthermore, the form of a jelly is easily taken and is also useful as an oral dosage form to infants, patients suffering from dysphagia, and aged persons.

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• 1999
  • 1999-07-26 BR BR9912533-1A patent/BR9912533A/pt not_active IP Right Cessation
  • 1999-07-26 WO PCT/JP1999/004046 patent/WO2000006122A1/en not_active Application Discontinuation
  • 1999-07-26 EP EP99931573A patent/EP1100466A1/en not_active Withdrawn
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• 2002
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