WO2013058496A1 - Taste-masked pharmaceutical composition for oral administration and a process for the preparation thereof - Google Patents

Taste-masked pharmaceutical composition for oral administration and a process for the preparation thereof Download PDF

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Publication number
WO2013058496A1
WO2013058496A1 PCT/KR2012/008230 KR2012008230W WO2013058496A1 WO 2013058496 A1 WO2013058496 A1 WO 2013058496A1 KR 2012008230 W KR2012008230 W KR 2012008230W WO 2013058496 A1 WO2013058496 A1 WO 2013058496A1
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Prior art keywords
pharmaceutical composition
active ingredient
tablet
oral
pharmaceutically active
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PCT/KR2012/008230
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English (en)
French (fr)
Inventor
Hee Chul Chang
Sang Han Park
Bok Ki Kang
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Daewoong Pharmaceutical Co., Ltd.
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Application filed by Daewoong Pharmaceutical Co., Ltd. filed Critical Daewoong Pharmaceutical Co., Ltd.
Priority to MX2014004811A priority Critical patent/MX347135B/es
Priority to JP2014536976A priority patent/JP5859664B2/ja
Priority to BR112014009438A priority patent/BR112014009438A2/pt
Priority to RU2014115287/15A priority patent/RU2583935C2/ru
Publication of WO2013058496A1 publication Critical patent/WO2013058496A1/en

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present disclosure relates to an off-taste-masked oral pharmaceutical composition including a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, and a method of preparing the oral pharmaceutical composition.
  • Two commercially available orally dosage forms of medicines are swallowable ones such as tablets or capsules, and ones that are solublized in the mouth such as chewable tablets or sublingual tablets.
  • the former may remove or significantly reduce off-taste of an active ingredient.
  • the latter may be more reluctant and less adaptable to take if the active ingredient tastes out. This may be more serious to children who are relatively less adaptable to drugs, because dosage forms for children are mostly prepared in oral liquid formulations that is unlikely to mask the off-taste, or oral tablets that are often crushed and mixed with water or syrup before being taken. Therefore, a variety of methods for blocking off off-tastes such as bitterness or sharpness of oral medicines have been suggested.
  • Reference 1 discloses a cyclic guanosine-3',5'-monophosphate phosphodiesterase (cGMP PDE) inhibitor-containing composition, the administration form of which is unacceptable by patients. Thus, the composition has a disadvantage of low compliance by patients.
  • References 2 and 3 disclose bitterness masking methods for drugs by addition of cyclodextrine. However, these methods have to use a large amount of excipient to at least partially reduce the bitterness of a drug, and thus, are not substantially be applicable in developing orally fast disintegrating tablet or chewable tablet which taken without water.
  • References 4 to 6 disclose off-taste masking methods involving coating bitter drug particles with celluloses, lipids, polymers, or the like.
  • Reference 7 discloses a method of preparing a bitter taste-masked orally disintegrating tablet containing sildenafile citrate, in which the bitterness is masked with a solubilization inhibitor and a sweetener such as aspartame.
  • a solubilization inhibitor such as aspartame.
  • release and absorption rates of the drug in the body may be limited by the solubilization inhibitor.
  • Reference 8 discloses a solid formulation of a bitterness-masked drug obtained by mixing a bitter-tasting drug with calcium silicate, and a method of preparing the same.
  • the bitterness-masked solid formulation is prepared by mixing a solution of a bitter drug in a solvent with calcium silicate, drying and powdering the solution mixture, and thus capturing the bitter drug into a porous network of the calcium silicate.
  • incomplete dissolution of the drug may cause that the undissolved drug cannot be captured within the porous network of calcium silicate, thus causing bitter taste in the mouth.
  • this method is not compatible with a poorly water-soluble drug and may need a huge amount of water if used along with a poorly water-soluble drug, which may take a long time and large energy during a subsequent drying process.
  • the method involves complicated processes including dissolving a bitter drug, mixing it with calcium silicate, and a powdering process.
  • the method is unsuitable for mass production and is not industrially applicable due to low productivity and low economical efficiency.
  • due to a very low drug capture efficiency of calcium silicate into a porous network the method needs a large amount of calcium silicate.
  • the use of a large amount of calcium silicate may result in low-density powder like candy fluffy, and thus, poor tabletability.
  • due to the inability to use a sufficient amount of essential excipients it is difficult to formulate tablets with high pharmaceutical characteristics.
  • Reference 9 discloses a bitterness-masked oral drug composition in which a bitter drug, an acidic material such as tannic acid, citric acid or acetic acid, and an alkali earth metal salt and/or earth metal salt are dissolved in purified water.
  • This method involves masking bitterness of a drug that is as any of a variety of salts by inducing a kind of ionic bonding reaction in an aqueous solution with the addition of an acid material and an alkali earth metal salt or the like.
  • the bitterness masking effect by ionic bonding is lost if the dissolved drug solution is dried, and thus, this method is unsuitable to prepare a solid formulation with a sustained bitterness blocking effect.
  • the present invention provides an oral pharmaceutical composition with an effective off-taste masking effect that does not affect a behavior and an effect of a pharmaceutically active ingredient in the body, and that can be prepared into a tablet with high productivity and economical efficiency as well as superior pharmaceutical properties.
  • the present invention provides a method of preparing the oral pharmaceutical composition.
  • a pharmaceutical composition for oral administration wherein taste of a pharmaceutically active ingredient is masked, prepared by wet granulation of a mixture comprising the pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier.
  • a method of preparing the pharmaceutical composition for oral administration wherein taste of the pharmaceutically active ingredient is masked, the method including wet-granulating a mixture comprising a pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier.
  • wet granulation of a pharmaceutically active ingredient along with magnesium aluminometasilicate and/or calcium silicate may effectively mask bitter taste even with the use of a small amount of magnesium aluminometasilicate and/or calcium silicate.
  • a pharmaceutical composition for oral administration wherein taste of a pharmaceutically active ingredient is masked, prepared by wet granulation of a mixture comprising the pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier.
  • taste-masking means eliminating or weakening off-taste of a pharmaceutically active ingredient or reducing the perception of the taste.
  • taste means any kind of taste, including bitter taste, a1, sour taste, and the like, that may be any off-flavor disgusting to a patient taking a medicine.
  • the oral pharmaceutical composition includes at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate as an additive for masking taste of the pharmaceutically active ingredient.
  • preparation by wet granulation does not require completely dissolving the active ingredient in a solvent, and thus, the oral pharmaceutical composition is compatible with both a water-soluble active ingredient and a poorly water-soluble active ingredient.
  • the preparation of the oral pharmaceutical composition by wet granulation does not require drying to remove a large amount of water, and does simplify manufacturing processes to have high industrial applicability due to high economical efficiency and productivity.
  • the oral pharmaceutical composition of the present disclosure may have a bitter-tasting compound masked with a high masking efficiency by magnesium aluminometasilicate and/or calcium silicate, which makes it possible to use magnesium aluminometasilicate and/or calcium silicate in a small amount for off-taste masking.
  • the use of magnesium aluminometasilicate and/or calcium silicate in a small amount allows sufficient use of a pharmaceutically acceptable carrier such as a disintegrant, a sweetener, or the like, in a further process for preparing another solid dosage form from the oral pharmaceutical composition, thereby enabling preparing any of a variety of solid dosage forms with improved pharmaceutical characteristics with the oral pharmaceutical composition.
  • bitter-tasting oral drugs i.e., sildenafil citrate (Examples 1-7), tramadol hydrochloride (Example 8), sumatriptan (Example 9), ranitidine (Example 10), ondansetron (Example 11), fexofenadine (Example 12), and a combination of hydrocodone/acetaminophen(Example 13) were mixed with magnesium aluminometasilicate, calcium silicate, or a mixture thereof to prepare a dosage form, and a sensory test was performed on the prepared dosage forms.
  • the drug mixtures were perceived as more sweet, but remarkably less bitter and less sour, than commercially available tablets including the same active ingredients (see Tables 4 and 5).
  • the prepared dosage forms exhibited the same dissolution behaviors as those of the commercially available reference drugs (see FIGS. 1, 3 to 8).
  • the prepared dosage forms exhibited similar pharmacokinetic (PK) profiles as those of the reference drugs (see FIG. 2), indicating that the prepared dosage forms have similar in vivo activities as those of the commercially available reference drugs.
  • Magneium aluminometasilicate is white powder that is also referred to as Silodrate or Simaldrate, represented by the formula of Al 2 O 2 .2Mg.3O 3 Si, which is water-insoluble and is hygroscopic at a relative humidity (RH) of about 70% or greater.
  • Silodrate or Simaldrate represented by the formula of Al 2 O 2 .2Mg.3O 3 Si, which is water-insoluble and is hygroscopic at a relative humidity (RH) of about 70% or greater.
  • RH relative humidity
  • magnesium aluminometasilicate is normally used as a gastroenteric disorder treatment agent such as an anti-ulcer drug, or an excipient of a solid dosage form for improving powder flowability, which is commercially available with the name of Neusilin (available from Fuji Chemical Industry).
  • Calcium silicate which is represented by the formula Ca 2 SiO 4 or 2CaO.SiO 2 , collectively refers to a group of compounds obtained by reacting calcium oxide and silica in various ratios.
  • Calcium silicate may be, in wider sense, any compound represented by one of the formulae 3CaO . SiO 2 , Ca 3 SiO 5 ; 2CaO . SiO 2 , Ca 2 SiO 4 ; 3CaO . 2SiO 2 , Ca 3 Si 2 O 7 ; and CaO . SiO 2 , CaSiO 3 , which is present as white solid power in a normal state with a low bulk density and is stable at normal temperature and normal pressure.
  • Calcium silicate is used pharmaceutically as an anti-caking agent and an antacid agent, but has not been used for taste-making purposes. Calcium silicate may be easily synthesized using known methods, and commercially available products thereof are Mico-cel, Calsil, Florite R, Marimet 45, Microcal ET, Silene EF, Silmos T, Solex, Starlex L, and the like.
  • An amount of magnesium aluminometasilicate and/or calcium silicate in the oral pharmaceutical composition may be appropriately selected depending on the kind of the pharmaceutically active ingredient, the dosage form, or the like. In some embodiments, the amount of magnesium aluminometasilicate and/or calcium silicate may be from about 1 wt% to about 80wt% based on a total weight of the oral pharmaceutical composition, but is not limited thereto.
  • the amount of magnesium aluminometasilicate, calcium silicate, or a mixture thereof may be from about 1 wt% to about 60 wt%, and in some embodiments, may be from about 1 wt% to about 50wt%, and in some other embodiments, may be from about 2wt% to about 30wt%, based on the total weight of the oral pharmaceutical composition. In still some other embodiments, the amount of magnesium aluminometasilicate, calcium silicate, or a mixture thereof may be from about 3 wt% to about 20 wt% based on the total weight of the oral pharmaceutical composition.
  • the terms "pharmaceutically active ingredient” means not only any pharmacological active agent for treatment purpose but also any reagent or any medical agent that may be administered into the human body for diagnostic or preventive purposes.
  • the pharmaceutically active ingredient may be any material, ingredient, or healthy functional food as a processed form thereof that may be intaken for health care purposes with nutrient regulatory functions or physiological functions on the body structure and functions.
  • the pharmaceutically active ingredient may have physical and chemical properties that are suitable for formulation into an oral dosage form.
  • the pharmaceutically active ingredient may not need to be reactive with a water-based or oil-based solvent of a binding solution (solvent or binding agent solution) and not need to lose activity during the wet granulation.
  • the pharmaceutically active ingredient may need to be stable against mechanical pressure such as a compressive force applied from a tabletting machine.
  • the pharmaceutically active ingredient may be at least one orally administrable material selected from the group consisting of peptide, protein, enzyme, DNA, RNA, a nutritional supplement, an anti-inflammatory agent, an antibiotic, an antihistamine, an antibacterial drug, an antifungal drug, a decongestant, an antidepressant, an antipsychotic drug, an antiviral drug, an antineoplastic, vaccine, an antiepileptic drug, an antiasthmatic agent, an antioxidant, and a plant extract.
  • a pharmaceutically active ingredient with an off-flavor disgusting to orally intake is suitable for use herein.
  • Non-limiting examples of the off-tasting pharmaceutically active ingredient are sildenafil citrate, tramadol hydrochloride, sumatriptan, ondansetron, fexofenadine, ranitidine, famotidine, cimetidine, hydrocodone, acetaminophen, aspirin, ibuprofen, dexibuprofen lysinate, naproxen, quinolones, macrolides, loperamide, ibesartan, captopril, lisinopril, nefazodone, buspirone, chlorpheniramine, astemiole, pseudoephedrine, dextromethorphan, cetirizine, nimesulide, ascorbic acid, hydrocortisone, 5-fluorouracil, cisplatin, paclitaxel, ampicilin, cefadroxil, clindamycin, neomycin, ny
  • the pharmaceutically active ingredient of the oral pharmaceutical composition may be one selected from the group consisting of sildenafil citrate, tramadol hydrochloride, sumatriptan, ondansetron, fexofenadine, ranitidine, hydrocodone, and acetaminophen.
  • the oral pharmaceutical composition may be formulated as an oral administrable form via masking of an off-taste of these pharmaceutically active ingredients.
  • the oral pharmaceutical compositioin is advantageous in that the pharmaceutically active ingredient may be either water-soluble or poorly water-soluble.
  • the terms “poorly water-soluble” refers to a degree of solubility from “sparingly soluble” to "very slightly soluble”.
  • the degree of solubility termed as “sparingly soluble” means that about 30 ml to about 100 ml of water is required to dissolve 1 g of the drug, and very slightly soluble” means that about 1000 ml to about 10,000 ml of water is required to dissolve 1 g of the drug.
  • Recently developed or purchasable drugs mostly have low solubility in water.
  • the oral pharmaceutical composition according to the present disclosure may be widely applied to off-taste masking.
  • the poorly water-soluble active ingredient are sildenafil citrate, sumatriptan, fexofenadine, and a combination of hydrocodone/acetaminophen.
  • the terms “pharmaceutically acceptable carrier” refer to any additive ingredients excluding the pharmaceutically active ingredient, and magnesium aluminometasilicate and calcium silicate added for off-taste masking.
  • pharmaceutically acceptable refers to the properties not to cause any pharmaceutically undesirable change via interaction between ingredients of the oral pharmaceutical compositions (for example, via interaction between carriers or via interaction between the pharmaceutically active ingredient and a carrier). Selection of the pharmaceutically acceptable carrier may be dependent on the properties and the administration method of a particular dosage form, the effects of the carrier on solubility and stability, and the like.
  • the pharmaceutically acceptable carrier contained in the oral pharmaceutical composition may be at least one selected from the group consisting of a diluent, a binder, a glidant (or a lubricant), a disintegrant, a stabilizer, a solubilizing agent, a sweetening agent, a coloring agent, and a flavoring agent.
  • the diluent refers to any excipient added to increase the volume of the oral pharmaceutical composition to formulate it into a target dosage form with an appropriate size.
  • Non-limiting examples of the diluent may be starch (for example, potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (for example, low-hydration microcrystalline cellulose), lactose (for example, lactose monohydrate, anhydrous lactose, spray lactose), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, anhydrous calcium hydrogenphosphate, or silicon dioxide, which may be used alone or as a mixture thereof.
  • starch for example, potato starch, corn starch, wheat starch, pregelatinized starch
  • microcrystalline cellulose for example, low-hydration microcrystalline cellulose
  • lactose for example, lactose monohydrate, anhydrous lactos
  • the excipient may be used from about 5 wt% to about 50 wt% based on a total weight of the oral pharmaceutical composition. In some other embodiments, the excipient may be used from about 10wt% to about 35wt% based on the total weight of the oral pharmaceutical composition for appropriate tabletting and quality maintenance.
  • the binder refers to a material that offers materials in powder form adhesiveness and facilitates compression of the materials.
  • the binder may be at least one selected from among starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, cellulose derivatives (for example, hydroxypropylmethylcellulose, hydroxypropyl cellulose, or low-substituted hydroxypropyl cellulose), natural gum, synthetic gum, povidone, co-povidone, and gelatin, but are not limited thereto.
  • the binder may be used from about 2 wt% to about 15 wt% based on a total weight of the oral pharmaceutical composition. In some other embodiments, the binder may be used from about 1 wt% to about 3 wt% based on the total weight of the oral pharmaceutical composition for appropriate tabletting and quality maintenance.
  • the disintegrant refers to a material added to facilitate disintegration of a solid dosage form when administrated into the body.
  • the disintegrant may be starch, such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch, or modified starch; clay, such as bentonite, montmorillonite, or veegum; cellulose, such as microcrystalline cellulose, hydroxypropyl cellulose, or carboxymethyl cellulose; an algin, such as sodium alginate or alginic acid; a cross-linked cellulose, such as croscarmellose sodium; gum such as guar gum or xanthan gum; a cross-linked polymer such as cross-linked polyvinylpyrrolidone (crospovidone); or an effervescent ingredient such as sodium bicarbonate or citric acid, which may be used alone or as a mixture thereof, but is not limited thereto.
  • starch such as sodium starch glycolate, corn starch, potato starch, or pre
  • the disintegrant may be used from about 2 wt% to about 15 wt% based on a total weight of the oral pharmaceutical composition. In some other embodiments, the disintegrant may be used from about 4wt% to about 10wt% based on the total weight of the oral pharmaceutical composition for appropriate drug formulation and quality maintenance.
  • the glidant or lubricant refers to a material that prevents cohesion of powders to a compressing system and improves flowability of granules.
  • the glidant may be hard anhydrous silicic acid, talc, stearic acid, a metal salt (magnesium salt, calcium salt, or the like) of stearic acid, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glycerylbehenate, glycerylmonostearate, or polyethylene glycol, which may be used alone or as a mixture thereof, but is not limited thereto.
  • the glidant may be used from about 0.1 wt% to about 5 wt% based on a total weight of the oral pharmaceutical composition. In some other embodiments, the glidant may be used from about 1 wt% to about 3 wt% based on the total weight of the oral pharmaceutical composition for appropriate tabletting and quality maintenance.
  • the adsorbent may be hydrated silicon dioxide, hard anhydrous silicic acid, colloidal silicon dioxide (Aerosil, available from Degussa), magnesium aluminometasilicate, microcrystalline cellulose, lactose, or a cross-linked polyvinylpyrrolidone, which may be used alone or as a mixture thereof, but is not limited thereto.
  • the stabilizer may be at least one selected from the group consisting of antioxidants, such as butylhydroxyanisol, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherolpolyethylene glycol succinic acid, or propyl gallate; cyclic sugar compounds such as cyclodextrin, carboxyethyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutylether, or cyclodextrin; and organic acids such as phosphoric acid, lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid, or glucuronic acid, but is not limited thereto.
  • antioxidants such as butylhydroxyanisol, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol
  • an additive known to improve the taste as well as mask the off-taste of the active ingredient may be included.
  • a sweetener such as sucralose, sucrose, fructose, erythritol, acesulfame potassium, sugar alcohol, honey, sorbitol, or aspartame may be added to more effectively mask bitterness and maintina the stability and quality of the formulation.
  • an acidifier such as citric acid or sodium citrate; a natural flavoring such as Japanese apricot flavor, lemon flavor, pineapple flavor, or herbal flavor; or a natural pigment such as natural fruit juice, chlorophyllin, or flavonoid may be used.
  • the oral pharmaceutical composition may be prepared by wet granulation of a mixture of the pharmaceutically active ingredient, a pharmaceutically acceptable carrier, and at least one compound of magnesium aluminometasilicate and calcium silicate.
  • the term “granulation” refers to a process of permanently agglutinating small particles to increase a total particle size of the resulting drug formulation.
  • wet granulation or “wet granulation method” refers to a granulation process of wetting small particles in a solvent or a binder solution to cohere together. As compared with dry granulation, wet granulation may improve cohesion and compression characteristics of powder, and the distribution uniformity of finely divided low amount of drugs,, and may retain shapes of granules whole even after drying without segregation of the ingredients.
  • the pharmaceutically active ingredient's off-taste masking in the oral pharmaceutical composition of the present disclosure is attributed to an interaction of magnesium aluminometasilicate or calcium silicate with the pharmaceutically active ingredient during the wet granulation.
  • Wet granulation on a small scale may be performed via mixing ingredients in a mortar or stainless vessel and wetting them with an appropriate solvent.
  • Wet granulation on a larger scale may be performed using a double shell mixer, a double-cone mixer, a differential mixer, a rotary granulator, a high-shear mixer, a spray dryer, or a fluid bed granulator.
  • a common wet granulation method is described in Pharmaceutical Dosage Forms (Volume 2) Ed., H.A.Lieberman, L.Lachman, J.B.Schwartz (1990), Marcel Dekker Inc., New York and Basel, pp.1 ⁇ 71.
  • the oral pharmaceutical composition since prepared using wet granulation, which involves wetting the pharmaceutically active ingredient in an appropriate solvent, the oral pharmaceutical composition may be compatible with a water-soluble drug or a poorly water-soluble drug. In the wet granulation, neither using an excess amount of solvent nor drying an excess amount of solvent is necessary, so that the wet granulation is highly productive and economical, and has industrial applicability.
  • the oral pharmaceutical composition may be in granules prepared by wet granulation, or may be in any of a variety of oral dosage forms prepared by further adding a pharmaceutically acceptable carrier, and/or an additional drug formulation process.
  • the oral dosage form may be a solid, semi-solid, or liquid form acceptable for oral administration.
  • Non-limiting examples of the oral solid form are tablets, pills, hard or soft capsules, powders, fine granules, granules, powders for reconstitution of solution or suspension, lozenges, wafers, oral strips, dragees, or chewable gum, but are not limited thereto.
  • Non-limiting examples of the oral liquid formulation are solution), suspension, emulsion, syrup, elixir, spirit, aromatic waters, lemonade, extract, and tincture.
  • Non-limiting examples of the semi-solid form are aerosol, cream, and gel.
  • the oral pharmaceutical composition may be formulated as an oral solid formulation, for example, as a tablet.
  • the tablet is selected from the group consisting of a compressed tablet, a multiple-compressed tablet, a chewable tablet, a troche, a sublingual tablet, a buccal tablet, an effervescent tablet, a fast-disintegrating tablet, a dispersible tablet, and an oral disintegrating tablet.
  • the off-taste masking effect of the oral pharmaceutical composition may be useful in a chewable tablet, a troche, a sublingual tablet, a buccal tablet, an effervescent tablet, a fast-disintegrating tablet, a dispersible tablet, or an oral disintegrating tablet that is rapidly dissolved and absorbed in the mouth, and thus, needs off-taste masking.
  • the oral pharmaceutical composition according to the present disclosure may be highly effective to mask drug-bitterness from magnesium aluminometasilicate and/or calcium silicate, which makes it possible to use a relatively small amount of agnesium aluminometasilicate and/or calcium silicate for off-taste masking. Then, the use of magnesium aluminometasilicate and/or calcium silicate in a small amount allows sufficient use of a pharmaceutically acceptable that is required in preparing some solid dosage forms, and in particular, tablets, via additional formulation.
  • a method of preparing the pharmaceutical composition for oral administration wherein taste of the pharmaceutically active ingredient is masked, the method comprising wet-granulating a mixture comprising a pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier
  • the method may include: i) mixing the pharmaceutically active ingredient, the at least one compound of magnesium aluminometasilicate and calcium silicate, and the pharmacologically acceptable carrier; and ii) kneading the mixture with a solvent or a binding agent solution and drying and granulating the mixture, thereby preparing granules.
  • step i) which is for preparing the mixture in powder
  • the amounts and ratio of the pharmaceutically active ingredient, and magnesium aluminometasilicate and/or calcium silicate are as those described above.
  • Types and an amount of the pharmaceutically acceptable carrier that may be used in preparing drugs in granule form are widely known in the art, and may be appropriately selected and adjusted as needed by one of ordinary skill in the art.
  • Step ii) which is for preparing granules from the mixture powder, may be performed using a granulator widely known in the art.
  • the granulation may be performed using a high-shear mixer granulator, a spray dryer, or a fluid bed granulator.
  • a solvent may be used alone, or a binder solution as a mixture of a binder and an additive in a solvent may be used.
  • the granulation may be performed using an aqueous wet granulation method, and the solvent may be water.
  • a stabilizer or a binder may be added to the solvent if required.
  • the resulting kneaded mixture may be dried using, for example, a hot-water circulation dryer or a fluid bed drier, and then be sieved to obtain granules with a uniform size distribution. If the drying is insufficient, a problem may occur during tabletting. If the drying is performed to excess, moisture re-absorption may likely occur, thus causing a problem during distribution and storage periods.
  • a moisture content of the kneaded mixture after drying may be, for example, from about 0.5 wt% to about 3.0 wt%.
  • the resulting granules obtained as described above may be directly available as oral dosage form, or may be further formulated via an additional process into another oral dosage form.
  • the method may further include, after step ii), adding a pharmaceutically acceptable additive and additional magnesium aluminometasilicate and/or calcium silicate to the granules resulting from operation ii) to obtain a final mixture for formulating a target dosage form.
  • the final mixture may be filled into capsules or may be compressed into tablets to prepare an oral solid dosage form, or may be prepared in an oral strip form via dissolution or dispersion in an appropriate solvent.
  • a method of preparing the pharmaceutical composition for oral administration may include: mixing a pharmaceutically active ingredient, a pharmacologically acceptable carrier, and at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate to obtain a mixture; kneading the mixture with a solvent or a binding agent solution, and drying and granulating the mixture, thereby preparing granules; mixing the granules with a pharmacologically acceptable additive, for example, a disintegrant, a stabilizer, or a glidant, and at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate to obtain a final mixture; and obtaining an oral dosage form made of the final mixture.
  • a pharmacologically acceptable additive for example, a disintegrant, a stabilizer, or a glidant
  • the oral dosage form obtained from the final mixture may be tablets.
  • the final step of the above-described method may be tableting the final mixture to obtain tablets.
  • the tablets may be, for example, compressed tablets, multiple-compressed tablets, dragees, chewable tablet, troches, sublingual tablets, buccal tablets, effervescent tablets, fast-disintegrating tablets, dispersible tablets, or oral disintegrating tablets. Methods of preparing these tablets are widely known in the art. Therefore, it is obvious to one of ordinary skill in the art that an additional or specific process may be further applicable with variations, if required, depending on a target dosage form.
  • the oral pharmaceutical composition according to the one or more embodiments of the present disclosure may be prepared without using a costly special manufacturing system or additive, have an off-taste masking effect on active ingredients, and exhibit an appropriate drug dissolution behavior in the body for manifestation of pharmaceutical effect.
  • the oral pharmaceutical composition is compatible with both a water-soluble active ingredient and a poorly water-soluble active ingredient, with high industrial applicability due to simple manufacturing processes and high economical efficiency and productivity.
  • the oral pharmaceutical composition may be formulated in any of a variety of solid dosage forms with improved pharmaceutical characteristics.
  • FIG. 1 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Viagra tablet 100 mg, Pfizer Korea Ltd.) containing sildenafil citrate, and oral dosage forms of sildenafil citrate prepared according to Examples 1 to 7;
  • FIG. 2 is a graph comparatively illustrating the change of the blood level after oral administration of the commercially available tablet (Viagra tablet 100 mg, Pizer Korea Ltd.) containing sildenafil citrate and the oral sildenafil citrate dosage form prepared according to Example 2;
  • FIG. 3 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Tridol soluble tablet, YUHAN Corporation) containing tramadol hydrochloride, and a tablet prepared according to Example 8;
  • FIG. 4 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Imigran tablet 50 mg, MYUNG IN PHARM. CO., LTD) containing sumatriptan, and a tablet prepared according to Example 9;
  • FIG. 5 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Zantac tablet 150 mg, GlaxoSmithKline (GSK) Korea) containing ranitidine, and a tablet prepared according to Example 10;
  • FIG. 6 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Zofran tablet 8 mg, GSK Korea) containing ondansetron, and a tablet prepared according to Example 11;
  • FIG. 7 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Allegra tablet 180 mg, HANDOK PHARMACEUTICALS CO., LTD) containing fexofenadine, and a tablet prepared according to Example 12; and
  • FIG. 8 is a graph comparatively illustrating results of a dissolution test on a commercially available tablet (Norco Tablet 5/325 mg) containing hydrocodone/acetaminophen, and a tablet prepared according to Example 13.
  • Examples 1-7 Preparation of sildenafil citrate tablets including magnesium aluminometasilicate and calcium silicate
  • sildenafil citrate magnesium aluminometasilicate, anhydrous dibasic calcium phosphate, a mixture of sprayed D-mannitol and croscarmellose sodium, crospovidone, acesulfame potassium, and aspartame
  • the mixture was uniformly grinded and sieved using a 25 ⁇ 35 mesh sieve.
  • the ground, sieved mixture was mixed with hydroxypropyl cellulose and purified water until granules were obtained. After dried, the granules were uniformly grinded and sieved using a 25 ⁇ 35 mesh sieve.
  • the granules were mixed with menthol flavor, magnesium aluminometasilicate or calcium silicate, crospovidone, a mixture of sprayed D-mannitol and croscarmellose sodium, enzyme-treated stevia, talc, and magnesium stearate.
  • the resulting mixture was pressed to obtain tablets having an appropriate hardness (kp) for an oral solid dosage form.
  • Examples 8-13 Preparation of sildenafil citrate tablets a variety of drug tablets including magnesium aluminometasilicate and calcium silicate
  • Tablets including tramadol hydrochloride, sumatriptan, ranitidine, ondansetron, fexofenadine, or a combination of hydrocodone/acetaminophen as an active ingredient were prepared in Examples 8-13, respectively. These effective ingredients are considered to be required to develop oral disintegrating tablets or chewable tablets in the art.
  • the tables were prepared with an optimal dosage form (Example 2 or 5) identified from among those of Examples 1 to 7, except that the active ingredients were used instead of sildenafil.
  • the tablets were prepared using magnesium aluminometasilicate, calcium silicate, a pharmaceutically acceptable excipient, a sweetening agent, and a disintegrant in Table 2 below in the same manner as in Examples 1 to 7.
  • Tablets including synthetic aluminum silicate or hard anhydrous silicic acid (Aeropearl 300) as an effective ingredient were prepared in Comparative Examples 1 and 2 in which synthetic aluminum silicate or hard anhydrous silicic acid (Aeropearl 300) was used instead of magnesium aluminometasilicate or calcium silicate.
  • the tablets including sildenafil citrate were prepared in the compositions of Table 3 below in the same manner as in the Examples 1-7, and used in the following experimental examples.
  • a sensory test on the tablets of Examples 1 to 7 was performed on 20 subjects. Each subject scored each sensory item from score 1 to 10, and the scores for each sensory item from the subjects were averaged. The results are shown in Table 4. The larger each sensory item score is, the higher a perception level of each sensor item.
  • the tablets of Examples 1-7 prepared using magnesium aluminometasilicate and/or calcium silicate were perceived to have markedly reduced bitter and acid tastes with an increased perception of sweetness.
  • the tablets of Comparative Examples 1 and 2 prepared using synthetic aluminum silicate or hard anhydrous silicic acid were found to have no bitterness masking effect, indicating that the dosage forms prepared by wet granulation of a mixture of sildenafil citrate as an active ingredient, and magnesium aluminometasilicate and/or calcium silicate have an impossible taste masking effect.
  • a dissolution behavior of each tablet sample was observed using a USP dissolution tester (VK7020, Varian, U.S.A).
  • a dissolution rate of sildenafil citrate from each tablet was measured using water as a dissolution medium, and a paddle type II dissolution apparatus at 50 rpm/900 mL.
  • the tablets of Examples 1-7 were found to have similar dissolution rates to that of the commercially available tablet Viagra (see FIG. 1).
  • sildenafil citrate tablet of the present disclosure provides substantially the same pharmaceutical effects in the body as the commercially available sildenafil citrate tablet.
  • a sensory test on the tablets of Examples 8-13 was performed on 20 subjects. Each subject scored each sensory item from score 1 to 10, and the scores for each sensory item from the subjects were averaged. The results are shown in Table 5. The larger each sensory item score is, the higher a perception level of each sensor sensory item score.
  • a comparative dissolution test was performed using the tablets of Examples 8-13 and commercially available drugs for comparison.
  • the commercially available drugs used as reference samples were Tridol soluble tablet (500 mg, YUHAN Corporation), Imigran tablet (50 mg, MYUNG IN PHARM. CO., LTD), Zantac tablet(150 mg, GlaxoSmithKline (GSK) Korea), Zofran tablet (8 mg, GSK Korea), Allegra tablet (180 mg, HANDOK PHARMACEUTICALS CO., LTD), and hydrocodone/acetaminophen (5/325 mg, Norco Tablet).
  • a dissolution behavior of each tablet sample was observed using a USP dissolution tester (VK7020, Varian, U.S.A).
  • a dissolution rate of an active ingredient from each tablet was measured using water as a dissolution medium, and a paddle type II dissolution apparatus at 50 rpm/900 mL.
  • the tablets of Examples 8-13 were found to have similar dissolution rates to those of the commercially available tablets used as reference drugs (see FIGS. 3-8).

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BR112014009438A BR112014009438A2 (pt) 2011-10-21 2012-10-11 composição farmacêutica para administração oral, e, método de preparação da composição farmacêutica para administração oral
RU2014115287/15A RU2583935C2 (ru) 2011-10-21 2012-10-11 Фармацевтическая композиция для перорального введения с маскированным вкусом и способ ее получения

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US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
CN108392639A (zh) * 2018-04-13 2018-08-14 江苏亚邦爱普森药业有限公司 一种含有枸橼酸西地那非的药物组合物及其制备方法
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
WO2019140516A1 (en) * 2018-01-16 2019-07-25 Appili Therapeutics Inc. Oral formulations of metronidazole and methods of treating an infection using same
EP3766483A1 (en) 2019-07-19 2021-01-20 BioPharma Synergies, S. L. Orodispersible powder composition comprising a triptan
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2021207336A1 (en) * 2020-04-08 2021-10-14 Verté Therapeutics, Llc Oral formulations for sustained release and gastrointestinal retention
WO2022106923A1 (en) 2020-11-18 2022-05-27 BioPharma Synergies, S. L. Orodispersible powder composition comprising an antihistamine compound

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Publication number Priority date Publication date Assignee Title
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2019140516A1 (en) * 2018-01-16 2019-07-25 Appili Therapeutics Inc. Oral formulations of metronidazole and methods of treating an infection using same
US11541035B2 (en) 2018-01-16 2023-01-03 Appili Therapeutics Inc. Oral formulations of metronidazole and methods of treating an infection using same
CN108392639A (zh) * 2018-04-13 2018-08-14 江苏亚邦爱普森药业有限公司 一种含有枸橼酸西地那非的药物组合物及其制备方法
EP3766483A1 (en) 2019-07-19 2021-01-20 BioPharma Synergies, S. L. Orodispersible powder composition comprising a triptan
WO2021014275A1 (en) 2019-07-19 2021-01-28 Biopharma Synergies, S.L. Orodispersible powder composition comprising a triptan
WO2021207336A1 (en) * 2020-04-08 2021-10-14 Verté Therapeutics, Llc Oral formulations for sustained release and gastrointestinal retention
WO2022106923A1 (en) 2020-11-18 2022-05-27 BioPharma Synergies, S. L. Orodispersible powder composition comprising an antihistamine compound

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