WO2013058496A1

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

Info

Publication number: WO2013058496A1
Application number: PCT/KR2012/008230
Authority: WO
Inventors: Hee Chul Chang; Sang Han Park; Bok Ki Kang
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 2011-10-21
Filing date: 2012-10-11
Publication date: 2013-04-25
Also published as: JP2014532081A; BR112014009438A2; MX2014004811A; RU2014115287A; JP5859664B2; RU2583935C2; MX347135B

Abstract

A pharmaceutical composition for oral administration, wherein taste of the pharmaceutically active ingredient is masked, prepared by wet granulation of a mixture of a pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmacologically acceptable carrier, and a method of preparing the pharmaceutical composition. The oral pharmaceutical composition 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. Also, 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.

Description

TASTE-MASKED PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION AND A PROCESS FOR THE PREPARATION THEREOF

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 awful. 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. However, partial cracking of a coating during tableting may produce unpleasant tastes. Furthermore, the disclosed methods are complicated and do not ensure controlled drug release and absorption rates. 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. However, 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. According to this technology, 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. However, in this method, 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. Therefore, 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. Furthermore, the method involves complicated processes including dissolving a bitter drug, mixing it with calcium silicate, and a powdering process. Thus, the method is unsuitable for mass production and is not industrially applicable due to low productivity and low economical efficiency. Furthermore, due to a very low drug capture efficiency of calcium silicate into a porous network, the method needs a large amount of calcium silicate. However, the use of a large amount of calcium silicate may result in low-density powder like candy fluffy, and thus, poor tabletability. In addition, 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. However, 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.

Other various preparation methods and dosage forms for masking off-taste of drugs have been suggested. However, these preparation methods are complicated, may cause quality deterioration, or may be applicable to limited drugs, thereby lacking universal and satisfactory effects. Therefore, there is a demand for the development of a bitterness-masked drug composition in which the off-taste of the drug is masked without a substantial reduction or loss of pharmaceutical effects, which may be industrially applicable with highly productivity and may be formulated into tablets, and a method of preparing the same.

[Prior art references]

[Patent-related references]

1. US Patent No. US 6,740,306

2. Korea Publication No. 2001-0014398

3. Korea Publication No. 2004-0012696

4. Korea Publication No. 1991-0004180

5. Korea Publication No.2001-0023384

6. Korea Publication No. 2002-0002321

7. US Publication No. 20060100214

8. Japan Publication No. 1988-243035

9. Korea Publication No. 2009-0113777

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.

According to an aspect of the present invention, there is provided 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.

According to another aspect of the present invention, there is provided 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.

Hereinafter, the present invention will now be described in more detail.

Unless otherwise defined, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Exemplary embodiments of methods or compositions according to the present disclosure are described below. The present disclosure may, however, be embodiments in many different forms, and other similar or equivalent forms should be construed as falling within the scope of the present disclosure. All references cited herein are incorporated herein in their entirety by reference.

As a result of efforts to develop bitterness-masked formulations that are compatible with both soluble and poorly water-soluble drugs and that may be formulated as tablets with high productivity, the inventors of the present disclosure found that 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.

According to as an aspect of the present disclosure, 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.

As used herein, the terms "taste-masking" means eliminating or weakening off-taste of a pharmaceutically active ingredient or reducing the perception of the taste. The term 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.

In the oral pharmaceutical composition according to the present disclosure, 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. Since prepared by wet granulation, 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. Then, 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.

In examples of the present disclosure, which will be described below in greater detail, 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. As a result, 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). As a result of a dissolution test on the dosage forms, the prepared dosage forms exhibited the same dissolution behaviors as those of the commercially available reference drugs (see FIGS. 1, 3 to 8). As a result of a blood active ingredient level measurement after oral administration into the body, 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.

"Magnesium aluminometasilicate" is white powder that is also referred to as Silodrate or Simaldrate, represented by the formula of Al₂O₂.2Mg.3O₃Si, which is water-insoluble and is hygroscopic at a relative humidity (RH) of about 70% or greater. In the pharmaceutical field, 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 Ca₂SiO₄ or 2CaO.SiO₂, 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^.SiO₂, Ca₃SiO₅; 2CaO^.SiO₂, Ca₂SiO₄; 3CaO^.2SiO₂, Ca₃Si₂O₇; and CaO^.SiO₂, CaSiO₃, 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. For example, 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.

As used herein, 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. In broader sense, 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. For example, since the oral pharmaceutical composition is prepared via wet granulation, 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. When the oral pharmaceutical composition is formulated as tablets, the pharmaceutically active ingredient may need to be stable against mechanical pressure such as a compressive force applied from a tabletting machine.

In some embodiments, 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. For example, 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, nystatin, polyphenols, hydroquinone, retinal A, zinc gluconate, copper gluconate, carbinoxamine malate, dextromethorphan hydrobromide, and glyceryl guaiacolate. In some embodiments, 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. As used herein, 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. In this regard, compatible with both water-soluble and poorly water-soluble pharmaceutically active ingredients, the oral pharmaceutical composition according to the present disclosure may be widely applied to off-taste masking. Non-limiting examples of the poorly water-soluble active ingredient are sildenafil citrate, sumatriptan, fexofenadine, and a combination of hydrocodone/acetaminophen.

As used herein, 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. The terms "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.

In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

In some other embodiments, an additive known to improve the taste as well as mask the off-taste of the active ingredient may be included. In some embodiments, 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. In some other embodiments, 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.

According to the present disclosure, 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.

As used herein, the term "granulation" refers to a process of permanently agglutinating small particles to increase a total particle size of the resulting drug formulation. As used herein, the terms "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.

According to the present disclosure, 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.

In some embodiments of the present disclosure, 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. For example, 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.

In some embodiments of the present disclosure, 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.

According to another aspect of the present disclosure, there is provided 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

In an embodiment, 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.

In 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. For example, the granulation may be performed using a high-shear mixer granulator, a spray dryer, or a fluid bed granulator. In step ii), to knead the mixture resulting from operation i), 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. In some embodiments, the granulation may be performed using an aqueous wet granulation method, and the solvent may be water. In this regard, 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. For the latter, 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. In some embodiments, 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.

In another embodiment of the present disclosure, 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. In an embodiment, the oral dosage form obtained from the final mixture may be tablets. In this regard, 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.

As described above, 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.

Also, 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.

One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Examples 1-7: Preparation of sildenafil citrate tablets including magnesium aluminometasilicate and calcium silicate

After uniformly mixing 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.

[Table 1]

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.

[Table 2]

Comparative Examples 1 and 2

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.

[Table 3]

Experimental Example 1: Sensory evaluation (Test of bitter taste masking effect)

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.

[Table 4]

As a result of the evaluation, 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 awful taste masking effect.

Experimental Example 2: Dissolution test of tablets of Examples 1-7

To investigate whether the oral tablets behave appropriately in the body to exhibit manifestation of pharmaceutical effects, a comparative dissolution test was performed using the tablets of Examples 1-7 and a commercially available film-coated sildenafil citrate tablet (Viagra 100 mg, Pfizer Korea Ltd.).

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. As a result, the tablets of Examples 1-7 were found to have similar dissolution rates to that of the commercially available tablet Viagra (see FIG. 1).

Experimental Example 3: Evaluation of chewable sildenafil citrate tablet's behavior in the body

The sildenafil citrate tablets (Test drug) of Example 2 and the commercially available Viagra tablets (100 mg, Reference drug) were administered to 12 healthy men to evaluate behaviors of the tablets in the body.

After oral administration of each of the two drug samples, an average blood level profile of each drug sample was obtained. As a result, a test to reference drug ratio of C_max was 1.008 and a test to reference drug ratio of AUC was 1.069 (see FIG. 2), which indicates that there is no substantial behavioral difference in the body between the two drugs. Therefore, it can be expected that the sildenafil citrate tablet of the present disclosure provides substantially the same pharmaceutical effects in the body as the commercially available sildenafil citrate tablet.

Experimental Example 4: Sensory evaluation of tablets of Examples 8-13

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.

[Table 5]

As a result, the tablets of Examples 8-13 were found to have a taste masking effect on various drugs with bitter taste.

Experimental Example 5: Dissolution test on tablets of Examples 8-13

To investigate whether the oral tablets behave appropriately in the body to exhibit manifestation of pharmaceutical effects, 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. As a result, 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).

Claims

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.
The pharmaceutical composition of claim 1, wherein the at least one compound is about 1 wt% to about 80 wt% of a total weight of the pharmaceutical composition.
The pharmaceutical composition of claim 2, wherein the at least one compound is about 3 wt% to about 20 wt% of a total weight of the pharmaceutical composition.
The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is at least one selected from among the group consisting of a diluent, a binding agent, a lubricant, a glidant, a disintegrant, a solubilizing agent, and a stabilizer.
The pharmaceutical composition of claim 1, wherein the pharmaceutically active ingredient is a poorly water-soluble drug.
The pharmaceutical composition of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of sildenafil citrate, tramadol hydrochloride, sumatriptan, ondansetron, fexofenadine, ranitidine, famotidine, cimetidine, hydrocodone, acetaminophen, aspirin, Ibuprofen, dexibuprofen lysinate, naproxen, ketoprofen, lactams, quinolones, macrolides, loperamide, irbesartan, captopril, lisinopril, nefazodone, buspirone, chlorpheniramine, astemizole, pseudoephedrine, dextromethorphan, cetirizine, nimesulide, ascorbic acid, hydrocortisone, 5-fluorouracil, cisplatin, paclitaxel, ampicilin, cefadroxil, clindamycin, neomycin, nystatin, polyphenols, hydroquinone, retinal A, zinc gluconate, copper gluconate, carbinoxamine malate, dextromethorphan hydrobromide, and glyceryl guaiacolate.
The pharmaceutical composition of claim 6, wherein the pharmaceutically active ingredient is selected from the group consisting of sildenafil citrate, tramadol hydrochloride, sumatriptan, ondansetron, fexofenadine, ranitidine, hydrocodone, and acetaminophen.
The pharmaceutical composition of claim 1, wherein the pharmaceutically active ingredient is sildenafil citrate.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is in oral dosage form selected from the group consisting of tablets, pills, hard or soft capsules, powders, fine granules, granules, powder for reconstitution of suspension, lozenge, wafers, dragees, oral strips, and chewable gum.
The pharmaceutical composition of claim 9, wherein the tablet is selected from the group consisting of a compressed tablet, a multiple-compressed tablet, an oral 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.
A method of preparing the pharmaceutical composition for oral administration, wherein taste of the pharmaceutically active ingredient is masked of any one of claims 1 to 10, 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 of claim 11, comprising:

mixing the pharmaceutically active ingredient, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier;

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 pharmaceutically acceptable additive, 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.