MX2014004811A - Taste-masked pharmaceutical composition for oral administration and a process for the preparation thereof. - Google Patents

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

PHARMACEUTICAL COMPOSITION OF MASKED FLAVOR FOR ORAL ADMINISTRATION, AND PROCESS FOR THE PREPARATION OF THE SAME Technical Field The present disclosure relates to an unpleasant masked oral pharmaceutical composition that includes a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, and a method of preparing the oral pharmaceutical composition.

Background of the Technique Two commercially available oral dosage forms of medicaments are swallowable forms such as tablets or capsules, and forms that are solubilized in the mouth such as chewable tablets or sublingual tablets. The former can eliminate or significantly reduce the unpleasant taste of an active ingredient. The latter may be reluctant and less adaptable to ingestion if the active ingredient has an extremely unpleasant taste. This can be more serious in the case of children who are relatively less adaptable to drugs, because the dosage forms for children are prepared in most cases in liquid oral formulations that have little chance of masking the unpleasant taste, or oral tablets that are often crushed and mixed with water or syrup before being swallowed. For this reason a variety of methods have been proposed for blocking off unpleasant flavors such as bitterness or acidity of oral medications.

Reference 1 discloses a composition containing an inhibitor of cyclic guanosine-3 ', 5'-monophosphate phosphodiesterase (cGMP PDE), whose administration form is unacceptable by patients. Thus, the composition has a disadvantage of low acceptance by patients. References 2 and 3 disclose bitterness masking methods for drugs by addition of cyclodextrin. Nevertheless, . these methods have to use a large amount of excipient in order to at least partially reduce the bitterness of a drug, and therefore, are not substantially applicable in the development of rapid oral disintegration tablets or chewable tablets that are taken without water. References 4 to 6 disclose unpleasant taste masking methods involving the coating of bitter drug particles with celluloses, lipids, polymers, or the like. However, partial cracking of a coating during the manufacture of a tablet can produce unpleasant tastes. Additionally, the methods disclosed are complicated and do not ensure controlled rates of drug release and absorption. The reference 7 discloses a method of preparing an orally disintegrating, masked bitter tablet containing sildenafil citrate, in which the bitterness is masked with a solubilization inhibitor and a sweetener such as aspartame. However, the rates of drug release and absorption in the body may be limited by the solubilization inhibitor.

Reference 8 discloses a solid formulation of a masked bitter drug obtained by mixing a bitter tasting drug with calcium silicate, and a method of preparing the same. According to this technology, the solid formulation of masked bitterness is prepared by mixing a solution of a bitter drug in a solvent with calcium silicate, drying and spraying the mixture in solution, and thereby capturing the bitter taste in a porous network. of calcium silicate. However, in this method, an incomplete dissolution of the drug can render the undissolved drug unable to be captured in the porous reticulum of calcium silicate, thus causing bitter taste in the mouth. Therefore, this method is not compatible with a drug poorly soluble in water, and may require a very large amount of water if used together with a drug poorly soluble in water, which may require a long time and a large amount of water. energy during a subsequent drying process. In addition, the method involves complicated processes that include dissolving a bitter drug, mixing it with calcium silicate, and a spraying process. Thus, the method is unsuitable for large-scale production and is not industrially applicable due to low productivity and low economic efficiency. Additionally, due to a very low efficiency of capture of the drug by the calcium silicate in a porous network, the method requires a large amount of calcium silicate. However, the use of a large amount of calcium silicate can result in a low density powder, such as a soft candy, and with it, poor susceptibility to tablet compression. In addition, due to the impossibility of using a sufficient quantity of essential excipients, it is difficult to formulate tablets with high pharmaceutical characteristics.

Reference 9 discloses a masked bitter oral drug composition in which a bitter drug, an acidic material such as tannic acid, citric acid or acetic acid, and an alkaline earth metal salt and / or earth metal salt are dissolved in purified water. This method involves masking the bitterness of a drug that is any of a variety of salts by induction of an ion-bond reaction class in a solution aqueous with the addition of an acidic material and an alkaline earth metal or analogous salt. However, the effect of masking the bitterness by ionic bond is lost if the solution of the dissolved drug is dried, and therefore, this method is unsuitable for preparing a solid formulation with a sustained effect of blockade of the bitterness.

Various other preparation methods and dosage forms have been proposed for masking the unpleasant taste of the drugs. However, these methods of preparation are complicated, can cause deterioration of quality, or can be applicable to limited drugs, thus lacking universal and satisfactory effects. Therefore, there is a demand for the development of a masked bitter drug composition in which the unpleasant taste of the drug is masked without a substantial reduction or loss of pharmaceutical effects, which can be industrially applicable with high productivity and can be formulated into tablets. , and a method of preparing it.

[References of the Prior Art] [References related to patents] 1. USNo Patent US 6,740,306 2. Korean Publication No. 2001-0014398 3. Korean Publication No. 2004-0012696 4. Korean Publication No. 1991-0004180 5. Korean Publication No.2001-0023384 6. Korean Publication No. 2002-0002321 7. Publication USNo. 20060100214 8. Publication of Japan No. 1988-243035 9. Korean Publication No. 2009-0113777 Description of the invention Technical problem The present invention provides an oral pharmaceutical composition with an effective unpleasant taste masking effect which does not affect the performance and effect of a pharmaceutically active ingredient in the body, and which can be prepared in the form of a tablet with high productivity and economic efficiency as well as excellent pharmaceutical properties.

The present invention provides a method of preparing the oral pharmaceutical composition.

Solution to the problem In accordance with one aspect of the present invention, there is provided a pharmaceutical composition for oral administration, wherein the flavor 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: group consisting of magnesium aluminometasilicate and calcium silicate, and a vehicle pharmaceutically acceptable.

In accordance with another aspect of the present invention, there is provided a method of preparing the pharmaceutical composition for oral administration, wherein the flavor of the pharmaceutically active ingredient is masked, including the wet granulation method of 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.

Next, the present invention will be described in greater detail.

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

As a result of the efforts to develop Masked bitterness formulations which are both compatible with soluble drugs and poorly soluble in water and which can be formulated as tablets with high productivity, the inventors of the present disclosure found that the wet granulation of a pharmaceutically active ingredient together with magnesium aluminometasilicate and / or calcium silicate can effectively mask the bitter taste even with the use of a small amount of magnesium aluminometasilicate and / or calcium silicate.

According to one aspect of the present disclosure, a pharmaceutical composition for oral administration, wherein the 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 by magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier.

As used herein, the term "taste masking" means elimination or weakening of the unpleasant taste of a pharmaceutically active ingredient or reduction of taste perception. The term "flavor" means any kind of flavor, including bitter taste, acid taste, and the like, which can be any unpleasant taste that is repugnant 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 taste masking of the pharmaceutically active ingredient.

In the oral pharmaceutical composition according to the present disclosure, the wet granulation preparation does not require complete dissolution of the active ingredient in a solvent, and therefore, the oral pharmaceutical composition is compatible with both a water-soluble active ingredient and an active ingredient. little soluble in water. The preparation of the oral pharmaceutical composition by wet granulation does not require drying to remove a large amount of water, and in fact simplifies manufacturing processes that have high industrial applicability due to high economic efficiency and productivity. Since it is prepared by wet granulation, the oral pharmaceutical composition of the present disclosure can have a masked bitter taste compound 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 masking the unpleasant taste. In addition, the use of magnesium aluminometasilicate and / or calcium silicate in a small amount it makes possible the 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 the preparation of 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 in more detail below, orally bitter-tasting drugs were mixed, namely, 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) with magnesium aluminometasilicate, calcium silicate, or a mixture thereof to prepare a form of dosage, and a sensory test was carried out on the dosage forms prepared. As a result, the drug mixtures were perceived as sweeter, but markedly less bitter and less acidic, than commercially available tablets that included the same active ingredients (see Tables 4 and 5), as a result of a dissolution test of the forms from In addition, the dosage forms prepared showed the same dissolution behaviors as those of the commercially available reference drugs (see FIGS 1, 3 to 8). As a result of measuring the level of active ingredient in blood after oral administration to the body, the dosage forms prepared exhibited pharmacokinetic (PK) profiles similar to those of the reference drugs (see FIG. 2), indicating that Prepared dosage forms have in vivo activities similar to those of commercially available reference drugs.

The "magnesium aluminometasilicate" is a white powder which is also referred to as Silodrate or Simaldrate, represented by the formula of AI2O2.2 g. -303 Yes, which is insoluble in water and is hygroscopic at a relative humidity (RH) of approximately 70% or greater. In the pharmaceutical field, magnesium aluminometasilicate as a treatment agent for gastrointestinal disorders such as an anti-ulcer drug, or an excipient of a solid dosage form for improving powder flowability, which is commercially available under the name Neusilin (available from Fuji Chemical Industry).

The "calcium silicate", which is represented by the formula Ca2SiC > 4 or 2 CaO.Si02, refers collectively to a group of compounds obtained by the reaction of oxide of calcium and silica in various ratios. The calcium silicate can be, in the broadest sense, any compound represented by one of the formulas 3CaO'SiC > 2, Ca3Si05; 2CaO'Si02, Ca2Si04; 3CaCT2Si02, Ca3Si207; and CaCTSi02, CaSi03, which is present as a white solid powder in normal state with a low bulk density and is stable at normal temperature and pressure. Calcium silicate is used pharmaceutically as an anti-caking agent and antacid agent, but has not been used for taste masking purposes. Calcium silicate can 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, et cetera.

An amount of magnesium aluminometasilicate and / or calcium silicate in the oral pharmaceutical composition can be suitably selected depending on the class of the pharmaceutically active ingredient, the dosage form, or the like. In some embodiments, the amount of magnesium aluminometasilicate and / or calcium silicate can be from about 1% by weight to about 80% by weight based on the total weight of the oral pharmaceutical composition, but without limitation. For example, the amount of magnesium aluminometasilicate, calcium silicate, or a mixture thereof it can be from about 1% by weight to about 60% by weight, and in some embodiments, it can be from about 1% by weight to about 50% by weight, and in some other embodiments, it can be from about 2% by weight to about 30% by weight, based on the total weight of the oral pharmaceutical composition. In still other embodiments, the amount of magnesium aluminometasilicate, calcium silicate, or a mixture thereof can be from about 3 wt% to about 20 wt% based on the total weight of the oral pharmaceutical composition.

As used herein, the term "pharmaceutically active ingredient" means not only any active pharmacological agent for the purpose of treatment, but also any reagent or any medical agent that can be administered to the human body for diagnostic or preventive purposes. In a broader sense, the pharmaceutically active ingredient can be any material, ingredient, or healthy functional food as a processed form thereof that can be ingested for health care purposes with regulatory nutrient functions or physiological functions on body structure and functions. .

The pharmaceutically active ingredient may have - Im ¬ physical and chemical properties that are suitable for formulation in an oral dosage form. For example, since the oral pharmaceutical composition is prepared by wet granulation, the pharmaceutically active ingredient may not need to be reactive with an aqueous-based or oil-based solvent of a fixing solution (solvent solution or fixing agent) and not necessarily lose activity during 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 compression force applied by a tablet compression 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 supplemental nutrient, an anti-inflammatory agent, an antibiotic, an anti-histamine. , an antibacterial drug, an antifungal drug, an anti-depressant, an antidepressant, an anti-psychotic agent, an antiviral drug, an antineoplastic, a vaccine, an antiepileptic drug, an antiasthmatic agent, an antioxidant, and a plant extract. For example, a pharmaceutically active ingredient with an unpleasant taste for Oral ingestion is suitable for use in this invention. Non-limiting examples of the pharmaceutically active ingredient of unpleasant taste are sildenafil citrate, scavenging hydrochloride, sumatriptan, ondansetron, fexofenadine, ranitidine, famotidine, cimetidine, hydrocodone, acetaminophen, aspirin, ibuprofen, dexibuprofen-lysinate, naproxen, quinolones, macrolides, loperamide, ibesartan, captopril, lisinopril, nefazodone, buspirone, chlorpheniramine, astemiol, pseudoephedrine, dextromethorphan, cetirizine, nimesulide, ascorbic acid, hydrocortisone, 5-fluorouracil, cisplatin, paclitaxel, ampicillin, cefadroxil, clindamycin, neomycin, nystatin, polyphenols, hydroquinone , retinal A, zinc gluconate, copper gluconate, carbinoxamine malate, dextromethorphan hydrobromide, and glyceryl guayacolate. 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 can be formulated as an orally administrable form by masking an unpleasant taste of these pharmaceutically active ingredients.

The oral pharmaceutical composition is advantageous in the sense that the pharmaceutically active ingredient can be soluble in water or sparingly soluble in water. As used herein, the term "poorly soluble in water" refers to a degree of solubility ranging from "poorly soluble" to "very slightly soluble." The degree of solubility designated as "poorly 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 approximately 1000 ml to about 10,000 ml of water to dissolve 1 g of the drug. Recently developed or acquirable drugs have in the majority of cases low solubility in water. In this regard, compatible at the same time with pharmaceutically active ingredients soluble in water and poorly soluble in water, the oral pharmaceutical composition according to the present description can be applied in a general sense for unpleasant taste masking. Non-limiting examples of the poorly soluble active ingredient in water are sildenafil citrate, sumatriptan, fexofenadine, and a combination of hydrocodone / acetaminophen.

As used herein, the term "pharmaceutically acceptable carrier" refers to any additive ingredients to the exclusion of the pharmaceutically active ingredient, and magnesium aluminometasilicate and calcium silicate added for masking of the Unpleasant taste. The term "pharmaceutically acceptable" refers to the properties that do not cause any pharmaceutically undesirable change by interaction between the ingredients of the oral pharmaceutical compositions (eg, by interaction between vehicles or by interaction between the pharmaceutically active ingredient and a vehicle). The selection of the pharmaceutically acceptable vehicle may depend on the properties and method of administration of a particular dosage form, the effects of the vehicle on solubility and stability, and so on.

In some embodiments, the pharmaceutically acceptable carrier contained in the oral pharmaceutical composition can 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, an agent sweetener, a coloring agent, and a flavoring agent.

The diluent refers to any excipient added to increase the volume of the oral pharmaceutical composition in order to formulate it into a dosage form with an appropriate size. Non-limiting examples of the diluent may be starch (e.g., potato starch, corn starch, wheat starch, pregelatinized starch), microcrystalline cellulose (e.g. microcrystalline cellulose with low hydration), lactose (for example, lactose monohydrate, lactose anhydrous, lactose spray), glucose, sorbitol, mannitol, sucrose, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, calcium hydrogen phosphate anhydrous, or silicon dioxide, which may be used alone or as a mixture thereof. In some embodiments, the excipient may be used in a ratio of about 5% by weight to about 50% by weight based on the total weight of the oral pharmaceutical composition. In some other embodiments, the excipient may be used in a ratio of about 10% by weight to about 35% by weight based on the total weight of the oral pharmaceutical composition for appropriate tablet compression and quality maintenance.

The binder refers to a material that offers the materials in the form of powder adhesiveness and facilitates the 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 (e.g., hydroxypropylmethylcellulose, hydroxypropylcellulose, or low substituted hydroxypropyl cellulose), natural rubber , synthetic rubber, povidone, co-povidone, and gelatin, but are not limited to same. In some embodiments, the binder can be used in a ratio of about 2% by weight to about 15% by weight based on the total weight of the oral pharmaceutical composition. In some other embodiments, the binder can be used in a ratio of about 1% by weight to about 3% by weight based on the total weight of the oral pharmaceutical composition for appropriate tablet compression and quality maintenance.

The disintegrant refers to an added material to facilitate the disintegration of a solid dosage form when administered to 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; a 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 without limitation. In In some embodiments, the disintegrant may be used in a ratio of about 2% by weight to about 15% by weight based on the total weight of the oral pharmaceutical composition. In some other embodiments, the disintegrant can be used in a ratio of about 4 wt% to about 10 wt% based on the total weight of the oral pharmaceutical composition for an appropriate drug formulation and quality maintenance.

The slider or lubricant refers to a material that prevents the cohesion of the powders to a compression system and improves the fluidity of the 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, stearyl fumarate of sodium, glyceryl behenate, glyceryl monostearate, or polyethylene glycol, which may be used alone or as a mixture thereof, but is not limited thereto. In some embodiments, the glidant can be used in a ratio of about 0.1 wt% to about 5 wt% based on the total weight of the oral pharmaceutical composition. In some other embodiments, the glidant can be used in a ratio of about 1% by weight to about 3% by weight based on the total weight of the oral pharmaceutical composition for appropriate tablet compression and quality maintenance.

The adsorbent can 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 can be used alone or as a mixture of the same, but without limiting nature.

The stabilizer may be at least one selected from the group consisting of antioxidants, such as butylhydroxyanisole, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol-polyethylene glycol succinic acid, or propyl gallate; cyclic sugar compounds such as cyclodextrin, carboxyethyl-cyclodextrin, hydroxypropyl-cyclodextrin, sulfobutyl ether, 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 without limiting character.

In some other embodiments, an additive known to improve taste as well as mask can be included the unpleasant taste of the active ingredient. In some embodiments, a sweetener such as sucralose, sucrose, fructose, erythritol, acesulfame potassium, sugar-alcohol, honey, sorbitol, or aspartame can be added in order to more effectively mask the bitterness and maintain the stability and quality of the formulation. In some other embodiments, an acidifier such as citric acid or sodium citrate may be used; 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.

According to the present disclosure, the oral pharmaceutical composition can be prepared by wet granulation of a mixture of the pharmaceutically active ingredient, a pharmaceutically acceptable carrier, and at least one aluminometasilicate compound of aluminum and calcium silicate.

As used herein, the term "granulation" refers to a process of permanent agglutination of small particles in order to increase a total particle size of the resulting drug formulation. As used herein, the terms "wet granulation" or "wet granulation method" refer to a process of granulating small wetting particles in a solvent or binder solution. to make them coherent. Compared to dry granulation, wet granulation can improve the cohesive and compressive characteristics of the powder, and the uniformity of distribution of the finely divided low amount of drugs, and can retain the forms of the whole granules even after drying without segregation of the ingredients. Masking of the unpleasant taste of the pharmaceutically active ingredient in the oral pharmaceutical composition of the present disclosure is attributed to an interaction of the magnesium aluminometasilicate or calcium silicate with the pharmaceutically active ingredient during the wet granulation.

Wet scale granulation can be performed by mixing the ingredients in a stainless mortar or vessel and wetting them with an appropriate solvent. Wet granulation on a larger scale can be carried out using a double shell mixer, a double cone mixer, a differential mixer, a rotary granulator, a high shear mixer, a nebulization dryer, or a fluid bed granulator. A common method of wet granulation 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.l ~ 71.

According to the present description, since it is 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 wet granulation, the use of an excessive amount of solvent or drying of an excessive amount of solvent is not necessary, so that 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 the form of beads prepared by wet granulation, or it may be in any of a variety of oral dosage forms prepared by further addition of a pharmaceutically acceptable carrier, and / or a additional process of drug formulation. For example, the oral dosage form can 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 the solution or suspension, lozenges, wafers, oral strips, dragees, or chewing gum, but are not limited to them. Non-limiting examples of the oral liquid formulation are solution, suspension, emulsion, syrup, elixir, alcohol solution, flavored waters, lemonade, extract, and tincture. Non-limiting examples of the semisolid form are aerosol, cream, and gel.

In some embodiments of the present disclosure, the oral pharmaceutical composition may be formulated as a solid oral formulation, for example, as a tablet. The tablet is selected from the group consisting of a compressed tablet, a multi-compressed tablet, a chewable tablet, a troche, a sublingual tablet, a buccal tablet, an effervescent tablet, a fast-disintegrating tablet, a dispersible tablet, and a tablet of oral disintegration. The masking effect of the unpleasant taste 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 a disintegration tablet. oral that dissolves and absorbs quickly in the mouth, and therefore, requires masking of unpleasant taste.

The oral pharmaceutical composition according to the present disclosure can be highly effective in masking the bitterness of the drug by magnesium aluminometasilicate and / or calcium silicate, which makes it possible to use a relatively small amount of magnesium aluminometasilicate and / or calcium silicate. for masking the Unpleasant taste. In addition, the use of magnesium aluminometasilicate and / or calcium silicate in a small amount allows sufficient use of a pharmaceutically acceptable one that is required in the preparation of some solid dosage forms, and in particular, tablets, by additional formulation.

According to another aspect of the present disclosure, there is provided a method of preparing a pharmaceutical composition for oral administration, in which the taste of the pharmaceutically active ingredient is masked, the method comprising wet granulation of a mixture comprising a pharmaceutically active ingredient. active, at least one compound selected from the group consisting of magnesium aluminometasilicate and calcium silicate, and a pharmaceutically acceptable carrier.

In one embodiment, the method may include: i) mixing the pharmaceutically active ingredient, the at least one magnesium aluminometasilicate compound and calcium silicate, and the pharmacologically acceptable carrier; and ii) kneading the mixture with a solvent or binder solution and drying and granulating the mixture, thereby preparing granules.

In step i), which is intended to prepare the powder mixture, the amounts and the ratio of the pharmaceutically active ingredient, and the aluminometasilicate of magnesium and / or calcium silicate are those described above. The types and amount of the pharmaceutically acceptable carrier that can be used in the preparation of drugs in the form of granules are generally known in the art, and can be appropriately selected and adjusted as necessary by a person of ordinary skill in the art.

Step ii), which has for its object the preparation of granules from the powder of the mixture, can be carried out using a granulator well known in the art. For example, the granulation can be performed using a high shear mixing granulator, a nebulization dryer, or a fluid bed granulator. In step ii), to knead the mixture resulting from step i), a solvent alone, or a binder solution can be used as a mixture of a binder and an additive in a solvent. In some embodiments, the granulation can be performed using an aqueous wet granulation method, and the solvent can be water. In this regard, a stabilizer or a binder may be added to the solvent as required. The resulting kneaded mixture can be dried using, for example, a dryer with hot water circulation or a fluid bed dryer, and then sieved to obtain granules with a uniform size distribution. If the drying is insufficient, a problem may occur during tablet compression. If the drying is carried out in excess, moisture reabsorption can probably occur, causing a problem during the distribution and storage periods. A moisture content of the kneaded mixture after drying can be, for example, from about 0.5 wt% to about 3.0 wt%.

The resulting granules obtained as described above may be available directly as an oral dosage form, or may be formulated further by an additional process in 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 step ii) to obtain a final mixture for formulation of a target dosage form. In some embodiments, the final mixture can be introduced into capsules or can be compressed into tablets to prepare a solid oral dosage form, or it can be prepared in an oral strip form by 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 an ingredient pharmaceutically active, 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 binder 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 constituted by the final mixture. In one embodiment, the oral dosage form obtained from the final mixture can be tablets. In this regard, the final step of the method described above can be tablet compression of the final mixture to obtain tablets. The tablets may be, for example, compressed tablets, multi-compressed tablets, dragees, chewable tablets, troches, sublingual tablets, buccal tablets, effervescent tablets, fast disintegrating tablets, dispersible tablets, or oral disintegrating tablets. The methods of preparation of these tablets are well known in the art. Therefore, it is obvious to a person with ordinary skill in the art that an additional or specific process can be further applicable with variations, if required, depending on a target dosage form. Advantageous Effects of the Invention As described above, the oral pharmaceutical composition according to the one or more embodiments of the present disclosure can be prepared without using a special expensive manufacturing system or additive, having an unpleasant taste masking effect on the active ingredients, and exhibit an appropriate behavior of drug dissolution in the body for manifestation of the pharmaceutical effect.

Also, the oral pharmaceutical composition is compatible both with a water soluble active ingredient and a poorly soluble active ingredient in water, with high industrial applicability due to simple manufacturing processes and high economic efficiency and productivity. The oral pharmaceutical composition can be formulated in any of a variety of solid dosage forms with improved pharmaceutical characteristics.

Brief Description of the Drawings FIG. 1 is a graph illustrating comparatively the results of a dissolution test on a commercially available tablet (Viagra 100 mg tablet, Pfizer Korea Ltd.) containing sildenafil citrate, and oral dosage forms of sildenafil citrate prepared from according to Examples 1 to 7; FIG. 2 is a graph illustrating comparatively the change of blood level after oral administration of the commercially available tablet (Viagra 100 mg tablet, Pfizer Korea Ltd.) containing sildenafil citrate, and the oral dosage form of sildenafil citrate prepared according to Example 2; FIG. 3 is a graph illustrating comparatively the 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 illustrating comparatively the results of a dissolution test on a commercially available tablet (Imigran 50 mg tablet, MYUNG IN PHARM. CO. LTD) containing sumatriptan, and a tablet prepared according to Example 9; FIG. 5 is a graph illustrating comparatively the results of a dissolution test on a commercially available tablet (Zantac 150 mg tablet, GlaxoSmithKline (GSK) Korea) containing ranitidine, and a tablet prepared according to Example 10; FIG. 6 is a graph that comparatively illustrates the results of a dissolution test on a commercially available tablet (Zofran 8 mg tablet, GSK Korea) containing ondansetron, and a tablet prepared according to Example 11; FIG. 7 is a graph illustrating comparatively the results of a dissolution test on a commercially available tablet (tablet Allegra 180 mg, HANDOK PHARMACEUTICALS CO. LTD.) Containing fexofenadine, and a tablet prepared according to Example 12; Y FIG. 8 is a graph illustrating comparatively the 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.

Mode of the Invention One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. These examples are for the purpose of illustration only and should not be considered as limiting 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 sulfate, a mixture of nebulized D-mannitol and croscarmellose sodium, crospovidone, acesulfame potassium, and aspartame, The mixture was uniformly ground and sieved using a 25 ~ 35 mesh sieve. The crushed and screened mixture was mixed with hydroxypropyl cellulose and purified water until granules were obtained. After drying, the granules were uniformly ground and sieved using a 25 ~ 35 mesh screen.

The granules were mixed with menthol flavor, magnesium aluminometasilicate or calcium silicate, crospovidone, a mixture of nebulized 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 a solid oral dosage form.

[Table 1] Examples 8-13: Preparation of sildenafil citrate tablets, a variety of drug tablets including magnesium aluminometasilicate and calcium silicate Tablets that included 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 necessary to develop orally disintegrating tablets or chewable tablets in the art. Tablets were prepared with an optimal dosage form (Example 2 or 5) identified from those of Examples 1 to 7, except that the active ingredients were used instead of sildenafil. The boards were prepared using magnesium aluminometasilicate, calcium silicate, a pharmaceutically acceptable excipient, a sweetening agent, and a disintegrant in the following Table 2 in the same manner as in Examples 1 to 7.

[Table 2] Comparative Examples 1 and 2 Tablets that included synthetic aluminum silicate or hard anhydrous silicic acid (Aeropearl 300) as the 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 aluminometasilicate of magnesium or calcium silicate. Tablets that included sildenafil citrate were prepared in the compositions of Table 3 below in the same manner as in Examples 1-7, and used in the following experimental examples.

[Table 3] Experimental Example 1: Sensory evaluation (Test of effect of masking the bitter taste) A sensory test was carried out on the tablets of Examples 1 to 7 on 20 individuals. Each individual recorded each sensory item from record 1 to 10, and the records for each sensory item of the individuals were averaged. The results are shown in Table 4. The greater the record of each sensory item, the greater the level of perception of each sensory item.

[Table 4] As a result of the evaluation, it was perceived that the tablets of Examples 1-7 prepared using magnesium aluminometasilicate and / or calcium silicate They had bitter and acid flavors markedly reduced with an increased perception of sweetness. It was found that the tablets of Comparative Examples 1 and 2 prepared using synthetic aluminum silicate or hard anhydrous silicic acid completely lacked a bitterness masking effect, indicating that the dosage forms prepared by wet granulation of a mixture of citrate Sildenafil as an active ingredient, and magnesium aluminometasilicate and / or calcium silicate have an extremely unpleasant taste masking effect.

Experimental Example 2: Dissolution test of the tablets of Examples 1-7 To investigate whether the oral tablets behave properly 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.). The dissolution rate of sildenafil citrate of each tablet was measured using water as a dissolution medium, and a dissolution with type II paddles at 50 rpm / 900 ml. As a result, it was found that the tablets of Examples 1-7 had dissolution rates similar to that of the Commercially available Viagra (see Fig. 1).

Experimental Example 3: Evaluation of the behavior of a chewable tablet of sildenafil citrate 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 the 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 Cmax reference drug-to-drug ratio was 1,008 and a AUC benchmark drug to drug ratio was 1,069 (see FIG 2), indicating that there is no substantial difference in behavior in the body between the two drugs. Thus, 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 the tablets of Examples 9-13 A sensory test of the tablets of Examples 8-13 was carried out on 20 individuals. Each individual recorded each sensory item from record 1 to 10, and the records for each sensory item of the individuals were averaged. The results are shown in Table 5. The greater the record of each sensory item, the higher the level of perception of the record of each sensory item of the sensor.

[Table 5] As a result, it was found that the tablets of Examples 8-13 have a taste masking effect on various bitter tasting drugs.

Experimental Example 5: Dissolution test on the tablets of Examples 8-13 To investigate whether the oral tablets behave properly in the body to exhibit the manifestation of pharmaceutical effects, a comparative solution test was carried out using the tablets of Examples 8-13 and commercially available drugs for comparison. The commercially available drugs used as reference samples were a soluble Tridol tablet (500 mg, YUHAN Corporation), Imigran tablet (50 mg, MYUNG IN PHARM. CO., LTD), a Zantac tablet (150 mg, GlaxoSmithKline (GSK) Korea), one tablet Zofran (8 mg, GSK Korea), one tablet Allegra (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.). The rate of dissolution of an active ingredient of each tablet was measured using water as a dissolution medium, and a dissolution apparatus with type II paddles at 50 rpm / 900 ml. As a result, it was found that the tablets of Examples 8-13 had dissolution rates similar to those of commercially available tablets used as reference drugs (see FIGS 3-8) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

1. A pharmaceutical composition for oral administration, wherein the 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 mixture excluding an acidic material such as a taste masking agent of the pharmaceutically active ingredient.

2. The pharmaceutical composition of claim 1, wherein the at least one compound represents about 1% by weight to about 80% by weight of the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of claim 2, wherein the at least one compound represents about 3% by weight to about 20% by weight of the total weight of the pharmaceutical composition.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of a diluent, a binder, a lubricant, a glidant, a disintegrant, a solubilizing agent, and a stabilizer.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutically active ingredient is a drug poorly soluble in water.

6. 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- lisinate, naproxen, ketoprofen, lactams, quinolones, macrolides, loperamide, irbesartan, captopril, lisinopril, nefazodone, buspirone, chlorpheniramine, astemizole, pseudoephedrine, dextromethorphan, cetirizine, nimesulide, ascorbic acid, hydrocortisone, 5-fluorouracil, cisplatin, paclitaxel, ampicillin , cefadroxil, clindamycin, neomycin, nystatin, polyphenols, hydroquinone, retinal A, zinc gluconate, copper gluconate, carbinoxamine malate, dextromethorphan hydrobromide, and glyceryl guayacolate.

7. 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.

8. The pharmaceutical composition of the claim 1, wherein the pharmaceutically active ingredient is sildenafil citrate.

9. 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, spherical caps, pills, dragees, oral strips, and chewing gum.

10. The pharmaceutical composition of claim 9, wherein the tablet is selected from the group consisting of a compressed tablet, a multi-compressed tablet, an oral tablet, a chewable tablet, a trochette, a sublingual tablet, a buccal tablet, an effervescent tablet , a rapid disintegration tablet, a dispersible tablet, and an oral disintegration tablet.

11. A method of preparing the pharmaceutical composition for oral administration, wherein the taste of the pharmaceutically active ingredient is masked of any one of claims 1 to 10, the method comprising wet granulation of 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 vehicle.

12. 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 binder 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; Y obtain an oral dosage form made from the final mixture.