KR20130135611A - Bitter taste masked oral pharmaceutical composition comprising pde-5 inhibitor - Google Patents

Abstract

The present invention relates to an oral composition having an unpleasant taste of a drug and improved dose compliance. More particularly, the present invention relates to an improved oral composition comprising a PDE-5 inhibitor as an active ingredient.

Description

BITTER TASTE MASKED ORAL PHARMACEUTICAL COMPOSITION COMPRISING PDE-5 INHIBITOR

The present invention relates to an oral composition having an unpleasant taste of a drug and improved dose compliance. More particularly, the present invention relates to an improved oral composition comprising a PDE-5 inhibitor as an active ingredient.

Phosphodiesterase-5 (PDE-5) inhibitors generally known as therapeutic agents for erectile dysfunction include cyclic guanosine 3 ', 5'-monophosphate-specific phosphodiesterase type 5 Udenafil (C ₂₅ H ₃₆ N ₆ O ₄ S), Sildenafil (C ₂₂ H ₃₀ N ₆ O ₄ S), Vardenafil (Vardenafil, a selective inhibitor of the (cGMP-specific PDE-5) enzyme C ₂₃ H ₃₂ N ₆ O ₄ S), and tadalafil (Cada Hfil, C ₂₂ H ₁₉ N ₃ O ₄ ) and the like, the drug is Korean Patent No. 353,014 (Udenafil), Korean Patent No. 262,926 (Sildenafil), Korean Patent No. 430,355 (Badenafil), and Korean Patent No. 357,411 (Tadalafil).

Such PDE-5 inhibitors are important for rapid dissolution and absorption in the oral cavity and good bioavailability when formulated. For this purpose, for example, Korean Patent Publication No. 2001-36527 discloses a foamed tablet of sildenafil, which is one of the PDE-5 inhibitors. Although it was configured to have a fast solubility using the technique such as, there was a problem that the citrate used for this has a bitter taste that can not be dissolved and eaten in the oral cavity. Therefore, especially for patients who need to take the drug for a long period of time for the treatment of gastric indications that need to be taken daily, improvement of bitter taste is necessary for convenience of convenience or improvement of dose compliance.

In this regard, an example of using a free base of sildenafil without a bitter taste instead of sildenafil citrate to improve the taste of sildenafil citrate is disclosed in Korean Patent Laid-Open Publication No. 1999-0088249. However, the present invention can reduce the bitter taste in the oral cavity, but there is a problem that the solubility is too low to show a rapid and good bioavailability which is the original purpose.

The rapid-release tablet development technology including an amorphous PDE-5 inhibitor is disclosed in Patent Publication No. 2007-0100023, but the present invention is a complex process, requires special equipment, changes in the physical properties of the drug or drug unstable There was a limit like losing.

In addition, Patent Publication No. 2010-0138768 (Patent No. 1074271) specifies the development of an oral fast-acting film using a sweetener. However, the use of sweetener alone does not improve the taste of udenafil, unlike other PDE5 inhibitors. there was.

Therefore, there is a need for the development of a formulation that can improve the taste and simultaneously exhibit the desired drug efficacy.

Accordingly, the present invention has been made to solve the problems of the prior art, effectively masking the unpleasant taste of the PDE-5 inhibitor drug to improve the patient's dosage compliance, and can be used quickly oral composition and method for producing the same The purpose is to provide.

In order to achieve the above object, the present inventors have studied that PDE-5 inhibitors having an unpleasant taste such as bitter taste are first formed to form a matrix with a polymer, and then secondly, the matrix is coated with lipids. It is effectively improved and can be dissolved quickly in the oral cavity without water to eat not only can significantly improve the patient's dose compliance, as well as rapid release and absorption is possible to manufacture the oral composition excellent in the efficacy of the present invention It was completed.

Thus, one preferred embodiment of the present invention, a drug-polymer matrix comprising a PDE-5 inhibitor and a water insoluble polymer; And it provides an improved oral composition comprising fine particles consisting of a lipid coating layer coating the matrix.

In another preferred embodiment of the present invention, there is provided a method for preparing the improved oral composition.

The preparation method comprises the steps of (1) dissolving a PDE-5 inhibitor and a water-insoluble polymer in an organic solvent; (2) mixing the solution obtained in step (1) with an aqueous solution to prepare a suspension in which fine particles are formed; And (3) dispersing lipids in the suspension to coat the microparticles contained in the suspension with lipids.

Hereinafter, the composition and the preparation method of the present invention will be described in more detail.

Phosphodiesterase-5 (PDE-5) inhibitors are preferably Udenafil, Sildenafil, Vardenafil, Mirodenafil, Tadalafil and their pharmaceutically acceptable It may be selected from the group consisting of possible salts.

In addition, the pharmaceutically acceptable salt may preferably be hydrochloride, citrate, butyrate, bicarbonate, mesylate, succinate, maleate, and the like of each drug, but is not limited thereto, and more preferably citrate or Hydrochloride.

Preferably the PDE-5 inhibitor may be included in 10 to 75% by weight based on the total weight of the composition. If it is less than the above range is not enough to obtain the expected efficacy, if it exceeds the above range is not preferred because there is a problem that the Gomi shielding effect is lowered, the dose compliance is lowered.

As the water-insoluble polymer, a water-insoluble polymer which is preferably pH independent or a water-insoluble polymer which is pH dependent (acid soluble) can be used.

The pH-independent water-insoluble polymer refers to a polymer that is insoluble in water in both acidic or basic conditions regardless of pH, preferably a polymer having a solubility in water of 0.0001 g / mL or less regardless of pH conditions.

In addition, the pH-insoluble water-insoluble polymer means an acid-soluble polymer which is soluble in acidic conditions, preferably in a condition of pH 1 to 5, in particular, solubility is more excellent at pH 1.5 to 3. Preferably, the pH-insoluble water-insoluble polymer may have a solubility of 0.03 g / mL or more at pH 1 to 5 and a solubility of 0.2 g / mL or more at pH 1.5 to 3.

More specifically, the water-insoluble polymer is, for example, polyvinyl acetal dimethyl aminoacetate, polyvinyl pyrrolidon, hydroxy propyl cellulose, ethyl cellulose, hydroxypropyl methyl Cellulose (hydroxy propyl methyl cellulose), hydroxy propyl methyl cellulose phthalate, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate Poly (ethylacrylate-methylmethacrylate) copolymer, poly (ethylacrylate-methyl methacrylate-trimethylaminoethylmethacrylate) copolymer, poly (ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate) copolymer, cellulose ether, cellulose Acylate, cellulose S Diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate propionate, methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose, Eudragit L100- 55, Eudragit L30 D55, Eudragit L100, Eudragit S 100, Eudragit E 100, Eudragit EPO, Eudragit RL 30D, Eudragit RL PO, Eudragit RL 100, Eudra Jit RS 30D, Eudragit RS PO, Eudragit RS 100, Eudragit NE 30, Eudragit NE 40, smart room 30D (smartseal 30 D) and mixtures thereof.

The drug-polymer matrix may preferably include a water insoluble polymer in a weight ratio of 100: 1 to 300, more preferably 100: 5 to 100, relative to the PDE-5 inhibitor. When the water-insoluble polymer is included in the above range, there is a problem in that the weight of the formulation is too large, and when the water-insoluble polymer is included in the range below, the Gummy shielding is not effectively performed, which is not preferable.

As such, the oral composition according to the embodiment of the present invention may mask the bitter taste by allowing the PDE-5 drug to form a matrix with the above-described polymer, which is also used for dissolution of the PDE-5 drug in the body. Can act as a channel.

In addition, the microparticles may further include a lipid coating layer for coating the drug-polymer matrix, thereby reducing the interfacial tension of the particles and further enhancing the masking effect.

Lipids for coating the drug-polymer matrix can be used without particular limitation so long as it can prevent water from penetrating, for example, arachidic acid, stearic acid, palmitic acid , Erucic acid, oleic acid, arachidonic acid, arachidonic acid, linoleic acid, linolenic acid, glyceryl dibehenate, glycerol distearate distearate, stearyl stearate, cetostearyl alcohol, stearyl alcohol, stearyl alcohol, glyceryl monostearate, glyceryl palmitostearate, Cetyl alcohol, polyoxyethylene stearate, sorbitan stearate, and sorbitan monopalmitate (s orbitan monopalmitate) may be used one or more selected from the group consisting of.

Preferably, the microparticles may include the lipid coating layer in a weight ratio of 100: 1 to 100, more preferably 100: 1 to 50, relative to the PDE-5 inhibitor. If the content of the lipid coating layer exceeds the above range, the release is delayed and there is a problem that can not expect a rapid medicinal effect, if less than the above range, including the lipid, there is a problem that the high unshielding effect is deteriorated.

The fine particles may have a size of micro units, preferably 1 to 200um, more preferably 5 to 100um. If it is less than the above range there is a problem that the Gomi shielding effect is inferior, and if it exceeds the above range Gomi shielding effect is increased, but there is a problem that can not be quickly dissolution is not preferable.

The composition according to the embodiment of the present invention may be formulated into various formulations including one or more additional pharmaceutically acceptable carriers in addition to those described above.

Throughout this specification, “pharmaceutically acceptable carrier” means a pharmaceutical excipient that is useful when formulating a pharmaceutical composition for administration and which is virtually nontoxic and insensitive under the conditions of use, and the specific content ratio of such excipients is active The solubility and chemical properties of the ingredients, as well as the route of administration chosen, can be determined by standard pharmaceutical practices.

More specifically, the oral compositions of the present invention are suitable as pharmaceutically acceptable carriers and physiologically acceptable excipients, disintegrants, sweeteners, binders, coatings, swelling agents, lubricants, lubricants, flavoring agents, fillers, Adjuvants such as extenders, wetting agents, surfactants, and the like may be used to formulate into a form suitable for the desired method of administration. In addition, the total amount of drug per dosage or dosage unit can be that amount that provides a dosage or dosage form convenient to the subject.

Formulations may preferably be in the form of oral preparations, for example, tablets (including chewable tablets), capsules containing microparticles, liquids or powders, pills, granules, powders, troches (Including, but not limited to, liquid-filled), multi- and nano-particulates, gels, solid solutions, liposomes, films (including muco-adhesives), ovals, and liquids Do not. Liquids include, but are not limited to, for example, suspensions, liquids, syrups, and elixirs.

Preferably oral composition according to a preferred embodiment of the present invention may be provided in the form of oral disintegrating film or solution.

When formulated in the form of solid preparations, such as tablets, it may further comprise a disintegrant in addition to the active ingredient. As a disintegrating agent, for example, starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, carboxy Celluloses such as methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, guar gum, Gums such as xanthan gum, crosslinked polymers such as crospovidone, effervescent agents such as sodium bicarbonate and citric acid, polyvinylpyrrolidone, bentonite, dextran, D-sorbitol, calcium citrate, silicic anhydride and the like Can be used but is not limited thereto.

The disintegrant may preferably include from about 1% to about 25% by weight of the dosage form, more preferably from about 2% to about 10% by weight of the dosage form, but is not limited thereto.

The tablet may also further comprise a binder for imparting tack. Binders include, for example, microcrystalline cellulose, calcium carbonate, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone (povidone), polyvinyl alcohol, copovidone Polyvinylpyrrolidone derivatives, glycerin, stearic acid, sodium caseinate, dextrin, pregelatinized starch, starch, highly dispersible silica, mannitol, sucrose, lactose, hydroxypropyl cellulose and hydroxypropyl methylcellulose can be used. This is not restrictive.

The binder may preferably include, but is not limited to, about 1% to about 40% by weight of the dosage form, more preferably about 2% to about 25% by weight of the dosage form.

In addition, the tablet may further comprise a diluent. As the diluent, for example, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate may be used, but not limited thereto. The diluent may preferably include, but is not limited to, about 1% to about 70% by weight of the dosage form, more preferably about 2% to about 50% by weight of the dosage form.

In addition, the tablet may further include a lubricant. Lubricants include, for example, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, glycerin monostearate, polyethylene glycol 4000, and the like. May be used but is not limited thereto. The glidant may preferably include, but is not limited to, from about 0.25% to about 5%, more preferably from about 0.5% to about 3% by weight of the dosage form.

In addition, the tablets may optionally include, for example, surfactants such as sodium lauryl sulfate, polysorbate 80 and glidants such as hard silicic anhydride and talc. Preferably the surfactant may comprise about 0.2% to about 5% by weight of the dosage form, and the glidant may include but is not limited to about 0.2% to about 1% by weight of the dosage form. .

Ingredients that may also be included include antioxidants, colorants, flavors, preservatives and taste-blocking agents.

The tablet may be formed by directly compressing the components included in the tablet as described above or by pressing with a roller. Alternatively, the components included in the tablet as described above may be wet-, dry-, melt-granulated or melt congealed or extruded prior to tableting. The form of the final formulation may comprise one or more layers and may or may not be coated additionally in addition to the lipid coating or may be encapsulated.

Depending on the timing of drug release, it may also be formulated in an immediate release and / or in a modified release, preferably in a fast-release tablet or for disintegrating orally disintegrating film.

In the preparation of fast dissolving tablets or films for fast disintegration in the oral cavity, additives other than the excipients described above may be further added in an appropriate amount according to the compounding purpose. Examples thereof include fillers, plasticizers, acidulants, anti-agglomerating agents, solubilizers, stabilizers, sweeteners, copulating agents, emulsifiers, other dissolution aids, coloring agents, flavoring agents, and the like.

In particular, the film may further include a film forming base, a thickening agent, an emulsifier, and other starch.

The film forming base may be used as long as it can impart flexibility to the film, disintegrate well and maintain viscosity for particle formation without particular limitation, and preferably hypromellose, hydroxypropyl cellulose, poly Polymers such as vinyl alcohol, polyethylene oxide or polyvinylpyrrolidone can be used. As the thickener, pullulan, starch, lactose, cellulose, carrageenan, gum arabic, guar gum, locust bean gum, xanthan gum, gellan gum, agar, alginic acid, sodium alginate and the like can be used.

Fillers reduce the slippery properties of the film in the oral cavity and serve to impart backbone to the film. It also reduces the stickiness between the films and can control the rate of dissolution of the film and the dissolution rate of the film in the oral cavity. As the filler, for example, microcrystalline cellulose, cellulose polymer, magnesium carbonate, calcium carbonate, limestone powder, silicate, clay, talc, titanium dioxide and calcium phosphate can be used, and as a plasticizer for adding flexibility of the film, for example, citric acid tree Ethyl, glycerin fatty acid ester, polyethylene glycol, sorbitol, maltitol, xylitol, glycerin, polyethylene glycol and the like can be used. In addition, the acidulant may be citric acid, malic acid, fumaric acid, tartaric acid, ascorbic acid, succinic acid, adipic acid, lactic acid, and the like, and anti-aggregation agents may be used, for example, talc, calcium stearate and the like. As the solubilizer, for example, sucrose fatty acid ester, sorbitan monostearate, sodium lauryl sulfate and the like can be used, and the stabilizer can be used, for example, light silicic anhydride, magnesium metasilicate aluminate, magnesium silicate, aluminum silicate, and calcium silicate. Can be. In addition, sweeteners include, for example, aspartame, saccharin, dipotassium glycyrrhinate, stevia, and the like, and copulation agents may include, for example, l-menthol, sodium chloride, acesulfame potassium, sucralose, and emulsifiers such as glycerin fatty acid esters and sucrose fatty acids. Esters, lecithin, enzymatically lecithin, polysorbates, sorbitan fatty acid esters, propylene glycol and the like can be used. Dissolution aids can be used, for example, cyclodextrin, arginine, lysine, trisaminomethane and the like.

In addition, when formulated into oral liquid preparations such as suspensions, liquid solutions, syrups and elixir agents, various excipients such as wetting agents, sweeteners, Fragrances, preservatives and the like may be further included.

For example, in preparing suspensions, purified water may be used as a solvent, and as a suspending agent, acacia, tragacanda, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethyl cellulose 1828, 2906, 2910 and the like can be used. Optionally, surfactants, preservatives, stabilizers, colorants, and the like may further be used.

In addition, the formulation and the pharmaceutically acceptable carrier of the pharmaceutical composition of the present invention is not particularly limited and may be appropriately selected according to techniques known in the art. The effective amount of the PDE-5 inhibitor drug may also include the type of disease, the severity of the disease, the type and amount of the active and other ingredients contained in the composition, the type of formulation and the patient's age, weight, general state of health, sex and diet, administration It can be adjusted according to various factors including time, route of administration and rate of composition, duration of treatment, drugs used concurrently.

Another preferred embodiment of the present invention provides a method for preparing a Gomi masked oral composition as described above.

The preparation method preferably comprises the steps of (1) dissolving the PDE-5 inhibitor and the water-insoluble polymer in an organic solvent; (2) mixing the solution obtained in step (1) with an aqueous solution to prepare a suspension in which fine particles are formed; And (3) dispersing the lipid in the suspension to coat the fine particles contained in the suspension with the lipid.

The organic solvent of step (1) is preferably methanol, ethanol, n-propanol, isopropanol, dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, N, N-dimethylformamide (DMF ), N, N-dimethylacetamide (DMA) or a mixed solvent thereof, and more preferably ethanol.

Also preferably, the PDE inhibitor and the organic solvent may be used in a weight ratio of 100: 200 to 1000 (PDE inhibitor: organic solvent).

The preferred weight ratio for the combination of the PDE-5 inhibitor and the water-insoluble polymer can be applied to the composition.

Step (2) is a step of mixing the aqueous solution and the solution in which the PDE-5 inhibitor and the water-insoluble polymer are dissolved, and through this process, a suspension in which drug-polymer matrix microparticles with a tare mask is formed may be prepared.

The aqueous phase solution preferably contains a film forming base, and may be prepared by dissolving the film forming base in an aqueous solvent such as water. The film forming base may be used as long as it can impart flexibility to the film as described above, disintegrate well and maintain viscosity for particle formation, without particular limitation, preferably hypromellose, hydroxy Polymers such as propylcellulose or polyvinylpyrrolidone can be used. Also preferably, the concentration in the aqueous solvent of the film-forming polymer may be 5 to 50 w / v%.

Preferably, the formation of the fine particles in step (2) may be performed using a solid dispersion method. In this case, it is preferable to use an aqueous solution in excess of the solution obtained in step (1). More preferably, the solution obtained through the step (1) and the aqueous solution may be made by mixing in a volume ratio of 1: 1 to 1: 10.

Step (3) is a step of coating the fine particles contained in the suspension obtained through the step (2) with a lipid, wherein the suspension is preferably heated under a heating condition of 40 to 100 ° C, more preferably 50 to 90 ° C. The lipids can be dispersed, and the particulates contained in the suspension can be coated with the lipids, preferably with stirring for 30 to 90 minutes. By performing the lipid coating as described above, it is possible to reduce the interfacial tension, thereby preventing the aggregation during the formation of the fine particles, which enables the formation of smaller particles and further enhances the goblet shielding effect.

Gomi masked oral composition according to a preferred embodiment of the present invention prepared according to such a manufacturing method is a variety of pharmaceutically acceptable carriers as described above by using a variety of pharmaceutically acceptable carriers appropriately selected according to techniques known in the art The process of formulating into a dosage form can be further carried out.

According to the Komi masked oral composition of the present invention and a method for preparing the same, the PDE-5 inhibitor, which has been difficult to take due to the bitter taste of the prior art, can be dissolved and eaten quickly in the oral cavity without water, thereby significantly improving the patient's dose compliance. Not only can it be improved, but also the rapid release and absorption of the drug can be expected to provide excellent drug efficacy.

Figure 1 shows the dissolution test results in pH 1.2 liquid of the Examples and Comparative Examples.
Figure 2 shows the results of the dissolution test in pH 6.8 liquid of the Examples and Comparative Examples.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only to more easily understand the present invention, but the scope of the present invention is not limited thereto.

Example  1. Preparation of aqueous solution

A water phase solution was prepared by dissolving 12.5 g of hypromellose, 2 g of concentrated glycerin, 0.5 g of D-sorbitol, 3 g of sucralose, and 2 g of stevia in 100 mL of purified water.

Example  2 to 11.

(1) Step 1: The eudenafil and the water-insoluble polymer were dissolved in ethanol in the formulation shown in Table 1 and then mixed with the solution of Example 1 to form fine particles.

(2) Step 2: After stirring for 60 minutes with lipids in the formulation shown in Table 1 at a heating condition of 80 ℃ to prepare a suspension in which the highly unshielded microparticles were formed.

Unit (g) Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 drug Eudenafil 100 100 100 100 100 100 100 100 100 100 Water insoluble
pH independent polymer Ethylcellulose 50 Polyvinyl acetate 50 Water insoluble
pH dependence
Polymer Eudragit EPO 50 50 50 50 50 50 5 Smartseal 50 Lipid Stearic acid 20 Palmitic acid 20 Glycerol distearate 20 Glyceryl dibehenate 20 20 20 20 10 One 10 Organic solvent ethanol 200 200 200 200 200 200 200 200 200 200 Water solution Solution of Example 1 (ml) 480 480 480 480 480 480 480 480 480 480

Example  12. Gomi  Contains shielded particulate Oral Disintegrating Film  Produce

640 g of the suspension prepared in Example 9 was applied thinly and then dried to prepare an intraoral disintegrating film.

Example  13. Gomi  Contains shielded particulate Solution  Produce

In 640 g of the suspension of Example 9, 2000 g of white sugar, 2000 g of high fructose, 1000 g of xylitol and 800 g of purified water were dissolved to prepare a liquid solution.

Example  14. Gomi  Contains shielded particulate Oral Disintegrating Film  Produce

(1) Step 1: After dissolving 100 g of udenafil and 50 g of Eudragit EPO in 200 g of ethanol, 60 g of hydroxypropyl cellulose, 8 g of concentrated glycerin, 2 g of D-sorbitol, 12 g of sucralose, and 8 g of stevia were dissolved in 400 mL of purified water. Mix with solution to form microparticles.

(2) Step 2: After stirring for 60 minutes with 10 g of Glyceryl dibehenate at a heating condition of 80 ℃ to prepare a suspension formed with finely shielded fine particles, it was applied thinly and dried to prepare an intraoral disintegrating film.

Example  15. Gomi  Contains shielded particulate Oral Disintegrating Film  Produce

(1) Step 1: 100 g of udenafil and 50 g of Eudragit EPO 50 g of ethanol, followed by 60 g of polyvinylpyrrolidone, 8 g of concentrated glycerin, 2 g of D-sorbitol, 12 g of sucralose, and 8 g of stevia in 400 mL of purified water To form fines.

(2) Step 2: After stirring for 60 minutes with 10 g of Glyceryl dibehenate at a heating condition of 80 ℃ to prepare a suspension formed with finely shielded fine particles, it was applied thinly and dried to prepare an intraoral disintegrating film.

Comparative Example  1-2. Drug microparticle formation using polymer Oral Disintegrating Film  Produce

After dissolving the eudenafil and the polymer in ethanol in the formulation shown in Table 2, and then mixed with the solution of Example 1 to form the fine particles were prepared as oral disintegrating film.

Comparative Example  3-4. Drug particulate formation using lipids, and Oral Disintegrating Film  Produce

After dissolving udenafil in ethanol by the formulation shown in Table 2, after mixing with the solution of Example 1 and dispersing lipids in the solution shown in Table 1 in the solution at 80 ℃ heating conditions, oral indwelling The film was prepared.

Comparative Example  5. Oral Disintegrating Film  Produce

After dissolving the udenafil in ethanol in the formulation shown in Table 2, and mixed with the solution of Example 1 was prepared as an oral disintegrating film.

Unit (g) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 drug Eudenafil 100 100 100 100 100 Water Insoluble Polymer Ethylcellulose 50 Eudragit EPO 50 Smartseal Polyvinyl acetate Lipid Stearic acid 10 Palmitic acid Glycerol distearate Glyceryl dibehenate 10 Organic solvent ethanol 200 200 200 200 200 Water solution Solution of Example 1 (ml) 480 480 480 480 480

Test Example  1. Sensory evaluation (n = 20)

The bitterness masking effect of the formulations prepared according to Examples 2-15 and Comparative Examples 1-5 were tested.

1) Test subjects: 20 healthy adult male volunteers were evaluated. Each sample was evaluated at 90 minute intervals.

2) Test method: After each product was placed in the mouth for 5 minutes, bitterness was selected from the following 5 items.

   ① No bitter taste

   ② Can feel a bit bitter

   ③ has a bitter taste

   ④ bitter and persistent

   ⑤ The bitter taste is severe and persistent

3) Test result: The sensory evaluation results are summarized by the number of people who chose each term and are shown in Table 3 below.

No bitter taste I can feel a bit bitter Have a bitter taste Bitter and persistent Bitter and persistent Example 2 One 7 10 2 0 Example 3 One 6 9 4 0 Example 4 0 3 12 5 0 Example 5 0 12 5 3 0 Example 6 One 8 8 3 0 Example 7 2 8 6 4 0 Example 8 6 11 3 0 0 Example 9 3 14 3 0 0 Example 10 2 9 8 One 0 Example 11 5 12 3 0 0 Example 12 15 5 0 0 0 Example 13 16 4 0 0 0 Example 14 14 6 0 0 0 Example 15 14 6 0 0 0 Comparative Example 1 0 2 8 10 0 Comparative Example 2 0 3 12 5 0 Comparative Example 3 0 3 11 4 2 Comparative Example 4 0 0 7 8 5 Comparative Example 5 0 0 0 2 18

As shown in Table 3 above, the formulations of Examples 2 to 15 prepared according to one preferred embodiment of the present invention are prepared using only water-insoluble polymers, only lipids, or without both. Compared with the formulations of Examples 1 to 5, it was found that the Gomi masking effect was remarkably excellent.

In particular, as a result of evaluation by the ratio of lipids in Example 3, Example 9, and Example 10, it was confirmed that the Gomi masking effect is excellent even in the ratio of 100: 1 to the drug, the lipid of 100: 10 It was found that the Gomi shielding effect of Example 9 including the ratio was the best.

In addition, as a result of evaluating the polymer ratio by Example 9 and Example 11, it was possible to confirm the Gomi masking effect even at a ratio of 100: 5 compared to the drug.

Looking at the gummy masking effect of each formulation of the formulation, when the suspension of Example 9 was formulated into a pharmaceutically acceptable oral dosage form, orally disintegrating film and a liquid solution, it was more excellent than the suspension of Example 2-11 The effect was confirmed.

In addition, when the orally disintegrating film was formulated with hypromellose, hydroxypropyl cellulose, polyvinylpyrrolidone and the like according to Examples 12, 14, and 15, the effect of the same invention was confirmed.

Test Example  2. Dissolution Evaluation

Dissolution test was performed on the preparations prepared according to Example 12 and Comparative Example 2. 4, or 5 of the Examples and Comparative Examples, and the results are shown in FIGS. 1 and 2.

1) Test method: The method was evaluated by the method of dissolution of the Korean Pharmacopoeia in pH 1.2 liquid (similar to the environment in the stomach) and pH 6.8 liquid (similar to the oral cavity).

-Test solution: pH 1.2 buffer, pH 6.8 buffer (pharmacopoeia)

-Test temperature: 37 ± 0.5 ℃

-Test Solution: 900mL

-Stirring Speed: 50rpm

2) test result

As shown in Figure 1, in the pH 1.2 solution dissolution test results, it was confirmed that the Example 12 formulation was released at a rapid rate similar to commercially available Zydenade tablet (Dong-A Pharmaceutical) 100mg, while prepared only by lipid coating It was found that the formulation of Comparative Example 4 showed a very slow release rate.

In addition, as shown in Figure 2, Comparative Example 5 prepared only by lipid coating in the pH 6.8 solution results showed a dissolution pattern similar to commercially available Zydena Na tablet 100mg, and was also prepared by forming a matrix with a polymer without a lipid coating In Comparative Example 2, the dissolution rate was 20% or more for 10 minutes, which is considered to be the time for the preparation to be maintained in the oral cavity, and it was confirmed that the Gomi shielding was incomplete. On the other hand, the preparation prepared according to Example 12 of the present invention showed that the dissolution rate was not even about 10% during the time the oral preparation is maintained, showing a very limited dissolution rate.

In the above results, the drug contained in the preparation according to Example 12 is not expected to be released in the oral cavity, and is expected to be rapidly released and absorbed in the gastrointestinal tract after taking the drug, so that the bitter taste of the drug is masked while the efficacy is equal. It is judged to be a very good formulation that can be represented.

Test Example  3. Particle size evaluation

Particle size evaluation was conducted for various compositions according to the examples and comparative examples.

1) Test method: The particle size of the suspension of Examples 9 and 10, the suspension of Comparative Examples 1 and 5, and the semi-finished product in the manufacturing process of Comparative Example 1 and Comparative Example 5 were measured using wet particle measurement according to the manufacturer's manual (Malvern, UK). Table 4 below.

-Equipment: Malvern mastersizer, Hydro 2000

Example 9 Example 10 Comparative Example 1 Comparative Example 5 Average particle size (D [4,3]) About 30um About 100um About 300um About 500um

As shown in Table 4, the fine particles of Example 9 prepared by the production method of the present invention had an average particle size of about 30um and the fine particles of Example 10 were measured to about 100um to be commonly used oral disintegrating film It can be seen that it has a particle size that can be prepared, and thus it is possible to prepare the oral solid compositions of Examples 12, 14 and 15 using the suspension of Example 9.

However, in the manufacturing process of Comparative Example 1 in which the polymer and the matrix were formed, the suspension particles, which were semi-finished products, were measured to have a particle size of about 300 μm. Formulations were prepared. Therefore, it is determined that the suspension particles which are semi-finished products prepared according to the comparative example have a particle size which is not suitable for making an oral solid composition.

In addition, in the case of the method of Comparative Example 5, that is, the semi-finished suspension particles during the manufacturing process without forming a matrix with a polymer or without lipid coating, it was confirmed that very large and nonuniform particles were obtained at about 500 μm.

Therefore, in the case of the composition according to an embodiment of the present invention, as described above, it was confirmed that the antimicrobial shielding effect and the effect of rapid drug exertion were very excellent, as well as the properties, and could be formulated into various formulations.

Claims (16)

Drug-polymer matrix comprising PDE-5 inhibitor and water insoluble polymer; And
Fine particles composed of a lipid coating layer coating the matrix
Gomi improved oral composition comprising a
The method of claim 1,
The PDE-5 inhibitor is selected from the group consisting of Udenafil, Sildenafil, Sildenafil, Vardenafil, Mirodenafil, Tadalafil, and pharmaceutically acceptable salts thereof. Will, composition.
The method of claim 1,
The PDE-5 inhibitor is 10 to 75% by weight based on the total composition weight, composition.
The method of claim 1,
The water-insoluble polymer is a pH-independent solubility in water, 0.0001g / mL or less, the composition.
The method of claim 1,
The water-insoluble polymer is a gas-soluble polymer having a solubility of at least 0.03g / mL at acidic conditions of pH 1 to 5.
The method of claim 1,
The water-insoluble polymer is polyvinyl acetal dimethyl aminoacetate, polyvinyl pyrrolidon, hydroxy propyl cellulose, ethyl cellulose, hydroxy propyl methyl cellulose cellulose, hydroxy propyl methyl cellulose phthalate, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate) copolymer ( poly (ethylacrylate-methylmethacrylate) copolymer), poly (ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate) copolymer (poly (ethylacrylate-methylmethacrylate-trimethylaminoethylmethacrylate) copolymer), cellulose ether, cellulose acylate, cellulose dia Silate, Cellulose Ostriacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, cellulose acetate propionate, methyl cellulose, ethyl cellulose, hydroxy ethyl cellulose, Eudragit L100-55, Eudragit L30 D55, Eudragit L100, Eudragit S 100, Eudragit E 100, Eudragit EPO, Eudragit RL 30D, Eudragit RL PO, Eudragit RL 100, Eudragit RS 30D, U The composition selected from the group consisting of Dragit RS PO, Eudragit RS 100, Eudragit NE 30, Eudragit NE 40, Smartseal 30D and mixtures thereof.
The method of claim 1,
Wherein the drug-polymer matrix comprises a water-insoluble polymer in a weight ratio of 100: 1 to 300 relative to the PDE-5 inhibitor.
The method of claim 1,
The lipid may be arachidic acid, stearic acid, palmitic acid, palmitic acid, erucic acid, oleic acid, arachidonic acid, linoleic acid ), Linolenic acid, glyceryl dibehenate, glycerol distearate, stearyl stearate, cetostearyl alcohol, stearyl alcohol alcohol, glyceryl monostearate, glyceryl palmitostearate, cetyl alcohol, polyoxyethylene stearate, sorbitan stearate ), And sorbitan monopalmitate.
The method of claim 1,
The microparticles will comprise the lipid coating layer in a weight ratio of 100: 1 to 100 compared to the PDE-5 inhibitor.
The method of claim 1,
The particle size is 1 to 200 um, the composition.
The method of claim 1, wherein
The oral composition is provided in the form of oral disintegrating film or a solution.
(1) dissolving the PDE-5 inhibitor and the water insoluble polymer in an organic solvent;
(2) mixing the solution obtained in step (1) with an aqueous solution to prepare a suspension in which fine particles are formed; And
(3) dispersing the lipid in the suspension to coat the particulates contained in the suspension with the lipid.
12. A method for preparing a masked oral composition according to any one of claims 1 to 11.
The method of claim 12,
The organic solvent is methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, N, N-dimethylformamide (DMF), N, N-dimethylacet Amide (DMA) or a mixed solvent thereof.
The method of claim 12,
The aqueous solution is prepared by dissolving hypromellose, hydroxypropyl cellulose, or polyvinylpyrrolidone in an aqueous solvent.
The method of claim 12,
Step (2) is a method of mixing the solution obtained in the step (1) and the aqueous solution in a volume ratio of 1: 1 to 1: 10,
The method of claim 12,
The coating of step (3) is made by dispersing a lipid under a heating condition of 40 to 100 ℃, manufacturing method.

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