KR101638452B1 - Sildenafil-Bentonite-AEA Nanohybrid, Pharmaceutical Composition Containing the Same and Method for Preparing the Same - Google Patents

Abstract

The present invention relates to a sildenafil-bentonite-AEA hybrid, a pharmaceutical composition containing the sildenafil-bentonite-AEA hybrid, and a method for producing the same. The sildenafil-bentonite-AEA hybrid according to the present invention exhibits high solubility while shielding bitter taste, Which is useful as an active ingredient of a pharmaceutical composition for the treatment of sexual dysfunction.

Sildenafil, Bentonite, AEA, Nanohybrid, Antimicrobial Shielding, Powder Treatment, Sexual Dysfunction

Description

The present invention relates to a sildenafil-bentonite-AEA hybrid, a pharmaceutical composition containing the sildenafil-bentonite-AEA hybrid and a pharmaceutical composition containing the sildenafil-bentonite-AEA nanohybrid,

The present invention relates to a sildenafil-bentonite-AEA hybrid, a pharmaceutical composition containing the sildenafil-bentonite-AEA hybrid and a preparation method thereof, and more particularly to a sildenafil-bentonite-AEA hybrid compound having sildenafil inserted between bentonite layers and coated with an AEA polymer, A pharmaceutical composition for treating a disorder, and a method for producing the same.

Methyl-3-propylpyrazolo [4,3-d] pyrimidin-4-yl) d] _{pyrimidin-7-one, C 22 H 3O N 6 O} 4 S, CAS No.171599-83-0) is to be used in the ED (erectile bulneungjeung) and the treatment of female sexual dysfunction in the male, International Is disclosed in Korean Patent Publication No. 94/28902. Oral administration is preferred, and for this purpose, the water-soluble salt form initially appears to be desirable for ensuring rapid absorption and good bioavailability, and is highly soluble and non-toxic salt Is a drug that is a major component of the product currently on the market under the trade name Viagra or Revatio, citrate sildenafil, in the form of a citrate salt.

However, sildenafil is known to be suitable for administration as a conventional capsule or tablet formulation, but it is not only bitter but also has a reversible reflux due to reflux esophagitis due to oxidative stress caused by excessive secretion of acid by gastric ulcer or gastritis There is a problem with the patient's compliance with the medicine because it is bitter, so it is necessary to shield the sildenafil and to facilitate its ingestion.

To address this bitter taste, the use of microencapsulation by polymer coating to protect the sildenafil component during its stay in the mouth or the use of a pharmaceutically active substance that is less soluble in water or the development of a rapidly disintegrating agent in the mouth (Korean Patent No. 10-0435514), or sildenafil free base (Korean Patent Laid-Open No. 1999-0088249). However, when a free base is used, the bitter taste in the oral cavity can be reduced But the solubility was so low that it did not show rapid bioavailability.

Accordingly, the present inventors have made efforts to develop a formulation having high bioavailability through easy dissolution of sildenafil for the treatment of sexual dysfunction and a high dissolution rate in the upper part of the patient. As a result, sildenafil was inserted between the bentonite layers used as a pharmaceutical excipient, Then, the hybrid obtained by coating with AEA polymer, which is a stain coating agent, showed a high bioavailability as compared with a commercial product containing a sildenafil raw material, at the same time, the dissolution rate was improved while the sildenafil of the sildenafil was shielded, and the sildenafil-bentonite- AEA hybrid can be prepared in various formulations, and the present invention has been completed.

It is an object of the present invention to provide a sildenafil-bentonite-AEA hybrid, a pharmaceutical composition containing the same, and a method for producing the same.

In order to achieve the above object, the present invention provides a sildenafil-bentonite-AEA hybrid compound represented by the following formula (1) and a pharmaceutical composition for treating sexual dysfunction comprising the same as an active ingredient:

[Chemical Formula 1]

(Al _{2 - x} Mg _x ) (Si ₄ ) O ₁₀ [OH] ₂ [C ₂₂ H ₃₀ N ₆ O ₄ S] _x [A] _y

In Formula 1,

The C ₂₂ H ₃₀ N ₆ O ₄ S is sildenafil,

A is AEA (polyvinyl acetal-diethyl-acetate)

X is from 0.2 to 0.7,

y is a positive number greater than zero.

(A) dissolving sildenafil in a solvent mixed with ethanol and methylene chloride to prepare a solution; (b) mixing the sildenafil-containing solution prepared in the step (a) with an aqueous solution containing bentonite dispersed therein and stirring the mixture to prepare a hybrid body having sildenafil inserted between the layers of bentonite; And (c) spray-drying AEA (polyvinyl acetal-diethyl-acetate) on the hybrid to produce a hybrid coated with an AEA. .

(A) dissolving sildenafil in a solvent mixed with ethanol and methylene chloride to prepare a solution; (b) mixing the sildenafil-containing solution prepared in the step (a) with an aqueous solution containing bentonite dispersed therein and stirring the mixture to prepare a hybrid body having sildenafil inserted between the layers of bentonite; (c) spray-drying AEA (polyvinyl acetal-diethyl-acetate) on the hybrid to produce an AEA-coated hybrid; And (d) formulating the coated hybrid into various formulations according to pharmaceutically acceptable formulations and processes. ≪ Desc / Clms Page number 2 >

According to the present invention, sildenafil is inserted between bentonite layers and coated with AEA to shield the bitter taste of sildenafil, thereby reducing the rejection feeling during oral administration and rapidly releasing sildenafil in the gastrointestinal tract in a short time, The formulation containing a hybrid substance can increase the bioavailability through solubilization and improvement of the dissolution rate, and can improve the convenience of use and the compliance with medicines, thereby enhancing the therapeutic effect of sexual dysfunction.

In one aspect, the present invention relates to a sildenafil-bentonite-AEA hybrid substance represented by the following formula (1) and a pharmaceutical composition for treating sexual dysfunction containing the same as an effective ingredient.

[Chemical Formula 1]

(Al _{2 - x} Mg _x ) (Si ₄ ) O ₁₀ [OH] ₂ [C ₂₂ H ₃₀ N ₆ O ₄ S] _x [A] _y

In Formula 1,

The C ₂₂ H ₃₀ N ₆ O ₄ S is sildenafil,

A is AEA (polyvinyl acetal-diethyl-acetate)

X is from 0.2 to 0.7,

y is a positive number greater than zero.

As used herein, the term "hybrid" refers to a form in which sildenafil is interposed between the layers of bentonite as a combination of electrostatic attraction, and the term "hybrid" Is coated with an electrostatic attraction force.

In the present invention, the term "comprising as an active ingredient" refers to all the pharmaceutical effects that can exert a pharmaceutical effect and affect sexual dysfunction such as treatment of sexual dysfunction or alleviating some symptoms, ≪ / RTI >

In the present invention, "sildenafil" is a drug having the structure of the following formula (2)

(2)

It is known as a potent inhibitor of cyclic adenosine 3 ', 5'-monophosphate phosphodiesterase (cGMP PDEs), and is widely known as a drug effective for pulmonary hypertensive heart disease or male erectile dysfunction.

In the present invention, the term "sexual dysfunction" means sexual and / or sustained damage in a normal or conventional form and includes sexual dysfunction, sexual arousal disorder, orgasm Impaired sexual dysfunction due to sexual pain disorders and the like, and male sexual dysfunction may be an erectile dysfunction, also commonly known as male erectile dysfunction, such as premature ejaculation or premature ejaculation, anorgasmia or male amblyopia disorder, .

 In the present invention, "bentonite" represented by the following formula (3) is an inorganic mineral existing in nature and used as a suspending agent, ointment agent, toothpaste and the like. Bentonite containing a large amount of calcium ion is used as an antioxidant, , Inorganic carriers, and the like.

(3)

(Al _{2 - x} Mg _x ) (Si ₄ ) O ₁₀ [OH] ₂ M ^{+ n} _{x / n}

In the above formula, M is an interlayer ion that can be substituted by a cationic organic substance, x is 0.2 to 0.7 in composition ratio of interlayer ions, and n is a valence.

In the present invention, "AEA" is a polyvinylacetal-diethylamino-acetate (Vinyl Acetal-Diethylamino-Acetate) stain coating agent capable of improving bioabsorption and bioavailability.

In the present invention, the sildenafil-bentonite-AEA hybrid may be formulated as a main component by adding a pharmaceutically acceptable additive. The additive may be an excipient, a disintegrant, a binder, a lubricant, a lubricant , A suspending agent, a surfactant, a sweetener, a preservative, a flavoring agent, a thickening agent, a pH adjusting agent, a humectant and a mixture thereof.

In addition, a solubilizing agent may be contained in the composition of the present invention, and various surfactants including pharmacologically acceptable anionic, cationic, nonionic or amphoteric surfactants may be used herein. Specific examples thereof include polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene fatty acid esters.

 In the present invention, the hybrid body may be a hybrid body in which sildenafil is interposed between the layers of bentonite and coated with an AEA. Wherein the coating is coated through spray drying.

According to another aspect of the present invention, there is provided a process for preparing a sildenafil comprising: (a) dissolving sildenafil in a solvent mixed with ethanol and methylene chloride to prepare a solution; (b) mixing the sildenafil-containing solution prepared in the step (a) with an aqueous solution containing bentonite dispersed therein and stirring the mixture to prepare a hybrid body having sildenafil inserted between the layers of bentonite; And (c) spray drying the AEA (polyvinyl acetal-diethyl-acetate) to the hybrid to produce a hybrid coated with the AEA. The present invention also provides a method for producing a sildenafil-bentonite-AEA hybrid .

In the present invention, the sildenafil-bentonite hybrid of steps (a) to (b) is prepared by an ion exchange method. The concentration of the solution containing bentonite is, for example, 0.01 to 10% And the solution in which the sildenafil is dissolved is, for example, 0.01 to 50% by weight, and the acidic solution to be added may be selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, and an aqueous solution containing the prepared acidic sildenafil Is preferably 2 to 4. The amount of the sildenafil component in the step (b) may be about 0.1 to 10 times the molar ratio of the bentonite.

The organic solvent used to prepare the solution containing sildenafil is an organic solvent having a solubility greater than that of the aqueous solvent for the drug, and refers to a non-aqueous solvent at the interface with the aqueous solvent. With respect to the solubility of sildenafil, the organic solvent preferably has an solubility of 10 times or more, more preferably 100 times or more, and still more preferably 1000 times or more the solubility in the aqueous solvent. Such organic solvents include methylene chloride, chloroform, octanol, and the like. Among them, methylene chloride and chloroform are preferable, and methylene chloride is particularly preferable.

The amount of sildenafil in the organic phase solution is within the solubility range. Thus, the volume ratio of the aqueous solvent and the organic solvent in the interfacial reaction is determined by the amount of sildenafil based on the amount of bentonite dispersed in the aqueous solvent, And the amount of the organic solvent capable of dissolving the same amount of sildenafil is also determined.

In the present invention, in step (c), coating of AEA may be performed by dispersing a hybrid substance in a solution containing AEA and then drying. It is preferable to use a spray drying method to exhibit excellent uniformity. It has the advantage of being able to make fine particles with a high drying speed and below 100 microns.

In the present invention, the content of sildenafil in the sildenafil-bentonite hybrid of step (b) and the sildenafil-bentonite-AEA hybrid of step (c) may be 1 to 50 wt%.

According to another aspect of the present invention, there is provided a process for preparing a sildenafil comprising: (a) dissolving sildenafil in a solvent mixed with ethanol and methylene chloride to prepare a solution; (b) mixing the sildenafil-containing solution prepared in the step (a) with an aqueous solution containing bentonite dispersed therein and stirring the mixture to prepare a hybrid body having sildenafil inserted between the layers of bentonite; (c) spray-drying AEA (polyvinyl acetal-diethyl-acetate) on the hybrid to prepare an AEA-coated hybrid; and (d) drying the coated hybrid to a pharmaceutically acceptable prescription and process To formulate the composition in various formulations according to the method of the present invention.

The sildenafil-bentonite-AEA hybrid according to the present invention may be formulated into various forms such as powder, granules, capsules, tablets, suspensions, chewable tablets, oral film formulations, oral cavity disintegrants, solutions, syrups, A pharmaceutical composition of any pharmaceutical form for the treatment of sexual dysfunction can be prepared.

The preferable unit dose of the pharmaceutical composition for treating sexual dysfunction according to the present invention varies depending on various factors such as the age and sex of the subject to be administered, but is generally 10 to 100 mg, preferably 25 to 100 mg on the basis of sildenafil .

In the present invention, in addition to the main ingredient sildenafil, the composition for treating sexual dysfunction may further include a substance conventionally effective for sexual dysfunction.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are merely illustrative of the present invention and that the present invention is not construed as being limited by these embodiments.

Example  1: Sildenafil-bentonite- AEA  Hybrid system

1-1: Preparation of sildenafil-bentonite hybrid

A solution of bentonite (0.1 M) in distilled water and a solution of citric acid sildenafil (0.15 M) in a pH of 2 was mixed and stirred for 4 hours. , A sintered body in which sildenafil was intercalated between the layers of bentonite was obtained.

1-2: Sildenafil-bentonite- AEA  Hybrid Production

The sildenafil-bentonite hybrid obtained in the above 1-1 was re-dispersed in a mixed solvent of ethanol and methylene chloride. To this dispersion solution, an AEA solution dissolved in methylene chloride was added and stirred. Then, (bentonite: AEA = 1 : 1 weight ratio), followed by spray drying, to obtain a sildenafil-bentonite-AEA hybrid material which was AEA-rocated.

Experimental Example  1: comparative dissolution test

Sildenafil-bentonite hybrid as a comparative group and 50 mg Viagra tablets (Pfizer Inc.) as a control group were subjected to the pharmacopoeial dissolution test second method paddle method in the same manner as in Example 1, except that the sildenafil-bentonite-AEA hybrid prepared in Example 1 was used. The eluate was prepared according to artificial gastric juice (pH 1.2), the paddle speed was set to 50 rpm, the temperature of the eluate was set to 37 ° C, the sample was filtered for a predetermined time, and then quantified by HPLC as shown in Table 1 below.

column Zorbax Eclipse XDB-C 18 detection UV 230 nm Constant 1.0 mL / min Injection capacity 10 μL Mobile phase Buffer solution: acetonitrile = 40: 60 (v / v%)

As a result, as shown in Fig. 1, the elution of sildenafil from the sildenafil-bentonite-AEA hybrid showed 80% within 90 minutes and 90% within 120 minutes, similar to that of the viagra used as a control. This elution pattern is due to the effect of AEA, a stomach coating agent that is degraded only in acid, at a much higher level than the comparative group of sildenafil-bentonite hybrids not coated with AEA.

Experimental Example  2: Pharmacokinetic evaluation by animal test

In order to demonstrate that the sildenafil-bentonite-AEA hybrid prepared in Example 1 was statistically equivalent to Viagra, which is a commercially available drug for treating sexual dysfunction, as a control, beer dogs (Marshall Beagle , Beijing).

The sildenafil-bentonite-AEA hybrid prepared in Example 1 and the Viagra tablets were orally administered to six beagle dogs (average body weight 9.5 kg) as a control group (dose: sildenafil 20 mg / kg) And the amount of sildenafil present in the plasma was measured by HPLC-ESI-MS / MS as shown in Table 2 below, and the results are shown in FIG. 2 and Table 3 . The bioequivalence between the test drug and the reference drug was assessed by T-test and the blood concentration-time curve (AUCt), maximum blood concentration (Cmax), maximum blood concentration The concentration reaching time (Tmax) was used.

column Xterra MS C18 Reversed-phase column Constant 180 μL Mobile phase Purified water: acetonitrile: acetic acid = 75.9: 24: 0.1 (v / v / v%)

Pharmacokinetic parameters Example 1 Control group Cmax ([mu] g / mL) 12.396 + 0.673 10.471 + 0.641 Tmax (hr) 2.333 + - 0.577 1.000 ± 0.000 AUCt (占 퐂 / mL) 77.267 ± 2.780 67.043 + - 3.132

As shown in FIG. 2 and Table 3, the sildenafil-bentonite-AEA hybrid according to the present invention exhibited all or more of the statistical treatment results, and showed high bioavailability, thus confirming that effective sexual dysfunction treatment is possible.

Example  2: Sildenafil-bentonite- AEA  Preparation of pharmaceutical compositions for treating sexual dysfunction disorders

The sildenafil-bentonite-AEA hybrid as a main ingredient was prepared by adding the ingredients shown in Table 4 below.

Ingredients usage Sildenafil-bentonite-AEA hybrid 10.0 g Lactose 60.0 g Di-sorbitol 20.0 g Beta-cyclodextrin 1.0 g Polyvinylpyrrolidone 2.5 g After masking, Suitable amount

After dissolving the prescribed beta-cyclodextrin in a predetermined amount of purified water, the sildenafil-bentonite-AEA hybrid and the excipient, which are the main components, were added and dried, and the weight per capsule was 1,000 mg by a conventional acid preparation method.

Comparative Example  1: pure sildenafil containing Acid formulations  Production of pharmaceutical composition for the treatment of sexual dysfunction

Comparative Example 1 was prepared in the same manner as in Example 2, except that pure sildenafil was used as the main component.

Experimental Example  3: Sildenafil-bentonite- AEA  Hybrid content Acid forming function  Of a pharmaceutical composition for the treatment of disorders Gummy shielding  evaluation

The composition containing the sildenafil-bentonite-AEA hybrid prepared according to Example 2 was orally administered to 30 healthy adults and the bitter taste was evaluated 5 minutes after administration. Evaluation results According to the 6th grade, the evaluation results are shown in Table 5 below. As a comparative example, a pure sildenafil containing composition was tested.

Roughness degree Comparative Example 1 Example 2 0: I do not feel bitter taste at all 0 people 30 people 1: Knowing bitter taste 0 people 0 people 2: Slightly written 0 people 0 people 3: Written 0 people 0 people 4: Write but bear 3 people 0 people 5: Too much to write 27 people 0 people

As a result of the sensory evaluation, it was found that the bitter taste of sildenafil was successfully inhibited in a composition containing a sildenafil-bentonite-AEA hybrid, thereby reducing the feeling of rejection and enhancing ease of taking at the time of oral ingestion of the agent for treating sexual dysfunction.

The pharmaceutical composition for the treatment of sexual dysfunction comprising sildenafil-bentonite-AEA hybrid according to the present invention exhibits a fast dissolution rate in a short period of time due to the effect of AEA ion exchange which is decomposed in artificial gastric juice, It can be seen that it is a drug exhibiting excellent bioavailability even in the equivalence test. Therefore, it has been confirmed that the present invention is industrially very useful invention.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

FIG. 1 is a graph showing the dissolution rate over time in artificial gastric juice (pH 1.2) according to paddle method conditions. FIG. (a: sildenafil-bentonite hybrid, b: sildenafil-bentonite-AEA hybrid, c: Viagra, d: sildenafil citrate)

2 is a graph of concentration-time of sildenafil in plasma according to bioequivalence test. (a: sildenafil-bentonite-AEA hybrid, b: Viagra)

Claims (7)

Wherein sildenafil is inserted between the interlayers of bentonite as a bond of electrostatic attraction and the sildenafil-bentonite having an AEA polymer coated with an electrostatic attraction on the bentonite interposed between the interlayers, -AEA hybrid: [Chemical Formula 1] (Al _2-x Mg _x ) (Si ₄ ) O ₁₀ [OH] ₂ [C ₂₂ H ₃₀ N ₆ O ₄ S] _x [A] _y In Formula 1, The C ₂₂ H ₃₀ N ₆ O ₄ S is sildenafil, A is AEA (polyvinyl acetal-diethyl-acetate) X is from 0.2 to 0.7, y is 1. delete A pharmaceutical composition for the treatment of sexual dysfunction comprising the sildenafil-bentonite-AEA hybrid of claim 1 as an active ingredient. [Claim 5] The pharmaceutical composition for treating sexual dysfunction according to claim 3, wherein the content of sildenafil in the sildenafil-bentonite-AEA hybrid is 1 to 50 wt%. The pharmaceutical composition for the treatment of sexual dysfunction according to claim 3, further comprising a pharmaceutically acceptable additive. 6. The composition of claim 5, wherein the additive is selected from the group consisting of excipients, disintegrants, binders, lubricants, suspending agents, surfactants, sweeteners, preservatives, flavoring agents, thickeners, pH adjusting agents, wetting agents, Or a pharmaceutically acceptable salt thereof. A method for producing a sildenafil-bentonite-AEA hybrid comprising the steps of: (a) dissolving sildenafil in a solvent mixed with ethanol and methylene chloride to prepare a solution; (b) mixing the sildenafil-containing solution prepared in the step (a) with an aqueous solution containing bentonite and stirring to insert the sildenafil between the layers of the bentonite; And (c) spray-drying AEA (polyvinyl acetal-diethyl-acetate) onto the bentonite having the sildenafil intercalated therebetween to prepare a hybrid coated with the AEA.

Images