KR101761983B1 - Fast dissolving oral thin film composite and preparing method thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration containing oral sustained-release microparticles containing 150 to 200 parts by weight of at least one selected from the group consisting of ethyl cellulose, ethyl cellulose and collidone, based on 100 parts by weight of fexofenadine or a pharmaceutically acceptable salt thereof, To provide a film composition.
Fexofenadine or a pharmaceutically acceptable salt thereof may be formulated as sustained release microparticles to maintain an effective blood concentration in the body of a patient so that it can be taken once a day, thereby greatly increasing the convenience of medication. In addition, the application of fexofenadine can be shielded to increase the adherence of medicines, and the film formulation can easily treat patients and aged people who have decreased gingival capacity.

Description

TECHNICAL FIELD [0001] The present invention relates to a disintegrating oral film composition and a preparation method thereof,

The present invention relates to an oral disintegrating film composition containing a sustained-release microparticle having a gummy-shielding effect so that a patient or an elderly person suffering from insufficient swallowing ability can easily take the drug, and the pharmaceutically active ingredient has a sustained-release property.

Fexofenadine hydrochloride (C ₃₂ H ₃₉ NO ₄ .HCl, MW = 538.13) is used by the US Food and Drug Administration (FDA) as the active ingredient of antihistamines known as Allegra ^® . The half-life is 14.4 hours and administered orally. Depending on the dose, it contains 30, 60, 120 or 180 mg of fexofenadine and the excipients are croscarmellose sodium, magnesium stearate, microcrystalline cellulose and pregelatinized starch. The tablets are coated with a film coating of titanium dioxide, silicon dioxide, povidone, polyethylene glycol, a mixture of iron oxide and hydroxypropylmethylcellulose, which is rapidly absorbed after administration and only a very small amount is metabolized and 80% , And 11% are excreted in the urinary tract.

For 30 mg dose of fexofenadine 30 mg once a day for children aged 6-11 years orally twice a day with water. Because of the bitter taste of fexofenadine, it caused difficulties for children to take their medicines.

Various types of fast-disintegrating fast-disintegrating preparations such as granules and syrups have been developed for the elderly and pediatric patients suffering from weak swallowing ability and can be easily taken without water. In particular, , It is required to provide a sustained-release function to a rapidly collapsing agent in the oral cavity according to the demand of various drugs because of its convenient use.

Korean Patent No. 1188594 discloses an oral oral rapid-release film formulation containing sildenafil citrate, which exhibits a very bitter taste, and sodium hydroxide, sodium hydrogencarbonate or a mixture thereof as a bitter taste blocker, but mitigates the feeling of discomfort when taking a bitter taste , It is necessary to provide an oral disintegrating film composition in which the sustained release of the drug is given, while the drug is rapidly disintegrated upon administration, while giving sustained release properties to the drug.

The present invention relates to a composition containing a sustained-release microparticle, which can be used for the elderly and pediatric patients having weak gonadal dysfunction, The aim of the present invention is to provide a sustained oral disintegration film.

The present invention relates to a pharmaceutical composition for oral administration containing oral sustained-release microparticles containing 150 to 200 parts by weight of at least one selected from the group consisting of ethyl cellulose, ethyl cellulose and collidone, based on 100 parts by weight of fexofenadine or a pharmaceutically acceptable salt thereof, To provide a film composition.

The sustained-release fine particles may be 0.5 to 1.0 mu m.

According to another aspect of the present invention, there is provided a method for preparing a mixed solution, comprising: dissolving fexofenadine or a pharmaceutically acceptable salt thereof and a sustained-release polymer to prepare a mixed solution; Spray-drying the mixed solution to prepare sustained-release fine particles; Dissolving the film forming agent in an alcohol, and dispersing the sustained-release fine particles to prepare a suspension; And applying the suspension and drying the suspension.

The sustained release polymer may be at least one selected from the group consisting of ethyl cellulose, udragit, and collidone, and ethyl cellulose and the remaining sustained-release polymer may be mixed in a weight ratio of 1: 1 to 2.

In addition, in the step of spray-drying the mixed solution, the air-drying temperature of the spray dryer may be 90 to 100 ° C, the exhaust temperature may be 70 to 80 ° C, and the solution speed may be 1.5 ml / min.

The film forming agent may be any one selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

In the step of preparing the suspension, any one selected from the group consisting of dextrin, mannitol, sorbitol and copovidone may be further added as a plasticizer.

According to the oral disintegration film composition of the present invention, fexofenadine or a pharmaceutically acceptable salt thereof can be manufactured as sustained-release fine particles to maintain effective blood concentration in the body of a patient so that it can be taken once a day, . In addition, the application of fexofenadine can be shielded to increase the adherence of medicines, and the film formulation can easily treat patients and aged people who have decreased gingival capacity.

FIG. 1 is a flowchart showing the steps of a method of manufacturing an oral disintegrating film composition according to an embodiment of the present invention.
2 is a graph showing dissolution rates of the sustained-release microparticles according to an embodiment of the present invention.
FIG. 3 is a graph showing dissolution rate of an oral disintegration film composition containing sustained-release microparticles according to an embodiment of the present invention. FIG.
4 is a graph comparing dissolution rates of an oral disintegrating film composition containing sustained-release microparticles and a film composition not containing sustained-release microparticles according to an embodiment of the present invention.

The present inventors have made efforts to produce sustained-release microparticles containing peptopetadine hydrochloride so as to be able to maintain effective blood levels of fexofenadine or a pharmaceutically acceptable salt thereof so as to be taken once a day, It has been confirmed that the sustained release of the drug is greatly increased when fexofenadine or a pharmaceutically acceptable salt thereof is surrounded by a polymer and is made into a sustained-release microparticle. The present inventors completed the present invention by confirming that when the sustained-release microparticles prepared are applied to a film formulation, they can easily be used for patients who are shielded from the artificial teeth, are rapidly disintegrated in the oral cavity,

The present invention relates to a pharmaceutical composition for oral administration containing oral sustained-release microparticles containing 150 to 200 parts by weight of at least one selected from the group consisting of ethyl cellulose, ethyl cellulose and collidone, based on 100 parts by weight of fexofenadine or a pharmaceutically acceptable salt thereof, To provide a film composition.

In the present invention, the sustained-release microparticles are defined as fine particles containing a drug and subjected to sustained release treatment and having an average particle diameter of about 500 to 850 nm.

In addition, the sustained-release treatment imparts a slow-release property known to be pharmaceuticals, and includes a treatment imparting a drug release property, a treatment imparting time-release properties, a treatment imparting release properties .

The fexofenadine (IUPAC name: (RS) -4- (1-hydroxy-4- (4- (hydroxydiphenylmethyl) -1-piperidyl) butyl) -?,? And is a fast and long acting antihistamine agent that selectively acts on peripheral H1 receptors. In the form of fexofenadine hydrochloride, it is used in the treatment of psoriasis fever and similar allergic rhinitis, and also in the treatment of chronic idiopathic urticaria, but due to its unique strong redness, means are needed to screen the active ingredient.

The pharmaceutically acceptable salt thereof means a preparation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound, and includes, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid and the like, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and salicinic acid, methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, p-toluenesulfonic acid, and the like, and acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion.

 The pharmaceutically acceptable carboxylate may be a metal salt or an alkaline earth metal salt formed by lithium, sodium, potassium, calcium, magnesium or the like, an amino acid salt such as lysine, arginine or guanidine, dicyclohexylamine, N- Organic salts such as glutamine, glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine, and the like, and fexofenadine hydrochloride is preferable.

The sustained-release microparticles may be slowly dissolved in the body after administration to the human body to control the drug release time of fexofenadine. Fexofenadine or fexofenadine may be added to the matrix structure formed by mixing ethyl cellulose with any one selected from the group consisting of eudragit and collidone. Its pharmaceutically acceptable salts are dispersed.

When the sustained-release microparticle is formed, it must contain ethyl cellulose. When the sustained-release base material does not contain ethylcellulose, the drug elutes at least 50% within 1 hour and does not exhibit sustained release.

At this time, the weight ratio of ethyl cellulose and ethyl cellulose is preferably 1: 1 to 2.

The sustained-release microparticle may contain 150-200 parts by weight of at least one selected from the group consisting of ethyl cellulose, eudragit and collidone, based on 100 parts by weight of fexofenadine or a pharmaceutically acceptable salt thereof.

When the above conditions are exceeded, the sustained release of the sustained-release microparticles may not appear, and the dosage of the film formulation containing the pexofenadine is 60 mg, which is a standard dose of 30 mg twice a day for children aged 6 to 11 years It is difficult to quantify.

The sustained-release fine particles may be 0.5 to 1.0 mu m.

When the above-mentioned conditions are exceeded, when the sustained-release microparticles are dispersed to make a film formulation, homogeneity can not be ensured. If it exceeds 1.0 탆, there is a problem that a foreign body feeling is felt when the film composition in the oral cavity is taken.

According to another aspect of the present invention, there is provided a method for preparing a mixed solution, comprising: dissolving fexofenadine or a pharmaceutically acceptable salt thereof and a sustained-release polymer to prepare a mixed solution; Spray-drying the mixed solution to prepare sustained-release fine particles; Dissolving the film forming agent in an alcohol, and dispersing the sustained-release fine particles to prepare a suspension; And applying the suspension and drying the suspension.

The sustained-release polymer may be at least one selected from the group consisting of ethyl cellulose, ethyl cellulose, and collidone, and the weight ratio of ethyl cellulose and the remaining sustained-release polymer may be 1: 1 to 2: 1.

If the above conditions are exceeded, the sustained release may not be exhibited.

In another embodiment of the present invention, the sustained-release polymer may be ethylcellulose, and may be contained in an amount of 300 to 500 parts by weight based on 100 parts by weight of fexofenadine or a pharmaceutically acceptable salt thereof.

If the condition is exceeded, the drug may be eluted by more than 10% within 1 hour.

The sustained-release microparticles can be characterized by 0.8 to 1.0 탆. If the sustained-release microparticles are dispersed to make a film formulation, the homogeneity can not be ensured. When the size of the sustained-release microparticles is more than 1.0 탆, There is a problem of feeling a foreign body feeling.

In the step of spray-drying the mixed solution, the spray dryer has an inlet temperature of 100 to 125 ° C, an exhaust temperature of 70 to 80 ° C, an injection pressure of 50 to 150 kPa, a solution speed of 1.5 to 10 Ml / min.

If the above conditions are exceeded, there is a problem that the particle size of the sustained-release fine particles is not formed to be 1 탆.

The film forming agent may be any one selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, and is not limited as long as it can be used as an excipient in a drug formulation.

In the step of preparing the suspension, any one selected from the group consisting of dextrin, mannitol, sorbitol and copovidone may be further added as a plasticizer.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the scope of the present invention is not limited to the following examples.

< Example  1>

30 mg of fexofenadine hydrochloride and 30 mg of ethylcellulose were added to ethanol, followed by stirring to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  2>

To 30 mg of fexofenadine hydrochloride, 90 mg of ethylcellulose was added to ethanol, and the mixture was stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  3>

To 30 mg of fexofenadine hydrochloride, 150 mg of ethylcellulose was added to ethanol, and the mixture was stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  4>

60 mg of fexofenadine hydrochloride, 90 mg of ethylcellulose and 90 mg of Eudragit RS PO were added to ethanol, and the mixture was stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  5>

60 mg of fexofenadine hydrochloride and 180 mg of Eudragit RS PO were added to ethanol and stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  6>

60 mg of fexofenadine hydrochloride and 180 mg of Eudragit RL PO were added to ethanol and stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  7>

60 mg of fexofenadine hydrochloride and 180 mg of colloid SR were added to ethanol and stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

< Example  8>

60 mg of fexofenadine hydrochloride, 90 mg of ethylcellulose and 90 mg of Eudragit RS PO were added to 10 ml of ethanol and stirred to prepare a mixed solution.

The mixed solution was put into a spray drier (EYELA, SD-1000), spray-dried at an inlet temperature of 100 캜, an exhaust temperature of 80 캜, and a solution speed of 1.5 ml / min to prepare sustained release fine particles.

500 mg of hydroxypropyl methylcellulose (HPMC E4H), 50 mg of low-substituted hydroxypropylcellulose (L-HPC LH11), 50 mg of microcrystalline cellulose 100 mg of polyethylene glycol (PEG 400), 100 mg of mannitol and 30 ml of distilled water were mixed, and the mixture was cast on a stainless steel base using a film coater, dried at 80 ° C, To prepare a uniform oral disintegrating film composition.

< Experimental Example  1> Sue castle  Experiment of dissolution of fine particles

The elution tests of the sustained release microparticle formulations prepared in Examples 1 to 3 were performed using a paddle method of Korean Pharmacopoeia (9th revision) using an elution machine (DST-600A, Labfine, Seoul, Korea).

At this time, the eluent was pH 1.2 and the buffer solution was 900 ml, the temperature was 37 ± 0.5 ° C, and the rotation speed of the paddle was 50 rpm. 5 ml of the sample was taken from the eluate and directly filtered using a PVDF syringe filter and then measured at 234 nm using high pressure liquid chromatography (hereinafter referred to as 'HPLC').

2 is a graph showing dissolution rates of the sustained-release microparticles according to an embodiment of the present invention.

As a result of measuring the dissolution rates of the sustained-release microparticles prepared in Examples 1 to 3 over time, it was found that when the content of ethylcellulose in the sustained-release microparticles was 30 mg, 90% or more of the drug was released within 1 hour, When the content was 90 mg, less than 70% of the drug was released in one hour, and in the case of 150 mg, less than 20% of the drug was released within 2 hours.

It was confirmed that the sustained-release microparticles had an emission control effect when 300 to 500 parts by weight of ethyl cellulose was added to 100 parts by weight of phexopenadine.

< Experimental Example  2> Depending on spray conditions Sue castle  Particulate

The sustained-release microparticles were prepared by the same spray drying conditions as in Example 2 to confirm the maximum particle size of the microparticles. The sustained-release microparticles were prepared by varying the injection pressure, the intake temperature and the solution speed during spray drying, and then the sustained-release microparticles were analyzed using an electrophoresis apparatus (Otsuka electronics, ELS-8000).

Table 1 shows the particle size of the sustained-release microparticles according to spray drying conditions.

Condition Injection pressure (kPa) Solution speed (ml / min ) Intake temperature (℃) Particle size (nm) One 100 5 125 912.3 2 100 5 100 703.5 3 100 8 100 859.9 4 100 10 100 904.6 5 150 5 100 540.9 6 50 5 100 1138.3

 Conditions 1 to 5, it was possible to produce sustained-release microparticles having a particle size of 1 탆 or less, and dispersion homogeneity was maintained when the film formulation was applied when an oral disintegration film composition was prepared. It was confirmed that the sustained release fine particles of Condition 6 were dispersed in the film in a non-uniform manner when the film composition was prepared by disintegration in the oral cavity, and there was a problem in the uniformity of the content and there was a difficulty in taking it due to the foreign body feeling.

Therefore, the optimal conditions of the spray drying process were limited to the particle size of the sustained - release microparticles below 1 ㎛ when the injection pressure was 100 kPa, the eluting solution speed was 5 ㎖ / min, and the inlet temperature was 125 ℃.

< Experimental Example  3> Oral Get out of here.  Physical Properties of Film Composition

For comparison, a film composition containing only a drug was prepared, and the oral dissolution-retarding film composition prepared in Example 8 and drug elution test were conducted. The elution test was carried out using an elution machine (DST-600A, Labfine, Seoul, Korea) using the basket method of Korean Pharmacopoeia (9th revision).

Table 2 shows a comparison of the components with and without a sustained-release base.

Example 8 Comparative Example HPMC E4H 500 500 L-HPC LH11 50 50 MCC PH101 12 12 PEG400 100 μl 100 μl Mannitol 1000 1000 Fexofenadine hydrochloride 60 60 Ethyl cellulose 45 cps 90 - Eudragit RS PO 90 - ethanol 10 ml 10 ml Distilled water 30 ml 30 ml

At this time, the eluent was artificial saliva (pH 6.75) and buffer solution 85 ml, the temperature was 37 ± 0.5 ° C, and the rotational speed of the paddle was 25 rpm. A 5 ml sample was taken from the eluate over time and immediately filtered using a PDVF syringe filter and measured at 234 nm using HPLC.

FIG. 3 is a graph showing dissolution rate of an oral disintegration film composition containing a sustained-release microparticle according to an embodiment of the present invention. FIG. 4 is a graph showing dissolution rate of an oral fast- Dissolution rate of a film composition containing no sustained-release microparticles and a dissolution rate of a film composition containing no sustained-release microparticles.

Referring to the drawings, in the oral disintegrating film composition containing sustained-release microparticles, less than 70% of the drug was released in 2 hours, and in the case of the film containing only drug, about 90% of the drug was released in 2 hours Respectively.

In the case of the oral disintegrating film composition containing the sustained-release microparticles, it was confirmed that the release was further increased as compared with the release of the sustained-release microparticles themselves, because the HPMC used for film formation was swollen while absorbing the water and the ethylcellulose It is considered that the release of the drug is promoted by generating cracks in the insoluble film formed.

However, in the oral disintegrating film composition containing the sustained-release microparticles, it was confirmed that the release of the drug was significantly delayed as compared with the film containing only the drug.

As described above, according to the present invention, fexofenadine or a pharmaceutically acceptable salt thereof is formed into sustained-release microparticles. 90 mg of ethylcellulose and 90 mg of Eudragit were mixed with 60 mg of fexofenadine hydrochloride, the injection pressure was 100 kPa, the eluting solution speed was 5 ml / min, and the particle size of the sustained release fine particles Can be formed to be 1 mu m or less. Therefore, the optimum conditions for producing the oral disintegrating film composition containing the sustained-release microparticles are confirmed.

While the invention has been described with reference to a limited number of embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims. Accordingly, the true scope of the present invention should be determined by the technical idea of the appended claims.

Claims (8)

delete delete Dissolving fexofenadine or a pharmaceutically usable salt thereof and a sustained-release polymer to prepare a mixed solution;
Spray-drying the mixed solution to prepare sustained-release fine particles;
Dissolving the film forming agent in an alcohol, and dispersing the sustained-release fine particles to prepare a suspension; And
Applying and drying the suspension,
The spray drying is preferably performed such that the inlet temperature of the spray dryer is 100 to 125 ° C, the exhaust temperature is 70 to 80 ° C, the injection pressure is 100 to 150 kPa, and the solution rate to be eluted is 5 to 10 ml / min A method for preparing a film composition in an oral cavity. [4] The method according to claim 3, wherein the sustained-release polymer is at least one selected from the group consisting of ethyl cellulose, udragit and collidone, and ethyl cellulose and the remaining sustained-release polymer are mixed in a weight ratio of 1: 1 to 2 Of the total amount of the composition. [Claim 4] The method according to claim 3, wherein the sustained release fine particle is 0.5 to 1.0 mu m. delete [Claim 4] The method according to claim 3, wherein the film forming agent is any one selected from the group consisting of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose. [Claim 5] The method according to claim 3, wherein any one selected from the group consisting of dextrin, mannitol, sorbitol and copovidone is further added as a plasticizer in the step of preparing the suspension.

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