KR101383430B1 - Composition for Oral Fast Dissolving film and pharmaceutical for Oral Fast Dissolving film containing PDE5 inhibitor drugs - Google Patents

Abstract

The present invention relates to film-forming compositions and film-like pharmaceutical preparations thereof which improve the properties of fast disintegrating films in the oral cavity.
The present invention provides a film-forming composition containing Pullulan and Hydroxypropyl Pea Starch and a fast disintegrating film-like pharmaceutical preparation containing oral drug.
Intraoral fast disintegrating film-forming composition according to the present invention is very excellent in film properties, can produce a film formulation that can exhibit a rapid intraoral disintegration rate, the fast disintegrating film-type pharmaceutical preparation of the present invention is an excipient By suppressing the drug content is limited by, and can be prepared in the oral disintegrating film formulations containing the drug in the PDE5 series, it improves the dosage compliance and convenience of taking the drug.

Description

Composition for Oral Fast Dissolving film and pharmaceutical for Oral Fast Dissolving film containing PDE5 inhibitor drugs

The present invention relates to a novel combination of film-forming compositions and PDE5 inhibitor drugs containing film-formulated pharmaceutical preparations that improve the properties of fast disintegrating films in the oral cavity.

Currently there are a variety of pharmaceutical preparations in the pharmaceutical field, typically orally administered in solid form such as tablets, caplets, capsules and granules, these formulations being swallowed whole with an appropriate amount of water to deliver the drug. Is designed to chew or chew. In the liquid form, suspensions and injections are administered orally or parenterally.

However, orally administered formulations often have difficulty swallowing or chewing in children, elderly patients and the like. In addition, taking solid preparations with liquids is reluctant to take these preparations because they can cause throat or esophagus. In addition, the availability of drinking water at the time of administering the drug may be limited for certain patients and may be limited for certain diseases and / or treatments.

Accordingly, as a result of various studies recently, formulations having a new drug delivery system have emerged. Oral disintegrating tablet (ODT), which developed a solid in the form of oral disintegration, is one such result. However, oral disintegrating tablets also dissolve the drug in the oral cavity, but it is common that all the drugs do not disintegrate at a constant fast time, and it is also necessary to take water again.

Formulations newly presenting a delivery system for such drugs are oral disintegrating film-type preparations that have recently been mentioned. Such film formulations offer several other advantages over conventional solids, solutions and orally disintegrating tablets.

In recent years, film formulations, which have been studied a lot, can be said that disintegration of drugs is more advanced than conventional formulations, and many attempts have been made to prepare oral film formulations of various technologies for film properties and patient compliance. ought.

Among them, the research on the film forming polymer for forming the film is the most important part in the film production technology, many researchers continue to study the polymer for forming the film. However, in the case of such a polymer, depending on the properties of the polymer itself, when injecting a drug may exhibit a variety of physical properties.

Currently, polymers that are widely used as film-forming agents for preparing oral film-type preparations are flulan, gelatin, pectin, low viscosity pectin, hydroxypropylmethyl cellulose, low viscosity hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and hydroxy. Roxypropyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, alginic acid, low viscosity alginic acid, sodium alginate, starch, casein, whey protein There are various polymers such as isolate, soy protein isolate, zein, levane, elcinan, gluten, acacia gum, carrageenan, arabic gum, guar gum, locust bean gum, xanthan gum, gellan gum and agar. In addition, many examples of the preparation of intraoral film-type preparations using such polymers are known.

However, these conventional intraoral film-type preparations are not the most basic of drugs and polymers, but there is a need to improve film properties caused by mixing of drugs and polymers.

In order to solve the above problems, Korean Patent Application Nos. 2007-0080677, 2008-0026953, 2005-7014063, 2010-7017866, 2010-7027980, 2009-0085522, 2002-7000868 , No. 2008-7014544, 2001-7009145, etc. discloses a film that improves the film properties by increasing the film's strength and tensile strength, but the prior art can not improve the film properties with the film forming agent alone, In most cases, film agents are formed by adding excipients such as stabilizers, softeners or plasticizers to improve physical properties.

Conventionally, the use of such polymers for film formation has a limitation in the ability to accommodate raw materials and / or medicaments by adding a lot of additional excipients, and thus has a limit in efficacy or effect expressed in actual intake. There was a downside.

By the way, oral film formulations may be used as medicines to aid the human body ingested in the human body should not affect physical properties as well as physical properties such as strength and flexibility of the film.

Accordingly, film formulations have been required to consider not only film properties but also physical compatibility of films and drugs. However, in the case of existing film preparations, the reality is that almost all of the film-forming polymers are used as a single polymer and the physical properties of the film are improved through various excipients.

Thus, the inventors of the present invention, while improving the physical properties of the polymer itself to form a film and can be used in combination with a drug to improve the film forming and physical properties, while studying a specific two kinds of film-forming polymer Is an oral film-forming polymer composition and the film having improved film properties (strength, tensile strength, flexibility and dissolution rate in the oral cavity) regardless of the use of excipients The present invention was completed by developing a film-type pharmaceutical formulation containing a PDE5 inhibitor drug using the forming polymer composition.

It is an object of the present invention to provide a new combination of film-forming compositions having improved film properties regardless of the use of excipients for improving the physical properties of fast disintegrating films in oral cavity.

In addition, an object of the present invention is to provide a fast disintegrating film-type pharmaceutical preparation in the oral cavity containing the PDE5 inhibitor drug in the film-forming composition.

Hereinafter, the present invention will be described in detail.

The present invention provides an edible film forming composition composed of Pullulan and Hydroxypropyl Pea Starch, which have improved film properties for fast disintegrating film preparation of PDE5 inhibitor drug.

Orally disintegrating film-forming composition in the oral cavity by Pullulan and Hydroxypropyl Pea Starch of the present invention may be mixed in a ratio of 95: 5 to 5:95 weight (w / w%). , 7: 3 to 3: 7 w / w% is preferred.

The film forming composition according to the present invention may be prepared by completely dissolving Pullulan and Hydroxypropyl Pea Starch in a suitable amount of purified water, and the intraoral film may be prepared using the film forming composition. It can be produced by casting on a stainless steel base using a coater.

Surprisingly, Pullulan and Hydroxypropyl Pea Starch compositions according to the present invention are better than other polymers alone or mixtures thereof (known from Korean Patent Application No. 2011-75179), which are widely known as conventional film forming agents. It is characterized by having a remarkably excellent effect on the strength, tensile strength, flexibility and dissolution rate of the oral cavity, which are physical properties of the film.

In particular, the present invention is remarkable in the strength, tensile strength, flexibility and oral dissolution rate of the film even if the use of excipients (stabilizers, softeners and plasticizers, etc.) as in the prior art to avoid the use of the fast disintegrating film in the oral cavity Excellent effect.

The present invention also provides a fast disintegrating film-type pharmaceutical preparation in the oral cavity containing the PDE5 inhibitor drug in the film-forming composition.

The fast disintegrating film-type pharmaceutical preparation in the oral cavity containing the PDE5 inhibitor drug according to the present invention is completely dissolved in a suitable amount of purified water, mixed with the film-forming composition, and then cast on a stainless steel base using a film coater. It can manufacture.

In particular, the present invention may enable the preparation of the desired intraoral film formulation without limiting the type and content of the PDE5 inhibitor drug, with or without the addition of excipients to improve the physical properties of the film.

In the present invention, it can be prepared by further adding a taste improving agent used in the conventional pharmaceutically acceptable film preparation, sodium hydroxide, sodium bicarbonate, peppermint oil, L-menthol, strawberry flavor, lemon flavor, pineapple flavor, ah Cesulfame potassium, aspartame, sucralose and citric acid can be selected from one or more.

The present invention provides an orally disintegrating film forming composition containing Pullulan and Hydroxypropyl Pea Starch to improve the physical properties of the film to improve the physical properties of the film of the desired film with or without excipients It can be prepared, the film properties (strength, elongation and flexibility) is very excellent, it can be prepared in the oral disintegrating film that can exhibit a rapid oral disintegration rate.

In addition, the present invention is to suppress the drug content is limited by the excipient, to enable the preparation of the desired fast disintegrating film-type pharmaceutical formulation in the oral cavity, and to be useful for preparing the film formulation irrespective of the improvement of physical properties through other excipients It can be used and improves the dose compliance and convenience of taking the drug.

Hereinafter, the present invention will be described in detail by Examples, Formulation Examples and Experimental Examples.

However, the following Examples, Formulation Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following Examples, Formulation Examples and Experimental Examples.

≪ Comparative Examples 1 to 4 > Preparation of Film by Single Polymer

Film formulations with known single polymers were prepared. Hydroxypropylmethylcellulose (HMC), Hydroxypropylcellulose (HPC), Pullulan, Hydroxypropyl Pystar (Hydroxypropyl Pea Starch, Lycoat RS720, ROQUETTE) in Table 1 Add 30 g each. The solution was completely dissolved by stirring with a homogenizer at 2,000 rpm for 30 minutes and allowed to stand at room temperature for 24 hours to remove bubbles. Each solution was cast on a stainless steel base using a film coater, dried at 80 ° C., and then separated to prepare a uniform film having a thickness of 300 μm, and Comparative Examples 1 to 4 were used.

<Experimental Example 1> Comparison of Physical Properties and Oral Dissolution Rates of Single Polymer Films

It is a test for comparing the mechanical properties of the film prepared in Comparative Examples 1 to 4 (film production using a single polymer) and the oral dissolution rate.

1) Tensile Strength Test

Tensile strength test (tensile strength test) is to compare the mechanical properties from the strength and elongation of the fast disintegrating film in the oral cavity.

Specimens of the films prepared in Comparative Examples 1 to 4 (sample size standard: ASTM D638 type IV) were stretched (AG-5000g, Shimadzu, Japan) with a tensile strength (strength) and elongation (Elongation) of the film. Was measured (measurement condition: Cross-head speed-10mm / min).

Elongation was determined by the following equation through the tensile test.

Elongation (%) = △ L / L X 100

                    △ L: length of specimen

L: length of initial specimen

2) flexibility test

This is an experiment to check the flexibility of the film. Each of the films prepared in Comparative Examples 1 to 4 was put in a dryer (80 ° C., 2 hours) to completely remove moisture in the film, and the angles of the films when they were folded in half were measured.

3) Oral dissolution rate comparison test

It is an experiment to examine the dissolution rate in the oral cavity of the prepared film. For five adults, the films prepared in Comparative Examples 1 to 4 in the oral cavity were cut into 25 mm X 32 mm, respectively, placed in the oral cavity, and the average time was measured by measuring the time for complete dissolution of the film by saliva. .

4) Test result

Table 2 shows test results in which tensile strength (film strength, elongation rate), flexibility, and dissolution rate in the oral cavity of the films prepared in Comparative Examples 1 to 4 were measured.

5) Evaluation

As can be seen in Table 2, among the fast disintegrating films (Comparative Examples 1 to 4) in the oral cavity by a film-forming agent of a single polymer, Comparative Examples 1 to 3 showed a good result in the film strength or elongation relatively, but Relatively poor in flexibility and oral dissolution rate. On the other hand, in the case of Comparative Example 4, the strength of the film is somewhat reduced, but it can be seen that the comparatively excellent results in the elongation rate, flexibility and dissolution rate of the oral cavity.

In particular, Comparative Examples 1 to 3 are almost inflexible as soon as a force is applied for measuring the flexibility, which means that the film can be broken even with a small force after the film is formed, which is in the form of a formulation when exposed to external force. It means that the role of is impossible.

Accordingly, the present inventors focus on the patent application No. 2011-75179 filed before the present invention, and the film used in Comparative Examples 1 to 3 based on hydroxypropyl pistachi, which is a film forming polymer having the best flexibility and dissolution rate in the oral cavity. Combinations of the forming polymers were considered and intraoral film formulations of each polymer combination were prepared as in Example 1 and Comparative Examples 5-6 below.

&Lt; Example 1 > Preparation of Film by Film Forming Composition of the Present Invention

30 g of a film forming composition (composition ratio = 50: 50 w / w%) mixed with 15 g of Pullulan and 15 g of Hydroxypropyl Pea Starch, Lycoat RS720, ROQUETTE was added to a suitable amount of purified water to obtain a homogenizer. After stirring for 1 hour at 2,000 rpm to completely dissolve, it was left at room temperature for 24 hours to remove bubbles. The solution was cast on a stainless steel base using a film coater and dried at 80 ° C. to produce a uniform film of 300 μm in thickness.

<Comparative Examples 5 to 6> Preparation of Film by Polymer Mixed Composition

30 g of the polymer composition shown in Table 3 was added to an appropriate amount of purified water, followed by mixing. Then, a film was prepared in the same manner as in Example 1 to prepare Comparative Examples 5 to 6, respectively.

<Experimental Example 2> Comparison of Physical Properties and Oral Dissolution Rate of Composite Polymer Films

Films prepared in Example 1 and Comparative Examples 5 to 6 according to the present invention in the same manner as Experimental Example 1 to compare the mechanical properties of the films prepared in Comparative Examples 5 to 6 and Example 1 and dissolution rate in the oral cavity Tensile strength (film strength, elongation rate), flexibility, and dissolution rate in the oral cavity were measured and shown in Table 4.

Surprisingly, the film forming composition of Example 1 according to the present invention had unexpected results unlike the physical properties of the film according to the prior art. In other words, the fast disintegrating film-forming composition in the oral cavity consisting of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) among various polymer combinations as film-forming agents, It was confirmed that satisfactory effects were shown in both flexibility and dissolution rate in the oral cavity.

On the other hand, it was confirmed that the combination of HPMC and hydroxypropyl pistachi of Comparative Example 5 did not show good results in the flexibility and elongation of the film, and in the case of Comparative Example 6 in which HPC and hydroxypropyl pistachi were combined In the elongation rate, a relatively good result was obtained, but it was confirmed from the results of Table 4 that the other films showed a remarkably poor result in strength, flexibility, and oral dissolution rate.

The film forming composition of Example 1 exhibits very surprising film strength, elongation, flexibility and dissolution rate in the oral cavity even though no excipient is added to improve the physical properties of the film. Pullulan selected in Example 1 And it was examined whether the properties of the film at various composition ratios for the fast disintegrating film forming composition in the mouth consisting of (Hydroxypropyl Pea Starch, Lycoat RS720, ROQUETTE).

<Examples 2 to 3> Preparation of Film by Polymer Composition Ratio of the Present Invention

30 g of the film-forming composition consisting of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) having a composition ratio shown in Table 5 was added to a suitable amount of purified water, and mixed to carry out the solution. An edible film was produced in the same manner as in Example 1 to obtain Examples 2 and 3, respectively.

<Comparative Examples 7 to 12> Preparation of film by polymer composition ratio

30 g of the film-forming composition consisting of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) having a composition ratio shown in Table 5 was added to a suitable amount of purified water, and mixed to carry out the solution. An edible film was produced by the method similar to Example 1, and it was set as Comparative Examples 7-12, respectively.

<Experimental Example 3> Measurement of physical properties and oral dissolution rate of the film of the present invention

Tensile strength (film strength, elongation rate), flexibility and dissolution rate in the oral cavity of the films prepared in Examples 2 to 3 and Comparative Examples 7 to 12 according to the present invention in the same manner as in Experimental Example 1 were measured and described in Table 5. Shown together.

As can be seen in Table 5, the film composition of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) is 70:30 ~ 30:70 weight ratio (w / w% Examples 2 to 3 with) showed remarkably excellent film properties (strength, elongation and flexibility).

On the other hand, the content of Pullulan (Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE)) has a weight ratio (w / w%) of 95: 5 ~ 80:20 of 7 to In the case of 9, the oral disintegration rate was unexpectedly poor, especially the flexibility of the film was very poor, and 90 ° flexibility (folding angle) was shown in the composition having a weight ratio (w / w%) of 80:20. It indicates that the critical point is represented in the 70:30 weight ratio (w / w%).

In addition, Comparative Examples 10 to 12 in which the contents of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) have a weight ratio (w / w%) of 20:80 to 5:95. In the results, the strength of the film was unexpectedly falling. In particular, in a composition having a weight ratio (w / w%) of 20:80, when the film is cast in a stainless steel base at the time of preparation, such as a drug, and attempted to be peeled off after drying, the film does not stick to the stainless steel base and does not fall off. The strength of (kgf / mm ² ) of 2.0 suggests that it represents a critical point that can be made into a film formulation.

Therefore, the film-forming polymer composition according to the present invention can produce the desired fast disintegrating film formulation in the oral cavity with or without the addition of excipients to improve the physical properties of the film, without worrying that the drug content is limited by the excipients It is expected that the preparation of the desired orally disintegrating film formulations will be possible.

In addition, the present invention was to find out whether it is possible to produce the desired oral disintegrating film formulation without limiting the film-forming polymer composition and drug content according to the present invention.

Various drugs of PDE5 inhibitors, namely vardenafil, sildenafil, mirdenafil, eudenafil, avananafil and tadanafil are drugs with differing effective contents of the drug. Intraoral disintegrating film formulations were prepared for effective contents of the drugs to evaluate film properties (strength, elongation and flexibility) and disintegration rate in the oral cavity.

<Formulation Example 1> Oral Disintegrating Film Formulation of Sildenafil Citrate

(1) Put a proper amount of sodium hydroxide into a proper amount of purified water to completely dissolve it.

(2) 46.82 weight (w / w%) of sildenafil citrate based on the total weight of the formulation was added to the solution of (1) and mixed at 2,000 rpm for 5 minutes.

(3) In the solution of (2), 33.33 weight (w / w%) of the film-forming composition prepared in Example 1 was added to the total weight of the formulation and mixed at 2,000 rpm for 30 minutes.

(4) Add an appropriate amount of sodium bicarbonate for further flavoring and mix for 5 minutes.

(5) In order to remove bubbles in the prepared solution, it is allowed to stand at room temperature for 24 hours.The solution is cast on a stainless steel base using a film coater, dried at 80 ° C, and separated, and then peeled off. Thickness 300㎛, size 25 mm * 32 mm The formulation of the uniform film formulation of was prepared.

&Lt; Formulation Example 2 > Oral Disintegrating Film Formulation of Myrodenafil Hydrochloride

A formulation of a film formulation was prepared in the same manner as in Formulation Example 1, using 56.50 wt% (w / w) of the main component mirdenafil hydrochloride and 33.33 wt% (w / w) of the film forming composition prepared in Example 1.

&Lt; Formulation Example 3 > Oral Disintegrating Film Formulation of Eudenafil

A formulation of a film formulation was prepared in the same manner as in Formulation Example 1, using 56.50 wt% (w / w) of the main component Eudenafil and 33.33 wt% (w / w) of the film forming composition prepared in Example 1.

<Formulation Example 4> Oral Disintegrating Film Formulation of Vardenafil Hydrochloride

A formulation of a film formulation was prepared in the same manner as in Formulation Example 1, using 23.41 wt% (w / w) of the main component vardenafil hydrochloride and 33.33 wt% (w / w) of the film forming composition prepared in Example 1.

&Lt; Formulation Example 5 > Intraoral disintegrating film preparation of tadanafil

A formulation of a film formulation was prepared in the same manner as in Formulation Example 1, using 23.41 wt% (w / w) of main ingredient tadanafil and 33.33 wt% (w / w) of the film forming composition prepared in Example 1.

&Lt; Formulation Example 6 > Intraoral Disintegrating Film Formulation of Avanafil

A film-forming formulation was prepared in the same manner as in Formulation Example 1, using 75.46 wt% (w / w) of the main component Avanafil (w / w) and 20.03 wt% (w / w) of the film forming composition prepared in Example 1.

<Formulation Example 7> Oral Disintegrating Film Formulation of Sildenafil Citric Acid with Excipients

(1) A proper amount of aspartame is added to an appropriate amount of purified water, and the temperature is added (80 ° C) to completely dissolve it.

(2) A proper amount of sodium hydroxide is added to the solution to completely flavor the film.

(3) 46.82 weight (w / w%) of sildenafil citrate based on the total weight of the formulation was added to the solution of (2) and mixed at 2,000 rpm for 5 minutes.

(4) The film-forming composition prepared in Example 1 was added to the solution of (3) at 33.33 weight (w / w%) and the appropriate amount of polyethylene glycol and glycerin, and mixed at 2,000 rpm for 30 minutes.

(5) Add an appropriate amount of sodium bicarbonate for further flavoring and mix for 5 minutes.

(6) It is allowed to stand at room temperature for 24 hours to remove bubbles of the prepared solution, and this solution is cast on a stainless steel base using a film coater, dried at 80 ° C, and then separated and separated. The formulation of the uniform film formulation of was prepared.

<Example 8> Intraoral disintegrating film preparation of tadanafil with excipient

A film formulation was prepared in the same manner as in Formulation Example 7, using 23.41 wt% (w / w) of main ingredient tadanafil and 33.33 wt% (w / w) of the film-forming composition prepared in Example 1.

<Comparative Example 1> Oral disintegrating film preparation of sildenafil citric acid (use of Comparative Example 10)

Intraoral disintegrating film formulations of sildenafil citric acid were prepared in the same manner as in Formulation Example 1 using Comparative Example 10.

However, in order to remove the bubbles of the prepared solution, the mixture was left at room temperature for 24 hours, and cast the solution on a stainless steel base using a film coater, dried at 80 ° C., and then peeled off, so that the film did not stick to the stainless steel base. Did. Therefore, it can be seen from Comparative Example 10 that the film formulation composition according to the present invention cannot be used as a product in the case of the film formulation whose strength measurement value is 2.0 or less regardless of the presence of a drug.

<Experimental Example 4> Measurement of Physical Properties and Oral Dissolution Rates of Film Preparations According to the Present Invention

Tensile strength (film strength, elongation rate), flexibility and dissolution rate in the oral cavity of the drug-containing intraoral disintegrating film prepared in the preparation examples according to the present invention in the same manner as in Experimental Example 1 were measured and shown in Table 6. It was.

As can be seen in Table 6, various PDE5 inhibitors using an edible film forming composition consisting of Pullulan and Hydroxypropyl Pea Starch (Lycoat RS720, ROQUETTE) according to the present invention Intraoral fast disintegrating film preparations containing drugs have intraoral fast disintegration, which shows remarkable effects in both tensile strength (film strength, elongation rate), flexibility and dissolution rate in the oral cavity, with or without additional excipients, as in Formulation Examples 1 to 8. It is possible to prepare a film formulation, it can be seen that it exhibits a very good effect in all the physical properties, such as film strength, elongation, flexibility and dissolution rate of the oral cavity without limiting the type and content of the drug of the PDE5 series.

Claims (4)

delete In the orally disintegrating film-like preparations comprising a PDE5 inhibitor, vardenafil, sildenafil, mirdenafil, eudenafil, avananafil, tadanafil, or a pharmaceutically acceptable salt thereof,
As a film forming composition, Pullulan and Hydroxypropyl Pea Starch are film forming compositions comprising a mixture of 70:30 to 30:70 weight (w / w%). Intraoral fast disintegrating film type preparation. delete delete