WO2013085276A1 - Film for oral administration containing mirodenafil or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a film preparation for oral administration comprising mirodenafil or a pharmaceutically acceptable salt thereof - preferably, the free-base form of mirodenafil. The present invention also provides a method for manufacturing a film preparation for oral administration comprising mirodenafil or a pharmaceutically acceptable salt thereof - preferably, the free-base form of mirodenafil.

Description

Oral administration film containing mirdenafil or a pharmaceutically acceptable salt thereof

The present invention relates to a film formulation for oral administration containing myrodenafil or a pharmaceutically acceptable salt thereof, preferably myrodenafil free base or myrodenafil hydrochloride.

This application claims priority based on Korean Patent Application No. 10-2011-0131278, filed December 8, 2011, and all the contents disclosed in the specification and drawings of the application are incorporated in this application.

Recently, film formulations for oral administration, in particular, dissolved on the tongue, are commercially available. Such a film formulation has the advantage of fast absorption compared to general tablets, capsules, etc., and is useful for patients who have difficulty swallowing.

In recent years, such film formulations have been made by applying various drugs, and since the inherent physical and chemical properties of each drug are different, the method applied to each drug is different. Due to the nature of the drug, the polymer that can be used may be limited or the prescription ratio may vary, and the solvent or plasticizer used in the manufacturing process may also be different for each drug.

Meanwhile, mirodenafil is a PDE5 inhibitor-based drug and is used as an erectile dysfunction treatment drug. Myrodenafil, a selective, reversible inhibitor of this cGMP-specific PDE5, increases the level of cGMP in the cavernous body when it causes local release of nitric oxide (NO) by sexual stimulation. This causes erection by leading to smooth muscle relaxation and blood inflow into the penis tissue.

For such mirdenafil or pharmaceutically acceptable salts thereof, no such oral dosage film formulation has been reported yet.

Therefore, the problem to be solved by the present invention is to provide an oral dosage film comprising mirdenafil or a pharmaceutically acceptable salt thereof.

In order to solve the above problems, the present invention provides an oral administration film comprising myrodenafil or a pharmaceutically acceptable salt thereof, preferably myrodenafil free base or myrodenafil hydrochloride.

In the present invention, pharmaceutically acceptable salts of mirdenafil include propionic acid, isobutyl acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic, fumaric acid and manderic acid , Phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, bromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, il There may be salts consisting of acids such as hydrosulfite, hydrogen iodide, phosphorous acid, salts of amino acids such as alginate, salts of analogs of organic acids such as glutonic or galactonic acid, lithium, sodium, potassium, calcium, There may be salts consisting of ammonium, magnesium or organic amino, but the invention is not limited thereto.

The oral administration film of the present invention is also referred to as oral dispersible film (ODF), strip, orally dissolving film, etc., and is taken by dissolving or finely dispersing in oral cavity Done. These films are usually placed on the tongue to melt, but can also be administered by adhering to the palate, sublingual, buccal, or the like. Film formulations according to the invention have the advantage that they can be taken without water.

In addition, mirodenafil or pharmaceutically acceptable salts thereof contained in the ODF may be dissolved or dispersed in the oral fluid in the oral cavity to be absorbed directly in the oral cavity, or swallowed with saliva, such as the esophagus, stomach, or small intestine. It may also be absorbed along the normal gastrointestinal absorption pathway.

Preferably, in a film formulation comprising a myrondenafil or a pharmaceutically acceptable salt thereof and a water-soluble polymer according to the present invention, the myrondenafil or a pharmaceutically acceptable salt thereof may have a particle size (d (0.9)). Is 280 um or less, more preferably 100 um or less, and most preferably 20 um or less.

In the present invention, unless otherwise defined, particle size means particle size measured by a Laser Diffraction method (see, for example, the measuring method of Example 1 below using Malvern's MasterSizer ^™ ), in particular the present invention. A particle size of d0.9 or D90 at s means that 90% of the particles are less than or equal to the particle size as shown in FIG. 1. That is, in the present invention, the particle size of 280 um or less means that 90% of the raw material particles used are 280 um or less in size.

If the particle size D90 of myrodenafil or its salt is too large in a film formulation containing myrodenafil or its salt, the particles are not evenly dispersed during film production, making it difficult to obtain a uniform drug distribution. It also negatively affects the appearance of the film. In particular, such particle size has a great influence when a manufacturing process is used in which a myrodenafil free base is used as a drug and does not dissolve the myrodenafil free base.

In the film formulation of the present invention, the drug is more preferably a mirodenafil free base rather than a mirdenafil salt in terms of taste of the film and the like.

In addition, preferably, in the mirdenafil film formulation according to the present invention, the LOD (loss on drying) value of the film is 1 to 8% by weight, more preferably 1 to 6% by weight. If the LOD is too low due to the nature of the myrodenafil, the film may be easily broken. On the contrary, if the LOD is too high, the film may be tacky, and thus, the film may fall off from the process films such as PET, PP, and PE used during the manufacturing process. It is hard to lose, and after packing, it may stick to the packaging material and may not fall well.

In the present invention, LOD can be measured by using a moisture analyzer MX-50 model of AND. When set to LO ACCURACY in the Standard mode, it means the weight percentage of the film weight before drying when about 1 g of the film is dried at a temperature of 105 ° C.

The film of the present invention comprises a water-soluble polymer for forming a film. Examples of the water-soluble polymer which means a polymer that is soluble in water can be used as starch, modified starch and the like; Water-soluble celluloses such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and hydroxyethyl cellulose; Carrageenan; Pullulan; gelatin; Alginic acid; Gums such as gellan gum, locust bean gum, xanthan gum and guar gum; Polyethylene oxide; Copovidone; pectin; dextrin; gelatin; Polyvinyl alcohols; Polyvinylpyrrolidones and the like may be used, but in the case of mirdenafil film preparation, pregelatinized starch, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, carboxymethyl cellulose, xanthan gum or the like A mixture is preferable, and especially hydroxypropyl cellulose is used. Thus preferably the present invention provides an oral dosage film formulation comprising mydenafil or a pharmaceutically acceptable salt thereof and hydroxypropylcellulose, and more preferably, the present invention is a myrodenafil, pregelatinized starch And hydroxypropylcellulose.

The present invention is also based on the surprising finding that it is preferable to use myrodenafil free bases rather than pharmaceutically acceptable salts of myrodenafil when considering the taste of the film as an active ingredient of the film formulation.

Furthermore, the present invention can significantly improve the taste of the film by using an alkalizing agent in the case of using the mirdenafil acid salt as the active ingredient of the film formulation. Is based on an amazing discovery. Accordingly, the present invention provides a mirdenafil film formulation comprising an acid salt of mirdenafil (eg, mirdenafil hydrochloride), a water soluble polymer, and an alkalizing agent.

As the alkalizing agent, a substance having a pKa of 7 or more, or a substance classified as an alkalizing agent by the Korea Food and Drug Administration may be used. For example, NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ , Ca (OH) ₂ , NH ₄ OH, Mg (OH) ₂ , AL (OH) ₃ , CaCO ₃ , trolamine, diethyl phthalate and the like can be used. . However, in consideration of compatibility with myrodenafil acid salt, film properties, etc., NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ or a mixture thereof is preferable.

The present invention may include a myrodenafil free base or a salt thereof, and may adjust the amount of prescription to be prescribed by increasing the amount proportionally while maintaining the same prescription ratio due to the characteristics of the film formulation. Therefore, it can be seen that maintaining the prescription ratio set forth in the present invention follows the method of the present invention. This only applies to 400 mg or less based on myrodenafil free base. Preferably, the film formulation according to the present invention comprises up to 100 mg of the active ingredient as mirodenafil per sheet of film.

Myrodenafil-containing film formulation according to the present invention comprises 10 to 80% by weight of mydenafil or a pharmaceutically acceptable salt thereof, 10 to 80% by weight of the water-soluble polymer and 0 to 20% by weight of the plasticizer relative to the total weight of the film.

The plasticizer according to the present invention refers to a material that serves to give flexibility and flexibility to a film made of a polymer. If the flexibility is not sufficient, the film breaks easily when bent. Representative plasticizers include pharmaceutically usable alcohols such as glycerin, propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, xylitol, malitol, erythritol, tributyl citrate, triethyl citrate, glycerol triacetate, ethanol One or more selected from streams, water, and the like can be used.

In the present invention, it was confirmed that the flexibility of the film is imparted even in the state of the above-mentioned plasticizers only alcohol or water and no other plasticizers. Water or alcohol is added in large quantities as a solvent in the stock solution preparation step, which is an intermediate step of making the film of the present invention, and most of them are evaporated away in the drying step of making the film. Therefore, it is very difficult to indicate the exact prescription amount compared to other excipients. However, after being prepared as a loss of drying, it is possible to know how much the amount is, and by adjusting the drying process, it is difficult to meet the exact prescription amount, but the approximate content can be controlled.

Film formulations according to the invention may also optionally comprise a flavoring agent and / or a colorant, the content of which is 0-5% by weight, respectively, relative to the total weight of the film.

More preferably, the present invention provides a mirdenafil oral administration film containing a myrodenafil free base as an active ingredient, and containing pregelatinized starch, hydroxypropylcellulose, sucralose and menthol as excipients. do. In the case of myrodenafil film formulations with this formulation, stability was ensured, mass productivity was easy, and sensoryly appropriate.

In addition to the above-mentioned components, the film formulation according to the present invention may further include a water-insoluble polymer, an antimicrobial substance, and the like within the scope of not impairing the object of the present invention.

The method for producing a mirdenafil-containing film according to the present invention differs depending on the case of using the myronadenafil free base and the case of using the mirdenafil salt.

In the case of using the myrodenafil free base as a main component, it is important to maintain the desired particle size of the above-mentioned mirdenafil free base, so it is preferable to prepare the suspension by dissolving it without dissolving it. That is, preferably, the present invention provides a technical idea that the particle size of the myrondenafil free base is preferably 280 um or less if the film formulation is prepared without dissolving in a solvent such as water.

Therefore, in the case of using the myrodenafil free base as a main component, the present invention is to prepare a liquid composition in which the myrodenafil free base is suspended and in which a water-soluble polymer is dissolved (S2) a film capable of release (representatively (P3, PET, PP, PE, etc.) to provide a manufacturing method comprising the step of applying the liquid composition, and (S3) by applying heat to the applied film and drying. Representative methods include drying in an oven at about 60-110 ° C. (preferably about 80 ° C.) but drying the LOD to about 1-8% by weight (preferably about 5% by weight). to provide. In particular, in such a manufacturing method, it may be agglomerated with each other in the process of preparing a stock solution containing a mirdenafil free base and a water-soluble polymer, and thus may be larger than the original particle size of the raw material itself.

On the other hand, when using the myrodenafil acid salt as the main component, it is preferable that the myrodenafil acid salt is dissolved during the manufacturing process of the film for the reaction with the alkalizing agent to be added.

Therefore, in the case of using the myrodenafil acid salt as a main component, the present invention is to prepare a liquid composition in which (S1) myrodenafil acid salt, an alkalizing agent and a water-soluble polymer is dissolved, (S2) a film capable of release (representatively The present invention provides a manufacturing method comprising the step of applying the liquid composition to a film of PET, PP, PE, etc., and (S3) by applying heat to the applied film and drying. Drying in an oven (preferably about 80 ° C.) but drying the LOD to about 1-8% by weight (preferably about 5% by weight).

The present invention provides ODF comprising mirdenafil or a pharmaceutically acceptable salt thereof, preferably mirdenafil free base. The present invention also provides a process for preparing ODF comprising mirdenafil or a pharmaceutically acceptable salt thereof, preferably mirdenafil free base.

1 is a graph showing D90 meaning the term “particle size” as used herein.

Hereinafter, examples and the like will be described in detail to help understand the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Preparation of Example 1

According to the following prescription was prepared a film formulation containing mirdenafil. First, the myronadenafil having a particle size of D90 of 280 um or less (actual value 242 um) was dispersed so as not to aggregate in water. The particle size was measured using a Malvern's MasterSizer ^™ 2000 instrument by a wet method (using the Hyro 2000S), and the particles were dispersed in distilled water (dispersant refractive index = 1.33) to obtain an obscuration concentration of 2-5%. It was measured by dispersion (particle refractive index = 1.52).

The stock solution was prepared by putting mirodenafil and pregelatinized starch, hydroxypropyl cellulose, glycerin, sucralose, and L-menthol together with ethanol to dissolve or mix uniformly. This was applied to a PET film and dried in an oven at 80 ° C., so that LOD was prepared to be 4.72 wt%. The dried film was cut to contain 50 mg (ie 50 mg / 1 sheet) of the desired mirdenafil prescription weight per sheet.

Table 1

Ingredient Name (Prescription (mg / 1 Sheet))	Example 1	ratio
Myrodenafil free base	50	44.64%
Pregelatinized starch	20	17.86%
Hydroxypropyl cellulose	30	26.79%
Glycerin	11	9.82%
Sucralose	0.5	0.45%
L-menthol	0.5	0.45%
Solids meter	112	100.00%
water	200	-
ethanol	100	-

<Production of Examples 1-1 to 3-1 and Comparative Example 1>

In a similar manner to Example 1, the mirodenafil free base-containing film formulation of Table 2 was prepared.

TABLE 2

	Example 1-1		Example 2		Example 3		Example 3-1		Comparative Example 1
Prescription Unit: mg	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio
Myrodenafil free base	100	44.64%	100	62.31%	50	44.64%	50	44.64%	50	44.64%
Pregelatinized starch	40	17.86%	-	-	20	17.86%	20	17.86%	20	17.86%
Hydroxypropyl cellulose	60	26.79%	40	24.92%	30	26.79%	30	26.79%	30	26.79%
glycerin	22	9.82%	18	11.21%	11	9.82%	11	9.82%	11	9.82%
Sucralose	One	0.45%	One	0.62%	0.5	0.45%	0.5	0.45%	0.5	0.45%
L-menthol	One	0.45%	1.5	0.93%	0.5	0.45%	0.5	0.45%	0.5	0.45%
	224	100.00%	160.5	100.00%	112	100.00%	112	100.00%	112	100.00%
API granularity (D90)	242um		242um		92um		48um		324um
LOD	4.55%		6.34%		1.28%		1.23%		4.45%

<Evaluation of Examples 1-3-1 and Comparative Example 1>

Content uniformity and post-production properties of the prepared Examples 1 to 3-1 and Comparative Example 1 were evaluated. Specifically, relative uniformity of the drug contained in the same film weight was used as the content uniformity. The results are shown in Table 3 below.

TABLE 3

	Example 1	Example 1-1	Example 2	Example 3	Example 3-1	Comparative Example 1
Uniform Standard Deviation	2.30%	1.24%	1.35%	0.58%	0.58%	7.65%
Uniqueness	Good	Good	Good	Good	Good	Aggregation of particles. Uniformity relative deviation too large
evaluation	Film made of pregelatinized starch and HPC	Manufactured by increasing the same ratio as in Example 1	Film made using only HPC	Use of raw material of smaller particle size as in Example 1	Use of raw materials of smaller particle size as in Example 3	Same as Example 1 but with a raw material particle size

Specifically, Example 1-1 had the same ratio as Example 1 or twice the drug content per sheet of film, and the same degree as that of Example 1 in several aspects, such as film manufacturing process, uniformity, and film properties after manufacture. It was good.

Through Example 2 it was confirmed that a good film can be made by HPC alone.

In Example 3 and 3-1, the effect of the mirodenafil free base as a main component was evaluated. In Example 3, the same prescription as in Example 1 was used, but the myronafil particle size D90 was 100 μm or less, and in Example 3-1, the myrodenafil particle size D90 was 50 μm or less. The film produced did not show any difference except particle.

The film was prepared using the same prescription or particle size myrodenafil (<400um) as in Example 1. The resulting film appeared to be of different particle size and had agglomerated particles, which observed variation in the particle distribution. The actual content uniformity was measured to be 7.65%, which is greater than the inventors' 5% standard for product quality.

<Production and Evaluation of Comparative Examples 2 and 3>

All conditions except for LOD were prepared and evaluated in the film formulations of Comparative Examples 2 and 3 in the same manner as in Example 3-1. In Comparative Example 2, the LOD was 0.8 wt%, and in Comparative Example 3, the LOD was 8.7 wt%.

As a result of the evaluation, the appearance of Comparative Example 2 was almost the same as that of Example 3-1, but it showed a phenomenon that easily broke even when weakly bent. It can be a problem during production, packaging and distribution.

In the case of Comparative Example 3, there was often a case in which the product did not fall off from the plastic film used during drying, that is, it did not peel off from the release film and thus the product was broken.

<Manufacture of Examples 4-6>

In a similar manner to Example 1, the mirodenafil free base-containing film formulation of Table 4 was prepared.

Table 4

	Example 4		Example 4-1		Example 5		Example 6
(Prescription weight: mg)	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio
Myrodenafil free base	100	67.11%	25	67.11%	50	49.50%	25	20.49%
Pregelatinized starch	-	-	-	-	20	19.80%	-	-
Hydroxypropyl cellulose	-	-	-	-	30	29.70%	60	49.18%
Hydroxymethylpropyl cellulose	-	-	-	-	-	-	30	24.59%
Carboxymethyl Cellulose	20	13.42%	5	13.42%	-	-	-	-
Xanthan Gum	One	0.67%	0.25	0.67%	-	-	-	-
glycerin	28	18.79%	7	18.79%	-	-	-	-
Propylene glycol	-	-	-	-	-	-	7	5.74%
Sucralose	-	-	-	-	0.5	0.50%	-	-
L-menthol	-	-	-	-	0.5	0.50%	-	-
	149	100.00%	37.25	100.00%	101	100.00%	122	100.00%
API granularity (D90)	39um		39um		39um		242um
LOD	6.13%		3.86%		5.54%		4.97%

<Evaluation of Examples 4-6>

The homogeneity and post-production properties of the prepared Examples 4 to 6 were evaluated. The results are shown in Table 5 below.

Table 5

	Example 4	Example 4-1	Example 5	Example 6
Uniform Standard Deviation	3.14	1.12	1.74	0.95
Uniqueness	Good	Good	Good	Good
evaluation	Use CMC	Film made by proportionally reducing the same prescription as Example 4	Same as Example 3-1 but containing only water as a plasticizer	Use of HPMC

As can be seen from the result of Example 4, a good film could be produced even by using carboxymethyl cellulose. In Example 4-1, a film was prepared in the same manner using the same stock solution prepared in Example 4. However, since the target prescription weight was about 25% by weight of Example 4, it was cut accordingly, and the individual weight of the film was about 25% by weight of Example 4.

In Example 5, the film except for glycerin was prepared in the same manner as in Example 3-1. The property of the film was good.

As can be seen from the result of Example 6, a good film could be produced even by using hydroxypropyl cellulose and hydroxymethylpropyl cellulose.

<Manufacture of Examples 7-11>

In a similar manner to Example 1, the mirdenafil-containing film formulations of Table 6 were prepared using mirdenafil hydrochloride as the main component (API).

Table 6

	Example 7		Example 8		Example 9		Example 10		Example 11
(Prescription weight: mg)	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio	Prescription weight	ratio
Myrodenafil hydrochloride	56.9	35.15%	56.9	34.51%	56.9	33.69%	56.9	31.81%	56.9	31.81%
Hydroxypropyl cellulose	60	37.06%	60	36.39%	60	35.52%	60	33.54%	60	33.54%
Polyvinylpyrrolidone
	10	6.18%	10	6.06%	10	5.92%	10	5.59%	10	5.59%
Pullulan
	10	6.18%	10	6.06%	10	5.92%	10	5.59%	10	5.59%
glycerin	20	12.35%	20	12.13%	20	11.84%	20	11.18%	20	11.18%
Sucralose	5	3.09%	5	3.03%	2	1.18%	2	1.12%	2	1.12%
NaOH	-	-	3	1.82%	-	-	-	-	-	-
KOH	-	-	-	-	10	5.92%	-	-	-	-
Na2CO3	-	-	-	-	-	-	-	-	20	11.18%
NaHCO3	-	-	-	-	-	-	20	11.18%	-	-
	161.9	100%	164.9	100%	168.9	100%	178.9	100%	178.9	100%
Ratio of alkalizing agent to drug			5.27%		17.57%		35.15%		35.15%
LOD	5.33%		2.49%		5.24%		5.34%		5.67%

<Evaluation of Examples 7-11>

The homogeneity and post-production properties of the prepared Examples 7 to 11 were evaluated. The results are shown in Table 7 below.

TABLE 7

	Example 7	Example 8	Example 9	Example 10	Example 11
Uniform Standard Deviation	2.31	3.12	2.21	1.45	3.48
Uniqueness	Taste	Taste good	Taste good	Taste good	Taste good
Remarks	Use hydrochloride	Use of NaOH in Hydrochloride	Use of KOH in Hydrochloride	Use of NaHCO3 in Hydrochloride	Use of NaHCO3 in Hydrochloride

In Example 7, mirdenafil hydrochloride was used instead of the mirdenafil free base. In the case of Example 7, the appearance of the film was good, but a bitter taste was felt in the film.

In Example 8-11, NaOH, KOH, NaHCO ₃ and Na ₂ CO ₃ were added to the formulation of Example 7 to prepare a film. The appearance of the film was good and the taste was improved.

Claims (8)

1. In the film formulation comprising a mirdenafil or a pharmaceutically acceptable salt thereof and a water-soluble polymer,

   Myronadenafil film formulation, characterized in that D90 means a particle size of 90% in the particle size distribution of the myrodenafil or a pharmaceutically acceptable salt thereof is 280 um or less.
2. The mirdenafil film formulation of claim 1, wherein the D90 is 100 um or less.
3. The method according to claim 1, wherein the film formulation is a drug-derived mirdenafil film formulation, characterized in that it contains a myrodenafil free base rather than a myrodenafil salt.
4. The mirdenafil film formulation of claim 1, wherein the loss on drying (LOD) value of the film formulation is 1-8 wt%.
5. 5. The mirdenafil film formulation of claim 4, wherein the LOD (loss on drying) value is 1 to 6% by weight.
6. The method according to claim 1, wherein the water-soluble polymer is pre-gelatinized starch, hydroxypropyl cellulose, hydroxymethylpropyl cellulose, carboxymethyl cellulose, xanthan gum or a mixture of these, the mirdenafil film formulation.
7. The mirdenafil film formulation of claim 1, wherein the film formulation comprises a mirdenafil acid salt and an alkalizing agent.
8. 8. The mirdenafil film formulation of claim 7, wherein the alkalizing agent is NaOH, KOH, NaHCO ₃ , Na ₂ CO ₃ or a mixture thereof.

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