KR20140000419A - Controlled release solid oral dosage formulation with improved bioavailability comprising fenofibric acid and preparation method thereof - Google Patents

Abstract

The present invention relates to a controlled-release type solid oral dosage formulation, with improved bio-availability, of active fenofibric acid component which includes: fenofibric acid; a pharmaceutically acceptable salt of the same; at least one among pharmaceutically acceptable diluting agents selected from the group consisting of alcohol of pH5-pH10 inclusive; pharmaceutically acceptable viscosity increasing agents; and pharmaceutically acceptable additives. [Reference numerals] (AA) Dissolution rate (%); (BB) Comparative example 1; (CC) Example 15 granulation; (DD) Example 15 refining; (EE) Time (min)

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a controlled-release solid oral preparation having improved bioavailability comprising phenobipuric acid and a preparation method thereof, and a method for producing the same. BACKGROUND ART < RTI ID = 0.0 >

FIELD OF THE INVENTION The present invention relates to a bioavailability-enhanced release-controlled solid oral dosage form comprising penofibric acid and a process for preparing the same.

2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid, known as fenofibrate, -methyl-propionic acid, 1-methylethyl ester) is a lipid-regulating agent that has been widely used worldwide since the 1980s and has excellent stability. Fenofibrate is available in a variety of different formulations and dosages and is used in the treatment of adult endogenous hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Fenofibrate is absorbed in the gastrointestinal tract after the duodenum after oral administration and is metabolized in the body after absorption to produce 2- [4- (4-chlorobenzoyl) fenofibric acid, which is known as the active form of fenofibric acid, Phenoxy] -2-methyl-propanoic acid.

In fact, since only phenobipurenic acid is detected at the blood concentration after oral administration of phenobibrate, the phenobibrate is a prodrug of phenobipuric acid and the actual effective ingredient is phenobipuric acid (International Patent No. WO 04/054568, 3,907,792, 4,895,726, 6,074,670 and 6,277,405).

The structure of the ester form prodrug, penofibrate and phenobipuric acid, which is an active metabolite, is as follows:

As in the above structure, the bioavailability of these compounds can be low because the prodrug, phenobibrate, is an insoluble drug having a very high hydrophobicity in water.

In general, the absorption of orally administered drugs is mostly through the absorption of digestive tracts. The most important factor that affects the digestive tract, the direct absorption site of the drug, is the ingestion of food. Due to the nature of the phenobibrate mentioned above, the absorption of phenobibrate in the digestive tract of an individual is greater than in the fasted state, rather than in the fasted state. When comparing the bioavailability of fenofibrate in the feeding state versus the fasting state, the effect of food on the absorption of fenofibrate is undesirable. Because of this difference in absorption, the patient must take the medication with food intake, so compliance of the patient with the medication affected by the food is also an issue.

U.S. Patent Publication No. 2003/0206949 relates to a dispersible solid preparation in which an insoluble drug such as phenobibrate exists as a nanometer or micrometric particulate solid in order to enhance bioavailability, And are composed of phospholipids such as phosphatidylcholine, phosphatidylethanolamine and the like, and optionally at least one surfactant and matrix forming agent.

U.S. Patent No. 5,827,536 improves bioavailability upon oral administration of phenobibrate by using diethylene glycol monoethyl ether (DGME), which is a nonionic surfactant as a solubilizing agent, and reduces the daily dose of 300-400 mg of penofibrate to 200 mg Respectively.

U.S. Patent No. 7,276,249 relates to a phenobibrate composition having improved pharmacokinetic profile and reduced food impact using nanoparticle technology, wherein the phenobibrate particles have an effective average particle size of less than about 2,000 nm.

The Tricor (R) formulation available from Abbott Laboratories also applied nanoparticle technology to minimize the effect of dieting and reduce the daily dose of fenofibrate to 145 mg.

Korean Patent Laid-Open No. 10-2011-0027778 relates to a phenobibrate preparation having improved oral bioavailability, which is characterized in that phenobipate, which is a prodrug, is dissolved in a lipophilic surfactant in order to minimize the influence of the diet and further a hydrophilic surfactant is contained .

Korean Patent Laid-Open No. 10-2008-0087845 relates to a pharmaceutical preparation of fenofibrate having improved bioavailability, which comprises non-mechanically finely divided fenofibrate microparticles, polyethylene glycol, and polyethylene-polypropylene glycol to improve bioavailability Lt; RTI ID = 0.0 > pharmaceutically < / RTI >

Thus, much efforts have been made to increase the bioavailability of the prodrug, phenobibrate, in order to improve the hydrophobic and resilient properties of the prodrug, by making the phenobiphate finer and lipophilic and using a hydrophilic surfactant.

On the other hand, phenobipuric acid, which is an active metabolite converted from the prodrug, phenobibrate, has a melting point of 184 ° C, which makes it easy for the pharmaceutical manufacturer to formulate it. However, phenobifric acid is a slowly dissolving or water-insoluble product (BCS II class) and a weakly basic drug with a dissociation constant pKa of 3.8, which is low in solubility in water and has a solubility Is an increasing drug.

Phenopiperic acid has a T _max of 2.5 hours faster than the prodrug of phenobibrate, which has a maximum blood concentration reaching time (T _max ) of 6 to 8 hours, since the absorption is rapid in the gastrointestinal tract.

Therefore, increased solubility by such solubilization techniques can cause safety problems due to an increase in the absorption rate and the degree of absorption of phenobibrate and the substantially active penofibric acid. The effective blood concentration of the active metabolite phenobipuric acid in humans is in the range of 5 to 35 [mu] g / mL, preferably not exceeding 10 [mu] g / mL ( Current Therapeutic Research , 1979, 26, 3, 357-362).

For example, U.S. Patent No. 7,259,186 discloses an immediate release dosage form comprising amorphous phenobipuric acid, which is not a form that improves the rate of dissolution and thereby releases it immediately to improve the bioavailability of the phenobibrate. Herein, when a formulation containing amorphous phenobipuric acid is administered to an individual, the blood concentration of phenobipuric acid is twice as high as that of the prodrug of the prodrug of the present invention described in Example 6, . Therefore, for reasons of stability as mentioned above, it is not easy to replace the conventional formulation containing phenobibrate with a formulation containing amorphous phenofibric acid.

In order to solve this problem, U.S. Patent 7,259,186 discloses a pharmaceutical composition comprising a salt or a derivative of phenobiphenyl acid and physiologically acceptable choline, ethanolamine, diethanolamine, piperazine, calcium or tromethamine and the like, Discloses a formulation for oral administration of phenobipuric acid which is pH dependent and consists of a binder component comprising a species of enteric binder.

Korean Patent Laid-Open No. 10-2011-0114073 relates to an oral pharmaceutical composition comprising 0.22 to 1 part by weight of an alkalizing agent based on 1 part by weight of phenobipuric acid, wherein an increase in pH by the addition of an alkalizing agent And increase the bioavailability by increasing the water solubility of lanthanum.

Thus, when the active metabolites phenobiphenyl acid, penofibric acid salt and / or buffered phenobifric acid are administered to a patient in solid dosage form, the Area Under the Concentration- time curve (AUC) is similar to the AUC of the phenobibrate and has a safe pharmacokinetic profile that does not exceed 125% of the highest peak C _max of the phenobibrate of the previously marketed hyperlipidemic drug, Lt; / RTI > are needed in the art.

Since weakly basic drugs such as phenobifric acid, which are BCS II drugs, are poorly soluble drugs with high in vivo permeability, there is a very high interindividual absorption deviation of the drug in absorption in the gastrointestinal tract. The inventors of the present invention have found that the use of an active ingredient, phenobipur, as an active ingredient, from a matrix preparation consisting of an excipient and an enhancer selected from the group consisting of at least one polyhydric alcohol having a pH of 5 or higher to reduce the variation of the interpersonal absorption of the drug in the body, The acid was gradually solubilized to adjust the dissolution rate to 80% or more within 6 hours, and the amount of the active ingredient to be added was reduced, thereby completing the release-controlled oral solid preparation exhibiting safe efficacy.

Accordingly, it is an object of the present invention to provide a release-controlled oral solid preparation which is an active metabolite of fenofibrate and improved bioavailability of the active ingredient penofibric acid.

In order to achieve the above object,

a) Penofibric acid and its pharmaceutically acceptable salts,

b) at least one pharmaceutically acceptable excipient selected from the group consisting of polyhydric alcohols having a pH of 5 to 10,

c) a pharmaceutically acceptable thickener, and

d) Pharmaceutically acceptable additives

Lt; RTI ID = 0.0 > a < / RTI > release-controlled oral solid preparation.

According to the present invention, there is provided a pharmaceutical composition for preventing or treating hyperlipemia and hypertriglyceridemia, which exhibits improved absorption due to the influence of individual differences and dietary effects of phenobipuric acid, which has a dissolution rate of 80% or more within 6 hours, It is possible to provide a release-controlled solid oral preparation improved in bioavailability comprising phenobipuric acid which can be usefully used for the treatment of hematopoiesis.

1 and 2 are graphs showing the dissolution rates for the phenobiphyric acid release controlling agent prepared in Examples 11, 12, 13, 14 and 15 conducted in Test Example 3. FIG.
3 is a graph showing dissolution rates for the solubilized granules and release-controlled tablets prepared in Comparative Example 1 and Example 15, respectively, of the active ingredient penofibric acid.
Figure 4 shows the pharmacokinetic profile of the controlled release formulation of penpiburic acid prepared in Example 15 according to the evaluation of food effects in beagle dogs.

The controlled-release oral solid preparation of the present invention

a) Penofibric acid and its pharmaceutically acceptable salts,

b) at least one pharmaceutically acceptable excipient selected from the group consisting of polyhydric alcohols having a pH of 5 to 10,

c) a pharmaceutically acceptable thickener, and

d) Pharmaceutically acceptable additives

And a control unit.

The oral solid preparations according to the present invention may preferably be formulated in the form of tablets, more preferably film-coated tablets.

Fenofibric acid and its pharmaceutically acceptable salts used as active ingredients in the present invention are active metabolites of fenofibrate and are useful for the treatment of adult endogenous hyperlipidemia and hypertriglyceridemia.

The active ingredient, including phenobipuric acid and its pharmaceutically acceptable salts, is included in a total amount of 5-70% by weight, preferably 10-50% by weight, especially 20-40% by weight of the tablet.

Pharmaceutically acceptable excipients for use in the present invention may include, for example, but are not limited to, fillers, lubricants, lubricants, solubility enhancers, wetting agents, and disintegrants.

Such fillers include, for example, lactose, lactose, sucrose, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol .

The lubricant includes calcium silicate, colloidal silicon dioxide, magnesium silicate, starch, talc, magnesium trisilicate, and the like.

The lubricant includes colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, active and combinations thereof, glyceryl behenate, glyceryl palmitostearate, magnesium stearate, sodium stearyl fumarate, and the like.

Such disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, sodium alginate and guar gum, croscarmellose, low substituted hydroxypropylcellulose carboxymethyl starch sodium, and the like do.

Preferably, the excipient may be selected from the group consisting of polyhydric alcohols having a pH of 5 or more, more preferably a pH of 5 to 10, in a slurry state. More preferably, the excipient may be at least one excipient selected from the group consisting of glutose, galactose, lactose, sucrose, maltose, mannitol, glycerol, sorbitol, xylitol, maltitol, lactitol and isomalt.

The excipient used in the present invention can enhance the solubilization of phenobipuric acid and its pharmaceutically acceptable salts having a pKa value of 3.8 as a weakly basic drug by keeping the environment in the formulation at pH 5 or higher.

Pharmaceutically acceptable thickeners for use in the present invention include, for example, polyvinylpyrrolidone, lactose, starch, modified starch, sucrose, acacia rubber, tragacanth gum, guar gum, pectin, But are not limited to, crystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone, gelatin, sodium alginate, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycol Corn starch, poloxamer, and the like. Preferably, the thickening agent is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, poloxamer, and polyvinylpyrrolidone. .

The excipients and thickeners are preferably present in a weight ratio of 1: 0.05 to 1: 1. More preferably, it is present in a weight ratio of 1: 0.1 to 1: 0.5.

The pharmaceutically acceptable additives used in the present invention are, for example, sodium hydroxide, sodium phosphate, calcium phosphate, calcium carbonate and the like, and when used together with one or more water-insoluble excipients having a pH of 5 or more, Results can be obtained. Preferably, the additive is selected from the group consisting of calcium phosphate, calcium carbonate, and tribasic calcium phosphate.

The release-controlled oral solid preparation according to the present invention contains an excipient of at least one kind of at least one of pH 5 or more to create an environment in which the active ingredient phenobipuric acid can be solubilized spontaneously, The rate of solubilization in the matrix is also controlled and the dissolution rate increases as it slowly dissolves after 2 hours of oral administration.

Generally, the granulating agent is dispersed within a few minutes due to an increase in surface area, and the dissolution rate increases with an increase in solubility to rapidly increase the dissolution rate. However, the release-controlled oral solid preparation according to the present invention has a dissolution rate of 80% or more within 6 hours.

Therefore, the present invention can improve the absorption rate which can cause safety problems, thereby controlling the highest blood concentration ( _Cmax ), and ultimately increasing the AUC of phenobarbic acid, indicating the degree of absorption, thereby reducing the effective dose there was. That is, the present invention reduces dosage through solubilization and release control and limits tablet size to weight to improve compliance.

The present invention will be described in more detail by the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the invention.

<Examples>

Example  1-5: Phenobipurenic Solubilization  Granule manufacture

Granulating, drying and sizing with 25 mesh in accordance with the usual wet granulation method by adding phenanthric acid, phenobiphenyl acid, ascorbic acid and excipient, isomalt, sorbitol and tribasic calcium phosphate, respectively, and adding anhydrous ethanol, To prepare a solubilized granule. The addition weights are shown in Table 1 below.

Solubilization  Granule dissolution test

In order to confirm the degree of solubilization in water, 105 mg of phenobiphilic acid corresponding to the active ingredient as a comparative example and the solubilized granules of Examples 1 to 5 prepared as described above were weighed and added to 900 mL of water by the USP second method (paddle method, Paddle rotation speed of 50 rpm) was applied to perform dissolution test. The results of the dissolution test are shown in Table 1 below.

ingredient Comparative Example Example 1 Example 2 Example 3 Example 4 Example 5 Phenobipuric acid
Lactose
Isomalt
Sorbitol
Tribasic calcium phosphate
Hydroxyethylcellulose 105.0 105.0
50.0
-
-
100.0
12.0 105.0
-
50.0
-
100.0
12.0 105.0
-
100.0
-
50.0
12.0 105.0
-
100.0
-
50.0
50.0 105.0
-
-
100.0
50.0
50.0 Dissolution rate (%) 30 minutes
60 minutes 9.7
13.3 48.6
57.1 50.9
58.7 62.1
71.3 63.0
78.1 46.5
62.0

As a comparative example, the active ingredient, phenobifric acid, showed a dissolution rate of 13.3% per hour, and as an excipient selected from the group consisting of polyhydric alcohols having a pH of 5 or more, a combination of at least one of isomalt, sorbitol, tribasic calcium phosphate, The solubilized granules prepared in Examples 1 to 5 containing a cellulose thickener exhibited a dissolution rate of more than 57%. It was confirmed that the dissolution rate was increased in this manner, indicating that the solubility of phenobiphenylic acid was improved.

Example  6-10: Phenobipuric acid Solubilization Granule manufacture

Calcium carbonate, calcium hydrogen phosphate, tribasic calcium phosphate, sodium hydroxide and thickener such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose were used as the excipients. Solubilized granules containing hydroxyethylcellulose were prepared. The addition weights are shown in Table 2 below.

Solubilization  Granule dissolution test

In order to confirm the degree of solubilization in water, the solubilized granules of Examples 6 to 10 prepared as described above were subjected to a dissolution test by applying USP Method 2 (paddle method, rotating speed of paddles: 50 rpm) to 900 mL of water. The results of the dissolution test are shown in Table 2 below.

ingredient Comparative Example Example 6 Example 7 Example 8 Example 9 Example 10 Phenobipuric acid
Isomalt
Calcium carbonate
Calcium hydrogen phosphate
Tribasic calcium phosphate
Sodium hydroxide
Hydroxypropylmethylcellulose
Hydroxyethylcellulose 105.0 105.0
50.0
100.0
-
-
-
30.0
- 105.0
50.0
-
100.0
-
-
30.0
- 105.0
50.0
100.0
-
-
-
50.0
- 105.0
50.0
-
-
100.0
-
-
30.0 105.0
50.0
-
-
100.0
2.5
-
30.0 Dissolution rate (%) 30 minutes
60 minutes 9.7
13.3 82.3
84.6 62.0
70.0 80.6
84.0 69.2
79.2 67.9
79.7

It was confirmed that the solubility of the solubilized granules of Examples 5 to 10 was improved to 70% or more for one hour.

Example  11-15: Phenobipuric acid  Preparation of release-controlled solid preparation

As in Examples 1 to 10, solubilized granules containing phenovibric acid as an active ingredient and having at least one excipient of pH 5 or higher and an increasing agent were prepared, and then granules were mixed with lactose, microcrystalline cellulose, crospovidone, croscarmellose Sodium, colloidal silica gel, magnesium stearate and the like were mixed as shown in Table 3 below, and the tableting process was carried out to prepare a release-controlled solid preparation.

ingredient Example 11 Example 12 Example 13 Example 14 Example 15 Phenobipuric acid
Isomalt
Tribasic calcium phosphate
Hydroxypropylmethylcellulose
Pollock Sommer
Co-povidone
Sodium hydroxide
Crospovidone
Croscarmellose sodium
Microcrystalline cellulose
Lactose
Magnesium stearate
Cloid silica gel 100.0
50.0
100.0
30.0
-
-
2.4
22.0
-
90.0
-
5.6
- 100.0
100.0
50.0
30.0
-
-
2.27
-
22.8
-
67.33
3.8
3.8 100.0
50.0
50.0
-
30.0
12.2
1.87
-
22.8
50.0
55.53
3.8
3.8 90.0
45.0
45.0
-
13.7
17.1
-
-
17.1
45.0
62.3
3.4
3.4 95.0
47.5
47.5
-
14.4
18.1
-
14.3
-
47.5
-
2.9
3.6 400.0 380.0 380.0 342.0 290.8

Release test of release-controlled solid preparation

The tablets prepared in Examples 11 to 15 were subjected to a dissolution test by applying USP second method (paddle method, rotating speed of paddles: 50 rpm) to 900 mL of water. The dissolution test results are shown in Figs. 1 and 2. Fig. The solubilization rate of the solubilized granules was more than 40% for one hour, and the improved solubility was confirmed. It was confirmed that the initial elution was controlled to be gradually released while gradually being solubilized from the tablet surface.

In addition, the dissolution rate in Comparative Example 1 and water was checked for the controlled-release tablets prepared in Example 15 and the tablet-controlled tablets manufacturing process. The solubilized granules comprising at least one polyhydric alcohol excipient having a pH of 5 or higher and the solubilizing agent having a solubility increased faster than the dissolution rate of about 13% per hour of the active ingredient of Comparative Example 1, and the dissolution rate was more than 80% per hour. As a result, in the tablets subjected to the tableting process for reducing the surface area of the granular state, a matrix composed of the active ingredient, one or more excipients and the thickening agent was constituted and solubilized more than Comparative Example 1, Controlled release tablets with a time within 6 hours.

In the present invention, the matrix environment inside the tablet is gradually released, such as the dissolution rate of the tablet, which is advanced using the granules. The matrix environment is composed of at least one polyhydric alcohol excipient having a pH of 5 or higher and an increasing agent, and the dissolution rate and dissolution rate It has been determined that a controllable phenobiphyric acid release controlling agent is a preferable formulation for improvement of absorption in vivo.

Pharmacokinetic Evaluation

160 mg of Lipidylsufura as a control preparation and 290.8 mg of a controlled-release purified mass of 95 mg of phenobipuric acid as the granule prepared in Example 15 were injected into a beagle animal model for the ratio of the active ingredient to the same release-controlled formulation to determine pharmacokinetic Respectively. Lipidusshupurajun is a formulation of 160mg of phenobibrate, which is a dose reduction and bioavailability increase by solid dispersion solubilization technique.

The beagle dogs were divided into 5 rabbits, and blood samples were collected at predetermined time intervals to confirm the respective pharmacokinetic profiles. The results are shown in Table 4 below.

C _max and AUC were obtained after Lipidyshylfura supplementation with increasing absorption rate. In the present invention, the postprandial equivalence was secured in beagle dogs as a controlled release formulation consisting of an active metabolite, phenobipric acid, one or more basic excipients and an increasing agent.

Equivalence was achieved with a small dose of 95 mg and 100 mg of phenobipuric acid less than 141.34 mg, a molecular equivalent equivalent to 160 mg of the comparator phenobibrate, so that the bioavailability of the controlled-release delayed-release formulation was increased and, as a result, Is expected to improve.

Lipidyshpuraj
(160 mg of phenobibrate) Example 15
(95 mg of phenobipric acid) T _max (hr)
C _max (μg / mL)
AUC (μg.hr / mL) 4.0 ± 4.8
8.7 ± 3.6
51.6 ± 11.7 3.2 ± 3.3
10.6 ± 3.5
54.6 ± 8.7

Food Impact Assessment

In order to evaluate the effect of food on the beagle dog animal model of the 95 mg release-controlled formulation of penofibric acid prepared in Example 15, the beagle dogs were divided into 12 dogs per group, and blood was collected at predetermined time intervals, and each pharmacokinetic The profile was confirmed and the results are shown in Table 5 and FIG.

After a meal ceremony P value T _max (hr)
C _max (μg / mL)
AUC (μg.hr / mL) 1.42 0.93
18.76 ± 2.71
54.21 + - 11.78 1.42 0.76
29.79 ± 11.29
54.6 ± 8.7 -
0.007
0.007

There was a statistically significant increase (p = 0.007) in the C _max and AUC before meals and no significant effect on food.

Claims (7)

a) fenofibric acid and its pharmaceutically acceptable salts,
b) at least one pharmaceutically acceptable excipient selected from the group consisting of polyhydric alcohols having a pH of from 5 to 10;
c) pharmaceutically acceptable thickeners, and
d) pharmaceutically acceptable additives
Wherein the physiologically acceptable salt of phenobipuric acid comprises phenobipuric acid. The method of claim 1,
Wherein said phenobipuric acid and its pharmaceutically acceptable salt are added in an amount of 5-70% by weight of the total tablet weight. The method of claim 1,
Wherein the release-controlled solid oral preparation is controlled to be eluted to 80% or more within 6 hours. The method of claim 1,
The excipient is controlled release solid oral, characterized in that it comprises at least one selected from the group consisting of glutose, galactose, lactose, sucrose, maltose, mannitol, glycerol, sorbitol, xylitol, maltitol, lactitol and isomalt Formulation. The method of claim 1,
Wherein the thickener comprises at least one or more selected from the group consisting of hydroxypropylmethylcellulose, crospovidone, croscarmellose, hydroxypropylcellulose, poloxamer, and polyvinylpyrrolidone. Controlled solid oral formulations. The method of claim 1,
Wherein the excipient and the thickening agent are present in a weight ratio of 1: 0.05 to 1: 1. The method of claim 1,
Wherein the additive is selected from the group consisting of calcium phosphate, calcium carbonate, and tribasic calcium phosphate.

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