KR20150036898A - Pharmaceutical composition of atorvastatin tablet and fenofibric acid pellts in capsule - Google Patents

Abstract

The present invention relates to a hard capsule compound formulation; and to a manufacturing method of the hard capsule compound formulation, wherein the hard capsule compound formulation comprises (a) a pellet comprising fenofibric acid or a pharmaceutically acceptable salt thereof and an alkalizer; and (b) a tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof and crospovidone in the weight ratio of 1:2.5 to 1:5.5. According to the present invention, the hard capsule compound formulation exhibits excellent dissolution rate and bioavailability and thus can be practically used for a therapeutic agent for hyperlipidemia and hypercholesteremia.

Description

TECHNICAL FIELD [0001] The present invention relates to a hard capsule composite preparation comprising atorvastatin tablet and phenobicyclic acid pellet exhibiting improved bioavailability,

The present invention relates to a hard capsule combination preparation containing crospovidone and atorvastatin tablets having improved dissolution rate and phenobicyclic acid pellets.

Hyperlipidemia refers to a state of abnormally elevated lipid such as cholesterol or triglyceride in plasma. In particular, cholesterolemia induces arterial thrombosis, which causes arterial sclerosis, which accumulates thick lipids along the blood vessels. This is a clinically important problem because it reduces blood flow and causes ischemic heart disease, angina pectoris and myocardial infarction. As such, hyperlipidemia and atherosclerosis are closely related to each other, and atherosclerosis can be prevented by treating hyperlipemia.

Elevated hyperlipidemia or elevated serum lipids is associated with an increased incidence of cardiovascular disease and arteriosclerosis. Specific types of hyperlipidemia include hypercholesterolemia, familial beta-lipoproteinemia, diabetic dyslipidemia, nephrotic dyslipidemia and familial hyperlipidemia. Hypercholesterolemia results in elevation of serum low-density lipoprotein-cholesterol and serum total cholesterol. Low density lipoproteins carry cholesterol in the blood. In addition, familial beta-lipoproteinemia, also known as type III hyperlipidemia, is characterized by the accumulation of very low density lipoprotein (beta VLDL), called ultra-low density lipoprotein cholesterol particles, in the serum. In addition, this symptom is associated with the replacement of normal apolipoprotein E3 by the heterologous apolipoprotein E2. Diabetic dyslipidemia leads to a number of lipoprotein abnormalities such as overproduction of VLDL-cholesterol, abnormal lipolysis of VLDL triglyceride, decreased LDL-cholesterol receptor activity, and Type III hyperlipidemia that often occurs. Nephrotic dyslipidemia is difficult to treat, and the most common cases are hypercholesterolemia and hypertriglyceridemia. Familial complex hyperlipidemia is divided into multiple phenotypic hyperlipidemia, Type IIa, IIb, IV, V, or Apo beta-lipoproteinemia.

Fenofibrate is used in the treatment of adult endogenous hyperlipidemias, hypercholesterolemias, and hypertriglyceridemias. A reduction of 20-25% in the case of hypercholesterolemia and a reduction of 40-50% in the case of hypertriglyceridemia can be achieved with 300-400 mg of fenofibrate treatment per day.

The major metabolite in the blood plasma of this phenobarbital is phenobiprin acid (chemical name: 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid). The half-life of phenobiphenyl acid from plasma is approximately 20 hours, and the time it takes for plasma to reach its maximum concentration on average is 5 hours after ingestion with the drug.

In the plasma, phenobibrate is metabolized to phenobiphenyl acid, which is effective. (LDL-C), apo-lipoprotein B, total triglyceride and triglyceride rich lipoprotein (VLDL), high density lipoprotein (HDL), apo-lipoprotein AI and Lt; RTI ID = 0.0 > AII. ≪ / RTI >

These fenofibrate and fenofibric acid are hydrophobic and poorly soluble in water, resulting in low bioavailability in the digestive tract and increased absorption of the individual in the digestive tract after ingestion of food (compared to the consumption of phenobibrate in the fasting state). In general, the gastrointestinal residence time of the drug is also much longer in the presence of food than in the fasting state. Thus, if the bioavailability of the drug is influenced at a particular time by the presence of food in the gastrointestinal tract, the drug is said to represent a food effect. In the case of fenofibrate, insufficient absorption of fenofibrate may be induced if the food is not ingested at the same time as the ingestion of the drug because the food increases absorption of fenofibrate. Commercially available phenobibrate-containing product Tricor (TM) (Abbot) increases its absorption by about 35% under feeding conditions compared to fasting conditions. On the other hand, phenobiphenyl acid exhibits higher solubility in high pH regions such as the small intestine region.

On the other hand, US Pat. No. 7,259,186 discloses a phenobiprphinate composition in which choline, ethanolamine, diethanolamine, piperazine, calcium or tromethamine salt is bound to phenobiphenylic acid to reduce the effect of food on phenobiphilic acid Lt; / RTI > In US Publication No. 2008/0152714, it has also been confirmed that the effect of food is reduced by preparing a phenophosphoric acid choline salt bound to a choline salt and evaluating its ionic strength in the examples.

Thus, there has been a continuing need for the development of a pharmaceutical composition of phenobiphenyl acid, which has improved water solubility, has high drug bioavailability, and is less influenced by food and has minimal drug absorption deviation in the gastrointestinal tract.

Atorvastatin, or a pharmaceutically acceptable salt thereof, is a selective and competitive HMG-CoA reductase inhibitor comprising atorvastatin calcium (chemical name: [R- (R *, R *)] (4-fluorophenyl) -?,? - dihydroxy-5- (1-methylethyl) Acid calcium salt (2: 1)) has been used to treat hyperlipidemia.

These compounds (HMG-CoA reductase inhibitors) are known to lower total cholesterol and LDL-cholesterol in the body and provide an effect of elevating HDL-cholesterol levels in some individuals. The step of converting HMG-CoA to mevalonate is an early step in the process of biosynthesis of cholesterol. The inhibition of HMG-CoA reductase, which inhibits mevalonate production, is based on the fact that HMG-CoA reductase inhibitors exert their total cholesterol-lowering effect and LDL-cholesterol lowering effect (Grundi SM, N Engl J Med, 319 (1): 24-32, 25-26, 31 (1998)).

According to the US FOOD and Drug Administration's (FDA) Summary basis of approval (SBA) for Warner-Lambert's Lipitor ™, atorvastatin It exists in multiple amorphous and crystalline forms. Originally, atorvastatin is formed in an amorphous form, but this form is known to be unstable and sensitive to moisture when exposed to oxygen. On the other hand, the later-developed crystalline form of atorvastatin exhibits improved bioabsorption (i.e., about 50% increase in Cmax) but is nonetheless sensitive to heat, moisture, low pH environment and light, Care must be taken.

Korean Patent Publication No. 2007-0104447 relates to a stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an HMG-CoA reductase inhibitor, which discloses the elution of a combination of fenofibrate and atorvastatin. However, in the above patent, the later time point (45 minutes) was compared and only the stability of the compound was evaluated. According to the above patent, the present inventors prepared each active ingredient of atorvastatin and phenobiphilic acid into a pellet and tablet form, filled in a hard capsule, and conducted a dissolution test to compare bioavailability. At this time, we found that the elution of atorvastatin among the two components of the complex in the early stage of the study was lowered by the capsules when the release of atorvastatin was compared with that of the existing commercial formulation (Lipitor tablets). Therefore, in order to study the actual combination drug, a different prescription study was required than the existing atorvastatin single agent.

Accordingly, the inventors of the present invention have studied to improve the dissolution rate and bioavailability of a combination preparation comprising atorvastatin and phenobic acid. As a result, it has been found that by containing crospovidone at a specific weight ratio of the constituent layer containing atorvastatin And exhibits an excellent effect on absorption and dissolution in the body, thereby completing the present invention.

[Patent Document 1] Korean Patent Publication No. 2007-0104447

[Patent Document 2] Korean Patent Registration No. 10-1202994

Accordingly, it is an object of the present invention to provide a pharmaceutical combination comprising phenobiphilic acid and atorvastatin exhibiting excellent bioavailability and optimal elution profile.

Another object of the present invention is to provide a process for preparing the above pharmaceutical combination.

In order to achieve the above object,

(a) pellets containing a phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent; And

(b) a tablet containing atorvastatin or a pharmaceutically acceptable salt thereof, and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5.

To achieve these and other objects,

1) preparing a pellet comprising a phenobicyclic acid or a pharmaceutically acceptable salt thereof;

2) preparing a tablet containing atorvastatin or a pharmaceutically acceptable salt thereof, and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5; And

3) filling the hard capsule with the phenobigic acid pellet and the atorvastatin tablet prepared in the above 1) and 2) together into a hard capsule.

The combined preparation of hard capsules according to the present invention comprises phenobiphilic acid and atorvastatin as an active ingredient to induce the synergistic effect of the two pharmacologically active ingredients and to inhibit the absorption and elution of the drug through the atorvastatin containing crospovidone And can be used as a therapeutic agent for hypercholesterolemia.

FIGS. 1 to 3 are graphs comparing the elution profiles of the penofibric acid-pellet-atorvastatin tablet combination preparation prepared in Comparative Examples 1 to 18 and Examples 1 to 3 with a commercial product (Lipitor tablets).
4 is a graph showing blood concentration-time profiles of atorvastatin of the combination product of penofibric acid-pellet-atorvastatin tablet prepared in Comparative Example 8, Comparative Example 15 and Example 2 and a commercial product (Lipitor tablets).

The present invention relates to a pharmaceutical composition comprising (a) a pellet containing a phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent; And (b) tablets containing atorvastatin or a pharmaceutically acceptable salt thereof and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5.

Hereinafter, the characteristics and kinds of each component constituting the combined hard capsule preparation of the present invention will be described in detail.

(i) Phenopricic acid pellets

The pellet of the hard capsule combination preparation according to the present invention comprises penopbic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent.

The phenobyric acid (compound name: 2- [4- (4-chlorobenzoyl) phenoxy] -2-methyl-propanoic acid) is known as hyperlipidemias, hypercholesterolemias, hypertriglyceridemias ), The half-life of phenobiphenyl acid from plasma is approximately 20 hours, and the time it takes for the plasma to reach its maximum concentration is approximately 5 hours after ingestion with the medication to be. In the plasma, phenobibrate is metabolized to phenobiphenyl acid, which is effective. Fenofibric acid reduces total cholesterol, low density lipoprotein (LDL-C), apolipoprotein B, total triglyceride and triglyceride rich lipoprotein (VLDL), high density lipoprotein (HDL), apo-lipoprotein AI and AII in treated patients It is known.

The drug contained in the phenobicyclic acid pellet according to the present invention includes all of the phenobiphilic acid or a pharmaceutically acceptable salt thereof, but is preferably phenobicyclic acid. The solubility of phenobiphilic acid is generally higher than that of phenobibrate, which is a precursor. In the case of phenobiphilic acid, there are salts in which choline, ethanolamine, diethanolamine, piperazine, calcium or tromethamine salt are bound, Although it is known that the solubility is high, the present inventors also exhibit properties of high solubility even in the case of phenobiphilic acid which does not contain a salt. Phenopribic acid which does not contain a salt is more preferable because it is possible to reduce the amount of raw materials contained in the final formulation by selecting a salt-free raw material, so that a more efficient preparation can be produced.

The phenobic acid according to the present invention may be contained in a therapeutically effective amount, for example, 40 to 160 mg, more preferably 100 to 150 mg per unit dosage form, but is not limited thereto.

Acceptable alkalizing agents of phenobicyclic acid in the present invention include calcium salts (calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate), magnesium salts (magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium oxide, magnesium aluminate, Alkaline metal salts such as aluminum magnesium, lithium salts (lithium hydroxide), potassium salts (potassium hydroxide), and sodium salts (sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide). Basic additives such as meglumine, arginine, and mixtures thereof can also be used. More preferably, the alkalizing agent may be calcium carbonate, magnesium carbonate, meglumine or a mixture thereof. The alkalizing agent is used in an amount of 22 to 100 parts by weight with respect to 100 parts by weight of phenobiphenylic acid or a pharmaceutically acceptable salt thereof, and when the amount is less than 22 parts by weight, the water solubility of phenobiphenylic acid is 1000 ppm or more If the amount is more than 100 parts by weight, the ratio of the length to the shortening ratio of the pellets in the production of the pellets exceeds 1.5, so that the sphericity of the pellets is poor and the pellets unsuitable for the coating process can be produced.

Examples of delayed-release coating materials usable in the phenobicyclic acid pellets according to the present invention include water-insoluble polymers or hydrophobic compounds. The water-insoluble polymer may be selected from the group consisting of hydroxypropyl methylcellulose (HPMCP), polyvinylacetate (e.g., Colicot SR 30D), water insoluble polymethacrylate copolymer (e.g., poly (ethyl acrylate- (Ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride) copolymer (e.g., Eudragit RSPO), etc.), and a poly Cellulose triacetate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof, and may be selected from the group consisting of phthalic acid, cellulose acetate, Hydroxypropyl methylcellulose (HPMCP), polyvinyl acetate, May be at least one selected from poly (ethyl acrylate-methyl methacrylate) copolymer, poly (ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride) copolymer, ethyl cellulose and cellulose acetate, Preferably, it may be at least one selected from hydroxypropylmethylcellulose phthalate (HPMCP), poly (ethyl acrylate-methyl methacrylate) copolymer, ethylcellulose, and cellulose acetate.

The hydrophobic compound may be selected from the group consisting of fatty acid and fatty acid esters, fatty acid alcohols, waxes, inorganic substances and mixtures thereof. Wherein the fatty acid and fatty acid esters are selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate, and stearic acid; The fatty acid alcohols include at least one selected from the group consisting of cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The waxes include one or more selected from carnauba wax, wax and microcrystalline wax; The inorganic material may be at least one selected from talc, precipitated calcium carbonate, calcium monohydrogenphosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and beads. Preferably, it may be at least one selected from glyceryl palmitostearate, glyceryl behenate, stearic acid, cetyl alcohol and carnauba wax, more preferably at least one selected from glyceryl behenate, stearic acid and carnauba wax It can be more than a species. The retarded release coating material may be used in an amount of 5 to 50 parts by weight per 100 parts by weight of the pellets corresponding to the core (pellets before coating). If the coating amount is less than 5 parts by weight, it is difficult to obtain a delayed release effect. If the coating amount is more than 50 parts by weight, the weight of the coated pellets is too large, .

     The spherical additives that can be used in the present invention include natural polymers such as carrageenan gum, guar gum, xanthan gum, locust bean gum, gellan gum, gum arabic, agar, alginic acid, propylene glycol alginate and sodium alginate, . The spheronizing additive may be used in an amount of 0.05 to 0.5 wt% of the total weight of the pellets corresponding to the cores (pellets before coating). If it is used in an amount of less than 0.05% by weight, it is difficult to obtain a sphering effect, and if it exceeds 0.5% by weight, it may lead to unexpected adherence to a production facility due to delayed release or stickiness upon extrusion.

As described above, preferably, the phenobicyclic acid is formulated in the form of pellets, specifically, (i) first wet mixing the phenobiphenylic acid or a pharmaceutically acceptable salt thereof with an alkalizing agent; (ii) adding a pharmaceutically acceptable excipient and optional sphering agent to the first mixture obtained in step (i) and secondarily wet mixing; (iii) preparing spherical granules from the secondary mixture obtained in step (ii) using an extruder and a spheronizer; And (iv) optionally, the step of coating the granules obtained in step (iii) with a delayed-release coating material, in the form of pellets.

(ii) atorvastatin tablets

The atorvastatin tablet of the combination of hard capsules according to the present invention contains atorvastatin or a pharmaceutically acceptable salt thereof and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5.

In the present invention, atorvastatin is a drug capable of preventing or treating hyperlipidemia and arteriosclerosis by lowering blood lipoprotein or lipid concentration.

The pharmaceutically acceptable salts of atorvastatin in the present invention may be any salts that can be easily used by those skilled in the art including calcium salts, hydrochlorides, sodium salts, potassium salts, calcium salts, magnesium salts, , And atorvastatin calcium salt are preferable.

The atorvastatin or pharmaceutically acceptable salt thereof according to the present invention may be contained in an amount of 5 to 40% by weight, preferably 15 to 25% by weight, based on the total weight of the tablet, and a therapeutically effective amount, For example, it may include 1 mg to 80 mg, more preferably 5 to 50 mg, per unit dosage form, but is not limited thereto.

In the present invention, crospovidone, which is a disintegrant, is present in the granules of atorvastatin, thereby playing a role in improving the dissolution rate and bioavailability of the compound. The crospovidone is a compound also referred to as crospolyvidone or cross-linked polyvinylpyrrolidone.

Crospovidone, croscarmellose sodium, sodium starch glycollate (SSG), and the like are commonly used disintegrants in the art. In the present invention, a disintegrant capable of reaching a desired dissolution rate among the disintegrants was selected through experiments to confirm a specific suitable amount to be added. As a result, crospovidone was selected as a disintegrant capable of securing the same level of dissolution rate as that of the control preparation and external stability during production and storage. The crospovidone was used at a weight ratio of 1: 2.5 to 1: 5.5 based on atorvastatin, Preferably in a weight ratio of 1: 3 to 1: 4.5. In the present invention, the dissolution rate of atorvastatin is slower than that of the conventional tablet due to the gelatin capsule, and when the amount of crospovidone to atorvastatin is less than 1: 2.5, the minimum therapeutic concentration is reached at the basal point, But the use of higher doses of atorvastatin is required. This method is practically impossible because the final content is different from the control agent. On the other hand, when the weight ratio of crospovidone to atorvastatin is more than 1: 5.5, the production efficiency is not meaningful, and manufacturing problems such as poor tablet hardness are caused. Thus, in the present invention, it is preferable that crospovidone is used in an amount of 1: 2.5 to 1: 5.5 by weight relative to atorvastatin.

The hard capsule combination preparation of the present invention may have a hardness of 4 kp or more, for example, a hardness of 3.8 to 7.0 kp, a degree of wrinkle of 1% or less, preferably 0.7% or less, for example, 0.4 to 0.7% The hardness and the degree of abrasion of such capsules are influenced by the weight ratio of crospovidone to atorvastatin, and the amount of crospovidone is appropriate to achieve the function of disintegration, and in addition, And it is preferable to select an appropriate amount of disintegrating amount because tablets containing the drug in capsules are highly likely to lose their contents in the process of breaking the corners inside the capsules or charging the capsules.

In addition, the atorvastatin tablets of the present invention may further comprise a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive may be selected from the group consisting of water-soluble diluents, binders, lubricants, and mixtures thereof have.

The water-soluble diluents usable in the present invention may be selected from the group consisting of microcrystalline cellulose, hydroxypropylcellulose, pregelatinized starch, glucose, sucrose, lactose, sorbitol, mannitol, dapsitol, ribitol and xylitol, However, the present invention is not limited thereto. The aqueous diluent may be used in an amount ranging from 1 to 80% by weight, preferably from 5 to 50% by weight, based on the total weight of the tablet.

Binders which can be used in the present invention include alginic acid, sodium alginate, sodium carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose, gelatin, povidone, starch and pregelatinized starch and A mixture thereof, but is not limited thereto. The binder may be used in an amount ranging from 0.1 to 5% by weight, preferably 0.5 to 2% by weight, based on the total weight of the tablet.

Lubricants usable in the present invention include calcium stearate, glyceryl monostearate, cliceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, Polyethylene glycol, sodium benzoate, talc, and mixtures thereof, but is not limited thereto. The lubricant may be used in an amount ranging from 0.1 to 5% by weight, preferably 0.5 to 2% by weight based on the total weight of the tablet.

As described above, preferably, atorvastatin is formulated in the form of tablets, and specifically, (i) atorvastatin or a pharmaceutically acceptable salt thereof is dissolved in a suitable disintegrant and, optionally, (The additive may include a diluent, a binder, and a lubricant); (ii) adding a granulating solvent to the primary mixture obtained in step (i), wherein preferred granulating solvents include water, ethanol and combinations thereof, and other Other ingredients (such as binders) may be added to the granulation solvent; (iii) drying the resultant obtained in the step (ii) through air drying, fluidized bed drying, oven drying or the like; (Iv) pulverizing or sieving the material obtained in step (iii); (V) mixing the material obtained in step (iv) with an additional adjuvant to form granules, and (vi) using a tablet machine to prepare tablets from the secondary mixture obtained in step (v) , ≪ / RTI >

(iii) Poly drug in capsule

 The hard capsule combination preparation according to the present invention comprises a pellet comprising a phenobiphilic acid or a pharmaceutically acceptable salt thereof, atorvastatin or a pharmaceutically acceptable salt thereof, and crospovidone at a ratio of 1: 2.5 to 1: 5 Is filled into a hard capsule, the contact between the two components is blocked as much as possible, thereby improving the stability and improving the dissolution rate and bioavailability.

For example, the hard capsule may be filled with 262 mg of pellet containing 135 mg of phenobic acid and 65 to 130 mg of tablet containing 10 to 20 mg of atorvastatin or a pharmaceutically acceptable salt thereof to complete the combined preparation, Is not limited thereto.

In summary, the hard capsule combination preparation according to the present invention comprises atorvastatin tablets at a ratio of crospovidone to atorvastatin in a weight ratio of 1: 2.5 to 1: 5.5 so that the dissolution rate of atorvastatin is the same as that of the control preparation And the bioavailability can be improved by minimizing the lag time of the tablet necessary for disintegration time of the capsules.

 The formulation can release 60% or more of atorvastatin at 10 minutes, the most discriminating time of the elution profile (see FIG. 2), which is similar or superior to the commercially available product Lipitor.

Therefore, the combined preparation according to the present invention can exert an excellent effect on the absorption and dissolution of the body, and thus can be effectively used as a therapeutic agent for combination of triglyceride and hypercholesterolemia.

The hard capsule combination preparation according to the present invention comprises the steps of: 1) preparing a pellet comprising a phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent; 2) preparing a tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5; And 3) filling the phenobiphic acid pellet prepared in 1) above and the atorvastatin tablets prepared in 2) together using a polycap charger.

[Example]

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

< Manufacturing example  1> Phenopric acid  Included Pellet  Produce

(Alembic, India) and magnesium carbonate were firstly wet-mixed in a certain amount of water and then povidone (BASF, Germany) and carrageenan gum (FMC biopolymer) Wet blend was made to produce the association. The resulting allied product was extruded with a 0.8 mm mesh sieve using an extruder (MG-55, Dalton), sphericized using a spheronizer (Spheronizer Q-230T, Dalton) for 3 minutes and dried at 60 ° C to produce pellets Respectively. Delayed-release coating was carried out using ethylcellulose (EC, Aqualon) as a delayed-release coating material. For smooth coating, hydroxypropylmethylcellulose (HPMC, Shinetsu, Japan) and propylene glycol (PEG) were added as a coating material to prepare a coating solution. Water and ethanol were used as a coating solution. And coated with a fluidized bed coater to be used to prepare coated pellets (unit: mg)

Manufacture of Pellets Containing Phenopric Acid Classification (Unit: mg) Production Example 1 Phenobicyclic acid 135 Magnesium carbonate 50 Carrageenan sword 35 EC 32 HPMC 12 PEG 6 <EtOH> &Lt; 350 & <Water> <35> Sum 253

< Manufacturing example  2-1 to 2-7> Atorvastatin  Preparation of tablets containing

Atorvastatin calcium trihydrate (Dr. Reddy's, India) was mixed with mannitol and croscarmellose sodium in the proportions shown in Table 2 below. This was combined with HPC (Nippon Soda, Japan) and Polysorbate 80 (Croda, USA) in a water-immobilized binding solution, and the mixture was sieved with 30 mesh sieve. Magnesium stearate was added thereto and mixed to prepare atorvastatin granules , And tabletted using a tablet machine (unit: mg)

division Manufacturing example
2-1 Manufacturing example
2-2 Manufacturing example
2-3 Manufacturing example
2-4 Manufacturing example
2-5 Manufacturing example
2-6 Manufacturing example
2-7 Atorvastatin calcium 10.82 10.82 10.82 10.82 10.82 10.82 10.82 (Atorvastatin content) (10) (10) (10) (10) (10) (10) (10) Mannitol 5 5 5 5 5 5 5 Cross camelose
salt 10.82 21.64 32.46 43.28 54.10 64.92 75.74 HPC 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Polysorbate 80 0.6 0.6 0.6 0.6 0.6 0.6 0.6 <Water> <75> <75> <75> <75> <75> <75> <75> Magnesium stearate 0.5 0.5 3 3 3 3 3 Sum 29.24 40.06 50.88 61.70 72.52 83.34 94.16 Disintegration / atorvastatin calcium trihydrate One 2 3 4 5 6 7

< Manufacturing example  3-1 to 3-7> Atorvastatin  Preparation of tablets containing

Atorvastatin calcium trihydrate (Dr. Reddy's, India) was mixed with mannitol and crospovidone at the ratio shown in Table 3 below. This was combined with HPC (Nippon Soda, Japan) and Polysorbate 80 (Croda, USA) in a water-soluble conjugate, dried, sieved in a 30 mesh sieve, and magnesium stearate was added thereto to prepare atorvastatin granules , And tabletted using a tablet machine (unit: mg)

Manufacturing example
3-1 Manufacturing example
3-2 Manufacturing example
3-3 Manufacturing example
3-4 Manufacturing example
3-5 Manufacturing example
3-6 Manufacturing example
3-7 Atorvastatin calcium 10.82 10.82 10.82 10.82 10.82 10.82 10.82 (Atorvastatin content) (10) (10) (10) (10) (10) (10) (10) Mannitol 5 5 5 5 5 5 5 Crospovidone 10.82 21.64 32.46 43.28 54.10 64.92 75.74 HPC 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Polysorbate 80 0.6 0.6 0.6 0.6 0.6 0.6 0.6 <Water> <75> <75> <75> <75> <75> <75> <75> Magnesium stearate 0.5 0.5 3 3 3 3 3 Sum 29.24 40.06 50.88 61.70 72.52 83.34 94.16 Disintegration / atorvastatin
Calcium trihydrate One 2 3 4 5 6 7

< Manufacturing example  4-1 to 4-7> Atorvastatin  Preparation of tablets containing

Atorvastatin calcium trihydrate (Dr. Reddy's, India) was mixed with mannitol and SSG in the ratio shown in Table 2 below. This was combined with HPC (Nippon Soda, Japan) and Polysorbate 80 (Croda, USA) in a water-immobilized binding solution, and the mixture was sieved with 30 mesh sieve. Magnesium stearate was added thereto and mixed to prepare atorvastatin granules , And tabletted using a tablet machine (unit: mg)

Manufacturing example
4-1 Manufacturing example
4-2 Manufacturing example
4-3 Manufacturing example
4-4 Manufacturing example
4-5 Manufacturing example
4-6 Manufacturing example
4-7 Atorvastatin calcium 10.82 10.82 10.82 10.82 10.82 10.82 10.82 (As atorvastatin) (10) (10) (10) (10) (10) (10) (10) Mannitol 5 5 5 5 5 5 5 SSG 10.82 21.64 32.46 43.28 54.10 64.92 75.74 HPC 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Polysorbate 80 0.6 0.6 0.6 0.6 0.6 0.6 0.6 <Water> <75> <75> <75> <75> <75> <75> <75> Magnesium stearate 0.5 0.5 3 3 3 3 3 Sum 29.24 40.06 50.88 61.70 72.52 83.34 94.16 Disintegration / atorvastatin
Calcium trihydrate One 2 3 4 5 6 7

< Comparative Example  1 to 18> Phenophosphoric acid pellets  - Atorvastatin  Charging of refined hard capsules

As shown in Table 5 below, a combination preparation containing penopical acid pellet and atorvastatin tablets was packed in combination with the above-mentioned preparation examples.

The capsules were packed with phenobipartic acid pellets and atorvastatin tablets using a Polycap charger to complete a combined preparation of 135 mg of phenobiproic acid and 10 mg of atorvastatin.

< Example  1 to 3> Phenophosphoric acid pellets  - Atorvastatin  Charging of refined hard capsules

As shown in Table 5 below, a combination preparation containing penopical acid pellet and atorvastatin tablets was packed in combination with the above-mentioned preparation examples.

The capsules were packed with phenobipartic acid pellets and atorvastatin tablets using a Polycap charger to complete a combined preparation of 135 mg of phenobiproic acid and 10 mg of atorvastatin.

Preparation of a combination preparation containing phenobic acid and atorvastatin Phenobicyclic acid Atorvastatin Example 1 Production Example 1 Production Example 3-3 Example 2 Production Example 1 Production example 3-4 Example 3 Production Example 1 Production Example 3-5 Comparative Example 1 Production Example 1 Production Example 2-1 Comparative Example 2 Production Example 1 Production example 2-2 Comparative Example 3 Production Example 1 Production Example 2-3 Comparative Example 4 Production Example 1 Production example 2-4 Comparative Example 5 Production Example 1 Production example 2-5 Comparative Example 6 Production Example 1 Production Example 2-6 Comparative Example 7 Production Example 1 Production example 2-7 Comparative Example 8 Production Example 1 Production example 3-1 Comparative Example 9 Production Example 1 Production example 3-2 Comparative Example 10 Production Example 1 Production Example 3-6 Comparative Example 11 Production Example 1 Production Example 3-7 Comparative Example 12 Production Example 1 Production Example 4-1 Comparative Example 13 Production Example 1 Production example 4-2 Comparative Example 14 Production Example 1 Production Example 4-3 Comparative Example 15 Production Example 1 Production Example 4-4 Comparative Example 16 Production Example 1 Production Example 4-5 Comparative Example 17 Production Example 1 Production Example 4-6 Comparative Example 18 Production Example 1 Production Example 4-7

< Experimental Example  1> Disintegration  exam

20 mg (Pfizer), a commercially available product, was used as a control and the comparative preparation prepared in Examples 1 to 3 and Comparative Examples 1 to 18, using a rotation speed of 30 rpm and 100 ml of purified water as a disintegrating solution according to the USP disintegration test Disintegration test was carried out. The results are shown in Table 6.

As a result, when disintegrants other than crospovidone were used, disintegration time was faster as more disintegrants were used, but 4 to 5 minutes was slower than the control drug. When crospovidone was used, it was confirmed that at least 3 times of atorvastatin had disintegration time similar to the control. This is because the crospovidone is slightly disintegrating time faster than the control, but it uses more than a certain amount, in order to set the same dissolution profile as the control, considering the speed at which the capsule dissolves when entering the capsule.

division Disintegration time Lipitor 4 minutes 00 seconds Comparative Example 1 9 minutes 30 seconds Comparative Example 2 9 minutes 20 seconds Comparative Example 3 8 minutes 00 seconds Comparative Example 4 7 minutes 30 seconds Comparative Example 5 6 minutes 40 seconds Comparative Example 6 6 minutes 25 seconds Comparative Example 7 6 minutes 30 seconds Comparative Example 8 5 minutes 50 seconds Comparative Example 9 5 minutes 20 seconds Example 1 4 minutes 05 seconds Example 2 2 minutes 50 seconds Example 3 2 minutes 50 seconds Comparative Example 10 2 minutes 40 seconds Comparative Example 11 2 minutes 35 seconds Comparative Example 12 7 minutes 25 seconds Comparative Example 13 7 minutes 20 seconds Comparative Example 14 7 minutes 05 seconds Comparative Example 15 6 minutes 50 seconds Comparative Example 16 6 minutes 25 seconds Comparative Example 17 6 minutes 30 seconds Comparative Example 18 6 minutes 10 seconds

< Experimental Example  2> Atorvastatin  Hardness test and appearance of tablets Whether it is maintained  Confirm

In the case of crospovidone having a disintegration rate similar to that of the comparative example in Experimental Example 1, in order to confirm the stability of the tablet according to the amount of the disintegrant, the results of the hardness test and the hardness- Table 7 shows the measurement results of the degree of abrasion of the atorvastatin tablet in the capsule when the same impact was applied.

division Hardness Massono Lipitor 12kp 0.12% Comparative Example 8 8.3kp 0.30% Comparative Example 9 7.4 0.32% Example 1 6.0kp 0.45% Example 2 5.8 0.52% Example 3 5.4 0.64% Comparative Example 10 3.7kp 3.48% Comparative Example 11 3.5kp 5.94%

In general, when the amount of the disintegrant is increased, the tablet hardness is weakened and the resulting degree of grinding may increase. The amount of disintegrant commonly used in the pharmaceutical industry is generally in the range of 10 to 20% of the total mass of the tablet, but the present invention uses a much larger amount of a particular excipient than the usual amount to increase the dissolution rate of atorvastatin, And it was used within a range that can maintain the external stability of the tablet itself as much as possible. If the hardness is lowered to 5kp or less, or if the degree of grinding is 1% or more, even if the tablets are present in the capsules, there is a high possibility of loss of the content in the process of filling the capsules with corners, .

As shown in Table 7, it can be seen that the range of the disintegrant in which the external stability is maintained up to the range of 1: 5.5 mass of crospovidone with respect to the mass of atorvastatin can be confirmed. Compared with the results of Experimental Example 1, it can be seen that the mass ratio of atobastatin and crospovidone ranges from 1: 2.5 to 1: 5.5 in the range of maintaining the appropriate hardness while exhibiting a disintegration rate similar to that of Lipitor.

< Experimental Example  3> Dissolution test of combination preparation

The compound preparation prepared in Examples 1 to 3 and Comparative Examples 1 to 18 and a commercially available product Lipitor tablets (Pfizer) were mixed at a rotation speed of 50 rpm according to the USP dissolution second method (Paddle method) and 900 ml of purified water , The test solution was taken at 5, 10, 15, 30 and 45 minutes, respectively, and the dissolution rate of atorvastatin was confirmed. The results are shown in Figs.

According to the results of Figs. 1 to 3, when croscarmellose sodium and SSG were used as the disintegrant, the elongation was improved when the disintegration was extended, but the dissolution profile was lower than that of the comparative agent. However, when crospovidone was used, the ratio of crospovidone showing a dissolution profile similar to the control as shown in Examples 1 to 3 can be found.

The similarity factor values (F2) of the respective dissolution profiles of FIGS. 1 to 3 with the reference drug are shown in Table 8. As a result, it can be concluded that when the similarity factor is a value between 50 and 100, both agents have a similar dissolution profile, the combined preparations of Examples 1 to 3 all exhibit a value of F2 between 50 and 100, And the dissolution rate were similar to each other without any significant difference. On the other hand, all of the combination preparations of Comparative Examples 1 to 18 showed a F2 value of less than 50 and a significant difference from the control.

Formulation F2 Formulation F2 Formulation F2 Example 1 67.1 Comparative Example 5 39.9 Comparative Example 12 34.1 Example 2 56.2 Comparative Example 6 39.8 Comparative Example 13 34.2 Example 3 56.3 Comparative Example 7 40.8 Comparative Example 14 35.6 Comparative Example 1 24.2 Comparative Example 8 28.8 Comparative Example 15 41.1 Comparative Example 2 32.1 Comparative Example 9 34.7 Comparative Example 16 42.2 Comparative Example 3 35.5 Comparative Example 10 34 Comparative Example 17 45.7 Comparative Example 4 39.3 Comparative Example 11 34.3 Comparative Example 18 48.8

< Experimental Example  4> Bioavailability test of combination preparation

In order to confirm the bioavailability of atorvastatin to the commercially available product Lipitor (Pfizer) as Comparative Example 8, Comparative Example 15, Example 2, and the reference product, a test for the blood concentration of atorvastatin in beagle dogs was conducted Respectively.

The number of subjects to be tested was 28 per 4 groups. Each of the tablets was pulverized and dispersed in a 0.5% carboxymethyl cellulose (CMC) solution, and 10 mg / kg of atorvastatin was orally administered. The bioavailability was measured by measuring the concentration of atorvastatin in the blood after the administration, and analyzing the pharmacokinetic parameter of atorvastatin. The results are shown in FIG. 4 and Table 9.

Pharmacokinetic parameters of atorvastatin Commercially available products Comparative Example 8 Example 2 Comparative Example 15 AUC (ng · hr / ml) 1345.1 962.3 1351.6 1724.5 Cmax (ng / ml) 1083.2 824.1 1102.6 1357.2 Tmax (hour) 0.8 0.7 0.8 0.7 AUC T / R ratio - 0.715 1.005 1.282

As shown in FIG. 4 and Table 9, when crospovidone was used at a ratio of 1: 4 (Example 2) to atovastatin, The bioavailability was similar to that of the control, and it can be concluded that the bioavailability is correlated with the dissolution rate. Thus, it can be confirmed that the combination preparation of Examples 1 to 3, which comprises the drug and crospovidone at a constant weight ratio, improves the dissolution and bioavailability of atorvastatin.

Claims (11)

(a) pellets containing a phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent; And
(b) a tablet containing atorvastatin or a pharmaceutically acceptable salt thereof, and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5.
The combination preparation according to claim 1, wherein the atorvastatin tablets have a hardness of 4 kp or more and a degree of grindability of 1.0% or less.
The combined preparation according to claim 1, wherein the amount of crospovidone is 63 wt% to 75 wt% based on 100 wt% of the atorvastatin tablet.
2. The combination preparation according to claim 1, wherein the atorvastatin or a pharmaceutically acceptable salt thereof is contained in an amount of 0.5 mg to 100 mg per unit dosage form.
2. The combination preparation according to claim 1, wherein the phenobiphilic acid or a pharmaceutically acceptable salt thereof is contained in an amount of 40 mg to 160 mg per unit dosage form.
2. The combination preparation according to claim 1, wherein the atorvastatin is in the form of a trihydrate.
2. The combination preparation according to claim 1, wherein the phenobicyclic acid pellet comprises an alkalizing agent in an amount of 0.22 to 1 part by weight based on 1 part by weight of phenobiphric acid.
The method of claim 1, wherein the alkanizing agent of the phenobiphic acid pellet is selected from the group consisting of calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium oxide, magnesium aluminate, Lithium, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, and mixtures thereof.
The method of claim 1, wherein the phenobicyclic acid pellet is a pellet comprising a core containing phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent and a delayed release coating layer applied to the outside of the core, Wherein the delayed release coating layer is contained in an amount of 5 to 50 parts by weight per 100 parts by weight of the delayed release coating layer.
2. The combination formulation of claim 1, wherein the atorvastatin tablet further comprises a pharmaceutically acceptable additive selected from the group consisting of a water-soluble diluent, a binder, a disintegrant, a lubricant, and mixtures thereof.
Preparing a pellet comprising phenobicyclic acid or a pharmaceutically acceptable salt thereof and an alkalizing agent;
Preparing a tablet comprising atorvastatin or a pharmaceutically acceptable salt thereof and crospovidone in a weight ratio of 1: 2.5 to 1: 5.5; And
The method of claim 1, comprising filling the capsule with the phenobic acid pellet and the atorvastatin tablet.

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