KR20150114657A - Pharmaceutical compositions and a method for manufacturing containing Ilaprazole and nonsteroidal anti-inflammatory drug or pharmaceutically acceptable salt - Google Patents

Abstract

The present invention relates to an oral pharmaceutical combination drug comprising nonsteroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof, ilaprazole or a pharmaceutically acceptable salt thereof, and a basic additive, a producing method thereof and a composition using the method.

Description

[0001] The present invention relates to a pharmaceutical composition comprising ilaprazole and a non-steroidal antiinflammatory drug or a pharmaceutically acceptable salt thereof, and a method for preparing the same,

The present invention relates to a pharmaceutical combination comprising ilaprazole and a nonsteroidal antiinflammatory drug or a pharmaceutically acceptable salt thereof, a process for their preparation and a composition therefor.

Non-steroidal anti-inflammatory drugs (NASID) have been used for the treatment of chronic rheumatoid arthritis and osteoarthritis, as well as analgesic and analgesic effects and pain, Is widely used for the treatment of pain from various pathologies such as cardiovascular diseases associated with the onset of thrombosis, colon cancer, ovarian cancer and Alzheimer's disease. On the other hand, it decreases platelet aggregation and suppresses the production of prothrombin associated therewith, and it has an anticoagulant effect of blood, thus delaying hemostasis. The mechanism of prostaglandin inhibition may lead to urticaria or asthma attacks. Initially, renal impairment is common and water is retained, resulting in partial edema and elevated blood pressure. Adverse effects such as gastrointestinal bleeding are common in older adults, and side effects associated with this include partial or systemic gastric and duodenal irritation symptoms, and gastrointestinal ulceration also occurs with the use of intestinal protective agents. Most of the side effects that occur in 20-40% of NSAID users occur in the stomach and small intestine, and can be caused by indigestion, erosion, symptoms such as gastritis / duodenitis and ulcer, and anemia due to hypertension, (Aliment Pharm Therap. 1997 11 (2): 283-291).

NSAIDs inhibit the activity of cyclooxygenase (COX), an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins G2 and H2, and prostaglandins are metabolized by specific synthetic enzymes to become one of the eicosanoids in target cells These cytostatic properties of lipid mediators of prostaglandins have been shown to protect the gastrointestinal tract from numerous ulcerogenic compounds or conditions. Thus, NSAIDs that inhibit COX activity cause fluid depletion in the tissues or cells of the gastrointestinal tract of prostaglandins, thereby promoting the inflammatory response (Gastroenterology 1979 Sep, 77 (3): 433-43).

Studies on the metabolism of arachidonic acid have shown that COX-1, which is constitutively expressed in most tissues including gastric mucosa, and COX-2, which can be induced by cytokines and other mediators of inflammation. Compounds that inhibit COX-2 have been developed as COX-2 is selectively expressed at inflammatory sites and is known to be expressed at low levels in inflammatory gastrointestinal mucosa (The Lancet 1999 353 (23) 307-314 ).

The researchers found that taking 25 mg of Viox, a treatment for arthritis, a three-fold increase in the risk of heart attack compared to people who did not use it. A daily dose of 25 mg or less was associated with a higher risk of heart attack, but not statistically significant (Clev Clin J MED 2004 71 (12)). Celebrex also has cardiovascular and gastrointestinal side-effects because it has a similar chemical structure and mechanism of action similar to that of Vioxx (Dig Dis Sci. 2001 46 (4) 779-784).

Iiraprazole, an anti-ulcer agent, is a 5-pyrroline-2-pyridylmethylsulfinyl benzimidazole derivative and has been developed by the present inventors and has been filed as a substance patent in 26 countries including Korea, Japan, As a registered new compound, it acts as a proton pump inhibitor (PPI) as well as well-known omeprazole or lansoprazole. This drug is a third-generation proton pump inhibitor, and its use is high because it significantly reduces the side effects of NSAID-based drugs and has a longer half-life than conventional PPI drugs (aliment pharmacol therapy 2004 19 (10) 1041 -1049).

Currently, Vimovo is one of the proton pump inhibitor and NSAID combination products. Non-mosquito-coated naproxen tablets coated with esomeprazole magnesium. However, the half-life of esomeprazole is generally between 1 and 1.5 hours, which limits the time and efficacy of protecting the gastrointestinal tract (URL: http: //dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm? Archiveid = 1931).

The pharmaceutical combination preparation for oral use according to the present invention includes ilaprazole and NSAIDs-based drugs, and provides a pharmaceutical combination having excellent specific effects in the prevention or treatment of gastrointestinal diseases upon long-term administration of NSAIDs.

Another object of the present invention is to provide a method for producing the oral pharmaceutical combination.

In order to achieve the above object, the present invention provides an oral pharmaceutical combination preparation containing ilaprazole containing an enteric coated nonsteroidal antiinflammatory drug or a pharmaceutically acceptable salt thereof and containing a basic additive.

In order to accomplish the above object, the present invention provides a method for producing a naproxen pellet, comprising: preparing a naproxen pellet using at least one excipient for enteric coating; A coating step for isolating ilaprazole from naproxen; Coated naproxen pellets and ilaprazole beads to provide tablets and capsules.

The oral pharmaceutical combination of the present invention improves the stability by blocking ilaprazole with other compositions and minimizes the drug interaction with ilaprazole by preparing naproxen tablets or pellets for intestinal epithelium so that gastrointestinal side effects of existing NSAIDs Can be minimized. In addition, ilaprazole has more than twice the half-life of esomeprazole, which is expected to be more effective in the prevention or treatment of gastrointestinal diseases than non-mobo, a typical commercial product.

The dissolution pattern of ilaprazole in the examples of this patent

The oral pharmaceutical combination preparation according to the present invention includes ilaprazole, which is an anti-ulcer agent, and may include at least one non-steroidal anti-inflammatory drug (NSAID).

The oral pharmaceutical composition can be used simultaneously, individually or sequentially to treat or prevent gastrointestinal diseases caused by a non-steroidal anti-inflammatory drug (NSAID).

In the present invention, gastrointestinal diseases include peptic ulcer, erosive esophagitis, gastric hyperplasia, gastroesophageal reflux disease and the like.

In the present invention, the NSAID is selected from the group consisting of Aspirin, Aceclofenac, Loxoprofen, Mefenamic acid, Flufenamic acid, Meclofenamic acid, But are not limited to, Piroxicam, Droxicam, Lornoxicam, Meloxicam, Tenoxicam, Diclofenac, Celecoxib, Flubiprofen, ), Miroprofen, Naproxen, Oxaprofen, Etoricoxib, Firocoxib, Lumiracoxib, Parecoxib, But are not limited to, Etodolac, Pirprofen, Dexibuprofen, Dexketoprofen, Fenbufen, Fenoprofen, Ketoprofen, But are not limited to, Ketorolac, Rofecoxib, Valdecoxib, Nimesulide, Deracoxib, Indo methacin, Nabumetone, Sulindac, Benoxaprofen, Carprofen, Flunoxaprofen, pharmaceutically acceptable salts thereof, precursors thereof, and pharmaceutically acceptable salts thereof. And mixtures thereof. Preferably, naproxen and pharmaceutically acceptable salts thereof may be used, but the present invention is not limited thereto.

In the present invention, the NSAID may be contained in an amount of 50 to 90% by weight based on the total weight of the composition.

In one embodiment of the present invention, the oral pharmaceutical combination preparation comprises 0.01 to 60% by weight of ilaprazole as an active ingredient, 50 to 90% by weight of an NSAID, and 1 to 50% by weight of a pharmaceutically acceptable adjuvant, 80% by weight.

In the present invention, the oral pharmaceutical combination preparation may be in the form of tablets and capsules, but it is not limited thereto and may be other formulations.

The pharmaceutical composition for oral use of the present invention blocks ilaprazole from other compositions and maximizes stability including basic additives. It also has the characteristics of ilaprazole, which has longer half-life than conventional PPI-based drugs, and minimizes gastrointestinal side effects indicated by NSAID There are advantages.

In the present invention, ilaprazole may be in the form of a racemate, an enantiomer or a pharmaceutically acceptable salt thereof. The amount of ilaprazole is not particularly limited, By weight to 60% by weight.

In the present invention, the oral pharmaceutical combination preparation can be prepared in the form of tablets and capsules, and the amount of the pharmaceutically acceptable adjuvant is controlled according to the amount of ilaprazole and NSAID, and the amount thereof is not specifically limited However, it may be contained in an amount of 1 to 80% by weight based on the total weight of the composition.

The oral pharmaceutical combination preparation may be an enteric layered tablet formulation containing an ilaprazole granule and a naproxen granule added with a basic additive.

The oral pharmaceutical combination preparation may be a tablet formulation consisting of two separate layers each containing naproxen in the form of enteric layered pellets and ilaprazole in the form of enteric layered pellets.

The above-described oral pharmaceutical combination preparation may be a tablet formulation coated with a sustained-release film containing naproxen and ilaprazole, which is an enteric-layered tablet form.

The oral pharmaceutical combination preparation may be a tablet formulation comprising naproxen in the form of an enteric layered pellet and ilaprazole coated with a sustained release film.

The oral pharmaceutical combination preparation may be an enteric coated layered capsule preparation containing ilaprazole and naproxen as granules together with a basic additive.

The oral pharmaceutical combination preparation may be in the form of capsules comprising naproxen in the form of enteric layered pellets and ilaprazole in the form of enteric layered pellets.

The oral pharmaceutical combination preparation may be a capsule formulation comprising ilaprazole coated with a sustained-release film in a seed and naproxen in the form of an enteric layered pellet.

Soluble core material for enteric layered pellets may be a water soluble seed comprising water insoluble seeds or various inorganic salts, sugars and other materials singly or in admixture, including various organic polymers, oxides, cellulose and other materials singly or as a mixture. Also, the binder, disintegrant, basic additive, surfactant, and pharmaceutically acceptable ingredients may be mixed prior to application of the layer to the seed.

May be coated with one or more separating layers of an excipient, optionally comprising an alkaline compound such as a pH-buffering compound, prior to enteric coating on each of the pellets. The separating layer should be water-soluble or rapidly disintegrate in water.

In order to facilitate enteric coating on the naproxen pellet, one more layer of cloth such as hydroxypropylmethylcellulose, carboxymethylcellulose sodium sugar, polyethylene glycol, polyvinyl alcohol, hydroxypropylcellulose, polyvinylacetate, methylcellulose, ethylcellulose, .

Polymers used for enteric coating of naproxen pellets include hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, polyvinylacetate phthalate, cellulose acetate phthalate, methacrylic acid Polylactic acid esters, triacetin, citric acid esters, triethyl citrate, cetyl alcohol, polysorbate, and the like can be used as the plasticizer, Can be used.

The pharmaceutically acceptable adjuvants according to the invention are selected from the group consisting of excipients, binders, disintegrants, plasticizers, lubricants, basic additives and mixtures thereof.

The pharmaceutically acceptable excipient according to the present invention may be selected from the group consisting of microcrystalline cellulose (Avicel PH101, 102), calcium monohydrogen phosphate, lactose, starch, light anhydrous silicic acid and mixtures thereof. It does not.

The pharmaceutically acceptable binder according to the present invention may be selected from the group consisting of povidone, copovidone, cellulose, starch, and mixtures thereof, but the present invention is not limited thereto.

The pharmaceutically acceptable disintegrant according to the invention is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, calcium carboxymethylcellulose (Ca-CMC), hydroxypropylcellulose, crospovidone and mixtures thereof But the present invention is not limited thereto.

The pharmaceutically acceptable lubricant according to the present invention may be selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, calcium silicate, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate , Sodium acetate, sodium stearyl fumarate, and mixtures thereof. However, the present invention is not limited thereto.

The pharmaceutically acceptable plasticizer according to the present invention may be selected from the group consisting of triacetyl, citric acid, ester, dibutyl sebacate, phthalic acid ester, cetyl alcohol, polyethylene glycol, polysorbate and mixtures thereof, The present invention is not limited thereto.

The pharmaceutically acceptable basic additive according to the present invention is selected from the group consisting of Mg (OH) 2, Na2HPO4, K2HPO4, NaHCO3, Na2CO3, K2CO3, KHCO3, Al (OH) 3, arginine, histidine, lysine and mixtures thereof But the present invention is not limited thereto.

Hereinafter, the present invention will be described in detail with reference to the following examples. The following examples are merely illustrative and are not intended to limit the scope of the invention.

Example  1 naproxen and Ilaprazole  Included Lining  Manufacture of tablets

Manufacturing example  1-1 naproxen and Ilaprazole  Preparation of tablets containing

Using the composition shown in the following Table 1-1, ilaprazole and magnesium hydroxide, microcrystalline cellulose, light silicic anhydride and talc were mixed. After mixing naproxen and croscarmellose sodium, povidone was combined with purified water to prepare a binding solution, which was then sieved through 30 mesh to prepare wet granules. Magnesium stearate was added to the mixture containing ilaprazole and the naproxen wet granulation, followed by mixing and tableting using a rotary tablet machine.

Table 1-1 Preparation of tablets containing naproxen and ilaprazole (unit: mg) division weight Naproxen 500 Ilaprazole 10 Microcrystalline cellulose 100 Povidone 15 Croscarmellose sodium 35 Magnesium hydroxide 10 Magnesium stearate 15 Light anhydrous silicic acid 13 Talc 13 gun 711

Manufacturing example  1-2 naproxen and Ilaprazole  Of tablets containing Long coat

Using the composition shown in Table 1-2 below, a naproxen-ilaprazole tablet prepared by dissolving a methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate, sodium lauryl sulfate in purified water was coated with a coater Respectively.

Production Example 1-2 Intestinal coating of tablets containing naproxen and ilaprazole (unit: mg) division Naproxen-ilaprazole 711.00 Methacrylic acid copolymer 42.66 Talc 22.89 Polyethylene glycol 3.56 Colloidal silicon dioxide 0.89 Sodium hydrogencarbonate 0.75 Sodium lauryl sulfate 0.36 gun 782.11

Example  2 with sodium naproxen Ilaprazole  Preparation of tablets containing

Manufacturing example  2-1 sodium naproxen and Ilaprazole  Preparation of tablets containing

Using the compositions shown in Table 2-1, ilaprazole, magnesium hydroxide, microcrystalline cellulose, light silicic anhydride, talc were mixed. After mixing naproxen sodium and croscarmellose sodium, povidone was combined with purified water to prepare a binding solution, which was then sieved through 30 mesh to prepare wet granules. Magnesium stearate was added to the wet granules of naproxen sodium mixed with the mixture containing ilaprazole, followed by tableting using a rotary tablet machine.

Production Example 2-1 Preparation of tablets containing naproxen and ilaprazole (unit: mg) division weight Sodium naproxen 550 Ilaprazole 10 Microcrystalline cellulose 100 Povidone 15 Croscarmellose sodium 35 Magnesium hydroxide 10 Magnesium stearate 15 Light anhydrous silicic acid 13 Talc 13 gun 761

Manufacturing example  2-2 With sodium naproxen Ilaprazole  Of tablets containing Long coat

A naproxen sodium-ilaprazole tablet prepared by dissolving a methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate, and sodium lauryl sulfate in purified water was coated with a coating machine using the composition shown in Table 2-2 below Respectively.

Production Example 2-2 Intestinal coating of tablets containing naproxen sodium and ilaprazole (unit: mg) division weight Naproxen sodium - iraprazole 761.00 Methacrylic acid copolymer 45.66 Talc 24.50 Polyethylene glycol 3.81 Colloidal silicon dioxide 0.95 Sodium hydrogencarbonate 0.80 Sodium lauryl sulfate 0.38 gun 837.1

Example  3 Lining  Naproxen and Lining Ilaprazole  Preparation of tablets containing

Manufacturing example  3-1 Naproxen Pellet  Produce

After mixing naproxen with croscarmellose sodium using the composition described in Table 3-1 below, povidone was combined with the binding solution dissolved in purified water, passed through a 18 mesh sieve using an extrusion granulator, and then granulated using a naproxen pellet .

Production Example 3-1. Manufacture of pellets containing naproxen (unit: mg) division weight Naproxen 500.00 Povidone 21.00 Croscarmellose sodium 35.00 gun 556.00

Manufacturing example  3-2 Naproxen Pellet Long coat

Methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate and sodium lauryl sulfate were dissolved in purified water in the prepared naproxen pellets (Production Example 3-1) using the composition shown in the following Table 3-2 The suspension was sprayed using a fluid bed coater.

Production Example 3-2. Enteric coating of naproxen pellets (unit: mg) division weight Naproxen pellets 556.00 Methacrylic acid copolymer 33.30 Talc 17.87 Polyethylene glycol 2.78 Colloidal silicon dioxide 0.70 Sodium hydrogencarbonate 0.58 Sodium lauryl sulfate 0.28 gun 611.51

Manufacturing example  3-3 microcrystalline cellulose On the bead Ilaprazole  Coating step

Hydroxylpropylmethylcellulose, triacetin, talc, and povidone were dissolved in purified water to make the pH of the suspension 9-13, and this was added to a microcrystalline cellulose bead in a fluidized bed coater Respectively.

Production Example 3-3. Illaprazole coating on microcrystalline cellulose beads (unit: mg) division weight Microcrystalline cellulose beads 200.00 Ilaprazole 10.00 Magnesium hydroxide 15.00 Hydroxypropylmethylcellulose 16.82 Triacetin 1.68 Talc 1.50 Povidone 2.00 gun 247

Manufacturing example  3-4 Ilaprazole  Coated Bead  Protective coating step

Using the composition described in the following Production Example 3-4, a suspension in which hydroxypropylmethylcellulose, triacetin, talc, and povidone were dissolved in purified water was sprayed onto a bead coated with ilaprazole using a fluidized bed coater.

Production Example 3-4. Shielding coating of ilaprazole beads (unit: mg) division weight Ilaprazole bead 247.00 Hydroxypropylmethylcellulose 7.80 Triacetin 0.78 Talc 0.70 Povidone 1.00 gun 257.28

Manufacturing example  3-5 Ilaprazole  Coated Bead Long coat  step

A suspension prepared by dissolving methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate, and sodium lauryl sulfate in purified water in a bead coated with ilaprazole was coated on a bead coated with a fluidized bed coater Respectively.

Production Example 3-5. Enteric coating of ilaprazole bead (unit: mg) division weight Ilaprazole bead 257.28 Methacrylic acid copolymer 14.54 Talc 7.80 Polyethylene glycol 1.21 Colloidal silicon dioxide 0.30 Sodium hydrogencarbonate 0.25 Sodium lauryl sulfate 0.12 gun 281.5

Manufacturing example  3-6 Lining  Naproxen and Lining Ilaprazole  Preparation of tablets containing

Layered naproxen pellets prepared by the method of Production Example 3-2 and the enteric layered ilaprazole beads prepared by the method of Production Example 3-5 and microcrystalline cellulose and copovidone Magnesium stearate was added to the mixture, mixed, and then tableted using a rotary tablet machine.

Production Example 3-6 Preparation of tablets containing naproxen and ilaprazole (unit: mg) division weight Layered naproxen pellets for enteral use 612.00 Layered ilaprazole beads for enteral use 281.5 Microcrystalline cellulose 100 Co-povidone 30 Magnesium stearate 15 gun 1038.5

Example  4 Lining  Sodium naproxen Lining Ilaprazole  Preparation of tablets containing

Manufacturing example  4-1 sodium naproxen Pellet  Produce

Using the composition described in the following Production Example 4-1, sodium naproxen was mixed with croscarmellose sodium, povidone was combined with a binding solution dissolved in purified water, passed through an 18 mesh sieve using an extrusion granulator, Naproxen pellets were prepared.

Production Example 4-1. Preparation of pellets containing sodium naproxen (unit: mg) division weight Sodium naproxen 550.00 Povidone 21.00 Croscarmellose sodium 35.00 gun 606.00

Manufacturing example  4-2 sodium naproxen Pellet Long coat

Methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate and sodium lauryl sulfate were added to the prepared naproxen sodium pellets (Production Example 3-1) using the composition described in Production Example 4-2 below, Was sprayed using a fluidized bed coater.

Production Example 4-2. Enteric coating of naproxen sodium pellet (unit: mg) division weight Naproxen sodium pellet 606.00 Methacrylic acid copolymer 33.30 Talc 17.87 Polyethylene glycol 2.78 Colloidal silicon dioxide 0.70 Sodium hydrogencarbonate 0.58 Sodium lauryl sulfate 0.28 gun 661.51

Manufacturing example  4-3 Lining  Sodium naproxen Lining Ilaprazole  Preparation of tablets containing

Layered naproxen sodium pellet prepared by the method of Production Example 4-2 and an enteric layered ilaprazole bead prepared by the method of Production Example 3-5, microcrystalline cellulose, copovidone Was mixed with magnesium stearate, and the mixture was compressed using a rotary tablet machine.

Production Example 4-3 Preparation of tablets containing naproxen and ilaprazole (unit: mg) division weight Narrow layered naproxen sodium pellets for enteral use 662.00 Layered ilaprazole beads for enteral use 281.50 Microcrystalline cellulose 100.00 Co-povidone 30.00 Magnesium stearate 15.00 gun 1088.50

Example  5 Ilaprazole  Coated Lining  Preparation of tablets containing naproxen

Manufacturing example  5-1 Preparation of Naproxen Tablets

Using the composition described in the following Production Example 5-1, naproxen and croscarmellose sodium were mixed, povidone was dissolved in purified water to prepare a binding solution, and the mixture was sieved through 30 mesh to prepare wet granules. Magnesium stearate was added to the naproxen wet granules and mixed, followed by tableting using a rotary tablet machine.

Production Example 5-1 Preparation of naproxen tablets (unit: mg) division weight Naproxen 500.00 Povidone 15.00 Croscarmellose sodium 35.00 Magnesium stearate 15.00 gun 565.00

Manufacturing example  5-2 of the naproxen tablets Long coat

A suspension in which a methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate, and sodium lauryl sulfate were dissolved in purified water was added to the prepared naproxen tablets using the composition described in Production Example 5-2 below, Respectively.

Production Example 5-2. Enteric coating of naproxen tablets (unit: mg) division weight Naproxen tablets 565.00 Methacrylic acid copolymer 33.60 Talc 18.03 Polyethylene glycol 2.8 Colloidal silicon dioxide 0.7 Sodium hydrogencarbonate 0.59 Sodium lauryl sulfate 0.28 gun 621

Manufacturing example  5-3 Lining  Shielding coating of naproxen tablets

A suspension in which hydroxypropylmethylcellulose, triacetin, talc, and povidone were dissolved in purified water was sprayed onto the enteric coated layered naproxen tablet using a coating machine using the composition described in Production Example 5-3 below.

Production Example 5-3. Shielding coating of enteric layered naproxen tablets (Unit: mg) division Production example 3-1 Tableted naproxen tablets for enteral use 621.00 Hydroxypropylmethylcellulose 20.72 Triacetin 2.07 Talc 1.85 Povidone 2.64 gun 648.28

Manufacturing example  5-4 Lining  To naproxen tablets Ilaprazole  Layer coating

Using a composition described in the following Production Example 5-4, a coating machine was prepared so that the pH of a suspension of ilaprazole, magnesium hydroxide, hydroxypropyl methylcellulose, triacetin, talc, and povidone dissolved in purified water was adjusted to the tabular naproxen intestinal tablets Respectively.

Production Example 5-4. Ilaprazole coating on enteric coated naproxen tablets (Unit: mg) division weight Tableted naproxen tablets for enteral use 643.28 Ilaprazole 10.00 Magnesium hydroxide 15.00 Hydroxypropylmethylcellulose 54.10 Triacetin 5.40 Talc 4.82 Povidone 6.88 gun 744.48

Example  6 Ilaprazole  Coated Lining  Preparation of tablets containing sodium naproxen

Manufacturing example  6-1 Preparation of sodium naproxen tablets

Using the composition described in the following Production Example 6-1, sodium naproxen and croscarmellose sodium were mixed, povidone was dissolved in a mixture of purified water and alcohol to prepare a binding solution, and the mixture was sieved through 30 mesh to prepare wet granules. Magnesium stearate was added to the naproxen sodium wet granules and mixed, followed by tableting using a rotary tablet machine.

Production Example 6-1 Preparation of sodium naproxen tablet (unit: mg) division weight Sodium naproxen 550.00 Povidone 15.00 Croscarmellose sodium 35.00 Magnesium stearate 15.00 gun 615.00

Manufacturing example  6-2 of sodium naproxen tablet Long coat

A suspension in which a methacrylic acid copolymer, talc, polyethylene glycol, colloidal silicon dioxide, sodium hydrogencarbonate, and sodium lauryl sulfate were dissolved in purified water was added to the prepared naproxen sodium tablets using the composition described in Production Example 6-2 below using a coater Respectively.

Production Example 6-2. Enteric coating of sodium naproxen tablet (unit: mg) division weight Sodium naproxen tablet 615.00 Methacrylic acid copolymer 33.60 Talc 18.03 Polyethylene glycol 2.8 Colloidal silicon dioxide 0.7 Sodium hydrogencarbonate 0.59 Sodium lauryl sulfate 0.28 gun 671

Manufacturing example  6-3 Lining  Shielding coating of sodium naproxen tablets

Using the composition described in the following Production Example 6-3, a suspension of hydroxypropylmethylcellulose, triacetin, talc, and povidone dissolved in purified water was sprayed onto an enteric layered naproxen sodium tablet using a coater.

Production Example 6-3. Shielding coating of enteric layered naproxen sodium tablets (Unit: mg) division weight Intestinal layered naproxen sodium tablets 671.0 Hydroxypropylmethylcellulose 20.72 Triacetin 2.07 Talc 1.85 Povidone 2.64 gun 698.28

Manufacturing example  6-4 Lining  To sodium naproxen tablets Ilaprazole  Layer coating

Using a composition described in the following Production Example 6-4, the suspension was adjusted to pH 9-13 of a suspension of ilaprazole, magnesium hydroxide, hydroxypropylmethylcellulose, triacetin, talc, and povidone in tablets of enteric layered naproxen sodium, .

Production Example 6-4. Ilaprazole coating on intramuscular naproxen sodium tablets (Unit: mg) division weight Intestinal layered naproxen sodium tablets 698.28 Ilaprazole 10.00 Magnesium hydroxide 15.00 Hydroxypropylmethylcellulose 54.10 Triacetin 5.40 Talc 4.82 Povidone 6.88 gun 794.48

Example  7 Lining  Naproxen and Lining Ilaprazole  Manufacture of capsules containing

Manufacturing example  7-1 Lining  Naproxen and Lining Ilaprazole  Manufacture of capsules containing

Layered naproxen prepared by the method of Production Example 3-2 and the long-term layered ilaprazole prepared by the method of Production Example 3-5 were filled into capsules.

Production Example 7-1 Preparation of Capsules Containing Long-Termed Layered Naproxen and Long-Termed Layered Ilaprazole (Unit: mg) division weight Layered naproxen pellets for enteral use 611.51 Layered ilaprazole beads for enteral use 281.50 gun 893.01

Example  8 Lining  Sodium naproxen Lining Ilaprazole  Manufacture of capsules containing

Manufacturing example  8-1 Lining  Sodium naproxen Lining Ilaprazole  Manufacture of capsules containing

The capsules were filled with enteric layered naproxen sodium prepared by the method of Production Example 4-2 and enteric layered ilaprazole prepared by the method of Production Example 3-5.

Production Example 8-1 Preparation of Capsules Containing Intra-Layered Napped Naproxene and Intra-Layered Ilaprazole (Unit: mg) division weight Narrow layered naproxen sodium pellets for enteral use 662.00 Layered ilaprazole beads for enteral use 281.50 gun 943.50

Example  9 Lining  Naproxen and Ilaprazole Bead  Manufacture of capsules containing

Manufacturing example  9-1 Lining  Naproxen and Ilaprazole Bead  Manufacture of capsules containing

The capsules were packed with the iloprazole beads prepared by the method of Production Example 3-4 and the intramuscular layered naproxen prepared by the method of Production Example 3-2.

Production Example 9-1 Preparation of Capsules Containing Long-Lived Layered Naphaxene and Ilaprazole Beads (Unit: mg) division weight Layered naproxen pellets for enteral use 611.51 Ilaprazole bead 257.28 gun 868.79

Example  10 Lining  Sodium naproxen Ilaprazole Bead  Manufacture of capsules containing

Manufacturing example  10-1 Lining  Sodium naproxen Ilaprazole Bead  Manufacture of capsules containing

The capsules were filled with enteric layered naproxen sodium prepared by the method of Production Example 4-2 and ilaprazole beads prepared by the method of Production Example 3-4.

Production Example 10-1 Preparation of Capsules Containing Long-Lived Layered Napped Nakroxene and Ilaprazole Beads (Unit: mg) division weight Narrow layered naproxen sodium pellets for enteral use 662.00 Ilaprazole bead 257.28 gun 919.28

Example  11 Ilaprazole  Coated Lining  Naproxen Pellet  Manufacture of capsules containing

Manufacturing example  11-1 Lining  Naproxen In pellet  Shielding Coating

A suspension in which hydroxypropyl methylcellulose, triacetin, talc, and povidone were dissolved in purified water was added to the enteric layered naproxen pellet prepared by the method of Production Example 3-2 using the composition described in Production Example 11-1 below using a fluid bed coater Respectively.

Production Example 11-1. Shielding coating on enteric layered naproxen pellets (Unit: mg) division weight Layered naproxen pellets for enteral use 611.51 Hydroxypropylmethylcellulose 20.59 Triacetin 2.06 Talc 1.84 Povidone 2.45 gun 638.45

Manufacturing example  11-2 Lining  Naproxen In pellet Ilaprazole  coating

A suspension in which ilaprazole, magnesium hydroxide, hydroxypropylmethylcellulose, triacetin, talc, and povidone were dissolved in purified water was added to enteric layered naproxen pellets prepared by the method of Production Example 11-1 using the composition described in Production Example 11-2 below Of PH 9 to 13 by using a fluidized bed coater.

Production Example 11-2. Ilaprazole coating on intestinal naproxen pellet (unit: mg) division weight Layered naproxen pellets for enteral use 638.45 Ilaprazole 10.00 Magnesium hydroxide 15.00 Hydroxypropylmethylcellulose 53.73 Triacetin 5.37 Talc 4.79 Povidone 6.39 gun 733.73

Manufacturing example  11-3 Ilaprazole  Coated Lining  Naproxen Pellet  Manufacture of capsules containing

The enteric coated layered naproxen pellets coated with ilaprazole were filled into capsules.

Production Example 11-3 Preparation of Capsules Containing Ilaprazole-Coated enteric Layered Naphroxene Pellets (Unit: mg) division weight Layered naproxen pellets for enteral application coated with ilaprazole 733.73 gun 734.21

Example  12 Ilaprazole  Coated Lining  Sodium naproxen Pellet  Manufacture of capsules containing

Manufacturing example  12-1 Lining  Sodium naproxen In pellet  Shielding Coating

A suspension in which hydroxypropylmethylcellulose, triacetin, talc, and povidone were dissolved in purified water in an enteric layered naproxen sodium pellet prepared by the method of Production Example 4-2 was subjected to a fluidized bed coater Respectively.

Production Example 12-1. Shielding coating on enteric layered naproxen sodium pellets (Unit: mg) division weight Narrow layered naproxen sodium pellets for enteral use 662.00 Hydroxypropylmethylcellulose 20.59 Triacetin 2.06 Talc 1.84 Povidone 2.45 gun 688.94

Manufacturing example  12-2 Lining  Sodium naproxen In pellet Ilaprazole  coating

PH 9 of a suspension of ilaprazole, hydroxypropylmethylcellulose, triacetin, talc, and povidone dissolved in purified water in the enteric layered naproxen pellet prepared by the method of Production Example 12-1 using the composition described in Production Example 12-2 below To 13 by using a fluidized bed coater.

Production Example 12-2. Ilaprazole coating on enteric layered naproxen sodium pellets (Unit: mg) division weight Narrow layered naproxen sodium pellets for enteral use 688.94 Ilaprazole 10.00 Magnesium hydroxide 15.00 Hydroxypropylmethylcellulose 53.73 Triacetin 5.37 Talc 4.79 Povidone 6.39 gun 784.22

Manufacturing example  12-3 Ilaprazole  Coated Lining  Sodium naproxen Pellet  Manufacture of capsules containing

The capsules were filled with ilaprazole-coated enteric layered naproxen sodium pellets.

Production Example 12-3 Preparation of Capsules Containing Ilaprazole-Coated Enteric Layered Nakroxene Sodium Pellets (Unit: mg) division weight Layered naproxen sodium pellets for enteral coated with ilaprazole 784.22 gun 784.22

Experimental Example  1 Stability test of preparation

The stability of the formulation was carried out with the tablet formulations Examples 1-6 and the capsule formulations Examples 7-12.

Each formulation was stored under accelerated conditions (40 ° C and 75% RH), and after 2, 4, and 6 months, the content of flexible substances A and B, representative degradation products of ilaprazole, was measured by liquid chromatogram. Are shown in Table 13 below.

Stability test of formulation (Unit:%) Flexible material A Flexible Substance B division Early 2 months 4 months 6 months Early 2 months 4 months 6 months Example 1 0.05 0.27 0.38 0.44 0.08 0.31 0.41 0.49 Example 2 0.04 0.10 0.12 0.15 0.06 0.11 0.15 0.21 Example 3 0.05 0.07 0.08 0.12 0.08 0.14 0.15 0.18 Example 4 0.03 0.04 0.06 0.07 0.08 0.09 0.11 0.12 Example 5 0.04 0.06 0.07 0.09 0.07 0.11 0.14 0.16 Example 6 0.04 0.04 0.05 0.06 0.09 0.09 0.10 0.11 Example 7 0.03 0.06 0.09 0.11 0.06 0.08 0.11 0.15 Example 8 0.06 0.07 0.07 0.08 0.05 0.07 0.08 0.10 Example 9 0.04 0.07 0.11 0.13 0.08 0.10 0.14 0.17 Example 10 0.07 0.09 0.11 0.14 0.07 0.09 0.13 0.17 Example 11 0.03 0.03 0.04 0.05 0.09 0.09 0.11 0.12 Example 12 0.05 0.05 0.06 0.06 0.06 0.06 0.06 0.08

As shown in the above table, it was confirmed that the stability of ilaprazole when blended with naproxen was slightly lower than that of blended with naproxen sodium. In particular, in Example 1 in which no coating treatment capable of blocking contact with naproxen was conducted, It was confirmed that the concentration of the substance was greatly increased. It can be seen that ilaprazole should block contact with acid-contacting naproxen or other acidic excipients.

Experimental Example  2 Evaluation of dissolution rate of preparation

According to the dissolution test method of General Test Methods of the Korean Pharmacopoeia, elution tests were carried out on the samples 1, 3, 5, 7, 9, and 11 according to the paddle method at 900 rpm and 50 rpm in pH 6.8 solution. After the test at pH 6.8, the test solutions were taken at 5, 10, 15, 30, 45 and 60 minutes, and the dissolution rates of naproxen and ilaprazole were confirmed. The results are shown in FIGS. 1, 2 and 3.

As shown in FIGS. 1 and 2, it can be generally seen that the capsule formulation has a faster dissolution rate than the tablet formulation, and that the dissolution rate of sodium naproxen is faster than that of naproxen. As shown in FIG. 3, the dissolution rate of ilaprazole was also found to be faster than that of the tablet formulation.

The oral pharmaceutical combination of the present invention improves the stability by blocking ilaprazole with other compositions and minimizes the drug interaction with ilaprazole by preparing naproxen tablets or pellets for intestinal epithelium so that gastrointestinal side effects of existing NSAIDs Can be minimized. In addition, ilaprazole has more than twice the half-life of esomeprazole, which is expected to be more effective in the prevention or treatment of gastrointestinal diseases than non-mobo, a typical commercial product.

Claims (22)

The active ingredient is a proton pump inhibitor Ilaprazole or a pharmaceutically acceptable salt thereof and a non-steroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable salt thereof.
2. The oral pharmaceutical combination preparation according to claim 1, wherein the proton pump inhibitor is ilaprazole or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the NSAID is selected from the group consisting of Aspirin, Aceclofenac, Diclofenac, Etodolac, Indometacin, Nabumetone, Sulindac, But are not limited to, benzoxaprofen, carprofen, Dexibuprofen, Dexketoprofen, Fenbufen, Fenoprofen, Flunoxaprofen, , Flubiprofen, Ketoprofen, Ketorolac, Loxoprofen, Miroprofen, Naproxen, Oxaprofen, Fatigue, But are not limited to, Pirprofen, Mefenamic acid, Flufenamic acid, Meclofenamic acid, Piroxicam, Droxicam, Lornoxicam, Such as Meloxicam, Tenoxicam, Celecoxib, Deracoxib, Etoricoxib, Pyrococcus, A pharmaceutically acceptable salt thereof, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, a prodrug, And mixtures thereof. ≪ Desc / Clms Page number 24 >
4. The oral pharmaceutical combination preparation according to claim 3, wherein the NSIAD is Naproxen or a pharmaceutically acceptable salt thereof.
3. The oral pharmaceutical combination preparation according to claim 2, wherein ilaprazole is contained in an amount of 1 mg to 50 mg per unit dosage form.
5. The oral pharmaceutical combination preparation according to claim 4, wherein naproxen or a pharmaceutically acceptable salt thereof is contained in an amount of 100 mg to 1000 mg per unit dosage form.
7. The composition of any one of claims 5 to 6 wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of excipients, binders, disintegrants, lubricants, basic additives, flow control agents, solubilizers, colorants, pH adjusters, stabilizers, , An emulsifier, a coating agent, and a mixture thereof.
The oral pharmaceutical combination preparation according to claim 7, wherein the binder is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose, povidone, gelatin, starch, and mixtures thereof.
The oral pharmaceutical combination according to claim 7, wherein the disintegrant is selected from the group consisting of starch, sodium starch glycolate, crospovidone, croscarmellose sodium, carboxymethylcellulose sodium, microcrystalline cellulose and mixtures thereof. .
The composition of claim 7, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, wax, glyceryl behenate, polyethylene glycol, sodium acetate, sodium benzoate, sodium stearyl fumarate, calcium silicate, Silicon dioxide, and mixtures thereof. ≪ Desc / Clms Page number 24 >
The method of claim 7 wherein the basic additive is _{CaCO 3, Mg (OH) 2} , Na 2 HPO 4, K 2 HPO 4, NaHCO 3, Na 2 CO 3, K 2 CO 3, KHCO 3, Al (OH) 3, Arginine, histidine, lysine, and mixtures thereof. ≪ RTI ID = 0.0 >
The composition according to claim 7, wherein the coating agent is selected from the group consisting of methacrylic acid polymer, enteric-coated polymer, cellulosic acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate, Ethylcellulose, purified shellac, and mixtures thereof. ≪ RTI ID = 0.0 >
8. The oral pharmaceutical combination preparation according to claim 7, wherein the oral pharmaceutical composition is a tablet or a capsule.
14. The oral pharmaceutical combination preparation according to claim 13, which comprises an ilaprazole granule in which granules of naproxen or a pharmaceutically acceptable salt thereof and basic additives are added. 14. The oral pharmaceutical combination preparation according to claim 13, which comprises ilaprazole in the form of enteric coated layer pellets or ilaprazole in the form of enteric coated beads, or a pharmaceutically acceptable salt thereof.
14. The oral pharmaceutical combination preparation of claim 13, wherein the naproxen is in the form of an enteric coated layer tablet or its pharmaceutically acceptable salt is coated with ilaprazole.
14. The oral pharmaceutical combination preparation of claim 13, which comprises naproxen in the form of an enteric layered pellet or its pharmaceutically acceptable salt and ilaprazole in the form of an enteric layered bead.
14. The oral pharmaceutical combination preparation of claim 13, which comprises naproxen or its pharmaceutically acceptable salt in the form of an enteric layered pellet and ilaprazole coated in beads.
14. The oral pharmaceutical composition according to claim 13, which is an encapsulated oral pharmaceutical composition coated with naproxen or pharmacologically acceptable salt thereof in the form of enteric coated pellets
14. The method of claim 13, further comprising the step of preparing a pellet comprising naproxen or a pharmaceutically acceptable salt thereof using an extruder and a spherical granulator
14. The method of claim 13, wherein naproxen or a pharmaceutically acceptable salt thereof in the form of pellets is coated with ilaprazole in an enteric layering step and microcrystalline cellulose beads.
14. The method of claim 13, wherein the capsule formulation comprises ilaprazole coated on microcrystalline cellulose beads comprising naproxen or a pharmaceutically acceptable salt thereof in the form of enteric layered pellets.

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