WO2012124982A2

WO2012124982A2 - Oral preparation having an enteric coating

Info

Publication number: WO2012124982A2
Application number: PCT/KR2012/001846
Authority: WO
Inventors: 이재걸; 전호성; 김진모
Original assignee: 현대약품 주식회사
Priority date: 2011-03-16
Filing date: 2012-03-14
Publication date: 2012-09-20
Also published as: KR20120105738A; WO2012124982A3

Abstract

The present invention relates to an oral preparation containing zoledronic acid, which reduces enteric injuries and improves bioavailability. More particularly, the present invention relates to an oral preparation having an enteric coating, which comprises zoledronic acid and the pharmaceutically acceptable salts thereof, and which has a core, the pH level of which is 3.5 to 7.

Description

【Specification】

[Name of invention]

Enteric-coated oral preparations

The present invention relates to oral preparations containing zoledronic acid with improved bioavailability while reducing intestinal damage, and more particularly, comprising zoledronic acid and pharmaceutically acceptable salts thereof and having a pH of 3.5 to 7 It relates to enteric-coated oral preparations.

Background Art

A third generation bisphosphonic acid derivative characterized by a side chain containing an imidazole ring of zoledronic acid, the chemical name being (1-hydroxy-2-imidazol-1-yl-phosphono-ethyl) phosphonic acid And has the chemical structure of formula (I):

Zoledronic acid is used to treat or prevent pain resulting from fractures, hypercalcemia, or bone metastases in cancer patients such as osteoporosis, metastatic bone cancer, Paget's disease, multiple myeloma or prostate cancer. Zoledronic acid is marketed under the trade name Z0META ™ and is available as a sterile powder as an injectable solution for vial or intravenous infusion. The injection is administered once a month containing 4 mg of zoledronic acid as an inhibitor of bone metastasis in cancer patients, and once a year containing 5 mg of zoledronic acid as a therapeutic agent for osteoporosis.

Zoledronic acid is used only as an injection and is a commercial oral preparation. Since there is no situation yet, there is a discomfort that should be administered only in the hospital and discomfort to be administered intravenously over 15 minutes.

As a representative attempt to develop zoledronic acid as an oral dosage form, Korean Patent Application No. 10-2006—7012523 is selected from bisphosphonic acid or salts thereof and esters of phosphated fatty acids or lipophilic polyethylene glycols. A pharmaceutical formulation comprising an oral dosage form containing an inactive ingredient having a hydrophilic-relative balance of 1 to about 30 is described. The patent provides an oral dosage form with improved bioavailability, but considers side effects in the stomach (esophagitis, gastritis, etc.) and intestinal side effects due to the properties of zoledronic acid that may occur during oral administration of zoledronic acid. There is a problem that is not.

In addition, Korean Patent Application No. 10-2008-7027154 describes an oral dosage form comprising an enhancer for enhancing intestinal delivery of bisphosphonic acid to the basal circulatory system in combination with bisphosphonic acid. The patent provides an oral dosage form with improved bioavailability which has an effect of inhibiting damage to the stomach by enteric coating, but there is also a problem of not considering the side effects of the intestine due to the properties of zoledronic acid.

Since zoledronic acid has a lower pH than other bisphosphonic acid classes of drugs, it can cause intestinal cell damage upon oral administration. However, no attempt has been made to study oral dosage forms of zoledronic acid in relation to intestinal side effects.

[Detailed Description of the Invention]

[Technical problem]

Accordingly, the present inventors have tried to develop oral preparations of zoledronic acid with improved bioavailability while reducing side effects in the intestine, and thus, by adjusting the pH of the core in the enteric coating preparations containing zoledronic acid, The present invention was completed by inhibiting intestinal damage caused by the intestinal tract and improving the bioavailability. Technical Solution

It is an object of the present invention to provide an enteric coated oral preparation comprising zoledronic acid and a pharmaceutically acceptable salt thereof and having a pH of 3.5 to 7 of the core. Advantageous Effects

The oral enteric-coated oral preparation containing zoledronic acid of the present invention has an improved bioavailability while reducing intestinal damage, thereby increasing the stability and convenience of oral administration, and reducing the amount of drug to be produced, thereby reducing the cost of production. It can be expected to improve the effect.

[Brief Description of Drawings]

Figure 1 shows the results of measuring the survival rate of the cells after the cells exposed to the acidic solution containing zoledronic acid and acidic solution containing zoledronic acid and sodium lauryl sulfate for 1 minute.

Figure 2 shows the results of measuring the improvement effect of bioavailability when oral administration of a formulation containing zoledronic acid and absorption accelerator; Zoledronate, zoledronic acid; SLS, sodium lauryl sulfate; Nacaprate, Sodium Caprate; Capmul ™ PG-12 propylene glycol monolaurate; Gelucire ™, polyethylene glycol glycerides; TPGS, D-alphatocopheryl polyethylene glycol succinate.

[Best form for implementation of the invention]

As one aspect for achieving the above object, the present invention relates to an enteric coated oral preparation comprising zoledronic acid and a pharmaceutically acceptable salt thereof and having a pH of 3.5 to 7 of the core.

In a preferred embodiment, the present invention relates to an enteric coated oral preparation comprising zoledronic acid and a pharmaceutically acceptable salt thereof and having a pH of 4 to 6 in the core.

In the present invention, the zoledronic acid is a chemical name of (1-hydroxy-2pyimidazol-1-yl-phosphono-ethyl) phosphonic acid, and a compound having a chemical structure of Say.

As used herein, the term 'pharmaceutically acceptable salt' includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-P-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfuric acid Phonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Salts derived from suitable bases may include alkaline earth metals such as alkali metal magnesium such as sodium potassium, and ammonium and the like. Preferably, the pharmaceutically acceptable salt of zoledronic acid may be, but is not limited to, zoledronic acid sodium salt or zoledronic acid disodium salt.

Since zoledronic acid has a lower pH than other bisphosphonic acid classes of drugs, it can cause intestinal cell damage when administered orally. As confirmed in the specific examples of the present invention, zoledronic acid showed a strong acidol of about pH 2 to 3.5 when dissolved in water (see Example 1), and the cells were exposed to the zoledronic acid-containing acid solution for 1 minute. As a result of measuring the survival rate of the cells, the survival rate of the cells was 15¾> or less (see Example 2). Thus, the possibility of intestinal cell damage may be expected upon oral administration.

Accordingly, the present invention is characterized by providing an enteric coating preparation for oral administration in which the pH of the zoledronic acid core is adjusted to 3.5 to 7, preferably 4 to 6. In the present invention, the term 'core' means an active ingredient-containing site present in the coating layer of the drug, specifically, zoledronic acid present in the enteric coating layer Mean containing layer. For example, when the oral preparation of the present invention is a tablet, the core means uncoated tablet, the capsule means a drug layer existing inside the coating layer, and the granule refers to granules present inside the coating layer. I can understand.

Preferably, a pH-adjusted enteric coating formulation may be provided by containing a pH adjusting agent in the zoledronic acid core. Generally, in the preparation of enteric coating formulations, it is rare to artificially adjust the pH of the core using a pH adjuster, etc., and there has been no study of artificially adjusting the pH of the core in the zoledronic acid-containing enteric coating formulation. In the present invention, by artificially adjusting the pH of the core using a pH adjuster it can reduce the damage in the intestine due to drug properties during oral administration.

The pH adjusting agent used in the present invention includes a chelating agent, and sodium or potassium bicarbonate, carbonate, phosphate or hydroxide, magnesium carbonate, magnesium hydroxide, ammonium carbonate, ammonium bicarbonate, magnesium oxide, calcium hydroxide or a combination thereof. One or more selected from the group consisting of, for example, sodium citrate, sodium bicarbonate, sodium phosphate dibasic and sodium phosphate tribasic can be used, but is not limited thereto.

In a specific example of the present invention, it was confirmed that the pH of the zoledronic acid-containing core rose to about 4 to 6 due to the pH adjusting agent contained in the core (see Table 2 and Table 3).

In a preferred embodiment, the enteric-coated oral formulation of the present invention may further comprise an absorption enhancer in the core.

Absorption accelerator can increase the bioavailability of zoledronic acid by controlling the mucopermeability of the absorption site, and can be used without limitation as long as it is excreted rapidly in vitro without pharmacologically activeol and promotes intestinal absorption of the drug. . Specifically, alcohols, polyhydric alcohols, fatty acids and derivatives, surfactants and the like can be used, and more specifically, sodium lauryl sulfate, sodium caprate, propylene glycol monolaurate (Capmul ™ PG-12), poly on Tylene glycol glycerides (Gelucire ™) or D-alpha tocopheryl polyethylene glycol succinate may be used, but is not limited thereto, preferably a group consisting of lauryl sulfate and salts thereof, caprylic acid and salts thereof More than one can be used.

In a specific embodiment of the present invention, when sodium lauryl sulfate was used as an absorption accelerator, in particular, the amount of urine excretion of zoledronic acid was high, and it was confirmed that it had excellent efficacy as an absorption accelerator (see FIG. 2).

The enteric coating agent can be used without limitation, generally used materials, for example, methacrylic acid-ethyl acrylate copolymer, shellac, carbopols (carbomer, carboxyvinyl polymer), hydroxypropyl methyl salo Osphthalates, cellulose acetate phthalates, cellulose acetate succinates, hydroxypropyl methylcellulose succinates, hydroxypropyl methyl acetate succinates, carboxymethyl salose, carboxybutylethyl cell cellulose , Cellulose acetate phthalates, hydroxypropyl cellulose, ethyl cellulose, pentyl cellulose, polyvinyl acetate phthalate, polyvinyl alcohol, and the like, may be used. Hydroxypropyl methylcellulose phthalate Nitrate (HP-55 ™), triethyl citrate, Eudragit L100-55, polyethylene glycol, and the like, but are not limited thereto. In the present invention, enteric coating of the zoledronic acid-containing core can improve gastric damage such as esophagitis and gastritis that may appear during oral administration.

The oral enteric coating formulation containing zoledronic acid of the present invention may further include a pharmaceutically acceptable carrier or additive, and may be formulated in the form of tablets, powders, granules, capsules or pellets, and controlled release dosage forms. Or in a sustained release dosage form, and may form a matrix dosage form such as a controlled release matrix application. They can be prepared by known methods, for example by conventional mixing, granulating, sugaring, dissolving, melting or lyophilizing.

A pharmaceutically acceptable carrier is an administration without significantly irritating the organism It refers to a carrier or diluent that does not inhibit the biological activity and properties of the compound. In addition, the additives can improve the preparation, compressibility, appearance and taste of the formulation, for example, stabilizers, surfactants, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, binders, binders , Suspending agent, curing agent, antioxidant, brightening agent, flavoring agent, flavoring agent, pigment, coating agent, wetting agent, wetting agent, layering agent, antifoaming agent, freshening agent, chewing agent, antistatic agent, coloring agent, sugar crab, isotonic agent, softener, Emulsifiers, pressure-sensitive adhesives, thickeners, foaming agents, pH adjusting agents, excipients, dispersants, disintegrating agents, waterproofing agents, preservatives, preservatives, dissolution aids, solvents, glidants and the like may be added as necessary.

Specific examples of the additives include refined white sugar, glucose, trehalose, lactose, maltose, manny, sorbitan, xylly, erytri, saccharin sodium, aspartame, acesulfame potassium and sucralose. Oz, licorice extract, stevia extract, lahan and extract, corn starch, potato starch, wheat starch, sodium bicarbonate, sodium chloride, crystalline salose, methylcellose, ethylcellose, hypromellose, hydride Loxyprofilelose, Carboxymethyl Salose, Carboxymethyl Salose Sodium, Carboxymethyl Cellulose Calcium, Hypromellose Phthalate, Cellulose Acetate Phthalate, Dextrin, Alpha Starch, Arabia Gum, tragacanth, gelatin, sodium alginate, polyvinyl pyridone, polyvinyl alcohol, carboxyvinyl polymer, stearic acid Magnesium, talc, hydrogenated vegetable oil, macrogol, polyoxyethylene hydrogenated castor oil 60, hydrous silicon dioxide, silicone oil, agar, shellac, glycerin, aromatic essential oils, water-soluble food coloring, iron sulfate, yellow ginseng iron dioxide, triacid Iron oxide, brown iron oxide, black iron oxide, titanium dioxide, lake pigment, benzoic acid, sodium benzoate, paraoxy benzoic acid, polysorbate 80, glycerin fatty acid ester, pewter, medium chain triglyceride, ascorbic acid, tocope, Plant essential oils such as sodium thiosulfate, sodium edetate, orange flavors such as oranges and lemons, coffee flavors, chocolate flavors, yogurt flavors, milk flavors, lemon oil, peppermint oil, spare mint oil and spice oil. Although it may be mentioned, it is not specifically limited if it is pharmaceutically usable.

The enteric coated oral preparation of the present invention may contain zoledronic acid in the range of 1 to 150 mg, more preferably in the range of 10 to 80 mg. can do.

The particular form and dosage of administration is chosen by the attending physician, taking into account the characteristics of the patient, in particular age, weight, lifestyle, activity level, hormonal status (eg postmenopausal) and, in some cases, bone mineral density. Can be. Preferably, it can be administered once a week to three months, more preferably once a month. The zoled, lonic acid-containing enteric coating formulations of the present invention can be used for the prevention and treatment of osteoporosis, metastatic bone cancer, Paget's disease, multiple myeloma, fractures, hyperkalemia or bone metastasis. For example, treatment of postmenopausal osteoporosis to reduce the risk of osteoporotic fractures, prevention of postmenopausal osteoporosis, prevention of postmenopausal bone loss, treatment or prevention of male osteoporosis, corticoid-induced osteoporosis, medication Treatment or prevention of bone loss, for example by diphenylhydantoin thyroid hormone replacement therapy, bone loss associated with rheumatoid arthritis, osteoplasia, hyperthyroidism, nervous anorexia, organ transplantation, and other medical conditions It can be used for the prevention and treatment of. In addition, these other medical conditions may include, for example, the prevention and treatment of periarticular osteoporosis in rheumatoid arthritis, the prevention and treatment of osteoarthritis, for example, the subchondral osteosclerosis, the subchondral bone sac, the formation of osteoclasts Treatment, prevention and treatment of hypercalcemia, prevention and treatment of metastatic bone cancer. [Form for implementation of invention]

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the present invention, the present invention is not limited by the following examples. Example 1. Measurement of pH of zoledronic acid

As a result of dissolving zoledronic acid in water and measuring the pH, as shown in Table 1, it can be seen that it exhibits a strong acidity of pH 2 to 3.5.

Table 1 In solution

0.01 0.02 0.03 0.04 0.06 0.08 0.1 0.12 0.5 1.0 Zoledronic acid%

pH 3.4 3.2 3.04 2.93 2.79 2.63 2.53 2.54 2.15 2.1 Example 2 Cytotoxicity of Zoledronic Acid

On the day before the experiment, two cells of human intestinal cell line Cac were dispensed into 96-well plates, and after 24 hours, the cell culture was removed and washed with DPBS (Dulbecco's Phosphate-Buffered Saline). After adding zoleronate or zoleronate + sodium lauryl sulfate (SLS) to each solution, each of 100 liters of solution prepared at pH 3.0 and pH 3.5 was added to 96 wells, and then reacted for 1 minute. Cell viability was calculated.

As a result, as shown in FIG. 1, the cell viability of the acidic solution containing zoledronic acid (about pH 3) and the acidic solution containing zoledronic acid and sodium lauryl sulfate (about _P H 3.5) were 15% or less. The cell viability was very low due to the physical properties (acidity) of zoledronic acid. Example 3 Measurement of Improvement of Bioavailability Using Hop Number Promoters

Rats were measured for improving the bioavailability by oral administration of a formulation containing zoledronic acid and an absorption accelerator.

SD rats (7 weeks old) were placed in metabolic cages and orally administered to control and experimental groups, and then measured by LC / MS / MS to determine the amount of zoledronic acid excreted in urine for 24 hours. Evaluated. The control and experimental groups used in the experiment were as follows:

Control group: zoledronic acid 5mg / kg oral administration (n = 9)

Experimental group 1: zoledronic acid 5mg / kg + sodium lauryl sulfate (SLS) oral administration (n = 16)

Experimental Group 2: Zoledronic Acid 5mg / kg + Sodium Caprate (S.C) Oral Administration (n = 9)

Experimental group 3: oral administration of zoledronic acid 5mg / kg + Capmul PG 12 (n 二 9) Experimental group 4: oral administration of zoledronic acid 5mg / kg + Gelucire (n = 9) Experimental Group 5: Zoledronic Acid 5 mg / kg + TPGS Oral Administration (n = 9) In urine analysis, risedronate was used as an internal standard. After sampling urine with zoledronic acid using CaCl ₂ , the precipitate was dissolved and loaded into a DEA (diethylamine) cartridge and washed. Thereafter, the reaction was derivatized with trimethyldiazomethane and analyzed by LC / MS / MS.

As a result, as shown in Figure 2, when sodium lauryl sulfate (SLS) was used, the bioavailability improvement effect was the best. Example 4 _P H Control of Uncoated Tablets of Zoledronic Enteric Coating Formulations

The pH of uncoated tablets was measured when the uncoated tablet did not contain a pH adjusting agent, and the results were shown in Tables 2 and 3, respectively.

Table 2

Table 3

Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8 Zoledronic Acid 21.33 21.33 42.65 42.65 63.98 63.98 85.3 85.3 or Lactose free 191.67 186.67 170.35 165.35 144.02 134.02 122.7 112.7 Microcrystalline Cell 80 80 80 80 80 80 80 80 80 tablet

Croscarmellose

6 6 6 6 6 6 6 6 Sodium Stearic acid

6 6 6 6 6 6 6 6 Calcium

Sodium Laurylsulf

15 20 15 20 20 30 20 30 Site

Sodium citrate 15-30-40-60-sodium bicarbo

-------25 Nights

Sodium phosphate

-11-20--ᅳ-Debate

Sodium phosphate

-----19--Tribejic

Uncoated pH 4.5 4.3 4.7 4.3 4.4 4.8 4.6 4.6 Example 5. Preparation of pH-adjusted zoledronic acid enteric coated tablets

PH-adjusted zoledronic acid enteric-coated tablets were prepared by containing a pH regulator and hops accelerator in uncoated tablets, and each preparation example (prescription) is shown in Table 4 below.

Table 4

Sodium Phosph

Eat Tree Bay 一----19--

HP-55 47.5 ᅳ 47.5-47.5-47.5-Triethyl Sheet

Chapter 2.5 ᅳ 2.5-2.5--2.5-Rate

for

Eudragit

Nose-47.5-47.5-47.5-47.5 L100-55

Ting

Polyethylene

2.5 2.5-2.5-2.5 Recall

Claims

[Range of request]

[Claim 1]

An enteric coated oral preparation comprising zoledronic acid and a pharmaceutically acceptable salt thereof and having a pH of 3.5 to 7 in the core.

[Claim 2]

The enteric coated oral preparation of claim 1 wherein the core has a pH of 4-6.

[Claim 3]

The enteric-coated oral preparation of claim 1 further comprising an absorption promoting agent in the core.

[Claim 4]

The enteric-coated oral preparation according to claim 3, wherein the absorption enhancer is at least one selected from the group consisting of lauryl sulfate and salts thereof, caprylic acid and salts thereof.

[Claim 5]

The enteric coated oral preparation of claim 1 comprising a pH adjusting agent in the core.

[Claim 6]

The enteric coated oral preparation of claim 5 wherein the pH adjusting agent comprises a chelating agent.

[Claim 7]

The enteric-coated oral preparation according to claim 5, wherein the pH adjusting agent is at least one selected from the group consisting of sodium citrate, sodium bicarbonate, sodium phosphate dibasic and sodium phosphate tribasic.

[Claim 8]

The enteric-coated oral preparation according to claim 1, which contains 1 to 150 mg of zoledronic acid.

[Claim 9]

The enteric-coated oral preparation according to claim 1, which contains 10 to 80 mg of zoledronic acid.

[Claim 10]

The enteric-coated oral preparation according to claim 1, which is administered once a week to three months.

[Claim 111]

The enteric-coated oral preparation according to claim 10, which is administered once a month.

[Claim 12]

The enteric-coated oral preparation according to claim 1, wherein the preparation is used for the prevention and treatment of osteoporosis, metastatic bone cancer, Paget's disease, multiple myeloma, fracture, hypercalcemia or bone metastasis.