WO2012124982A2 - Préparation orale ayant un enrobage entérique - Google Patents

Préparation orale ayant un enrobage entérique Download PDF

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Publication number
WO2012124982A2
WO2012124982A2 PCT/KR2012/001846 KR2012001846W WO2012124982A2 WO 2012124982 A2 WO2012124982 A2 WO 2012124982A2 KR 2012001846 W KR2012001846 W KR 2012001846W WO 2012124982 A2 WO2012124982 A2 WO 2012124982A2
Authority
WO
WIPO (PCT)
Prior art keywords
enteric
oral preparation
zoledronic acid
acid
coated oral
Prior art date
Application number
PCT/KR2012/001846
Other languages
English (en)
Korean (ko)
Other versions
WO2012124982A3 (fr
Inventor
이재걸
전호성
김진모
Original Assignee
현대약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 현대약품 주식회사 filed Critical 현대약품 주식회사
Publication of WO2012124982A2 publication Critical patent/WO2012124982A2/fr
Publication of WO2012124982A3 publication Critical patent/WO2012124982A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • 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.
  • 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 TM 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 TM PG-12 propylene glycol monolaurate; Gelucire TM, polyethylene glycol glycerides; TPGS, D-alphatocopheryl polyethylene glycol succinate.
  • 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.
  • 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.
  • 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.
  • the term 'pharmaceutically acceptable salt' includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
  • 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.
  • the pharmaceutically acceptable salt of zoledronic acid may be, but is not limited to, zoledronic acid sodium salt or zoledronic acid disodium salt.
  • zoledronic acid 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 153 ⁇ 4> or less (see Example 2). Thus, the possibility of intestinal cell damage may be expected upon oral administration.
  • 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.
  • 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.
  • 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
  • the granule refers to granules present inside the coating layer. I can understand.
  • a pH-adjusted enteric coating formulation may be provided by containing a pH adjusting agent in the zoledronic acid core.
  • a pH adjuster 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.
  • 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.
  • a chelating agent sodium or potassium bicarbonate, carbonate, phosphate or hydroxide, magnesium carbonate, magnesium hydroxide, ammonium carbonate, ammonium bicarbonate, magnesium oxide, calcium hydroxide or a combination thereof.
  • sodium citrate, sodium bicarbonate, sodium phosphate dibasic and sodium phosphate tribasic can be used, but is not limited thereto.
  • 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. .
  • 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 TM PG-12), poly on Tylene glycol glycerides (Gelucire TM) 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.
  • sodium lauryl sulfate, sodium caprate, propylene glycol monolaurate (Capmul TM PG-12), poly on Tylene glycol glycerides (Gelucire TM) 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
  • 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.
  • methacrylic acid-ethyl acrylate copolymer shellac
  • carbopols carboxyvinyl polymer
  • hydroxypropyl methyl salo Osphthalates cellulose acetate phthalates
  • 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.
  • 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
  • additives include refined white sugar, glucose, trehalose, lactose, maltose, manny, sorbitan, xylly, erytri, saccharin sodium, aspartame, acesulfame potassium and sucralose.
  • 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.
  • 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.
  • 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.
  • Example 1 Measurement of pH of zoledronic acid
  • 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.
  • Rats were measured for improving the bioavailability by oral administration of a formulation containing zoledronic acid and an absorption accelerator.
  • Experimental group 3 oral administration of zoledronic acid 5mg / kg + Capmul PG 12 (n ⁇ 9)
  • 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.
  • 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.
  • 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
  • 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.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une préparation orale contenant de l'acide zolédronique, qui réduit des lésions entériques et améliore la biodisponibilité. Plus particulièrement, la présente invention concerne une préparation orale ayant un enrobage entérique, qui comprend de l'acide zolédronique et les sels pharmaceutiquement acceptables de celui-ci, et qui présente un noyau, dont le niveau de pH est de 3,5 à 7.
PCT/KR2012/001846 2011-03-16 2012-03-14 Préparation orale ayant un enrobage entérique WO2012124982A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2011-0023362 2011-03-16
KR1020110023362A KR20120105738A (ko) 2011-03-16 2011-03-16 장용코팅된 경구용 제제

Publications (2)

Publication Number Publication Date
WO2012124982A2 true WO2012124982A2 (fr) 2012-09-20
WO2012124982A3 WO2012124982A3 (fr) 2012-11-08

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PCT/KR2012/001846 WO2012124982A2 (fr) 2011-03-16 2012-03-14 Préparation orale ayant un enrobage entérique

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WO (1) WO2012124982A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2997378A1 (fr) * 2015-09-18 2017-03-23 Grunenthal Gmbh Procede de cristallisation et biodisponibilite

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009785A1 (fr) * 1991-11-22 1993-05-27 Procter & Gamble Pharmaceuticals, Inc. Compositions de risedronate a liberation lente
US5431920A (en) * 1993-09-21 1995-07-11 Merck Frosst, Canada, Inc. Enteric coated oral compositions containing bisphosphonic acid antihypercalcemic agents
WO2000061111A1 (fr) * 1999-04-09 2000-10-19 Astrazeneca Ab Formulation pharmaceutique comprenant un bisphosphonate et un agent d'addition favorisant l'absorption du bisphosphonate
WO2001032185A1 (fr) * 1999-11-02 2001-05-10 Cipla Ltd. Composition pharmaceutique renfermant au moins un acide bisphosphonique ou un de ses sels et son procede de preparation
US6676965B1 (en) * 1999-10-20 2004-01-13 U&I Pharmaceuticals Ltd. Enteric coated formulation for bisphosphonic acids and salts thereof
US20050260262A1 (en) * 2004-05-24 2005-11-24 The Procter & Gamble Company Dosage forms of bisphosphonates
KR100631873B1 (ko) * 2004-07-30 2006-10-09 주식회사 유유 생체이용율이 증진된 알렌드론산 제제
US20070134319A1 (en) * 2003-12-23 2007-06-14 Novartis Ag Pharmaceutical formulations of bisphosphonates

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993009785A1 (fr) * 1991-11-22 1993-05-27 Procter & Gamble Pharmaceuticals, Inc. Compositions de risedronate a liberation lente
US5431920A (en) * 1993-09-21 1995-07-11 Merck Frosst, Canada, Inc. Enteric coated oral compositions containing bisphosphonic acid antihypercalcemic agents
WO2000061111A1 (fr) * 1999-04-09 2000-10-19 Astrazeneca Ab Formulation pharmaceutique comprenant un bisphosphonate et un agent d'addition favorisant l'absorption du bisphosphonate
US6676965B1 (en) * 1999-10-20 2004-01-13 U&I Pharmaceuticals Ltd. Enteric coated formulation for bisphosphonic acids and salts thereof
WO2001032185A1 (fr) * 1999-11-02 2001-05-10 Cipla Ltd. Composition pharmaceutique renfermant au moins un acide bisphosphonique ou un de ses sels et son procede de preparation
US20070134319A1 (en) * 2003-12-23 2007-06-14 Novartis Ag Pharmaceutical formulations of bisphosphonates
US20050260262A1 (en) * 2004-05-24 2005-11-24 The Procter & Gamble Company Dosage forms of bisphosphonates
KR100631873B1 (ko) * 2004-07-30 2006-10-09 주식회사 유유 생체이용율이 증진된 알렌드론산 제제

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WO2012124982A3 (fr) 2012-11-08
KR20120105738A (ko) 2012-09-26

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