WO2008007796A1 - Préparation médicamenteuse à libération contrôlée et son procédé de production - Google Patents

Préparation médicamenteuse à libération contrôlée et son procédé de production Download PDF

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Publication number
WO2008007796A1
WO2008007796A1 PCT/JP2007/064047 JP2007064047W WO2008007796A1 WO 2008007796 A1 WO2008007796 A1 WO 2008007796A1 JP 2007064047 W JP2007064047 W JP 2007064047W WO 2008007796 A1 WO2008007796 A1 WO 2008007796A1
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Prior art keywords
drug
particles
sustained
release
calcium phosphate
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PCT/JP2007/064047
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English (en)
Japanese (ja)
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Toshiyuki Ikoma
Tomohiko Yoshioka
Toru Tonegawa
Junzo Tanaka
Tetsuya Abe
Masataka Sakane
Naoyuki Ochiai
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National Institute For Materials Science
University Of Tsukuba
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Priority to JP2008524869A priority Critical patent/JP5273657B2/ja
Publication of WO2008007796A1 publication Critical patent/WO2008007796A1/fr

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a sustained-release pharmaceutical preparation that releases a therapeutic agent gradually and over a long period in a living body, and a method for producing the same.
  • DDS Drug Delivery System
  • the main role of DDS is to gradually release the drug at a constant rate over a period of time.
  • Targeting slow drug release
  • selective transport to the target affected area targeting drug
  • Various inorganic materials and polymer materials have been used so far for sustained drug release. For example, hydroxyapatite is slowly decomposed in vivo and has the property of binding or encapsulating various drugs, so it is used as a safe carrier for various drugs. .
  • a hydrogel obtained by bridging a biocompatible polymer compound such as sodium alginate collagen can also encapsulate the drug in the gel and can be slowly decomposed to release the drug, so that only the drug can be used. It is also used in food and cosmetics. Hybrid materials of both are also being developed.
  • apatite particles are mixed with an alginate solution, dropped into a hardened aqueous solution, dried and dried.
  • the drug (Biocidel) dispersed in tanol is formulated by dripping it onto the surface of the dry particles.
  • the sustained release time has been improved compared to the conventional method.
  • a mixed solution of hydroxyapatite and alginic acid derived from koji is dropped into a polymethyl methacrylate (PMMA) solution.
  • composite microparticles are produced by adding chlorinated chloride as a crosslinking agent.
  • the drug is loaded onto the composite micro-mouth particles by immersing the particles in a phosphate buffer solution in which the drug is dissolved, and the sustained release time is zero-dimensional (approximately 3 days). ) Is displayed.
  • the drug loading method is important for drug delivery (DDS) by the apatite nolginate complex. It has been reported that the method of adsorbing to the apatite particles and then combining with alginic acid has the best sustained release.
  • sustained release of the drug is at most several hours to several days.
  • the drug is an anticancer agent
  • sustained release is not sufficient, and a sustained release over a long period of at least 14 days is required.
  • PLGA polylactic acid-dalycolic acid copolymer
  • anticancer agents are poorly water-soluble, and it is difficult to prepare an aqueous solution and impregnate the composite. Disclosure of the invention
  • the problem of the present invention is that long-term sustained release, which could not be expected in the past, is possible, and even if the sustained release drug is poorly water-soluble, such as an anticancer agent. It is an object of the present invention to provide a sustained-release pharmaceutical preparation capable of long-term sustained release and a method for producing the same. Further, the present invention further provides a material having a high affinity with bone tissue, preventing bone formation, and maintaining a material strength that can withstand bone grafting, even when cancer tissue having bone metastasis is targeted. At the same time, it is to provide a drug sustained-release preparation having a deformation characteristic that can be adapted to the shape of the bone defect site and a method for producing the same.
  • Sustained-release pharmaceutical preparation characterized in that a large number of porous calcium phosphate particles composed of aggregates of calcium phosphate nanocrystals, to which the drug is dried and fixed, are contained in a biocompatible polymer matrix .
  • the calcium phosphate contains at least one or more divalent metals selected from the group consisting of magnesium, zinc, strontium, and barium together with calcium or as a part of calcium.
  • the drug sustained-release preparation according to any one of (1) to (4).
  • the biocompatible polymer is at least one selected from the group consisting of sodium alginate, locust bean gum, xanthan gum, dextran sodium, carrageenan, bectin, chitosan, hyaluronic acid, carboxymethylcellulose, and derivatives thereof.
  • the sustained-release pharmaceutical preparation according to any one of (1) to (5), wherein
  • the drug sustained-release preparation according to any one of (1) to (6).
  • said particle size of the calcium phosphate nanocrystals is 1 ⁇ 1 X 1 0 3 nm, the drug sustained-release preparation according to any one of (7) (1).
  • a drug sustained-release medicament comprising the drug sustained-release preparation according to any one of (1) to (1 0).
  • the hardening aqueous solution is an aqueous solution of a salt of a divalent metal selected from the group consisting of magnesium, calcium, strontium, barium, and zinc.
  • Figure 1 shows a scanning electron microscope (SEM) photograph of each particle produced by spray-drying (sample A: no paglitaxel, sample B: paclitaxel 2.4%, sample C: paclitaxel 7.3%).
  • Figure 2 shows the particle size distribution measurement results of paclitaxel-containing (2.4%) apatite particles (Sample B).
  • FIG. 3 shows the thermal analysis (TG-DTA) of each particle obtained by spray drying (sample A: no paclitaxel, sample B: 2.4% paclitaxel, sample C: 7.3% paclitaxel).
  • Figure 4 shows the IR spectrum of each particle obtained by the spray drying process (Sample A: No Notaxel, Sample B: Paclitaxel 2.4%, Sample C: Paclitaxel 7.3%) o
  • Figure 5 shows photographs of the resulting particles before and after compression (left: before compression, right: after 90% compression).
  • Figure 6 shows the changes in the compressive strength of the particles produced as a result of the immersion time in the cured aqueous solution.
  • Figure 7 shows the correlation between the diameter and strength of the particles produced.
  • Figure 8 shows the change in compressive strength depending on the content of the particles in the produced particles.
  • Figure 9 shows the change in compressive strength of the produced particles with the concentration of alginic acid.
  • FIG. 10 shows the results of a drug elution test in PBS (+ Ca, Mg) to which Tween-80 added to the prepared paclitaxel-containing particle preparation was added.
  • FIG 1 Photographs of cells cultured with clitaxel-containing particles are shown ((a) —week, (b) week 4).
  • Figure 12 shows the results of lower limb motor function evaluation (B-B-B score) in the local treatment group and the control group.
  • Figure 13 shows the Kaplan-Meier survival curves for the local treatment group and the control mouth group.
  • Figure 14 shows a histopathological section of a rat breast cancer spinal metastasis model (left figure: normal. Spinal canal, right figure: tissue invaded by tumor tissue).
  • Figure 16 shows a SEM photograph and EDX analysis of a cross section of hydroxyapatite toalginic acid particles cross-linked with barium ions.
  • Figure 17 shows the expansion coefficient of hydroxyapatite toalginic acid particles crosslinked with barium ions.
  • Figure 18 shows the cumulative release of paclitaxel from hydroxide alginate and alginate particles crosslinked with barium ions.
  • This application claims the priority of Japanese Patent Application No. 2006-189259 filed on Jul. 10, 2006. Description of the patent application The contents described in the above are included. The present invention is described in detail below.
  • the drug sustained-release preparation of the present invention is that a large number of porous calcium phosphate particles composed of aggregates of calcium phosphate nanocrystals, to which the drug is dry-adhered around, are contained in the matrix of the biocompatible polymer.
  • the drug sustained-release preparation of the present invention is granular, and its size is the amount of calcium phosphate mixed, the biocompatible polymer concentration, the diameter of the needle of the dropping device, the size of the droplet, the dropping method, and the hardening aqueous solution. Although it can be controlled by the type / concentration and curing time, etc., it can be visually observed, specifically 0.1 to 5 mm, preferably about 1 to 3 mm.
  • the above “size” means a value obtained by measuring the particle diameter of at least 5 gel particles and calculating the average.
  • the porous calcium phosphate particles included in the drug sustained-release preparation of the present invention are prepared by spray-drying an aqueous organic solvent dispersion suspension of calcium phosphate nanocrystals and a drug as described above, and firing is performed. Absent. Therefore, there is no decrease in the specific surface area by calcination, the specific surface area is 30111 2 Roh 8 or more, preferably 50 m 2 Bruno g or more.
  • “calcium phosphate” is represented by the general formula C a 10 (P0 4 X) 6 Y 2 (X represents a carbonate group or a deficiency, and ⁇ represents a hydroxyl group, a carbonate group, a halogen group, or a deficiency).
  • This concept includes the hydroxyl, carbonate, fluorine, and chlorine apatites.
  • at least one divalent metal selected from the group consisting of magnesium, zinc, strontium, and barium may be contained together with or in place of calcium.
  • the porous particle particles are spherical microparticles, and the particle diameter is 1 X 10 2 jum or less, preferably: ⁇ 5 X 10 ⁇ m.
  • biocompatible polymers include sodium alginate, locust bean gum, xanthan gum, dextran sodium, carrageenan, bectin, chitosan, hyaluronic acid, carboxymethylcellulose, and derivatives thereof.
  • the content of the drug in the drug sustained-release preparation of the present invention varies depending on the sustained-release period, 1 X 1 0- 3 ⁇ 1 X 1 0 2 wt 0/0 for calcium phosphate by weight, preferably. 1 to 5 X 1 0% by weight.
  • the content of the porous calcium phosphate particles in the particles is 1 to 5 X 10% by weight, preferably 1 X 10 to 3
  • X 10% by weight and the content of the biocompatible polymer may be 1 X 10 ⁇ 3 to 1 X 10% by weight, preferably 1 to 3% by weight.
  • the sustained release property of the drug sustained-release preparation of the present invention can be controlled by the type of biocompatible polymer, the concentration of the biocompatible high molecule, the apatite content, etc., and is at least 14 days, preferably 30 Sustained release over more than a day is possible.
  • the drug sustained-release preparation of the present invention can be produced by the following method.
  • a water-organic solvent dispersion suspension of calcium phosphate nanocrystals and a drug is spray-dried, and the drug is dried and fixed around the crystal to produce porous calcium phosphate particles that are aggregates of the crystals.
  • the calcium phosphate nanocrystals used here have a particle size of 1 to 1 X 10
  • the type of the organic solvent used depending on the type of the drug and the ratio with water can be determined.
  • ethanol, methanol, etc. can be used as the organic solvent
  • the mixing ratio of water and organic solvent should be in the range of 1 X 10 4 : 1 to 1: 1 X 10 4 .
  • the type of the drug is not particularly limited, but a poorly water-soluble drug that is difficult to impregnate calcium phosphate particles in the form of an aqueous solution can also be used.
  • poorly water-soluble anticancer agents include paclitaxel, adriamycin, camptothecin, cisplastin, daunomycin, pinorbin, methotrexate, mitomycin c, etoposide, gefitinib, irinotecan hydrochloride, topotecan hydrochloride, docetaxol, vinbrathol sulfate Vincristine sulfate, vindesine sulfate, teniposide, pinorelvin tartrate, busunolevane, carbocon, thiotepa, cyclophosphamide, melphalan, estramustine sodium phosphate, mechlorethamine oxide hydrochloride, ifosfamide, ramustine hydroch
  • Spray drying can be performed by a conventional method using a commercially available apparatus equipped with a two-fluid nozzle and a four-fluid nozzle such as Buchi, Yamato Kagaku, and Okawara Kogyo Co., Ltd.
  • the liquid mixture is made into fine droplets of about 1 to 5 X 10 2 m, blown into hot air at 100 to 300 ° C., and dried.
  • porous calcium phosphate spherical particles are mixed and dispersed in a biocompatible polymer aqueous solution, and then dropped into a cured aqueous solution to be granulated.
  • the particles are kept dripped in the aqueous curing solution for about 1 minute to 2 hours. It is preferable to immerse in the aqueous solution.
  • the porous calcium phosphate particles are 1 to 5 10% by weight, preferably 1 X 10 to 3 X 10% by weight, based on the biocompatible polymer aqueous solution.
  • the aqueous hardening solution may be an aqueous solution of a divalent metal salt selected from the group consisting of magnesium, calcium, strontium, barium, and zinc.
  • the salt may be either an inorganic acid salt or an organic acid salt.
  • calcium chloride, zinc chloride, barium chloride, strontium chloride, calcium acetate, zinc acetate, etc. can be used. Calcium chloride is particularly preferred.
  • concentration of the divalent metal ion in the curable aqueous solution is 1 X 10 ⁇ 3 to 5 mol 1, preferably 2 X 10 0 — 2 to 2 m o 1/1.
  • the biocompatible polymer By dispersing the porous calcium phosphate spherical particles in the biocompatible polymer aqueous solution, the biocompatible polymer is coated on the porous calcium phosphate spherical particles, and when this is dropped into the cured aqueous solution, the metal of the biocompatible polymer is added.
  • a salt for example, calcium alginate
  • a salt is formed, forming a three-dimensional network structure and gelling.
  • Collect and wash the final particles The collection is performed by filtration or the like, and the recovered particles can be further classified as necessary to obtain particles having a desired particle size distribution.
  • drying treatment after washing is preferable in terms of storage and sterilization. Drying is performed, for example, from 0 to: I 0 0 ° C. from 6 to: I for 2 hours.
  • the drug sustained-release preparation of the present invention exhibits a long-term sustained release of at least 14 days or more
  • the drug sustained-release preparation has a function of having sufficient strength even when transplanted into bone and having excellent affinity with bone tissue. Therefore, the drug sustained-release preparation of the present invention can be used alone or in combination with pharmaceutically acceptable additives as a drug sustained-release drug, particularly a drug sustained-release drug for cancer treatment.
  • cancers that cause bone lesions such as primary bone tumors such as osteosarcoma, chondrosarcoma, Ewing sarcoma, other organs / organs (lung, stomach, mammary gland) It is also effective for metastatic bone tumors in which cancer of the thyroid, kidney, prostate, etc. has metastasized to bone, and blood cancers such as myeloma and lymphoma.
  • the sustained-release drug of the present invention can be prepared in various dosage forms and administered systemically or locally orally or parenterally.
  • the medicament of the present invention When orally administering the medicament of the present invention, it is formulated into tablets, force capsules, granules, powders, pills, water for internal use, suspensions, emulsions, syrups, etc., or redissolved when used. It may be a dry product.
  • the pharmaceutical of the present invention is administered parenterally, it is formulated into intravenous injection (including infusion), intramuscular injection, intraperitoneal injection, subcutaneous injection, suppository, etc. Are provided in unit-dose samples or in multi-dose containers.
  • compositions include excipients, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, preservatives,
  • a flavoring agent, a soothing agent, a stabilizer, a tonicity agent and the like can be appropriately selected and produced by a conventional method.
  • the administration route is preferably administration by injection, and the dosage form is preferably injection.
  • administration by injection include subcutaneous administration, intraperitoneal administration, arterial administration, intravenous administration and the like. Of these, arterial injection into the artery near the affected area or direct administration to the affected area is most preferable.
  • the sustained-release medicament of the present invention may contain other drugs used for cancer therapy.
  • contrast media such as ribiodol or vascular occlusive agents
  • apoptosis inducers such as staurosporine
  • immunosuppressants such as steroids and cyclosporine
  • angiogenesis inhibitors such as morphine for pain relief.
  • narcotics such as morphine for pain relief.
  • the dosage of the medicament of the present invention is the age, sex, symptom, route of administration, number of times of administration. Varies and can vary widely.
  • the effective amount of drug included is: 0.1 mg / kg body weight at a time!
  • a dose in the range of OO Omg can be selected, preferably administered once to several times a day.
  • a potassium suspension (1 liter) was added dropwise to a 0.25 mol / l calcium hydroxide suspension (2 liters) to synthesize an apatite suspension.
  • the synthesized suspension
  • the particle diameter (diameter) measured from 100 particles is 3.31 ⁇ 0.83 urn (maximum 6.1 ⁇ , minimum 1.9 / 1 m) for sample A (without paclitaxel), and 3.42 for sample B (contains 2.4% paclitaxel).
  • FIG. 2 shows the particle size distribution measurement results for Sample B (containing paclitaxel 2.4%). It can be seen that the spray-dried particles are all distributed from 1 to 20 / zm. From this result, it is considered that particles of 10 zm or more aggregated during the measurement.
  • the average particle size is 4.0 ⁇ 0.2 ⁇ for sample A (without paclitaxel), and the average particle size for sample ⁇ (containing 2.4% paclitaxel).
  • paclitaxel 300 mg was dispersed in 50 ml of ethanol, and mixed with 250 ral (3 g of apatite content) of an apatite suspension synthesized in the same manner as described above.
  • the mixed apatite paclitaxel / ethanol suspension was spray-dried with a spray dryer manufactured by Buchi under the same conditions as above to synthesize paclitaxel-containing (7.3%) porous apatite spherical particles (sample) C).
  • Figure 1 also shows a scanning electron microscope (SEM) image of Sample C.
  • the paclitaxel content contained in each particle produced in Example 1 was quantified by UV method and thermal analysis method.
  • Paclitaxel eluted by dispersing Sample B 13.2, 10.6, and 8 mg in 10 ml of purified water ethanol mixed solvent (50:50) was quantified at a wavelength of 230 nm. As a result, it was found that the content was 2.4 ⁇ 0.2% per weight of the produced particles.
  • Samples C 4.26, 6.03, and 7.19 mg were quantified in the same manner. As a result, it was found that 7.3 ⁇ 0.4% was contained per particle weight.
  • Figure 3 shows the results of thermal analysis measurement.
  • a gentle weight loss up to 1200 ° C was observed.
  • the weight loss was 11.6 wt%, and almost no exotherm was observed.
  • samples containing paclitaxel samples containing paclitaxel (samples B and C)
  • exothermic peaks were observed at 242, 347, and 455 ° C.
  • the weight loss to 1200 ° C was 13.6% (Sample B) and 19.6% (Sample C), respectively.
  • the paclitaxel content was calculated by subtracting the weight loss (sample B—sample A, sample C one sample A).
  • the paclitaxel content was 2.0 wt% (Sample B) and 8.0 wt% (Sample C).
  • Example 3 FT-IR analysis of paclitaxel-containing porous apatite spherical particles
  • Fig. 4 shows the results of FT-IR analysis of paclitaxel-containing porous apatite spherical particles prepared in Example 1. Absorption peaks due to paclitaxel are 1742, 1711, 1577,
  • a 1% aqueous alginate solution was prepared using sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd .; viscosity 500-600 cps (lw / v%. 20 ° C), pH 7.3)). After mixing sodium alginate mechanically with purified water using Cell Master (As one), centrifuge for 10 minutes at 12,000 rpm (Tomy Seye) to remove insoluble matter and degas Went. The pure porous apatite spherical particles prepared in Example 1 (Sample A) lg were mixed with lOral aqueous alginate solution.
  • This mixed solution was dropped into a hardening aqueous solution (100 ml of 2 mol / 1 calcium chloride solution) using a pipette with a microphone (200 1).
  • the obtained particles were all spherical.
  • the time-series strength change (compression test) was examined by changing the time of immersion in the cured aqueous solution to 10 minutes, 1, 2, 4, and 24 hours. Using a texture analyzer, the probe was pushed into purified water at a speed of 0.1 lram / s and compressed 90%.
  • Figure 5 shows the outer shape of the particles produced and the morphology of the particles after the compression test.
  • the average particle diameter of the 25 particles produced was also calculated using a texture analyzer.
  • the average value was 2.04 ⁇ 0.03 mm (maximum particle diameter: 2.07 mm, minimum particle diameter: 1.90 mm).
  • Fig. 6 shows the time-series changes in strength when strain stresses of 10, 20, and 30% are applied. Particles with sufficient strength to be obtained even after immersion for 10 minutes were obtained. The compressive strength increased slightly by changing the time of immersion in the curable aqueous solution.
  • Example A Pure porous apatite spherical particles (Sample A) of 5 10, 20, 30, and 40 wt% were mixed with the 1% alginate aqueous solution prepared in the same manner as in Example 4, and the resulting cured aqueous solution was the same as in Example 4. Dropped and dipped for 10 minutes to produce particles. The obtained particles were washed and similarly subjected to a compressive strength test using a texture analyzer. The size of the particles prepared at each concentration was 1.81 ⁇ 0.03, 2.02 ⁇ 0.04, 2.11 ⁇ 0.04, 2.21 ⁇ 0.01. 2.13 ⁇ 0.03 mm. In order to correct the intensity depending on the size, the plot was made with the diameter corrected to 2 mm (Fig. 8). It was found that the strength increased linearly with increasing the content of the ferrite.
  • paclitaxel-containing porous apatite spherical particles containing paclitaxel 7.3%) prepared in Example 1
  • particles alginic acid concentration 1%; 10 wt% apatite with respect to the alginate aqueous solution
  • the resulting particle preparation was subjected to a paclitaxel elution test using water / ethanol (50-50).
  • One particle formulation was added to 5 ml of solution and allowed to stand for up to 12 hours. The supernatant was collected and subjected to UV measurement (wavelength: 230 nm).
  • paclitaxel-containing porous apatite spherical particles (containing paclitaxel 2.4%) prepared in Example 1, particles (alginic acid concentration: 1%; with respect to aqueous alginate solution) in the same manner as in Example 4. 10wt%, 20% containing).
  • the amount of paclitaxel contained in the obtained particles is water / ethanol.
  • the 10 and 20 wt% 7-partite particle formulations contained 0.035 mg and 0.08 mgZ paclitaxel, respectively.
  • PBS phosphate buffer solution
  • the CRL-1666 breast cancer cell line (Rockville, MA, USA) was used as the cultured cancer cells.
  • the cells are Dulbecco Modified Eagle Medium supplemented with 10% fetal bovine serum and 80.5 pg / ral streptomycin and 80.5 U / ral penicill in and 1% L-glutaraine. All products are from Gibco Invitrogen TM 5% C0 2 at 37 ° C (purchased from Corp, CA, USA) Incubation was performed under humidified pressure conditions. The medium was changed approximately every 3 days at a concentration of 10 6 cel ls / ml.
  • CRL-1666 breast cancer cell line (Rockville, MA, USA) was used.
  • Cells were Dulbecco Modified Eagle Medium supplemented with 10% fetal bovine serum, 80.5 pg / ml streptomycin, and 80.5 U / ml penici ll in and 1% L-glutaraine (all products from Gibco Invitrogen TM Corp , CA, and cultured under conditions of 5% C0 2 humidified pressure at 37 ° C for at purchased from USA). The medium was changed approximately every 3 days at a concentration of 10 6 cel ls / ml.
  • Confluent cells were detached with 0.01 M EDTA, and proliferating cells were removed from the ventral skin of 8-week-old female Fischer 344 rats (weight 150-180 g, Charles River Laboratories, JAPAN). Injecting 1 ⁇ 10 6 cells to produce solid tumor pieces for transplantation. The tumor mass on the 10th day after injection was removed and placed in sterile physiological saline to a size of 1 X 1 X 1 ram. A CRL-1666 solid tumor fragment was transplanted into the lumbar spine of a rat to obtain a rat breast cancer spinal metastasis model.
  • the obtained rat breast cancer spinal metastasis model was divided into a control group and a local treatment group.
  • the rats in the control group closed the bone hole containing the tumor pieces with a paclitaxel-free particle preparation.
  • particles containing paclitaxel 2.4% prepared in Example 9 (alginate concentration 1%, containing 10% apatite with respect to alginate aqueous solution) were administered.
  • the following tests were performed, and the control group and the local treatment group were compared using a log-rank test. For statistical evaluation, P ⁇ 0.05 was considered significant.
  • BBB score was used every day.
  • BBB score is based on a rat gait of 21 points It is a score. Rats were placed in a 57 x 38 x 30 cm plastic enclosure and observed for 4 minutes. In the early stages of tumor growth, rotation of toes and heels is observed, corresponding to 20 to 14 points. When a neurological deficit symptom appears, a trauma or lameness appears, which corresponds to 13 to 8 points. When spinal cord compression progresses, continuous movement of the lower limbs is not observed, which corresponds to 7 to 0 points. All tests were done in a double blind study. The control group died of paralysis of the lower extremities in about 2 weeks, as reported previously. The average BBB scale at 15 days after surgery is 5.2 days for the control group and 16.4 days for the local treatment group (Fig.
  • the period until the occurrence of paralysis was expressed as a Kaplan-Meier curve as a disease-free time, and was compared between the control group and the local treatment group.
  • the survival rate of each group was expressed by Kaplan-Meier curve, and the average survival time was compared between the control group and the local treatment group.
  • paclitaxel-containing apatite gel preparations significantly prolonged the occurrence of spinal paralysis and improved survival in a rat breast cancer spinal transition model.
  • Extraosseous tumors were evaluated by extravertebral soft tissue growth, and the maximum diameter (a) X minimum diameter (b) of the tumor was determined, and the tumor weight (mg) was calculated from the formula 0.5ab 2 *. All cases of extraskeletal lesions (extravertebral soft tissue) Tumor weight is shown in Table 1 below. The mean tumor weights in the control mouth group and the local treatment group at the end of the experiment were 6.14 g and 6.09 g, respectively, and there was no statistically significant difference. table 1
  • the incised spine and tumor were fixed with 10% formalin solution, decalcified, and embedded in paraffin.
  • a 3 ⁇ m section obtained by horizontally cutting the spinal column containing the tumor was stained with hematoxylin-eosin (H & E staining).
  • the degree of vertebral body invasion and occupancy in the spinal canal was evaluated.
  • the H & E-stained transverse section of the spine showed a strong infiltration of the tumor, which occupied the spinal canal extensively and pressed the spinal cord ( Figures 14 and 15).
  • 344 rats (8-week-old female) were prepared and classified into the control group and the systemic treatment group (5 mg / Kg paclitaxel was administered from the tail vein on days 1, 7, and 14) and the local treatment group.
  • the topical treatment group included particles containing paclitaxel 7.2 wt% (alginate concentration 1%; algin A dried product containing 10 wt% apatite with respect to the acid aqueous solution was used.
  • the evaluation method was performed in the same manner as in Example 11.
  • Rats in the control group began to paralyze on average 9 days and died on average 14-75 days.
  • paralysis began to occur on averages of 10.4 days and 12.8 days, respectively, and died on averages of 14.22 days and 17.45 days, respectively.
  • the average weight of the rats at the start of the experiment was 144.lg (129-181g).
  • the change in body weight of each group was evaluated using a paired t test for rats whose body weight at 2 weeks could be measured.
  • the systemic treatment group there was no statistically significant difference between the start of the experiment and 2 weeks in the control group, but the local administration group tended to have less weight change at 2 weeks.
  • the body weight of the whole body treatment group and the control group tended to decrease compared to the time when the experiment was started (control group 3.2 g, whole body treatment group 5.3 g, local treatment Treatment group 0.18g; p-value in the control group and local treatment group is 0.62 0.
  • Sodium alginate (Wako Pure Chemical Industries, Ltd.;. The viscosity 500_600cps (lw / v% 20 ° C), P H7 3) was dissolved in distilled water in a concentration of l 3% (w / v) , was prepared alginate solution.
  • 5 40% (w / w) paclitaxel-containing porous apatite spherical particles (containing 2.6% paclitaxel) prepared in the same manner as in Example 1 were uniformly mixed at room temperature. .
  • Hydroxyapatite toalginic acid mixture was dropped into a hardening aqueous solution (2.0 M barium chloride solution) using a micropipette (200 / zl) to prepare a spherical gel having a size of 2.02.8 mm.
  • the resulting hydroxyapatite toalginic acid spherical gel was dried for at least 24 hours to obtain firm hydroxyapatite toalginic acid particles.
  • This particle was named AxHy-Ba (where x and y represent alginate concentration and potassium content, respectively).
  • the internal structure of the particles was sputter coated with platinum and then examined with a scanning electron microscope (SEM) and EDX. Mechanical properties were examined using a texture analyzer (Stable Micro Systems, UK). The compressive strength was measured using a cylindrical probe (5.0mra diameter) with a speed of 0.1 / s. The expansion rate of the particles was measured in D-PBS according to the following formula.
  • paclitaxel release was examined at 37 ° C in D-PBS containing 1% Tween_80.
  • the amount of paclitaxel was quantified by high performance liquid chromatography (HPLC) in which the mobile phase consisted of acetonitrile and water (volume ratio 60 40), and the flow rate was l. O ml / min.
  • Paclitaxel was detected at 227 nm using a UV detector.
  • Figure 16 shows SEM photographs and EDX analysis of the cross section of hydroxide apatite toalginic acid particles cross-linked with barium ions.
  • the SEM photograph of A1H40-Ba showed that the mic mouth particles of the hydroxyapatite having a particle size of 1 10 jura were uniformly dispersed in the particles. Hydroxide microparticles did not appear on A1H05-Ba and A3H05-Ba.
  • all of the types of particles examined were subjected to hydroxide activity. Uniform dispersion of the mouthpiece particles was shown. Valium ions cross-linked with alginic acid were also uniformly dispersed in the particles.
  • the compressive strength of hydroxyapatite-alginate particles increased in the order of AlH40_Ba ⁇ AlH05-Ba A3H05-Ba. This result shows that the compressive strength increases as the ratio of alginic acid to hydroxylapatite increases.
  • the ratio of alginic acid to hydroxyapatite was more influenced by compressive strength than hydroxyapatite content.
  • it has been found that hydroxyapatite toalginic acid particles tend to collapse due to alginate when compressed.
  • the hydroxyapatite-alginate particles obtained in the present invention became firm as the gel was dehydrated.
  • Figure 17 shows the expansion coefficient of hydroxyapatite toalginic acid particles crosslinked with barium ions.
  • the expansion characteristics differed depending on the composition of the particles. The higher the ratio of alginic acid to hydroxyapatite, the better the expansion. This result was thought to be due to the strong hydration properties of alginic acid.
  • Figure 18 shows the cumulative release of paclitaxel from hydroxyapatite to alginate particles crosslinked with barium ions. Paclitaxel was gradually released from the particles into the culture medium. The release behavior of A1H05-Ba and A3H05-Ba was the same. Since the expansion coefficient of A3H05-Ba is higher than that of A1H05-Ba (Fig. 17), it was found that the release behavior of paclitaxel is not related to the expansion coefficient of the particles.
  • A1H20-Ba The release behavior from A1H20-Ba was almost the same for A1H05-Ba and A3H05_Ba. After 5 hours, A1H05-Ba and A3H05_Ba did not release paclitaxel, whereas A1H20-Ba still had a lot of release. The release of paclitaxel. Therefore, the release behavior of paclitaxel was considered to depend on the amount of hydroxyapatite to alginate particles supported. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety. Industrial applicability
  • the drug sustained-release preparation of the present invention is excellent in sustained-release property and can maintain its effect for at least 14 days.
  • a sustained release effect over a long period of time of the drug sustained-release preparation of the present invention is that the drug is dried and fixed around the calcium phosphate nanocrystals, and porous calcium phosphate particles that are aggregates thereof.
  • This is considered to be achieved by incorporating a large number of bioaffinity in a biocompatible high molecular matrix.
  • the adhesion of the drug is increased by drying and fixing around the nanocrystal, so that the drug is not separated but the crystal is not separated. More parts are released into the body due to disintegration.
  • the collapse of the calcium phosphate nanocrystals in vivo can be mitigated.
  • the drug sustained-release preparation of the present invention has sufficient strength even when transplanted into bone, has excellent affinity with the bone tissue, and does not change the sustained-release effect. Furthermore, in manufacturing such sustained-release pharmaceutical preparations, the spray-dry method has been used to fix even poorly water-soluble anticancer agents to calcium phosphate nanocrystals. Then, the possibility of use for diseases for which sustained release action could not be utilized can be greatly expanded. Therefore, the drug sustained-release preparation of the present invention is very useful as a sustained-release pharmaceutical for treating bone metastasis cancer.

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Abstract

La présente invention vise à fournir une particule de libération de médicament qui présente une libération contrôlée prolongée, une force suffisante même si elle est implantée dans l'os, et une grande affinité pour le tissu osseux. À cet effet, l'invention fournit une préparation médicamenteuse à libération contrôlée, caractérisée en ce qu'elle contient un grand nombre de particules poreuses de phosphate de calcium composées d'un agrégat de nanocristaux de phosphate de calcium à la périphérie desquels un médicament adhère par séchage dans une matrice polymère biocompatible, ainsi qu'un procédé de production de cette préparation.
PCT/JP2007/064047 2006-07-10 2007-07-10 Préparation médicamenteuse à libération contrôlée et son procédé de production WO2008007796A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
JP2012526144A (ja) * 2009-05-06 2012-10-25 ラボラトリー スキン ケア インコーポレイテッド 活性物質−リン酸カルシウム粒子複合体を含む経皮送達組成物およびその使用方法
JP2015187107A (ja) * 2009-05-06 2015-10-29 ラボラトリー スキン ケア インコーポレイテッド 活性物質−リン酸カルシウム粒子複合体を含む経皮送達組成物およびその使用方法
JP2017218456A (ja) * 2009-05-06 2017-12-14 ラボラトリー スキン ケア インコーポレイテッド 組成物
US10350168B2 (en) 2009-05-06 2019-07-16 Laboratory Skin Care, Inc. Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same

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