WO2011013359A1 - イオントフォレーシス用薬剤組成物 - Google Patents
イオントフォレーシス用薬剤組成物 Download PDFInfo
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- WO2011013359A1 WO2011013359A1 PCT/JP2010/004779 JP2010004779W WO2011013359A1 WO 2011013359 A1 WO2011013359 A1 WO 2011013359A1 JP 2010004779 W JP2010004779 W JP 2010004779W WO 2011013359 A1 WO2011013359 A1 WO 2011013359A1
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- composition according
- drug
- phosphate
- sodium phosphate
- pharmaceutical composition
- Prior art date
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Images
Classifications
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0428—Specially adapted for iontophoresis, e.g. AC, DC or including drug reservoirs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/20—Applying electric currents by contact electrodes continuous direct currents
- A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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- A61N1/0448—Drug reservoir
Definitions
- the present invention relates to a pharmaceutical composition for iontophoresis suitable for transdermal and transmucosal application.
- Iontophoresis is a method in which components such as ionic drugs useful for the living body are permeated into the living body using so-called electrophoresis, which is also called ion osmosis therapy or iontophoresis, and is mainly systemic. It is used for the administration of drugs.
- An iontophoresis device generally has a working electrode structure that holds a drug solution that dissociates medicinal ingredients (bioactive substances) into positive or negative ions (drug ions), and a non-acting function that acts as a counter electrode of the working electrode structure.
- a drug is provided by applying a voltage having the same polarity as the drug ion to the working electrode structure from the power supply device in a state where both structures are in contact with the skin of a living body (human or mammal). Ions are administered into the living body.
- both poles may contain a physiologically active substance, and both poles may be an action structure.
- water-soluble steroids are administered intra-articularly as injections in the treatment of rheumatoid arthritis, osteoarthritis and the like.
- it has pain during injection, requires advanced techniques of a doctor, and may cause infections from the administration site, so it was never a simple and highly safe pharmaceutically useful administration method. .
- Non-patent Document 1 dermal administration of dexamethasone sodium phosphate, which is a kind of water-soluble steroid, using DC iontophoresis is known.
- lidocaine which is a local anesthetic
- an object of the present invention is to provide a pharmaceutical composition for iontophoresis that is excellent in drug stability, easy to prepare and fill during production, and can be produced at low cost.
- the present inventors have conducted extensive research on the relationship between water-soluble steroids and long-term stability in order to achieve the above object, and as a result have found the present invention.
- the pharmaceutical composition for iontophoresis of the present invention is characterized by containing a nonionic synthetic polymer, betamethasone sodium phosphate, and a solvent.
- the nonionic synthetic polymer substance is polyvinyl alcohol (PVA).
- the blending amount of polyvinyl alcohol (PVA) is 0.5 to 30% by weight.
- the amount of the polyvinyl alcohol (PVA) is 20% by weight or less.
- the amount of betamethasone sodium phosphate is 1 to 12% by weight.
- the amount of betamethasone sodium phosphate is 1 to 4% by weight.
- the solvent is at least one selected from the group consisting of water and a phosphate buffer.
- the pH on the surface of the composition is in the range of 7-8.
- the pharmaceutical composition further contains ethylenediaminetetraacetic acid (EDTA).
- EDTA ethylenediaminetetraacetic acid
- the blending amount of ethylenediaminetetraacetic acid (EDTA) is 0.05 to 0.15% by weight.
- the concentration of the phosphate buffer is 1 to 10 mM.
- the preparation of the present invention is characterized by having the composition according to any one of claims 1 to 11 and an adhesive layer.
- the adhesive layer is composed of at least one selected from the group consisting of acrylic, silicone, synthetic rubber, natural rubber, and the like. To do.
- the iontophoresis administration method of the present invention is characterized in that betamethasone sodium phosphate is administered using the pharmaceutical composition of the present invention.
- betamethasone sodium phosphate is transdermally distributed from the support layer through the pericardium to the medial pericardium and synovium in a band shape and delivered to the joint. It is characterized by.
- the method for treating rheumatoid arthritis, osteoarthritis, tendonitis, tenosynovitis, or peritonitis of the present invention comprises administering rhematoid arthritis and deformity by administering betamethasone sodium phosphate according to the administration method of the present invention. It is characterized by treating at least one disease selected from the group consisting of osteoarthritis, tendonitis, tenosynovitis, peri-tendonitis (all limited to non-infectious).
- the present invention there is an advantageous effect that the residual rate of the drug composition is stable over a long period of time and the drug is excellent in stability. Further, according to the present invention, since the minimum necessary components are used except unnecessary components as much as possible, it is possible to achieve an excellent drug effect without causing problems such as water separation in the conventional components. It has the advantageous effect of being.
- FIG. 1 shows the drug residual rate at various pH values.
- FIG. 2 shows the results of an accelerated test at 40 ° C. for the pharmaceutical composition in one example of the present invention.
- Fig. 3 shows the residual rate of drug in the accelerated test at 40 ° C for gel preparations when EDTA is added or under phosphate buffer (no EDTA added for accelerated test with 1 mM phosphate buffer) Indicates.
- FIG. 4 shows a schematic view of a normal rabbit right knee joint to which 3H-labeled betamethasone phosphate was transdermally administered by electrification.
- FIG. 5 shows a semi-micro autoradiograph of a normal rabbit right knee joint that was transdermally administered with 3H-labeled betamethasone phosphate for 30 minutes.
- FIG. 6 shows a semi-microautoradiograph of a normal rabbit right knee joint to which 3H-labeled betamethasone phosphate was transdermally administered for 30 minutes by electrification.
- FIG. 7 shows a semi-micro autoradiograph of a normal rabbit right knee joint that was transdermally administered with 3H-labeled betamethasone phosphate for 120 minutes.
- FIG. 8 shows a semi-microautoradiograph of the left knee joint on the non-administration side of a normal rabbit in which 3H-labeled betamethasone phosphate was transcutaneously administered to the right leg by electrification.
- FIG. 9 shows the relationship between time and the cumulative permeation profile at a phosphate concentration of 0 mM to 100 mM.
- FIG. 10 shows the relationship between the time-dependent slope of the cumulative permeated profile (flux) at a phosphate concentration of 0 mM to 100 mM and time.
- the pharmaceutical composition for iontophoresis of the present invention contains a nonionic synthetic polymer substance, betamethasone sodium phosphate, and a solvent.
- the nonionic synthetic polymer substance used in the pharmaceutical composition for iontophoresis of the present invention is not particularly limited as long as it is a hydrophilic and nonionic synthetic polymer substance.
- polyvinyl alcohol examples thereof include synthetic polymer substances such as polyvinyl formal, polyvinyl methyl ether, polyvinyl methacrylate, polyvinyl pyrrolidone, polyvinyl pyrrolidone / vinyl acetate copolymer, polyethylene oxide, and polypropylene oxide.
- polyvinyl alcohol, polyvinyl pyrrolidone, and polyethylene oxide are preferable from the viewpoint of easy production. These are used alone or in combination of two or more.
- the blending amount of such a nonionic synthetic polymer substance is preferably 0.5 to 30.0% by weight in the iontophoretic drug composition.
- the amount of the polyvinyl alcohol (PVA) is 20% by weight or less. This is because threading with a nonionic synthetic polymer substance and prevention of a decrease in productivity due to an increase in viscosity are prevented. More preferably, it is 16% by weight or less, and further preferably 14 to 16% by weight.
- the amount of betamethasone sodium phosphate is not particularly limited, but is 1 to 12 weights from the viewpoint of the permeation promoting effect by the electric field on the drug concentration of the donor. %, More preferably 1 to 4% by weight from the viewpoint of permeation promoting efficiency.
- the solvent is at least one selected from the group consisting of water and a phosphate buffer.
- the water formulated in the iontophoretic pharmaceutical composition of the present invention is a very important ingredient in iontophoretic administration because of swelling of the stratum corneum, relaxation of irritation, and dissolution and permeation of the administered drug. It is.
- the blending amount of water is preferably 10 to 80% by weight, more preferably 30 to 60% by weight, based on the total weight of the iontophoretic pharmaceutical composition.
- the blending amount is less than 10% by weight, the solubility of the water-soluble drug in the composition is decreased, crystals are precipitated, the amount of free water in the composition is decreased, and an increase in diffusion resistance occurs. As a result, there is a possibility that the amount of drug absorption may decrease.
- the blending amount exceeds 80% by weight, it becomes difficult to form a sufficient gel body, the volatility becomes high, and quality assurance at the time of storage and administration becomes difficult.
- the pH on the surface of the pharmaceutical composition of the present invention is not particularly limited because it varies depending on the stability of the drug and the administration electrode. However, in view of drug stability, safety to the skin, and gel physical properties, preferably pH 4 In the range of ⁇ 9, more preferably in the range of pH 7-8.
- the pharmaceutical composition of the present invention may further contain ethylenediaminetetraacetic acid (EDTA).
- Ethylenediaminetetraacetic acid (EDTA) can adjust the curing of the metal-based compound, and can capture metal ions, particularly Ag +, with a chelate, which in turn contributes to the stability of the drug.
- the blending amount of ethylenediaminetetraacetic acid (EDTA) is not particularly limited, but it is preferably 0.05 to 0.15% by weight from the viewpoint of preventing the drug from permeating the skin.
- the pharmaceutical composition of the present invention from the viewpoint that pH change on the gel surface can be reduced over a long period of time and competition with betamethasone sodium phosphate in skin permeation during energization can be suppressed.
- the concentration of the liquid is 1 to 10 mM, more preferably 1 to 5 mM.
- the preparation of the present invention has the above-described pharmaceutical composition of the present invention and an adhesive layer.
- the adhesive layer is composed of at least one selected from the group consisting of acrylic, silicon, synthetic rubber, and natural rubber.
- the adhesive layer is preferably acrylic.
- the scope of the present invention that is, a scope that does not depart from the spirit of providing a stable pharmaceutical composition while removing the harmful effects of additives using the minimum necessary components. And may contain preservatives and preservatives.
- a solvent and a nonionic synthetic polymer substance are added to a suitable container and stirred as necessary. Immerse in a heated oil bath, heat with stirring for 20-60 minutes, and cool at room temperature with stirring if necessary.
- betamethasone sodium phosphate is administered using the pharmaceutical composition of the present invention.
- the above description can be referred to.
- the pharmaceutical composition of the present invention is spread on an electrode formed by printing a conductive paste in advance on the plaster surface of a support, or on a film or molded cup once subjected to a peeling treatment.
- An electrode for iontophoresis can be obtained by spreading or filling the electrode with a drug composition and then pressing it onto the electrode.
- the electrode can be used for administration using a conventional iontophoresis device.
- an iontophoresis device is constructed using the above-described pharmaceutical composition of the present invention, and betamethasone sodium phosphate is transcutaneously passed from the support layer through the pericardial membrane to the inner muscle. It can be distributed in the form of a band to the peripheries and synovium and delivered to the joint.
- Rheumatoid arthritis, osteoarthritis, tendonitis, tenosynovitis, peritonitis (all are limited to non-infectious) by administering betamethasone sodium phosphate using the iontophoresis administration method of the present invention. It is possible to treat at least one disease selected from the group consisting of:
- Purified water was added to prepare 100 g. Stir again until homogeneous. When sufficiently stirred, the mixed solution was sucked with a syringe. About 1 g of the prepared solution was dispensed into a preparation prepared with foam tape (manufactured by 3M, closed-cell foam tape, model 9773). PVA gelation was promoted by freezing it in a freezer at -80 ° C. After freezing for about one night, the mixture was allowed to stand at room temperature and thawed. This was packaged one by one in an aluminum wrapping material, placed in a thermo-hygrostat set at various temperatures, and a stability test was performed.
- foam tape manufactured by 3M, closed-cell foam tape, model 9773
- Example 1 the composition prepared according to Example 1 was subjected to an acceleration test at 40 ° C. when the amount of EDTA was changed.
- the stability of the drug was examined by measuring the pH of the gel at this time.
- Table 1 and FIG. 2 show the results of an accelerated test at 40 ° C. for the pharmaceutical composition in one example of the present invention.
- (a) is 0% EDTA
- (b) is 0.05% EDTA
- (c) is 0.15% EDTA
- pH of 1, 2, 3, 6 months later It shows a change.
- Table 2 and FIG. 3 show the residual ratio of the drug in the accelerated test at 40 ° C. of the gel preparation when EDTA is added and the phosphate buffer is used.
- Example 3 As a result, as estimated in Example 3, it is possible to prevent a decrease in pH by using a phosphate buffer or the like, and thus it is possible to suppress a decrease in the drug residual rate. I understand that.
- Table 3 shows the pH change in the aqueous solution with the drug added.
- BSP represents betamethasone sodium phosphate.
- Tables 4 and 5 show the pH change on the gel surface with the drug added.
- Table 5 (a) shows the average value obtained by measuring the pH of one gel surface 7 to 8 times.
- Table 5 (b) summarizes the average values obtained in Table 5 (a).
- Beta-P represents betamethasone sodium phosphate.
- the stability of the drug in the wide-area buffer pH 2 to pH 8 was examined. More specifically, Briton-Robinson's broad-area buffer was used, the pH was adjusted to 2-8, and 3% (w / v) betamethasone sodium phosphate solution was prepared with each solution.
- the stability of the drug was examined after 2 weeks, 1 month, 4 months, and 6 months at 4 ° C, 40 ° C, 50 ° C, and 60 ° C.
- Table 6 shows the results of examining the stability of the drug after 2 weeks at 4 ° C and 60 ° C.
- Table 7 shows the results of examining the stability of the drug after one month at 4 ° C, 40 ° C, 50 ° C and 60 ° C.
- Table 8 shows the results of examining the stability of the drug after 4 months at 4 ° C, 40 ° C, 50 ° C and 60 ° C.
- Table 9 shows the results of examining the stability of the drug after 6 months at 4 ° C, 40 ° C and 50 ° C.
- W means purified water (ion-exchanged water)
- N2-W indicates purified water that has been bubbled with nitrogen gas.
- FIG. 1 shows the drug residual rate after 6 months at 40 ° C. It can be seen from FIG. 1 that the drug residual rate gradually increases from pH 5 and above.
- the radioactivity concentration in the plasma of rabbits was measured after transdermal administration with energization treatment.
- 120-minute-administered individuals it gradually increased from 10 minutes after the administration and showed the highest value after 120 minutes, but it was still on an upward trend.
- the individual administered 30 minutes it gradually increased from 10 minutes after the administration, and still showed an increasing trend after 30 minutes.
- Table 10 shows the contents of the purity measurement of the labeled compound.
- Table 11 shows the contents of the measurement of plasma radioactivity concentration.
- transdermal administration with energization treatment was as follows. Dosage: 18.5 MBq (500 ⁇ Ci) / 1 mL / head.
- Table 12 shows the contents of the semi-micro autoradiography of the rabbit knee joint.
- transdermal administration with energization treatment was as follows. Dosage: 18.5 MBq (500 ⁇ Ci) / 1 mL / head.
- Table 13 shows the measurement contents of semi-micro autoradiography (non-administration site) of the rabbit knee joint.
- the labeling compound was as follows. Labeled compound name: [ 3 H] Betamethasone-21-phosphate disodium salt Supplier: GE Healthcare Life Science Co., Ltd. Radiochemical purity: 99.4% Radioactivity concentration: 185 MBq (5 mCi) / mL Specific activity: 407 GBq (11 Ci) / mmol Shape: Liquid Storage method: Shading, airtight, frozen ( ⁇ 20 °C)
- Betamethasone-21-phosphate disodium salt purity test In order to confirm the radiochemical purity of [ 3 H] Betamethasone-21-phosphate disodium salt, a test was performed using the TLC method when the compound was received (lot number TRQ40214). The analysis conditions were as follows. ⁇ TLC analysis conditions> Date of test: November 18, 2008 (at the time of compound acceptance) TLC plate: Silica gel 60 F 254 (Merck) Mobile phase: n-BuOH / AcOH / DW (8: 1: 1)
- ⁇ Test animal> Two NZ male rabbits for the test were purchased from Kitayama Labes (Nippon Charles River Co., Ltd.). One animal was housed per cage, and after 3 days of preliminary breeding, it was confirmed that it was in good health and used for the test (rabbit weight: 2.49 kg and 2.43 kg). The animals were observed daily during the preliminary breeding and during the test in a general state such as hair, skin and excrement.
- ⁇ Administration method and dose> The administration method and dose were as follows. Route of administration: Transdermal administration with electrification treatment Dose: 18.5 MBq (500 ⁇ Ci) / 1 mL / head
- FIG. 4 shows a schematic diagram of a normal rabbit right knee joint to which 3 H-labeled betamethasone phosphate was transdermally administered by electrification. Electrode A was used for individuals administered for 120 minutes, and electrode B was used for individuals administered for 30 minutes (Table 14). Table 14 shows the radioactivity and drug amount in the drug solution / drug-containing gel.
- Plasma radioactivity concentration was measured as follows. Blood was collected by centrifugation (4 ° C., 3000 rpm, 15 minutes) with a heparin-treated syringe at a predetermined time after administration, and plasma was prepared as a sample for radioactivity measurement.
- the sample for measurement was treated with a solubilizing agent and measured using a liquid scintillation counter (LSC-1000, ALOKA).
- LSC-1000 liquid scintillation counter
- ND liquid scintillation counter
- knee joint sites were removed from animals euthanized by an overdose of anesthetic (Nembutal), respectively, and frozen using liquid nitrogen.
- the embedded frozen block was fixed to the microtome (CRYOMACROCUT, Leica) stage table with the thighs in front and the shins in front, with the back of the legs in close contact with the stage. .
- the blade contacted the rectangular block in the direction perpendicular to the short side, and the upper surface was cut into a thin slice and the slice was brought into close contact with the adhesive tape and taken out.
- This operation was repeated several tens of times, cutting from the front to the rear of the knee, and the sections leading to the administration / energized portion were sequentially (from front to back) (1) to (7).
- the section of interest was exposed in close contact with an imaging plate (Fuji Photo Film Co., Ltd.), exposed for 168 hours, and then imaged with a bioimaging analyzer (BAS1800, Fuji Photo Film Co., Ltd.).
- the drug-converted concentration converted to unchanged form was calculated by the following formula.
- Table 15 shows the plasma radioactivity concentrations in rabbits after transdermal administration with 3 H-labeled betamethasone phosphate energization treatment.
- the plasma radioactivity concentration gradually increased from 10 minutes after administration, and showed the highest value after 120 minutes, but it was still on the rise.
- the average drug conversion value 120 minutes after administration was 1.17 ⁇ g eq / mL. Even in the 30-minute administration individuals, it gradually increased from 10 minutes after administration, and still showed an upward trend after 30 minutes.
- the average drug conversion value was 0.09 ⁇ g eq / mL.
- FIG. 4 shows a schematic diagram of a rabbit right knee joint semi-microautoradiograph that was transdermally administered with energization from the outside to the inside of the knee joint.
- the semi-micro autoradiograph of the rabbit knee joint administered for 30 minutes is shown in FIGS. 5 to 6, and the semi-micro auto radiograph of the rabbit knee joint administered for 120 minutes is shown in FIG.
- a semi-micro autoradiograph based on BAS1800 is shown on the left side, a section image is shown on the right side, and a composite image in which the BAS image is superimposed on the section image is shown in the center.
- the section numbers (2), (3), (5), and (6) were sequentially cut from the front to the rear of the knee. (5) was shown.
- the radioactivity concentration [(PSL-BG) / area] quantified according to the degree of blackening is shown in Table 16 (120 minutes administration) and Table 17 (30 minutes administration).
- Synovial of skeletal tissue especially focused on joint, fibrous encapsulation and, in the synovium (synovium membrane), showed a very slight blackening image by 3 H recording.
- perimysial tissue pericardial membrane
- pericardial membrane following the high density 3 H blackening image up to the reticular dermis located inside the epidermal tissue, blackening of the perimyal outer periphery Observed. This image reached the tendon, and a blackened image invaded the inner circumference around the muscle circumference and reached the periosteum. In this case, the blackening density was extremely dilute.
- the radioactivity intensity was 807.0 [PSL-BG / area] at the highest darkened area and 39.93 [ PSL-BG / area], 18.03 [PSL-BG / area] on the inner pericardium, and 0.41 [PSL-BG / area] on the tissue around the joint capsule.
- FIG. 8 shows a semi-micro autoradiograph of a non-administered / untreated knee joint.
- the dose of radioactivity was 538.3908 ⁇ Ci for the 30-minute individual and 545.6088 ⁇ Ci for the 120-minute individual, but the 30-minute individual had a higher concentration in the epithelium than the 120-minute individual.
- the 30-minute individual had a higher concentration in the epithelium than the 120-minute individual.
- the drug concentration was 1.35 times higher was observed. For this reason, it seems that in the 30-minute individual, the systemic dispersion is fast due to absorption from the epithelium.
- Table 18 shows the case with a phosphate concentration of 0 mM
- Table 19 shows the case with a phosphate concentration of 1 mM
- Table 20 shows the case with a phosphate concentration of 3 mM
- Table 21 shows the phosphate concentration.
- Table 22 shows the case of phosphate concentration 10 mM
- Table 23 shows the case of phosphate concentration 10 mM (second time)
- Table 24 shows the case of phosphate concentration 50 mM.
- Table 25 shows the case with a phosphate concentration of 100 mM.
- FIG. 9 shows the relationship between the amount of drug accumulated in the skin at a phosphate concentration of 0 mM to 100 mM and time.
- FIG. 10 shows the relationship between the time course of the cumulative amount permeated flux and the time at phosphate concentrations from 0 mM to 100 mM.
- the unit of cumulative transmission is [mol / cm 2 ] (eg No. 1 [mol / cm 2 ] etc.), and the unit of flux is [mol / cm 2 / hour]. ].
- the phosphate concentration is low, especially about 0mM to 10mM does not affect the permeation and can be expected to improve the stability of the drug (study only at 1mM. Stable after 18 months. I understand.
- This relates to preparations for administering physiologically active substances transdermally and transmucosally using electrical energy, and can be used mainly in the medical field.
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Abstract
Description
<作製手順(100gスケールとして)>
セパラブルビーカーにPVAを15g入れ精製水を加えた(EDTAを添加する場合はこの時に添加した。また、緩衝液を用いる場合は精製水の部分を緩衝液にして作製した。)。ビーカーのふたを閉め、撹拌用のパドルを装着した。120℃のオイルバスに浸し、撹拌しながら30分加熱した。オイルバスから取り出し、撹拌しながら室温下で冷却した。約60℃まで温度が下がったら3%となるようにリン酸ベタメタゾンナトリウム溶液を加え撹拌した。精製水を加え100gに調製した。均一になるまで再度撹拌した。十分に撹拌したらこの混合溶液をシリンジで吸い取った。フォームテープ(3M社製, 独立気泡フォームテープ、型番9773。)で作製した製剤に作製した溶液を約1g分注した。-80℃の冷凍庫に入れ凍結させる事によりPVAのゲル化を促進させた。1晩程度凍結させた後、室温下に静置して解凍した。これをアルミ製の包材に1つずつ分包し、種々の温度に設定された恒温恒湿機に入れ、安定性試験を行った。
表10は、標識化合物の純度測定の内容を示す。
表11は、血漿中放射能濃度測定の内容を示す。
表13は、ウサギ膝関節のセミミクロオートラジオグラフィー(非投与部位)の測定内容を示す。
標識化合物については、以下の通りであった。
標識化合物名 : [3H] Betamethasone-21-phosphate disodium salt
供給者: GE ヘルスケアライフサイエンス株式会社
放射化学的純度: 99.4%
放射能濃度: 185 MBq (5 mCi)/mL
比放射能: 407 GBq (11 Ci)/mmol
形状: 液体
保管方法: 遮光、気密、冷凍(-20 ℃)
[3H] Betamethasone-21-phosphate disodium salt放射化学的純度を確認するため、化合物受入れ時(ロット番号TRQ40214)にTLC法を用いて検定を行った。分析条件は下記のとおりとした。
<TLC分析条件>
検定日 : 2008年11月18日(化合物受入れ時)
TLCプレート: Silica gel 60 F254 (Merck)
Mobile phase: n-BuOH/AcOH/DW (8:1:1)
[3H]-Betamethasone-21-phosphate disodium salt約18.5MBq(500mCi/1g)のゲルを作製した。トリチウムで標識した[3H]-Betamethasone-21-phosphate disodium saltと非標識体のBetamethasone-21-phosphate disodium saltの混合溶液を作製し、融解したPVA溶液と混合した。これを電極と粘着層から成るパッチに流し込み-80℃で冷却して目的とする製剤を得た。
試験に供するNZ系雄性ウサギ2匹は、北山ラベス(日本チャールズリバー株式会社)より購入した。1ケージ当たり1匹で収容し、3日間の予備飼育後、健康状態が良好であることを確認し試験に使用した(ウサギ体重:2.49 kgと2.43 kg)。予備飼育中および試験中における動物の観察は被毛および皮膚、排泄物などの一般状態とし、毎日行った。
投与方法及び投与量については、以下の通りであった。
投与経路: 通電処置を伴う経皮投与
投 与 量: 18.5 MBq (500 μCi)/1 mL/head
3H標識リン酸ベタメタゾンのゲル製剤(陰極)と薬物を含まないリファレンスゲル製剤(陽極)を予め徐毛したウサギ膝関節に適用し、通電装置(VI 1002、プレサイスゲージ株式会社)を接続した。0.968mAの電流(電流密度0.2mA/cm2)を30分または120分通電した。通電処置の模式図を図4に示した。図4は、3H標識リン酸ベタメタゾンを通電により経皮投与した正常ウサギ右膝関節の模式図を示す。120分間投与個体には電極Aを、30分間投与個体には電極Bを用いた(表14)。
表14は、薬液/薬物含有ゲル中放射能及び薬物量を示す。
投与放射能量(dpm)/投与薬物量(μg)
<血漿中放射能濃度測定について>
3H標識リン酸ベタメタゾン通電処置を伴う経皮投与後ウサギの血漿中放射能濃度を表15に示した。
膝関節の外側から内側に向かって通電処置を伴う経皮投与を行ったウサギ右膝関節セミミクロオートラジオグラフの模式図を図4に示した。上皮、筋周膜、骨膜、骨、骨髄などの黒化度に着目した。
非投与・未処置の膝関節のセミミクロオートラジオグラフを図8に示す。120分間投与個体において、168時間という長期露出を行った結果、極めて希薄な上皮組織の黒化が確認できたが、何れもバックグランドレベルであったため放射能強度の定量は不能であった。
Claims (16)
- 非イオン性高分子物質と、リン酸ベタメタゾンナトリウムと、溶媒とを含有するイオントフォレーシス用薬剤組成物。
- 前記非イオン性高分子物質が、ポリビニルアルコール(PVA)である請求項1記載の組成物。
- 前記ポリビニルアルコール(PVA)の配合量が、0.5~30.0重量%であることを特徴とする請求項1記載の組成物。
- 前記ポリビニルアルコール(PVA)の配合量が、20重量%以下であることを特徴とする請求項3記載の組成物。
- 前記リン酸ベタメタゾンナトリウムの配合量が、1~12重量%であることを特徴とする請求項1~3項のいずれか1項に記載の組成物。
- 前記リン酸ベタメタゾンナトリウムの配合量が、1~4重量%であることを特徴とする請求項5項に記載の組成物。
- 前記溶媒が、水、リン酸緩衝液からなる群から選択される少なくとも1種である請求項1~6項のいずれか1項に記載の組成物。
- 前記組成物の表面におけるpHが、7~8の範囲である請求項1~7項のいずれか1項に記載の組成物。
- さらに、エチレンジアミン四酢酸(EDTA)を含有する請求項1~8項のいずれか1項に記載の組成物。
- エチレンジアミン四酢酸(EDTA)の配合量が、0.05~0.15重量%であることを特徴とする請求項1~9項のいずれか1項に記載の組成物。
- リン酸緩衝液の濃度が、1~10mMであることを特徴とする請求項7~10項のいずれか1項に記載の組成物。
- 前記請求項1~11項のいずれか1項に記載の組成物と、粘着層とを有するイオントフォレーシス用製剤。
- 前記粘着層が、アクリル系、シリコン系、合成ゴム系、および天然ゴム系からなる群から選択される少なくとも1種で構成される請求項10項記載の製剤。
- 請求項1~11項のいずれか1項に記載の薬剤組成物を用いて、リン酸ベタメタゾンナトリウムを投与するイオントフォレーシス投与方法。
- リン酸ベタメタゾンナトリウムを経皮的に、支持層から筋周膜を経由し、内側筋周膜並びに滑膜へ帯状に分布させ関節に送達することを特徴とする請求項14記載の投与方法。
- 請求項14又は15記載の投与方法によりリン酸ベタメゾンナトリウムを投与することにより、慢性関節リウマチ、変形性関節症、腱炎、腱鞘炎、腱周囲炎(いずれも非感染性に限る)からなる群から選択される少なくとも1種の疾患を治療する治療方法。
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CA2769008A CA2769008A1 (en) | 2009-07-31 | 2010-07-28 | A pharmaceutical composition for an iontophoresis |
AU2010277012A AU2010277012B2 (en) | 2009-07-31 | 2010-07-28 | Medicinal composition for iontophoresis |
US13/388,295 US8652522B2 (en) | 2009-07-31 | 2010-07-28 | Pharmaceutical composition of an iontophoresis |
CN2010800339612A CN102573849A (zh) | 2009-07-31 | 2010-07-28 | 用于离子电渗法的药物组合物 |
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US (1) | US8652522B2 (ja) |
EP (1) | EP2460524B1 (ja) |
JP (1) | JP6116790B2 (ja) |
KR (1) | KR20120042900A (ja) |
CN (1) | CN102573849A (ja) |
AU (1) | AU2010277012B2 (ja) |
CA (1) | CA2769008A1 (ja) |
TW (1) | TW201106992A (ja) |
WO (1) | WO2011013359A1 (ja) |
Families Citing this family (3)
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JP6211033B2 (ja) * | 2015-05-19 | 2017-10-11 | 帝國製薬株式会社 | イオントフォレーシス用薬剤組成物 |
US11806520B2 (en) | 2017-10-31 | 2023-11-07 | Tusker Medical, Inc. | Systems, apparatus, and methods for delivery of therapeutic substance to nasal cavity |
RU2709141C1 (ru) * | 2018-12-11 | 2019-12-16 | Федеральное государственное автономное образовательное учреждение высшего образования "Крымский федеральный университет имени В.И. Вернадского" (ФГАОУ ВО "КФУ им. В.И. Вернадского") | Способ лечения ревматоидного артрита |
Citations (3)
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JPH09248344A (ja) * | 1996-03-17 | 1997-09-22 | Hisamitsu Pharmaceut Co Inc | イオントフォレーシス用電極デバイス |
WO2004019902A1 (ja) * | 2002-08-30 | 2004-03-11 | Hisamitsu Pharmaceutical Co., Inc. | イオントフォレーシス製剤用粘着ゲル組成物及びその製造方法 |
WO2005021008A1 (ja) * | 2003-08-29 | 2005-03-10 | Hisamitsu Pharmaceutical Co., Inc. | イオントフォレーシス投与組成物 |
Family Cites Families (5)
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US20040043949A1 (en) * | 2002-08-30 | 2004-03-04 | Christopher Richardson | Therapeutic system targeting pathogen proteases and uses thereof |
JP4969812B2 (ja) * | 2005-07-22 | 2012-07-04 | 久光製薬株式会社 | ハイドロゲル組成物 |
US20080188791A1 (en) * | 2007-02-02 | 2008-08-07 | Difiore Attilio E | Active iontophoresis delivery system |
US9421356B2 (en) * | 2007-08-28 | 2016-08-23 | Teikoku Pharma Usa, Inc. | Transdermal methods and systems for the delivery of corticosteroid compounds |
WO2010054356A1 (en) * | 2008-11-10 | 2010-05-14 | Nitric Biotherapeutics, Inc. | Pharmaceutical formulations for iontophoretic delivery of a corticosteroid |
-
2009
- 2009-07-31 JP JP2009179895A patent/JP6116790B2/ja active Active
-
2010
- 2010-07-28 WO PCT/JP2010/004779 patent/WO2011013359A1/ja active Application Filing
- 2010-07-28 CA CA2769008A patent/CA2769008A1/en not_active Abandoned
- 2010-07-28 EP EP10804110.4A patent/EP2460524B1/en active Active
- 2010-07-28 US US13/388,295 patent/US8652522B2/en active Active
- 2010-07-28 TW TW099124928A patent/TW201106992A/zh unknown
- 2010-07-28 AU AU2010277012A patent/AU2010277012B2/en not_active Ceased
- 2010-07-28 KR KR1020127002729A patent/KR20120042900A/ko not_active Application Discontinuation
- 2010-07-28 CN CN2010800339612A patent/CN102573849A/zh active Pending
Patent Citations (3)
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JPH09248344A (ja) * | 1996-03-17 | 1997-09-22 | Hisamitsu Pharmaceut Co Inc | イオントフォレーシス用電極デバイス |
WO2004019902A1 (ja) * | 2002-08-30 | 2004-03-11 | Hisamitsu Pharmaceutical Co., Inc. | イオントフォレーシス製剤用粘着ゲル組成物及びその製造方法 |
WO2005021008A1 (ja) * | 2003-08-29 | 2005-03-10 | Hisamitsu Pharmaceutical Co., Inc. | イオントフォレーシス投与組成物 |
Non-Patent Citations (5)
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GLASS, J.M. ET AL.: "The quantity and distribution of radiolabeled dexamethasone delivered to tissue by iontophoresis", INTERNATIONAL JOURNAL OF DERMATOLOGY, vol. 19, no. 9, 1980, pages 519 - 525, XP008149730 * |
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KAMATH, S.S. ET AL.: "Electrophoretic evaluation of the mobility of drugs suitable for iontophoresis", METHODS AND FINDINGS IN EXPERIMENTAL AND CLINICAL PHARMACOLOGY, vol. 17, no. 4, 1995, pages 227 - 232, XP008149717 * |
See also references of EP2460524A4 |
Also Published As
Publication number | Publication date |
---|---|
CN102573849A (zh) | 2012-07-11 |
AU2010277012A1 (en) | 2012-02-09 |
US8652522B2 (en) | 2014-02-18 |
CA2769008A1 (en) | 2011-02-03 |
EP2460524A1 (en) | 2012-06-06 |
AU2010277012B2 (en) | 2014-10-02 |
JP2011032209A (ja) | 2011-02-17 |
EP2460524B1 (en) | 2017-10-25 |
KR20120042900A (ko) | 2012-05-03 |
JP6116790B2 (ja) | 2017-04-19 |
TW201106992A (en) | 2011-03-01 |
US20120165782A1 (en) | 2012-06-28 |
EP2460524A4 (en) | 2012-12-26 |
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